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PSYCHOPHARMACOLOGY
DOPAMINE RECEPTORS
OUTLINE
bullFunctions of Dopamine
bullDopamine Receptors Types
bullRegulation of Dopamine
Roles of Dopamine
bullRole in movement
bullRole in pleasure and motivation
bullControls the flow of information from other areas of the brain
Dopamine Receptors
bullThere are five types of dopamine receptorsD1D2D3D4D5
bullWe can categorize dopamine receptors in two main subtypes
bullD1 like receptor family the Gs protein is involved and adenylyl cyclase would be activated The action of the enzyme causes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP)
bullD2 like receptor family which is the receptor combining with the Gi protein and its activated alpha-subunit then inhibits adenylyl cyclase so that the concentration of cAMP is reduced
Effectors Pathways Associated with G-Protein-
Coupled Receptorsbull PN08060JPG
DOPAMINE
D1-D5
Dr Mejiacutea 2004
D2-D3-D4
Ziprasidone binds with high affinity to D2 receptors (Ki=31nM) (Ki=72 nM) to the D3 moderate affinity (Ki=32 nM) to D4Low affinity (Ki=130 nM) to the D1 and D5
Efficacy
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
DOPAMINE RECEPTORS
OUTLINE
bullFunctions of Dopamine
bullDopamine Receptors Types
bullRegulation of Dopamine
Roles of Dopamine
bullRole in movement
bullRole in pleasure and motivation
bullControls the flow of information from other areas of the brain
Dopamine Receptors
bullThere are five types of dopamine receptorsD1D2D3D4D5
bullWe can categorize dopamine receptors in two main subtypes
bullD1 like receptor family the Gs protein is involved and adenylyl cyclase would be activated The action of the enzyme causes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP)
bullD2 like receptor family which is the receptor combining with the Gi protein and its activated alpha-subunit then inhibits adenylyl cyclase so that the concentration of cAMP is reduced
Effectors Pathways Associated with G-Protein-
Coupled Receptorsbull PN08060JPG
DOPAMINE
D1-D5
Dr Mejiacutea 2004
D2-D3-D4
Ziprasidone binds with high affinity to D2 receptors (Ki=31nM) (Ki=72 nM) to the D3 moderate affinity (Ki=32 nM) to D4Low affinity (Ki=130 nM) to the D1 and D5
Efficacy
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
OUTLINE
bullFunctions of Dopamine
bullDopamine Receptors Types
bullRegulation of Dopamine
Roles of Dopamine
bullRole in movement
bullRole in pleasure and motivation
bullControls the flow of information from other areas of the brain
Dopamine Receptors
bullThere are five types of dopamine receptorsD1D2D3D4D5
bullWe can categorize dopamine receptors in two main subtypes
bullD1 like receptor family the Gs protein is involved and adenylyl cyclase would be activated The action of the enzyme causes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP)
bullD2 like receptor family which is the receptor combining with the Gi protein and its activated alpha-subunit then inhibits adenylyl cyclase so that the concentration of cAMP is reduced
Effectors Pathways Associated with G-Protein-
Coupled Receptorsbull PN08060JPG
DOPAMINE
D1-D5
Dr Mejiacutea 2004
D2-D3-D4
Ziprasidone binds with high affinity to D2 receptors (Ki=31nM) (Ki=72 nM) to the D3 moderate affinity (Ki=32 nM) to D4Low affinity (Ki=130 nM) to the D1 and D5
Efficacy
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Roles of Dopamine
bullRole in movement
bullRole in pleasure and motivation
bullControls the flow of information from other areas of the brain
Dopamine Receptors
bullThere are five types of dopamine receptorsD1D2D3D4D5
bullWe can categorize dopamine receptors in two main subtypes
bullD1 like receptor family the Gs protein is involved and adenylyl cyclase would be activated The action of the enzyme causes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP)
bullD2 like receptor family which is the receptor combining with the Gi protein and its activated alpha-subunit then inhibits adenylyl cyclase so that the concentration of cAMP is reduced
Effectors Pathways Associated with G-Protein-
Coupled Receptorsbull PN08060JPG
DOPAMINE
D1-D5
Dr Mejiacutea 2004
D2-D3-D4
Ziprasidone binds with high affinity to D2 receptors (Ki=31nM) (Ki=72 nM) to the D3 moderate affinity (Ki=32 nM) to D4Low affinity (Ki=130 nM) to the D1 and D5
Efficacy
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Dopamine Receptors
bullThere are five types of dopamine receptorsD1D2D3D4D5
bullWe can categorize dopamine receptors in two main subtypes
