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Antipsychotics. Psychosis. a state in which a person’s mental capacity to recognize reality, communicate, and relate to others is impaired delusions, hallucinations (auditory, visual, tactile, olfactory), grossly disorganized thinking in a sensible manner - PowerPoint PPT Presentation
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Antipsychotics
Psychosis a state in which a person’s mental capacity
to recognize reality, communicate, and relate to others is impaired
delusions, hallucinations (auditory, visual, tactile, olfactory), grossly disorganized thinking in a sensible manner
thus interfering with the capacity to deal with life’s normal everyday demands
Psychotic Disorders Schizophrenia Manic phase of bipolar (manic-
depressive) illness Senile Psychosis Drug induced psychosis Post surgical delirium Amphetamine intoxication Acute idiopathic psychotic illness
Schizophrenia Characterized by delusions, hallucinations
(hearing voices), thinking and speech disturbances
Often affected during adolescence Strong genetic component Characterized by 2 components;
breakdown of personalityloss of contact with reality
Considered neurodevelopmental disorder possibly overactivity of mesolimbic
dopaminergic neurons
Schizophrenia Etiology Dopamine Hypothesis
no longer considered to cover all aspects of schizophrenia
Important in understanding pos./neg. symptoms
Serotonin Hypothesis5-HT stimulation responsible for hallucinationsAtypical antipsychotics – MOA
Glutamate HypothesisHypofunction of NMDAr - decreased GABAergic
inhibitory activity
Manic Phase of Bipolar Disorder two phases that cycle back and forth --
mania and depression.
cyclic attacks of mania induce paranoid schizophrenia (grandiosity, bellicosity, paranoia, and overactivity)
Mechanism of Action of Antipsychotics
○ 5 DA receptors (D1-D5)D1 like – D1 and D5 activate adenyl cyclaseD2 like – D2, D3 and D4 inhibit adenyl cyclase involved in psychotic disordersBlockade of D2 receptor is antipsychotic action
Efficacy of the typical neuroleptic drugs correlate to their ability to block D2 receptors in the mesolimbic system. (high EPS)
Antagonized by levodopa and amphetamineThe Atypical antipsychotics, Clozapine has a high
affinity for the D4 receptor (low EPS)
Dopaminergic Systems Until 1959, DA was not recognized as a NT
in CNS, but a precursor to NE.
Neurons that secrete dopamine are primarily located in three discreet regions of the brain
Douglas L. Geenens, D.O. 2000
Dopamine Pathways Nigrostriatal
Mesocortical / Mesolimbic
Tuberoinfundibular
Medullary-Periventricular
Incertohypothalamic
Major Dopamine Pathways
Mesolimbic pathway•Hyperactivity on this pathway is
associated with positive symptoms of schizophrenia
Mesocortical pathway•Deficit in dopamine in this pathway is
associated with negative and cognitive symptoms of schizophrenia
Major Dopamine Pathways
Nigrostriatal pathway•Part of extrapyramidal system,controls motor movement•Blockade of D2 receptors causes:-- deficiency in dopamine in this pathway and thus movement
disorder such as Parkinson’s disease-- hyperkinetic movement such as tardive dyskinesia
Tuberoinfundibular pathway•Increased neuronal activity of this pathway inhibits prolactin
release•Blockade of D2 receptor increases prolactin release and causes:-- galactorrhea-- amenorrhea
Antipsychotic Actions positive symptoms reduced by typical
neuroleptics
Negative symptoms not as responsive to typical, but respond to atypical.
All have a calming effect, reduce spontaneous physical movement.
Onset of action of Antipsychotic – 2 weeks
Positive and Negative Symptoms of Schizophrenia
Positive symptoms - symptoms that most individuals do not normally experience but are “added” in schizophrenia.
Negative symptoms - symptoms that reflect the loss or absence of normal traits or abilities (motivation). feelings that are "taken away" such as motivation
Antipsychotics Referred to as antischizophrenic, antipsychotic or major
tranquilizers
Typical (neurolelptics) properties due to dopamine receptor antagonism first generation, 1950’s, D2 High EPS
Atypical properties due to Serotonin and DA receptor antagonism Second generation
Not curative, does not eliminate thinking disorder, but allow patient to function in supportive environment
Antipsychotics Reserpine and chlorpromazine were first drugs used for
schizophrenia/psychosis Typical antipsychotics are divided into 5 major classifications based on
structure. Side chains have significant effect on potencies
Typical (neuroleptics) 1. Phenothiazines - Chlorpromazine (Thorazine) 2. Butyrophenones – Haloperidol (Haldol) 3. Thioxanthenes – Thiothixene (Navane) 4. Dibenzoxazepines – Loxapine (Loxapac)
Atypical○ Clozapine (Clozaril), Risperidone (Risperdal), Quetiapine (Seroquel),
Olanzapine (Zyprexa), Ziprasidone (Geodon)○ Aripiprazole (Abilify)
Proper management of psychotic disorder can be determined by familiarity of side effects of drugs in each class
Phenothiazine( Typical Antipsychotics)
1. Aliphatic – least potent, intermediate, EPS, intermediate anticholinergic action, high sedative action Chlorpromazine (Thorazine)
2. Piperidine – least potent, lower incidence of EPS, high incidence of anticholinergic action Thioridazine (Mellaril)
3. Piperazine – most potent, selective and effective, increased incidence of Tardive dyskinesia Fluphenazine (Prolixin) Perphenazine (Trilafon) Trifluperazine (Stelazine)
Pharmacological Action of Phenothiazine
Basal Ganglia – blockade of D1 or D2 results in EPSCardiovascular – depressed by antipsychotics –
hypotensionChemoreceptor trigger zone (CTZ) - These
receptors are blocked by phenothiazines (anti-emetic action).
