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Transcript
抗精神失常药 PHARMACOLOGY OF ANTIPSYCHOTIC DRUGS (NEUROLEPTICS) دکتر محمد بهداد متخصص روانپزشکی 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 antiemetics, 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. Extrapyramidal Symptoms Description and Management Akathesia / Dystonia Akathesia - feeling of restlessness, desire to move legs or walk Dystonia -slow sustained contractions or spasms that result in involuntary movement Drug Induced Parkinsonism Muscle stiffness/ Cogwheeling Shuffling gait Stooped posture Masked facies Tremor Management of Akathesia/Dystonia/Drug Induced Parkinsonism Akathesia - Symptoms usually abate with reduction of dose or discontinuation of the medication - Addition of anxiolytic or b-blocker may be helpful Dystonia / Drug Induced Parkinsonism -require immediate intervention -administration of anticholinergic or antiparkinson medication -reduce dose or change medication Tardive Dyskinesia Repetitive rhythmic involuntary movements Examples -Tongue thrusting -Lip smacking -Chewing movements -Grunting/Humming Mangement of Tardive Dyskinesia Prevention is the key Screening recommended every 3 to 6 months using tools such as the Abnormal Involuntary Movement Scale (AIMS) When identified, reduce or eliminate the causative agent Neuroleptic Malignant Syndrome High Fever Muscle Rigidity Change in Mental Status Autonomic Instability Profuse Diaphoresis Fatality rate of 10-30% Management of Malignant Neuroleptic Syndrome Hospital transfer Withhold neuroleptic medication Hydration to correct fluid losses and hypotension Benzodiazepines and physical restraints as needed Cooling with antipyretics, cooling blankets Dopamine agonists (Bromocriptine, amatadine) Avoid Dantrolene Psychiatry, neurology, and renal consults as appropriate (Benzor 2009) Hyperprolactinemia Symptoms and management Hyperprolactinemia Symptoms Men Women Galactorrhea Galactorrhea Gynecomastia Amenorrhea/Oligomennorrhea Decreased libido Acne/Hirsutism Infertility Infertility Erectile Dysfunction Dyspareunia Osteoporosis Osteoporosis Hyperprolactinemia Management Do not check prolactin levels in asymptomatic patients In symptomatic patients, evaluate other potential causes of symptoms (thyroid disease, pregnancy, low testosterone) Consider an MRI in patients whose history may suggest a pituitary lesion or not well explained by the drug in question Consider endocrinology referral Consider discontinuing drug in consultation with patient and psychiatrist (Miller 2004) Metabolic Syndrome Monitoring and Management Metabolic Syndrome In 2004, FDA issued a black box warning on hyperglycemia and diabetes associated with atypical antipsychotics The American Diabetic Association published a consensus statement in conjuction with the American Psychiatric Association, the American College of Endocrinology outlining management of metabolic sequelae of antipsychotic use (ADA, Diabetes Care 2004) Baseline Monitoring Document any Personal/Family History of Obesity, Diabetes, Hyperlipidemia, or Heart Disease Weight and Height Measurements (BMI) Waist Circumference Fasting Plasma Glucose Fasting Lipid Profile Baseline Monitoring Initiate standard treatment for any patients found to be hypertensive, diabetic, or with elevated lipids Nutritional and physical activity counseling for patients who are overweight or obese Patients and family should be informed of the risks of weight gain and diabetes. Patients and families should be advised on how to recognize the signs and symptoms of diabetes. Weight measurements Weight should be monitored monthly for the 1st 3 months For patients who have gained > 5%; consider changing agent Rapid discontinuation of medication should be avoided 3 Months Weight Fasting plasma glucose Lipid profile Blood Pressure Patients who develop worsening blood sugar or lipids should consider switching agents Annual Assessments Family / Personal history Weight Blood pressure Fasting Plasma Levels Waist Circumference Lipids (may be done every 5 years) Monitoring Schedule Baseline 4 8 12 Every weeks weeks weeks 3 Months Every Year Personal/ Family history x Weight x Waist x Blood Pressure x x x Fasting glucose x x x Lipid Profile x x Every 5 years x x x x x x x x Epilogue Morrato et al examined the testing of fasting glucose and lipids in patients receiving atypical antipsychotic medications Laboratory claims for 18, 876 US patients enrolled in a commercial health plan receiving antipsychotic medications from 2001 through 2006 Comparisons before and after the FDA letter campaign and ADA consensus statement Survey Question #3 (1) (2) (3) (4) (5) Which of the following best describes the percentage of patients on antipsychotic medication who had an annual fasting glucose in study by Morrato et al ? 20% 40% 60% 80% 95% Effect of ADA and FDA on Annual Glucose Screening Extrapyramidal syndromes include the following: Acute dystonia: sustained muscle contractions cause 1. twisting and repetitive movements or abnormal postures 2. This condition is often elicited during the first week of therapy. Akathisia is the irresistible compulsion to be in motion. This condition can develop as early as the first 2 weeks of treatment or as late as 60 days into therapy. Parkinsonian-like syndrome 3. • • Parkinsonian-like syndrome is characterized by tremors, bradykinesia, rigidity, and other signs of parkinsonism. This syndrome can develop from 5 days to weeks into treatment. Acute dystonia b. Tardive dyskinesia (10—20%) CNS disorder characterized by: • • twitching of the face and tongue involuntary motor movements of the trunk and limbs More likely with conventional antipsychotic agents. Tardive dyskinesia generally occurs after months to years of drug exposure; it may be exacerbated or precipitated by the discontinuation of therapy. Orofacial movements Dystonic posture Tardive dyskinesia is often irreversible. more likely to occur in the elderly or in institutionalized patients who receive long-term, highdose therapy. The only effective treatment for tardive dyskinesia is the discontinuation of treatment. Cholestatic jaundice, which is caused c. primarily by chlorpromazine d. Photosensitivity 1. The effect is specific to chlorpromazine 2. it includes dermatitis (5%), rash, sunburn, and pigmentation, and it may be irreversible. Chlorpromazine and high-dose thioridazine also produce retinitis pigmentosa