bullD1 like receptor family the Gs protein is involved and adenylyl cyclase would be activated The action of the enzyme causes the conversion of adenosine triphosphate to cyclic adenosine monophosphate (cAMP)
bullD2 like receptor family which is the receptor combining with the Gi protein and its activated alpha-subunit then inhibits adenylyl cyclase so that the concentration of cAMP is reduced
Effectors Pathways Associated with G-Protein-
Coupled Receptorsbull PN08060JPG
DOPAMINE
D1-D5
Dr Mejiacutea 2004
D2-D3-D4
Ziprasidone binds with high affinity to D2 receptors (Ki=31nM) (Ki=72 nM) to the D3 moderate affinity (Ki=32 nM) to D4Low affinity (Ki=130 nM) to the D1 and D5
Efficacy
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Effectors Pathways Associated with G-Protein-
Coupled Receptorsbull PN08060JPG
DOPAMINE
D1-D5
Dr Mejiacutea 2004
D2-D3-D4
Ziprasidone binds with high affinity to D2 receptors (Ki=31nM) (Ki=72 nM) to the D3 moderate affinity (Ki=32 nM) to D4Low affinity (Ki=130 nM) to the D1 and D5
Efficacy
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Dopamine Receptors
bullFive subtypes of dopamine receptor have been cloned
TheD1 andD5 receptors are closely related and couple toGs
Alpha and stimulate adenylylcyclase activity In contrast
theD2 D3 andD4 receptors couple to Gi
Alpha and inhibit the formation of cAMP
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
bull D1 receptors
1048707Most abundant receptor in the central nervous system
1048707Highly expressed in basal ganglia
1048707Stimulate AC
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
D5
bull50 homology with D1
bullExpression in nucleus of thalamus suggesting that role in pain stimuli
bullStimulate AC
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
D2
bullInhibti AC phospoinositide turnover
bullActivation of potassium channel potentiation of arachidonic acid release
Two isoformsD2L and D2s by alternative splicing
bullSimilar profiles in terms of affinity but different in regulation
bullHighly expressed in basal ganglia septi ventral tegmental area
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
D3
bullAs a functional receptor remains uncertain
bullSimilarity to D2 and the expression areas
Recent study shows it might mediate positive regulatory influences on production of neurotension
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
D4
bullHomology with D2 and D3 41 and 39
bullHippocampus and frontal cerebral cortex
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Dopamine 1 (DA1) Receptor agonists
bullFenoldopam
bullPiribedil
bullIbopamine
bullSKF 3893
bullApomorphine
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Therapeutic uses of DA1 Receptor Agonists
bullDecreases peripheral resistance
bullInducing lowering of arteriel blood pressure-increases in heart rate and increases in sympathetic tone
bullIncreases in activity of the reninaldosterone system
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Dopamine 2 (DA 2) Receptor Agonists
bullBromocriptine
bullPergolid
bullLisuride
bullGuinpirole
bullCarmoxirole
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Theraputicuses of DA2 receptor agonists
bullUsed for treating Parkinsonrsquos disease
bullInhibits prolactin release (which decreases tumor size)
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
DA 1 Receptor Antagonists
bullClozapine( used for treating schizophrenia
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
SEROTONIN RECEPTORS
Introduction Definition
Chemistry of serotonin and synthesis Pharmacokinetics
Receptors classification Mechanism of action
Pharmacological actions Specific agonists and antagonists
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
INTRODUCTION
5-HT is an amine autocoid The Autocoid is derived from a Greek word
where autos means self and akos means healing or remedy or medicinal substance These
autacoids are substances that are produced in a wide variety of cells in the body and they have widely differing structures amp pharmacological
activities
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
They generally act on the tissues which produce them at the site of synthesis amp are hence called as local hormones Prostaglandins histamines amp serotonin
belongs to the group of autocoids Serotonin was the name given to a vasoconstrictor substance found in the serum when blood clotted It was chemically identified as 5- hydroxytryptamine It was found in GIT and CNS
and was observed to be functioning as a neurotransmitter and as local hormone in peripheral