Hypothalmus - stimulate release of prolactinMisc. – no physical dependence, decrease seizure
thresholdAutonomic effects – anticholinergic action
(piperidines – strongest, piperizines – weakest)α – adrenergic antagonist - hypotension
Side Effects of Phenothiazines
Orthostatic hypotension – due to α- blockade, dose/effect response
Extrapyramidal Syndrome – increased cholinergic activity (Piperazine – highest, Piperidines – lowest)Parkinson-like SyndromeAkathesia – uncontrollable restlessness, distress, anxietyTardive Dyskinesia – develops late in antipsychotic therapy,
usually at high doses x 6 months, rhythmic motions of head, face and shoulders, may be irreversible
Do not use DA or Levo-Dopa, use diphenhydramine (Benadryl), benztropine (Cogentin) or trihexephenidyl (Artane)
Therapeutic use of Phenothiazines Tx psychotic disorders
Schizophrenia, senile dementia, extreme paranoia, manic phase of manic depressive syndrome
Anti-emetics – radiation toxicity, anticancer meds, opioids, gastroenteritis
Phenothiazines○ Control positive symptoms – Hallucinations,
delusions, hostility, hyperactivity○ Not negative symptoms – social withdrawal, lack of
expression, decrease in speech patterns
Butyrophenone Haloperidol (Haldol)
alleviates positive symptoms
manic phase of bipolar disorder
severe EPS, < α - adrenergic blockade
< sedation than phenothiazines
Used in Huntington’s Chorea, Tourette’s Syndrome
Thioxanthenes• very specific for D2 receptor
• very low affinity for 5-HT receptor
• very potent
• intermediate EPS
• sedative action and hypotension
Atypical Antipsychotics In the last decade new "atypical" antipsychotics
have been introduced
More effective, less side effects
appear to be equally effective for helping reduce the positive symptoms like hallucinations and delusions but may be better than the older medications at relieving
the negative symptoms of the illness, such as withdrawal, thinking problems, and lack of energy.
Mechanism of Action of Atypical Antipsychotics
Blockade of DA2 (weak) and / or 5-HT receptors. Many also block cholinergic, adrenergic, and histamine receptors – variety of side effects (low D2)
DA receptor antagonism in brain (typical and atypical antipsychotics) Neuroleptics are antagonized by agents that increase DA
concentration (L-dopa and amphetamines)
Serotonin receptor antagonism in brain (atypical)
NEUROBIOLOGY OF CLOZAPINE
Here you can see that Clozapine will not bind to any Dopamine receptor, it is selective, it has an affinity for the D4 receptor subtype.
Atypical Antipsychotics Clozapine (Clozaril)
Risperidone (Risperdal
, Quetiapine (Seroquel)
Olanzapine (Zyprexa)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Atypical Antipsychotics Admin PO QD or BID
Low or no EPS
5-HTr antagonist 5-HT2A receptor
No effect on prolactin Exception (Compared to clozapine and quetiapine)
Increase prolactin release, low risk of tardive dyskinesia
Control both positive and neg. symptoms
Atypical Antipsychotics Low or no EPS
5-HT2A antagonist
Control both positive and neg. symptoms
Atypical Antipsychotics(second generation)
Clozapine (prototype)little to no EPS, high incidence of agranulocytosis
(regular CBC’s), high incidence of siezures, blood dyscrasia, weight gain
Olanzapine (Zyprexa)sedation, weight gain, no agranulocytosis, low
incidence of siezures Quetiapine (Seroquel)
sedation, low incidence of all side effects
Summary of Antipsychotics
Atypical antipsychotics can be distinguished from the classsic neuroleptics by three main characteristics;
Less likely to induce EPS More effective against negative symptoms of
schizophrenia Able to effectively treat patients unresponsive
to classic neuroleptics.
Treatment of Bipolar Disorder Manic Phase
many symptoms of paranoid schizophrenia (grandiosity, excitement, impulsivity, disinhibition, aggression, diminished need for sleep, paranoid thoughts and overactivity)
Decrease in activity of DA and NE relieve mania
Depressive Phase Similar to major depression, depressed mood, sleep
disturbance, anxiety, and sometimes psychotic symptoms
Mixed manic and depressive symptoms are sometimes seen, high risk of suicide
Strong genetic component, no effect on normal individuals
Treatment of Mania Lithium - Closely related to Na+ and K+ in
generating AP
MOA involves interference of second messengers inositol triphosphatase (IP3)
and diacylglycerol (DAG)neurotransission mechanisms.
○ Important in α-adrenergic and muscarinic transmission
Lithium Drug Interactions
Diuretics - renal clearance is reduced by 25%, dose may need to be reduced.Same w/ some anti-inflammatory drugs that
block prostaglandin synthesis.
Neuroleptics (typical) – produce more EPS when combined w/ Lithium
Adverse Effects of Lithium
Tremors Propranolol and atenolol alleviate lithium induced tremors
Decreased thryoid function (reversible) Nephrogenic Diabetes Insipidus
Resistant to vasopressin – treated w/ Amiloridepts. should avoid dehydration
Edema Related to Na+ retention
PregnancyIncreased renal clearance during, and lowered
postpartum
Other Antimanic Mood-Stabilizing agents
Valproic Acid Shows efficacy equivalent to LithiumEffective in pts not responding to LithiumMay be used in combinationS/E – GI distress weight gain and alopecia
CarbamazepineOxcarbazepine not effectiveMay be used prophylactic therapyMay be used w/ Lithium but not Valproic
Acid