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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. Antipsychotic Agents & Schizophrenia • Antipsychotic Agents: – Two major groups: • Conventional Antipsychotics – Block receptors for dopamine D2in the CNS • Atypical Antipsychotics – Only produce moderate blockage of receptors for dopamine D2 and much stronger blockade of receptors for serotonin 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 • Conventional Antipsychotic Group Properties: – 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, histamine, and norepinephrine. • Relief of positive symptoms respond better to conventional antipsychotic drugs; less effect on negative symptoms Extrapyramidal Symptoms Reaction Onset Features Acute dystonia Hours to 5 days Spasm of muscle of tongue, neck, face & back Parkinsonism 5 – 30 days Tremor, rigidity, shuffling gait, drooling, stooped posture, instability Restlessness 5 – 60 days Compulsive, repetitive motions; (Akathesia) agitation Tarditive Months to years Lip-smacking, worm-like tongue dyskinesia movement, ‘fly-catching’ Antipsychotic Agents & Schizophrenia • Conventional Antipsychotics: – Low potency: Prototype = Chlorpromazine (Largactile) • 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. – Norepinephrine. – Dopamine. Monoamines – Seratonin. • Goal is to regulate excitory/inhibitory neurotransmitters. Anti-Psychotic Drugs (Neuroleptics) • Schizophrenia – Loss of contact with reality & disorganized thoughts – Probable cause: increased dopamine release – Tx. Aimed at decreasing dopamine activity • Phenothiazines Two Chemical • Chlorpromazine Classes: • Butyrophenones • haloperidol (Haldol®) Other Uses for Antipsychotics • Bipolar depression • Mania • Prevention of emesis (H1 block) • Psychotic symptoms of Alzheimer • Temporary psychoses from other illness Antipsychotic mechanism of action (MOA) • Mechanism is similar • Strength vs. Potency – Phenothiazines – low potency – Butyrophenones – high potency • Receptor Antagonism – Dopamine2 in brain Therapeutic effects – Muscarinic cholinergic – Histamine Uninteded effects – Norepi at alpha1 Antipsychotic Side Effects • Dose dependent Extrapyramidal symptoms (EPS) • Tarditive dyskinesia may be irreversible. • Anticholinergic effects (atropine-like) – Dry mouth, blurred vision, photophobia, tachycardia, constipation) • Orthostatic hypotension α1 adrenergic block • Sedation • Decreased seizure threshold • Sexual dysfunction Antipsychotic Side Effects • Hyperprolactinemia • Gynecomastia • Amenorrhea-glactorrhia and infertility. • Dopamine is inhibitory of prolactin secretion. • Weight gain • Neuroliptic malignant syndrome (malignant hyperthermia, muscle rigidity, sweating, autonomic instability ttt by dantrolene, diazepam, and dopamine agonist. Extrapyramidal Symptoms Reaction Onset Features Acute dystonia Hours to 5 days Spasm of muscle of tongue, neck, face & back Parkinsonism 5 – 30 days Tremor, rigidity, shuffling gait, drooling, stooped posture, instability Restlessness 5 – 60 days Compulsive, repetitive motions; (Akathesia) agitation Tarditive Months to years Lip-smacking, worm-like tongue dyskinesia movement, ‘fly-catching’ Treatment of EPS • Likely caused by blocking central dopamine2 receptors responsible for movement • Anticholinergic therapy rapidly effective – diphenhydramine (Benadryl®) Antipsychotic Agents Classic drugs (D2-Affinity) • chlorpromazine (Largactile®) • thioridazine (Mellaril®) • trifluoperazine (Stelazine®) • haloperidol (Haldol®) Antipsychotic Agents Newer drugs (5HT2-Affinity) • Clozapine. • Olanzapine. • Quetiapine. • Risperidone. • Ziprasidone.
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