vascular system
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Chemistry and Synthesis
Serotonin is synthesized in biologic systems from the amino acids L- TRYPTOPHAN by HYDROXYLATION of
Indole ring After synthesis the free amines undergoes inactivation by the action of MAO (Mono Amine
Oxidase)
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
1 5-HT1 RECEPTOR
Occurs mainly in brain and its subtypes are 5-HT1 A B DEF And are distinguished based on their distribution and pharmacological specificity All subtypes of 5-HT1 receptors inhibits adenyl cyclase These receptors are related to mood
and behavior migraine and used to treat acute attacks Moreover they activates potassium channels and inhibits
calcium channels 5-HT1D receptors inhibit noradrenaline
2 5-HT2 RECEPTOR
There are 3 subtypes A B and C These are linked to phospholipase C It has peripheral effects on smooth muscles and platelets which are mediated by 5-HT2A receptors 5-HT2C receptor present on endothelium
produces vasodilation
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
3 5-HT3 RECEPTOR These occur mainly in the peripheral nervous system mainly on autonomic and enteric neurons These are of 2 types 5HT3A amp 5HT3B These receptors have reflex effects on Somatic and autonomic nerve endings shows pain itch and other visceral effects Nerve endings in myenteric plexus increase of peristalsis emetic reflex Region of medulla nausea vomiting
4 5-HT4 RECEPTOR These are present in brain and peripheral organs such as GIT bladder and heart In GIT they produces neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis Ex Cisapride Renzapride
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
PHARMACOLOGICAL ACTIONS
Cardiovascular system Arteries are constricted (by the action on smooth muscles) as well as dilated (through
EDRF release) In microcirculation 5HT dilates the arterioles and constricts venules Smooth muscles 5-
HT is a potent stimulation of git both by direct action as well as through enteric plexus Peristalsis is
increased and diarrhoea can occur
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
5-HT ANTAGONISTS 5-HT2A AND 5-HT2C ANTAGONISTS
Methysergide Pharmacological effects On central nervous system it exerts mild CNS stimulation On
smooth muscles it shows vasoconstriction and oxytocic effect In migraine it is used only as a prophylactic
agent MOA It stimulates the receptors located in the brain Adverse effects such as Nausea vertigo drowsiness GIirritation bradycardia insomnia
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
THERAPEUTIC USES It is used as a prophylactic agent in migraine Other antagonist drugs are Pizofen It
shows antihistaminic and antidepressant effect Causes drowsiness urine retention and weight gain
Clozapine It is antipsychotic agent which is dopaminergic antagonist as blocks 5-HT2A and 5-
HT2C receptors
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
2 5-HT2A ANTAGONIST
Ketanserin It is the prototype for the drugs having 5-HT2 receptor blocking activity It produces
antihypertensive activity It acts on platelets and prevents its aggregation It also causes
bronchocostriction Adverse effects are nausea dryness of mouth tiredness Clinical use as a
prophylactic agent in Reynauds disease Cyproheptadine It has anticholinergic and ca2+
channel blocking effect It shows mild CNS depressant activity and causes sedation It improves appetite by
acting on hypothalamus Used in curing Cushingrsquos syndrome and allergies
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
bull 5-HT3 ANTAGONISTS
bull Ondansetron It is a prototype drug for antiemetic activity which was developed to control emesis induced by cancer therapy and radiotherapy It acts by blocking the depolarizing action of 5-HT on the 5-HT3 receptors located in brain Adverse effects are headache constipation diarrhoea abdomen pain etc Used as prophylaxis and postoperative nausea and vomiting Granisetron It is 15 times more potent than Ondansetron It is similar to Ondansetron Adverse effects fever dizziness anxiety etc
bull
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
OTHER DRUGS AFFECTING 5-HT SYSTEM
Chlorophenylalanine it inhibits the enzyme tryptophan hydroxylase and reduces the levels of HT
Tricyclic antidepressants inhibit 5-HT uptake along
with noradrenaline
Reserpine blocks the uptake of 5-HT into storage granules
