Dr. Womble

Antipsychotics

Psychosis Psychosis is defined as a state in which a

person’s mental capacity to recognize reality, communicate, and relate to others is impaired, thus interfering with the capacity to deal with life’s normal everyday demands

most common mental disorder in which psychotic sx may be present is schizophrenia.

Schizophrenia a general term for a mental disorder

characterized by delusions, loosening of associations, decrease

speech content, auditory hallucinations, disturbed sense of self, and withdrawal from the external world.

Onset early adulthood prior to normal function

Antipsychotics (Neuroleptics)

Referred to as antischizophrenic, antipsychotic or major tranquilizers

Typical properties due to dopamine receptor antagonism 1950’s, first generation, 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

Pathogenesis of schizophrenia is unknown

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

Antianxiety agents not useful for psychotic disorders Considered neurodevelopmental disorder

Structural and functional changes present in utero

Schizophrenia Positive symptoms - symptoms that most

individuals do not normally experience but are present in schizophrenia. Delusions, auditory hallucinations, thought

disorder, regarded as manifestations of psychosis Negative symptoms - symptoms that reflect

the loss or absence of normal traits or abilities.Blunted affect and emotion, poverty of speech,

inability to experience pleasure, lack of desire to form relationships, and lack of motivation

Schizophrenia Etiology Serotonin Hypothesis

5-HT stimulation responsible for hallucinations Atypical antipsychotics - MOA

Dopamine Hypothesis Firtst NT based MOA, no longer considered to cover all

aspects of schizophrenia Important in uderstanding pos./neg. symptoms

Glutamate Hypothesis Hypofunction of NMDAr - decreased GABAergic inhibitory

activity

Antipsychotics Reserpine and chlorpromazine were first drugs used

for schizophrenia / psychosis Divided into five major classifications based on

structure. Side chains have significant effect on potencies1. Phenothiazines2. Benzisoxazoles3. Dibenzodiazepines4. Butyrophenones5. Thioxanthenes

Management of psychotic disorder can be determined by familiarity of effects drugs in each class

Typical Antipsychotics(1. Phenothiazine)

3 subclasses

1. Aliphatic – least potent Chlorpromazine –intermediate extrapyramidal side effects and intermediate

anticholinergic action, high incidence of sedative action

2. Piperazine – most potent, selective and effective, increased incidence of Tardive dyskinesia Fluphenazine (Prolixin) Prochlorperazine (Compazine) Perphenazine (Trilafon)

3. Piperidine – least potent, lower incidence of extrapyramidal side effects, high incidence of anticholinergic action Thioridazine (Mellaril) Mesoridazine (Serentil)

Action of Phenothiazine CNS – reduces anxiety, response to external stimuli,

intelligence is not diminished, reflexes not suppressed, mild sedation Limbic system Da receptors involved in mood/feeling

○ 5 subclasses of DA receptors (D1-D5) D1/5 activate, D2/3 inhibit adenyl cyclase D2 involved in psychotic disorders

- Blockade of D2 receptor is antipsychotic action

Autonomic effects – antimuscarinic action (piperidines – strongest, piperizines – weakest) urinary retention, ortho hypo, dry mouth, sedation, inh of GI smooth muscle - constipation

Alpha-antagonist – ortho hypo, poikilothermia, inc. prolactin release Basal Ganglia – blockade of D1 or D2 results in EPS Cardiovascular – depressed by antipsychotics – hypotension Chemoreceptor trigger zone (CTZ) - (anti-emetic action) Hypothalmus – DA receptors inhibit release of prolactin, phenothiazines block DA

receptors - stimulate release of prolactin – hormonal side effects Misc. – no physical dependence, mild CNS depressant (toxic dose), decrease

seizure threshold

Side effects of Phenothiazine

Side effects Orthostatic hypotension – due to alpha blockade,

dose/effect response Extrapyramidal Syndrome – increased cholinergic

activity (Piperazine – highest, Piperidines – lowest) Parkinson-like Syndrome Akathesia – uncontrollable restlessness, distress, anxiety Tardive 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

Douglas L. Geenens, D.O. 2000

Dopamine Pathways Nigrostriatal

Mesocortical – Mesolimbic

Tuberoinfundibular

Incertohypothalamic

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal Projects from the substantia niagra to

the basal gangliapart of extrapyramidal systemThus side effects are called “extrapyramidal”

Chronic blockade can cause Potentially irreversible movement disorder

○ “Tardive Dyskinesia

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysNigrostriatal Controls movements

Types of movement disorders caused by this pathway include:Akathisia

Dystonia

Tremor, rigidity, bradykinesia ○ Drug-induced Parkinsonism

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysMesolimbic - Mesocortical

Blockade may help reduce negative symptoms of schizophrenia

May be involved in the cognitive side effects of antipsychotics “mind dulling”

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysTuberoinfundibular

DA released at this site regulates the secretion of prolactin from the anterior pituitary gland.

Blockade produces galactorrhea

Dopamine=PIF

Douglas L. Geenens, D.O. 2000

Dopamine PathwaysIncertohypothalamic

Connects the hypothalamus and the limbic system

Regulates sexual desire

Classes of Antipsychotics1. Phenothiazines2. Benzisoxazoles3. Butyrophenones4. Thioxanthenes 5. Dibenzodiazepines

Atypical Antipsychotics In the last decade new "atypical" antipsychotics

have been introduced, >effective, <s/e typical antipsychotics 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 DA (D1 and D4) 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 Low or no EPS

5-HT2A antagonist

Control both positive and neg. symptoms

Aripiprazole (Abilify),Risperidone (Risperdal), Clozapine (Clozaril), Olanzapine (Zyprexa), Quetiapine (Seroquel), and Ziprasidone (Geodon).

Atypical Antipsychotics(second generation)

Clozapine (prototype)Little to no EPS, high incidence of agranulocytosis

(regular CBC’s), High incidence of siezures Olanzapine (Zyprexa)

Sedation, weight gain, no agranulocytosis, low incidence of siezures

Quetiapine (Seroquel)Sedation, low incidence of all side effects

Action of Atypical Antipsychotics

Antipsychotic – reduce hallucinations, agitation, require several weeks to occur

EPS – Parkinsonian symptoms, akathisia, tardive dyskinesia.(clozapine, risperidone show low incidence)

Antiemetic – D2 receptor antagonist in CMZ of medulla (except thioridazine)

Antimuscarinic – blurred vision,dry mouth, sedation, confusion, inhibition of GI and urinary smooth muscle – constipation, urinary retention. (all esp. thioridazine and chlorpromazine)

α-blockade – orthostatic hypotension, lightheadedness, alter temperature regulating mechanisms, block D2 receptors in pituitary – prolactin release

Therapeutic application of antiemetic agents

Vertigo – meclizine, dimenhydrinate Motion sickness – scoopolamine,

promethazine Cancer chemo – droperidol, haloperidol,

metoclopramide, prochloperazine Radiation therapy – thiethylperazine,

domperidone