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Antipsychotic agents final PHARMACOLOGY.pdf
- 1.
- 2. Introduction Neuroleptic: synonymfor antipsychotic drug; originally indicated drug with antipsychotic efficacy but also neurologic (extrapyramidal motor) side effects, now claimed as subtype of antipsychotic drugs Typical neuroleptic: older agents fitting this description atypical" antipsychotic : newer agents: antipsychotic efficacy with reduced or no neurologic side effects
- 3. History Reserpine Chlorpromazine:neuroleptic agent The discovery of clozapine was in 1959 antipsychotic drugs need not cause EPS (Extrapyramidal symptoms)
- 4. Nature of Psychosis& Schizophrenia Chronic Psychosis. The presence of delusions (false beliefs) Various types of hallucinations, usually auditory or visual, but sometimes tactile or olfactory Disorganized thinking in a clear sensorium
- 5. The Serotonin Hypothesis ofSchizophrenia Hallucinogens such as LSD (lysergic acid diethylamide) and mescaline are serotonin (5-HT) agonists 5-HT2A-receptor blockade is a key factor in the mechanism of action of the main class of atypical antipsychotic drugs such as clozapine and quetiapine. 5-HT2C-receptor stimulation provides a further means of modulating
- 6. The Dopamine Hypothesis ofSchizophrenia Was the first neurotransmitter-based concept Excessive limbic dopaminergic activity plays a role in psychosis Many antipsychotic drugs strongly block postsynaptic D2 receptors: Includes partial dopamine agonists, such as aripiprazole and bifeprunox Drugs that increase dopaminergic activity either aggravate schizophrenia psychosis or produce psychosis de novo Dopamine-receptor density is high postmortem The atypical antipsychotic drugs Much less effect on D2 receptors Role of other dopamine receptors and to nondopamine receptors
- 7. The Glutamate Hypothesis ofSchizophrenia Glutamate is the major excitatory neurotransmitter in the brain Phencyclidine and ketamine are noncompetitive inhibitors of the NMDA receptor Hypofunction of NMDA receptors, located on GABAergic interneurons
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- 9. Antipsychotic Drugs: Relationof Chemical Structure to Potency and Toxicities Chemical Class Drug D2/5-HT2A Ratio1 Clinical Potency Extrapyramidal Toxicity Sedative Action Hypotensive Actions Phenothiazines Aliphatic Chlorpromazine High Low Medium High High Piperazine Fluphenazine High High High Low Very low Thioxanthene Thiothixene Very high High Medium Medium Medium Butyrophenone Haloperidol Medium High Very high Low Very low Dibenzodiazepin e Clozapine Very low Medium Very low Low Medium Benzisoxazole Risperidone Very low High Low2 Low Low Thienobenzodiaz epine Olanzapine Low High Very Low Medium Low Dibenzothiazepi ne Quetiapine Low Low Very Low Medium Low to Medium Dihydroindolone Ziprasidone Low Medium Very Low Low Very Low Dihydrocarbostyr il Aripiprazole Medium High Very Low Very Low Low
- 10. Pharmacokinetics Absorption andDistribution Readily but incompletely absorbed Significant first-pass metabolism Highly lipid-soluble and protein-bound Metabolism Almost completely metabolized Drug-drug interactions should be considered
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- 12. KEY CONCEPTS: Allneuroleptics 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. show a significant delay before they become effective. produce significant adverse effects.
- 13. GENERAL CHARACTERISTICS OFTYPICAL 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.
- 14. GENERAL CHARACTERISTICS OFTYPICAL 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.
- 15. GENERAL CHARACTERISTICS OFTYPICAL NEUROLEPTICS Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms.
- 16. Positive/active symptomsinclude thought disturbances, delusions, hallucinations Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech, impaired personal hygiene
- 17. THERAPEUTIC EFFECTS OFTYPICAL NEUROLEPTICS All appear equally effective; choice usually based on tolerability of side effects Most common are haloperidol ,chlorpromazine and thioridazine 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
- 18. THERAPEUTIC EFFECTS OFTYPICAL NEUROLEPTICS (Continued) Relapse, recurrence of symptoms is common ( approx. 50% within two years). Noncompliance is common. Adverse effects are common.
- 19. ADVERSE EFFECTS OFTYPICAL NEUROLEPTICS Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension , reflex tachycardia Sedation Antihistamine effect: sedation, weight gain
- 20. ADVERSE EFFECTS OFTYPICAL 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) Leukopenia , agranulocytosis (rare; w/ phenothiazines) Retinal pigmentopathy (rare; w/ phenothiazines)
- 21. MECHANISMS OF ACTION OFTYPICAL NEUROLEPTICS and Some Side Effects 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
- 22. 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
- 23. HYPOTHESIZED MECHANISMS OF ACTIONOF ATYPICAL NEUROLEPTICS Combination of Dopamine-4 and Serotonin-2 receptor blockade in cortical and limbic areas for the “pines” like clozapine Combination of Dopamine-2 and Serotonin-2 receptor blockade (esp. risperidone)
- 24. ADDITIONAL CLINICAL USESOF TYPICAL NEUROLEPTICS Adjunctive in acute manic episode Tourette’s syndrome (Haloperidole ) Control of psychosis in depressed patient Phenothiazines are effective anti-emetics, Esp. prochlorperazine Also, anti-migraine effect
- 25. PHARMACOLOGY OF CLOZAPINE 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
- 26. PHARMACOLOGY OF CLOZAPINE (Continued) Other adverse effects; Weight gain Increased salivation Increased risk of seizures Risk of agranulocytosis requires continual monitoring
- 27. PHARMACOLOGY OF OLANZAPINE Olanzapine is clozapine without the agranulocytosis. Same therapeutic effectiveness Same side effect profile
- 28. PHARMACOLOGY OF QUETIAPINE Quetiapine is olanzapine without the anticholinergic effects. Same therapeutic effectiveness Same side effect profile
- 29. Resperidone Highly effectiveagainst 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