抗精神失常药 PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS)

SOME DEFINITIONS Neuroleptic: synonym for antipsychotic drug; originally indicated drug w/antipsychotic efficacy but with neurologic (extrapyramidal motor) side effects Typical neuroleptic: older agents fitting this description Atypical neuroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effects

NEUROLEPTICS ON THE UUHSC DRUG LIST TYPICAL NEUROLEPTICS: PHENOTHIAZINES: Chlorpromazine (Thorazine ® ) Thioridazine (Mellaril ® ) Fluphenazine (Prolixin ® ) THIOXANTHENE Thiothixene (Navane® ) OTHER Haloperidol (Haldol ® )

NEUROLEPTICS ON THE UUHSC DRUG LIST (Continued) ATYPICAL NEUROLEPTICS: Risperidone (Risperdal ® ; most frequently prescribed in U.S.) Clozapine (Clozaril ® ) Olanzapine (Zyprexa ® ) Quetiapine (Seroquel ® )

KEY CONCEPTS: All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability. All neuroleptics block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects. All neuroleptics show a significant delay before they become effective. All neuroleptics produce significant adverse effects.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS The older, typical neuroleptics are effective antipsychotic agents with neurologic side effects involving the extrapyramidal motor system. Typical neuroleptics block the dopamine-2 receptor.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression Abuse, addiction, physical dependence do not develop to typical neuroleptics.

GENERAL CHARACTERISTICS OF TYPICAL NEUROLEPTICS Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.

Positive/active symptoms include thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene

THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS All appear equally effective; choice usually based on tolerability of side effects Most common are haloperidol (Haldol ® ), chlorpromazine (Thorazine ®) and thioridazine (Mellaril ®) Latency to beneficial effects; 4-6 week delay until full response is common 70-80% of patients respond, but 30-40% show only partial response

THERAPEUTIC EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Relapse, recurrence of symptoms is common ( approx. 50% within two years). Noncompliance is common. Adverse effects are common.

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension w/ reflex tachycardia sedation

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Antihistamine effect: sedation, weight gain

KEY CONCEPT: DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS). DYSTONIA NEUROLEPTIC MALIGNANT SYNDROME PARKINSONISM TARDIVE DYSKINESIA AKATHISIA

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Increased prolactin secretion (common with all; from dopamine blockade) Weight gain (common, antihistamine effect?) Photosensitivity (v. common w/ phenothiazines) Lowered seizure threshold (common with all) Leucopenia , agranulocytosis (rare; w/ phenothiazines) Retinal pigmentopathy (rare; w/ phenothiazines)

ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS (Continued) Chlorpromazine and thioridazine produce marked autonomic side effects and sedation; EPS tend to be weak (thioridazine) or moderate (chlorpromazine). Haloperidol, thiothixene and fluphenazine produce weak autonomic and sedative effects, but EPS are marked.

MECHANISMS OF ACTION OF TYPICAL NEUROLEPTICS DOPAMINE-2 receptor blockade in meso-limbic and meso-cortical systems for antipsychotic effect. DOPAMINE-2 receptor blockade in basal ganglia (nigro-striatal system) for EPS DOPAMINE-2 receptor supersensitivity in nigrostriatal system for tardive dyskinesia

LONG TERM EFFECTS OF D2 RECEPTOR BLOCKADE: Dopamine neurons reduce activity. Postsynaptic D-2 receptor numbers increase (compensatory response). When D2 blockade is reduced, DA neurons resume firing and stimulate increased # of receptors >> hyper-dopamine state >> tardive dyskinesia

MANAGEMENT OF EPS Dystonia and parkinsonism: anticholinergic antiparkinson drugs Neuroleptic malignant syndrome: muscle relaxants, DA agonists, supportive Akathisia: benzodiazepines, propranolol Tardive dyskinesia: increase neuroleptic dose; switch to clozapine

ADDITIONAL CLINICAL USES OF TYPICAL NEUROLEPTICS Adjunctive in Rx of acute manic episode Tourette’s syndrome (esp. Haldol ® ) Rx of drug-induced psychoses Phenothiazines are effective anti-emetics, Esp. prochlorperazine (Compazine ® ) Also, anti-migraine effect

GENERAL CHARACTERISTICS OF ATYPICAL NEUROLEPTICS Effective antipsychotic agents with greatly reduced or absent EPS, esp. reduced Parkinsonism and tardive dyskinesia All atypical neuroleptics block dopamine and serotonin receptors; other neurochemical effects differ Are effective against positive and negative symptoms of schizophrenia; and in patients refractory to typical neuroleptics

PHARMACOLOGY OF CLOZAPINE (CLOZARIL ®) FDA-approved for patients not responding to other agents or with severe tardive dyskinesia Effective against negative symptoms Also effective in bipolar disorder Little or no parkinsonism, tardive dyskinesia, PRL elevation, neuro-malignant syndrome; some akathisia

Blockade of alpha-1 adrenergic receptors Blockade of muscarinic cholinergic receptors Blockade of histamine-1 receptors

PHARMACOLOGY OF CLOZAPINE (Continued ) Other adverse effects; Weight gain Increased salivation Increased risk of seizures Risk of agranulocytosis requires continual monitoring

PHARMACOLOGY OF OLANZAPINE (ZYPREXA ® ) Olanzapine is clozapine without the agranulocytosis. Same therapeutic effectiveness Same side effect profile

PHARMACOLOGY OF QUETIAPINE (SEROQUEL ®) Quetiapine is olanzapine without the anticholinergic effects. Same therapeutic effectiveness Same side effect profile

Highly effective against positive and negative symptoms Adverse effects: EPS incidence is dose-related Alpha-1 receptor blockade Little or no anticholinergic or antihistamine effects Weight gain, PRL elevation

HYPOTHESIZED MECHANISMS OF ACTION OF ATYPICAL NEUROLEPTICS Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)

General Therapeutic Principles for Use of Neuroleptics in Schizophrenia (NIH Consensus Statement, 1999) Use atypical for: 1st acute episode w/ + or +/- symptoms Switch to atypical if: Breakthrough after Rx w/ typical Use typical (depot prep) when: Patient is noncompliant

General Therapeutic Principles for Use of Neuroleptics in Schizophrenia If response is inadequate to: Typical; switch to Atypical Atypical; raise dose or switch to another Atypical Typical and Atypical; switch to Clozaril ® For maintenance, lifetime Rx is required.