Ereshefsky L, Watanabe M D, Tran-Johnson T K
College of Pharmacy, University of Texas, Austin.
Clin Pharm. 1989 Oct;8(10):691-709.
The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed. Clozapine is a dibenzazepine compound chemically similar to loxapine but with a distinct pharmacologic profile. Unlike currently available medications, clozapine has a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity. It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors. Clozapine given orally is nearly completely absorbed and readily metabolized. Urinary excretion is the major route of metabolite elimination. Clozapine has been used to treat schizophrenia, nonschizophrenic psychotic states, depression, neuroses, and behavioral disorders. Double-blind comparative studies have shown clozapine to be superior to haloperidol, chlorpromazine, and placebo in treating the symptoms of schizophrenia, as measured with validated psychiatric rating scales. Adverse effects include orthostatic hypotension, tachycardia, benign hyperthermia, hypertension, seizures, and sedation. Many of these effects are transient. Because of the risk of agranulocytosis, a comprehensive case-management system has been developed. In treating acute psychosis, the optimum dosage of clozapine is 300-450 mg/day given orally in divided doses. The high cost of clozapine may be offset by improved patient response and reduced hospital costs. Clozapine may be superior to other agents in the treatment of refractory schizophrenia and is associated with a negligible incidence of extrapyramidal symptoms.
本文综述了非典型抗精神病药物氯氮平的药理学、药代动力学、临床疗效、不良反应、剂量及成本。氯氮平是一种二苯并氮䓬化合物，化学结构与洛沙平相似，但具有独特的药理学特性。与现有药物不同，氯氮平引起锥体外系症状的可能性较低，且不会诱发多巴胺2型受体超敏反应。它在体外不仅对多巴胺1型和2型受体有亲和力，还对组胺1型、α-肾上腺素能1型和2型、5-羟色胺2型及毒蕈碱受体有亲和力。口服氯氮平几乎可完全吸收并易于代谢。尿液排泄是代谢物消除的主要途径。氯氮平已被用于治疗精神分裂症、非精神分裂症性精神病状态、抑郁症、神经症及行为障碍。双盲对照研究表明，以经过验证的精神病评定量表衡量，氯氮平在治疗精神分裂症症状方面优于氟哌啶醇、氯丙嗪及安慰剂。不良反应包括体位性低血压、心动过速、良性高热、高血压、癫痫发作及镇静作用。其中许多效应是短暂的。由于存在粒细胞缺乏症的风险，已开发出一套全面的病例管理系统。在治疗急性精神病时，氯氮平的最佳口服剂量为每日300 - 450毫克，分剂量服用。氯氮平的高成本可能会因患者反应改善及医院成本降低而得到抵消。在治疗难治性精神分裂症方面，氯氮平可能优于其他药物，且锥体外系症状的发生率可忽略不计。