Ergot alkaloids they exert their effect through 5-HT adrenoreceptors or dopamine receptors Clinically they are used in treatment of attacks of migraine Also used to treat carcinoid tumors Adverse effects are muscle cramps weakness nausea vomiting etc
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
schizophreniaschizophrenia
positive symptomspositive
symptoms
negative symptomsnegative
symptoms
anxdepanxdep aggressive symptomsaggressive symptoms cognitive
symptomscognitive
symptoms
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Mechanism of Action of Antipsychotic DrugsMechanism of Action of Antipsychotic DrugsDopaminergic PathwaysDopaminergic Pathways
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
GoalsTo quiet hyperactive
DA neurons that mediate psychosis
To trigger underactive DA neurons that mediate negative and cognitive symptoms
To preserve physiologic function in DA neurons that regulate movement and prolactin secretion
Presynaptic Dopaminergic
Neuron
AutoreceptorAutoreceptor
Postsynaptic receptor
Postsynaptic neuronPostsynaptic neuron
Antipsychotic drug
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
H1
D2
Conventional AntipsychoticsConventional Antipsychotics
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
Positive symptom efficacy
Can aggravate negative and cognitive symptoms
High incidence of EPS
High non-compliance rates
D2D2
α1α1
MM
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
The Dopamine Hypothesis of Schizophrenia
bull All conventional antipsychotics block the dopamine D2 receptor
bull Conventional antipsychotic potency is directly proportional to dopamine receptor binding
bull Dopamine enhancing drugs can induce psychosis (eg chronic amphetamine use)
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
ldquoTypicalrdquo antipsychotic medications(aka first-generation conventional neuroleptics major tranquilizers)
bull High Potency (2-20 mgday)(haloperidol fluphenazine)
bull Mid Potency (10-100 mgday)(loxapine perphenazine)
bull Low Potency (300-800+ mgday)(chlorpromazine thioridizine)
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Dopamine blockade effects
bull Limbic and frontal cortical regions antipsychotic effect
bull Basal ganglia Extrapyramidal side effects (EPS)
bull Hypothalamic-pituitary axis hyperprolactinemia
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Typical Antipsychotic limitation
Extrapyramidal side effects (EPS)
bull Parkinsonism
bull Akathisia
bull Dystonia
bull Tardive dyskinesia (TD)-- the worst form of EPS-- involuntary movements
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Typical Antipsychotic limitation
bull Anticholinergic side effects dry mouth constipation blurry vision tachycardia
bull Orthostatic hypotension (adrenergic)
bull Sedation (antihistamine effect)
bull Weight gain
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Typical Antipsychotic limitation Treatment Resistance
bull Poor treatment response in 30 of treated patients
bull Incomplete treatment response in an additional 30 or more
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
10
The First ldquoAtypicalrdquo AntipsychoticClozapine
bull FDA approved 1990bull For treatment-resistant schizophreniabull 30 response rate in severely ill
treatment-resistant patients (vs 4 with chlorpromazineThorazine)
bull Receptor differences Less D2 affinity more 5-HT
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Clozapine pros and consbull Superior efficacy for positive symptomsbull Possible advantages for negative symptomsbull Virtually no EPS or TDbull Advantages in reducing hostility suicidalitybull Associated with agranulocytosis (1-2)
ndash WBC count monitoring required
bull Seizure risk (3-5)bull Warning for myocarditisbull Significant weight gain sedation orthostasis tachycardia
sialorrhea constipationbull Costlybull Fair acceptability by patients
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Atypical antipsychotics(aka second-generation novel)
FDA approval Generic Name (Brand Name) bull 1990 clozapine (Clozaril)
bull 1994 risperidone (Risperdal) bull 1996 olanzapine (Zyprexa)bull 1997 quetiapine (Seroquel)bull 2001 ziprasidone (Geodon)bull 2002 aripiprazole (Abilify)
bull 2003 risperidone MS (Consta)
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Defining ldquoatypicalrdquo antipsychoticRelative to conventional drugs
bull Lower ratio of D2 and 5-HT2A receptor antagonism
bull Lower propensity to cause EPS (extrapyramidal side effects)
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Atypical Antipsychotics Efficacy
bull Effective for positive symptoms bull (equal or better than typical antipsychotics)
