PHARMACOLOGY

Neuropharmacology – 2009 John Schriefer, Ph.D. ANTIPSYCHOTIC AGENTS Objectives: The student shall be able to: 1. describe the symptoms of schizophrenia and relate the effects of antipsychotic medications on these symptoms. explain the proposed mechanism of action of the typical (e.g., chlorpromazine) and atypical (e.g., clozapine) antipsychotic drugs and their pharmacological properties. list the probable sites of action of the therapeutic and side effects of these agents. describe the important side effects of these agents. list the therapeutic uses of antipsychotic drugs. describe the important drug interactions of the antipsychotic agents. list the advantages and disadvantages of the atypical antipsychotics clozapine and risperidone compared to the typical antipsychotics such as chlorpromazine, or haloperidol Classify antipsychotics as either typical or atypical. 2. 3. 4. 5. 6. 7. 8. 1 I. Psychotic illnesses - the most severe psychiatric disorders. A. schizophrenia - a disorder in which thought processes diverge from reality. Patients may manifest disorders of perception, thinking, speech, emotion or physical activity. The symptoms have been divided into 2 broad categories. 1. positive symptoms – delusions, hallucinations, disorganized speech and catatonic behavior negative symptoms – flattened affect, alogia, and avolition 2. B. organic psychoses - associated with definable toxic, metabolic or neuropathologic changes comparison Evaluation of antipsychotic agents There is no animal model for mental illness. This makes evaluation of new drugs difficult. C. D. 2 II. Agents used in treatment of psychoses Advantages Generic, inexpensive Slight extrapyramidal syndrome; generic Depot form also available (enanthate, decanoate) Generic, inexpensive Parenteral form also available; (?) decreased tardive dyskinesia Parenteral form also available; generic (?) No weight gain May benefit treatmentresistant patients; little extrapyramidal toxicity Broad efficacy; little or no extrapyramidal system dysfunction at low doses Effective against negative as well as positive symptoms; little or no extrapyramidal system dysfunction Little or no extrapyramidal system dysfunction less weight gain than other atypicals; rapid acting IM formulation little or no EPS, less weight gain, or Q-T changes Disadvantages Many adverse effects, especially autonomic 800 mg/d limit; no parenteral form; cardiotoxicity (?) Increased tardive dyskinesia Moderate risk of EPS, sedation Uncertain Drug Chlorpromazine (Thorazine) Thioridazine (Mellaril) Fluphenazine (Permitil, Prolixin) Perphenazine (Trilafon) Thiothixene (Navane) Haloperidol (Haldol) Loxapine (Loxitane) Clozapine (Clozaril)* (klo´ za peen) Risperidone (Risperdal)* (ris per´ i dōn) (paliperidone; Invega) Olanzapine (Zyprexa)* (oh lan´ za peen) Severe extrapyramidal syndrome Uncertain May cause agranulocytosis in up to 2% of patients; weight gain, hyperglycemia, diabetes, dyslipidemia May cause extrapyramidal syndrome or hypotension with higher doses; weight gain, hyperglycemia, diabetes, dyslipidemia weight gain, hyperglycemia, diabetes, dyslipidemia Quetiapine (Seroquel)* (kwe ty´ a peen) Ziprasidone (Geodon)* (zi praz´ i dōn) Aripiperazole (Abilify)* (Ari pip´ ra zole) Weight gain, hyperglycemia, diabetes, dyslipidemia; cataracts (?) prolongs Q-T interval, but no arrhythmias reported yet; Somnolence, some EPS Akathesia, insomnia, anxiety. Caution in patients with epilepsy or Alzheimer’s *Atypical (or second generation) antipsychotics 3 A. Pharmacological properties Receptor Interactions of Antipsychotic drugs All antipsychotics block D2 receptors but the importance of this in relation to other receptor actions varies from drug to drug. Many receptors are involved in antipsychotic effects. The receptor binding profiles of three