Antipsychotic Agents & Schizophrenia ‡ Antipsychotic Agents

:
± A chemically diverse group of compounds employed to treat a broad spectrum of psychotic disorders.
‡ Schizophrenia, delusional disorders, acute mania, depressive psychoses, drug induced psychoses.

Chemical Classification
‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ Phenothiazines Thioxanthenes Butyrophenones Benzazepines Benzoxazoles Benzodiazepines Anxiolytics Miscellaneous : CPZ, Triflu,Thiori,Mesori,Perphen,Fluphe : Thiothixene,Chlorprothixene : Haloperidol, Dro, Triflu,Spiperone : Clozapine,Loxa,Olanza,Quetia : Benzisoxazoles: Risperidone,Ziprasi : Chlordiazepoxide,Diazepam,Flura,Oxa : Esopiclone,Zolpidem, Zalpidem : Aripiprazole,Molindone,Sertindole

Receptors: D1 and D2, both of which activate 2nd messenger systems. D1 (found mostly in retina) causes increase in cAMP, D2 (nigrostriatal and mesolimbic) causes decrease in cAMP. Also DA autoreceptors (inhibitory feedback). Action of DA terminated by reuptake.

Antipsychotic Agents
Classic drugs (D2-Affinity) ‡ chlorpromazine (Largactile®) ‡ thioridazine (Mellaril®) ‡ trifluoperazine (Stelazine®) ‡ haloperidol (Haldol®)

Atypical Antipsychotic Agents
Newer drugs (5HT2-Affinity) ‡ Clozapine. ‡ Olanzapine. ‡ Quetiapine. ‡ Risperidone. ‡ Ziprasidone.

Antipsychotic Agents & Schizophrenia ‡ Antipsychotic Agents:
± Two major groups:
‡ Conventional Antipsychotics
± Block receptors for dopamine D2 in the CNS

‡ Atypical Antipsychotics
± Only produce moderate blockage of receptors for dopamine D2 and much stronger blockade of receptors for serotonin but more on D3 & 4

Antipsychotic Agents & Schizophrenia
‡ Schizophrenia:
± Chronic psychotic illness characterized by disordered thinking and a reduced ability to comprehend reality.
‡ Positive symptoms:
± Hallucinations, delusions, disordered thinking, disorganized speech, combativeness, agitation, paranoia

‡ Negative symptoms:
± Social/emotional withdrawal, lack of motivation, poverty of speech, blunted affect, poor insight, poor judgment, poor self-care

‡ Etiology is unknown

Antipsychotic Agents & Schizophrenia
‡ Properties of Conventional Antipsychotic Group:
± Because of extrapyramidal side effects (serious movement disorders) they are known as neuroleptics. ± Classified by potency (low, high) or by chemical structure. ± Mechanism of Action:
‡ Varying degrees; these drugs block receptors for dopamine, acetylcholine, serotonin, histamine, and nor-epinephrine. ‡ Relief of positive symptoms respond better to conventional antipsychotic drugs; less effect on negative symptoms

Extrapyramidal Symptoms
Reaction
Acute dystonia Parkinsonism

Onset
Hours to 5 days 5 ± 30 days

Features
Spasm of muscle of tongue, neck, face & back Tremor, rigidity, shuffling gait, drooling, stooped posture, instability Compulsive, repetitive motions; agitation Lip-smacking, worm-like tongue movement, µfly-catching¶

Restlessness (Akathesia) Tarditive dyskinesia

5 ± 60 days Months to years

Antipsychotic Agents & Schizophrenia
‡ Conventional Anti-psychotics:
± Low potency: Prototype = Chlorpromazine (Largactil)
‡ Use: Schizophrenia and other psychotic disorders, manic phase of bipolar disorder, suppression of emesis and relief of intractable hiccups.

± High Potency: Prototype = Haloperidol (Haldol)
‡ Can cause more early extrapyramidal symptoms (EPS) but less sedation, orthostatic hypotension. Preferred for initial therapy. ‡ Use: Schizophrenia and acute psychosis

Antipsychotic Agents & Schizophrenia
‡ Atypical Antipsychotic Agents:
± Cause few or no EPS, can relieve both positive and negative symptoms of schizophrenia. ± Prototype: Clozapine (Clozaril)
‡ Use: Schizophrenia ‡ Blocks receptors for dopamine D4 and serotonin

Psychotherapeutic Medications
‡ Dysfunction related to neurotransmitter imbalance.
± Nor-epinephrine. ± Dopamine. ± Serotonin.

Monoamines

‡ Goal is to regulate excitory/inhibitory neurotransmitters.

AntiAnti-Psychotic Drugs (Neuroleptics)
‡ Schizophrenia
± Loss of contact with reality & disorganized thoughts ± Probable cause: increased dopamine release ± Tmt. is aimed at decreasing dopamine activity Two Chemical Classes: ‡ Phenothiazines
‡ Chlorpromazine

‡ Butyrophenones
‡ haloperidol (Haldol®)

Other Uses for Antipsychotics
‡ ‡ ‡ ‡ ‡ Bipolar depression Mania Prevention of emesis (H1 block) Psychotic symptoms of Alzheimer Temporary psychoses from other illness

AntiAnti-psychotics ± Mechanism of action (MOA)
‡ Mechanism is similar to most compounds ‡ Strength vs. Potency
± Phenothiazines ± low potency ± Butyrophenones ± high potency

‡ Receptor Antagonism
± ± ± ± Dopamine2 in brain Muscarinic cholinergic Histamine Norepi at alpha1 Therapeutic effects Uninteded effects

Antipsychotics - Side Effects
‡ Dose dependent Extrapyramidal symptoms (EPS) ‡ Tarditive dyskinesia may be irreversible. ‡ Anti-cholinergic effects (atropine-like)
± Dry mouth, blurred vision, photophobia, tachycardia, constipation)

‡ ‡ ‡ ‡

Orthostatic hypotension by Sedation Decreased seizure threshold Sexual dysfunction

1

adrenergic block

Antipsychotics - Side Effects
‡ ‡ ‡ ‡ ‡ ‡ Hyperprolactinemia Gynecomastia Amenorrhea-glactorrhia and infertility. Dopamine is inhibitory of prolactin secretion. Weight gain Neuroleptic malignant syndrome (malignant hyperthermia, muscle rigidity, sweating, autonomic instability by dantrolene, diazepam, and dopamine agonists.

Treatment of EPS
‡ Likely caused by blocking central dopamine2 receptors responsible for movement ‡ Anti-cholinergic therapy rapidly effective
± diphenhydramine (Benadryl®)

EXTRAPYRAMIDAL PATHWAY

Butyrophenones

Benzoxaxoles