bull Clozapine is more effective than conventional antipsychotics in treatment- resistant patients
bull Atypicals may be better than conventionals for negative symptoms
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Atypical Antipsychotics Efficacy for Cognitive and Mood
Symptoms
bull Atypical antipsychotics may improve cognitive and mood symptoms(Typical antipsychotics tend to worsen cognitive function)
bull Dysphoric mood may be more common with typical antipsychotics
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Atypical Antipsychotics Side Effects
bull Atypical antipsychotics tend to have better subjective tolerability (except clozapine)
bull Atypical antipsychotics much less likely to cause EPS and TD but may cause morebull Weight gainbull Metabolic problems (lipids glucose)bull ECG changes
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
5-HT25-HT2
D2D2
Ideal AntipsychoticIdeal Antipsychotic
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Broad efficacy
Amelioration of cognitive dysfunction and affective symptoms
Earlier and more globally these manifestations are arrested the better the long-term prospects
Overall safetydarrdarrEPSdarrdarrHyperprolactinemiaMetabolically neutral
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Current consensus on antipsychotics
bull Atypical antipsychotics (other than clozapine) are first choice drugs-superiority on EPS and TD-at least equal efficacy on + and ndash symptoms-possible advantages on mood and cognition
bull BUT-long-term consequences of weight gain and metabolic effects may alter recommendation-atypicals are very expensive
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
mesolimbic overactivity = positive symptoms of psychosis
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
primary dopamine deficiency
D2 receptor blockade
secondary dopamine deficiency
mesocortical pathway
increase in negative and cognitive symptoms
increase in negative and cognitive symptoms
10-11 Stahl S M Essential Psychopharmacology (2000)
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Binding to Dopamine ReceptorsBinding to Dopamine Receptors
Ziprasidone
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Tight Loose
Dosage Low High
EPS Yes No
Prolactin High Normal
TD High risk
Low riskLess lipophilic
Aspects of tight and loose Aspects of tight and loose antipsychotic binding at Dopamine antipsychotic binding at Dopamine DD22 receptors receptors
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
serotonin neuronserotonin neuron
dopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
dopaminedopamine
5HT2A receptor serotoninserotonin
5HT2A receptor5HT2A receptor
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
serotonin neuronserotonin neuron
dopamine neurondopamine neuron
Substantia nigraSubstantia nigra
RapheRaphe
5HT2A receptor5HT2A receptor
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Differences among Antipsychotic Drugs
bull All effective antipsychotic drugs block D2 receptorsbull Chlorpromazine and thioridazine
ndash block α1 adrenoceptors more potently than D2 receptorsndash block serotonin 5-HT2 receptors relatively strongly ndash affinity for D1 receptors is relatively weak
bull Haloperidol ndash acts mainly on D2 receptorsndash some effect on 5-HT2 and α1 receptors ndash negligible effects on D1 receptors
bull Pimozide and amisulpridedagger
ndash act almost exclusively on D2 receptors
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Differences among Antipsychotic Drugs
bull Clozapine ndash binds more to D4 5-HT2 α1 and histamine H1
receptors than to either D2 or D1 receptorsbull Risperidone
ndash about equally potent in blocking D2 and 5-HT2 receptors
bull Olanzapinendash more potent as an antagonist of 5-HT2
receptorsndash lesser potency at D1 D2 and α1 receptors
bull Quetiapinendash lower-potency compound with relatively similar
antagonism of 5-HT2 D2 α1 and α2 receptors
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Differences among Antipsychotic Drugs
bull Clozapine olanzapine and quetiapinendash potent inhibitors of H1 histamine
receptorsndash consistent with their sedative properties
bull Aripiprazolendash partial agonist effects at D2 and 5-HT1A
receptors
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Differences among Antipsychotic Drugs
bull Chlorpromazine α1 = 5-HT2 gt D2 gt D1
bull Haloperidol D2 gt D1 = D4 gt α1 gt 5-HT2
bull Clozapine D4 = α1 gt 5-HT2 gt D2 = D1
Thank you
Thank you