antipsychotics illustrates this point. Chlorpromazine: α1 = 5 HT2 > D2 > D1 haloperidol: D2 > D1 = D4 > α1 > 5 HT2 clozapine: D4 = α1 > 5 HT2 > D2 = D1 “Atypical” antipsychotics have different receptor binding profiles, but they all tend to be less potent at D2 receptors than chlorpromazine or halperidol and more potent at 5HT2 and D4 receptors. Aripiprazole is a partial agonist at DA2 and 5HT1a and blocks 5HT2A receptors, claimed to represent a “new generation” of antipsychotics. Newest approach involves agonists at metabotropic glutamate receptors. Blocking D2 receptors alleviates positive symptoms of schizophrenia (tension, hostility, hyperactivity, combativeness, hallucinations, delusions, insomnia, and anorexia. Blocking D4 and 5HT2 receptors may alleviate negative symptoms (apathy, withdrawal, unresponsiveness). 4 1. CNS effects a. b. cortex - little known; EEG changes; antipsychotic effects limbic system - antipsychotic effects. Combine with cortical effects to produce psychomotor slowing and affective indifference (emotional quieting and sedation). basal ganglia - antidopaminergic action appears to be responsible for Parkinson-like extrapyramidal effects. hypothalamus - increased prolactin secretion; temperature regulation medullary chemoreceptor trigger zone (CTZ) - antiemetic action DMV - increased eating c. d. e. 2. Peripheral effects; a. autonomic nervous system - peripheral cholinergic block, α-adrenergic block endocrine - alterations in the secretion of many hormones cardiovascular system - direct depressant effect on heart, direct vasodilation plus indirect effects due to ANS effects 5 b. c. B. Disposition Absorption after oral administration varies from drug to drug; can be as low as 25%. Distribution – highly lipid soluble and are sequestered in lipids, leading to long duration of action. Metabolized by oxidation and glucuronide conjugation. Some active metabolites formed. It is thought that an active metabolite of clozapine, norclozapine, is responsible for the serious side effect of clozapine. Elimination T 1/2 - 10-20 hours. Biological effects last 24 hours or more. C. Adverse reactions – most important ones are those on CV, endocrine, and central and autonomic nervous systems. Other dangerous effects include seizures, agranulocytosis, and pigmentary degeneration of the retina. 1. Neurologic side effects – alteration of extrapyramindal system (EPS) function. EPS alteration is related to high D2 potency (e.g., haloperidal) and less likely with atypicals (e.g., clozapine). Early onset – acute dystonia, akathisia, parkinsonism and neuroleptic malignant syndrome. Late onset – perioral tremor and tardive dyskinesia 6 NEUROLOGICAL SIDE EFFECTS OF ANTIPSYCHOTIC DRUGS REACTION FEATURES TIME OF MAXIMAL RISK 1 to 5 days PROPOSED MECHANISM Unknown TREATMENT Acute dystonia Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria Motor restlessness: not anxiety or "agitation" Many treatments can alter, but effects of antimuscarinic agents are diagnostic and curative.* Reduce dose or change drug; antimuscarinic agents, diphenhydramine, benzodiazepines, or propranolol ++ may help Antimuscarinic agents helpful+ Akathisia 5 to 60 days Unknown Parkinsonism Bradykinesia, rigidity, variable tremor, mask facies, shuffling gait Catatonia, stupor, fever, unstable blood pressure, myoglobinemia; can be fatal Perioral tremor (may be a late variant of parkinsonism) Oral-facial dyskinesia; widespread choreoathetosis or dystonia 5 to 30 days Antagonism of dopamine Neuroleptic Malignant syndrome Weeks; can persist for days after stopping neuroleptic After months or years of treatment After months or years of treatment (worse on withdrawal) Antagonism of dopamine may contribute Stop antipsychotic immediately; dantrolene or bromocriptine may help §; antimuscarinic agents not effective Antimuscarinic agents often help + Perioral tremor ("rabbit" syndrome) Tardive dyskinesia Unknown Up regulation of striatal D2 receptors Prevention crucial; clozapine or olanzapine may help *Many drugs have been claimed to be helpful for acute dystonia. Among the most commonly employed treatments are diphenhydramine hydrochloride, 25 or 50 mg intramuscularly, or benztropine mesylate, 1 or 2 mg intramuscularly or slowly intravenously, followed by oral medication with the same agent for a period of days to perhaps several weeks thereafter. ++ Propranolol is often effective in relatively low doses (20-80 mg per day). Selective β1-adrenergic antagonists are less effective. § Despite the response to dantrolene, there is no evidence of an abnormality of Ca +2 transport in skeletal muscle; with lingering antipsychotic effects, bromocriptine may be tolerated in large doses (10-40 mg per day). Seizures with clozapine 2.  Cardiovascular and cerebrovascular effects orthostatic hypotension (α block) is the most common CV effect 7   3. QT prolongation (thioridazine, ziprasidone, haloperidol, pimozide) increased risk of stroke in elderly (risperidone, olanzapine) Weight gain and metabolic effects Weight gain is prominent with clozapine and olanzapine. Uncommon with ziprasidone and aripiprazole. Can increase risk of type 2 diabetes. 4. Blood dyscrasias Mild leukocytosis, leucopenia, and eosinophilia can occur. Bone marrow suppression or agranlucytosis with clozapine. 5. Others Skin reactions – typicals – dermatitis, photosensitivity and sunburn, pigmentary retinopathy. Quetiapine may cause cataracts. GI and hepatic effects – jaundice with chlorpromazine; ileus and sialorrhea with clozapine. endocrine – hyperprolactinemia sedation – due to H1 block Anticholinergic effects (mainly typicals) SOME ADVERSE EFFECTS OF SECOND-GENERATION ANTIPSYCHOTICS EXTRAPYRAMIDAL ELEVATED QTc WEIGHT SYMPTOMS PROLACTIN PROLONGATION GAIN Aripiprazole +/+ +/+/+/Clozapine* ++++ +/+/+ ++++ Olanzapine ++++ + +/+ ++++ Quetiapine ++ +/+/+/+++ Risperidone ++ +++ +++ + ++ Ziprasidone +/+ + ++ +/*Clozapine is also associated with myocarditis and agranulocytosis; the other second-generation antipsychotics are not. DRUG DIABETES 8 COMPARISON OF SOME ANTIPSYCHOTIC AGENTS DRUG RELATIVE ANTIPSYCHOTIC POTENCY + + +++ +++ ++ ++ ++ +++ SEDATION EXTRAPYRAMIDAL ANTICHOLINERGIC HYPOTENSION chlorpromazine (Thorazine) thioridazine (Mellaril) fluphenazine (Prolixin) haloperidol (Haldol) loxapine (Loxitane) molindone (Moban) clozapine (Clozaril) risperidone (Risperdal) +++ +++ + + + ++ +++ + +++ + +++ +++ ++ + +/+ + +++ + +/+/+ +++ + +++ +++ ++ + + + +++ ++ D. E. Drug interactions - potentiate the effects of opioids, barbiturates and ethanol Therapeutic uses 1. Psychoses - All agents improve positive symptoms. Atypicals also improve negative symptoms. CATIE trial (NEJM 9/22/05) suggests atypicals may not be much better than less expensive typicals. Risperidone approved (2007) for treatment in children and teenagers. 9 2. 3. 4. Nausea and vomiting (prochlorperazine – Compazine) Hiccough Other neuropsychiatric diseases - Tourette’s syndrome - haloperidol or pimozide (Orap) - Agitation associated with Alzheimers and other dementias. Careful with using atypicals to treat dementia in the elderly (Black box warning!) - Bipolar disorder - Major Depressive Disorder – aripiprazole approved to augment effects of anti-depressants. 10 LONG-ACTING ANTIPSYCHOTIC DRUGS DRUG Fluphenazine Decanoate Prolixin Decanoate Fluphenazine Enanthate Prolixin Enanthate Haloperidol Decanoate Haldol Decanoate Risperidone (Risperdal Consta) CLASSIFICATION Typical ROUTE OF ADMINISTRATION Intramuscular Subcutaneous Intramuscular Subcutaneous Intramuscular Intramuscular DURATION OF ACTION 2-3 weeks Typical 2 weeks Typical Atypical 3-4 weeks 2 weeks 11