Jann M W
Department of Pharmacy Practice, Mercer University, Southern School of Pharmacy, Atlanta, Georgia 30312.
Pharmacotherapy. 1991;11(3):179-95.
Clozapine is a neuroleptic agent whose structure consists of a dibenzodiazepine derivative with a piperazinyl side chain. It has been classified as an atypical neuroleptic drug due to its unique neuropharmacologic profile. Clozapine has a weak binding affinity for dopamine D-1 and D-2 receptors by its slightly greater preference for D-1 receptors, as noted with a D-1:D-2 receptor binding ratio of 1.3. Other neuroreceptors are involved, as the drug has potent binding affinity for serotonin receptors 5-HT1A and 5-HT2. Clozapine also has antihistaminic, anticholinergic, and alpha-adrenergic antagonistic properties. Electrophysiologic studies show that it differs from other typical neuroleptics in that its actions appear to be specific for the cortical-limbic dopamine A-10 tract. In animal paradigms, in contrast to typical neuroleptics, clozapine did not produce catalepsy and had only transient effects in antagonizing other dopamine agonists. The drug is rapidly absorbed orally with a bioavailability of 0.27. After a single oral dose the elimination half-life was approximately 8-10 hours, but with several doses it increased to 14.1 hours. The agent is extensively metabolized by hepatic microsomal enzymes that forms the N-desmethyl and N-oxide metabolites. It is an effective neuroleptic that has been studied in short-term and long-term clinical trials, and multicenter trials. Clozapine was superior to chlorpromazine in the treatment of refractory schizophrenia that failed to respond to previous neuroleptic therapy. Reports of extrapyramidal side effects are minimal, and no case reports of tardive dyskinesia have been published. Indeed, clozapine has been used to treat tardive dyskinesia and other movement disorders. Agranulocytosis is the major adverse effect and its prevalence appears to differ among various ethnic groups. Other adverse effects that have been reported include hypersalivation, orthostatic hypotension, and constipation. Clozapine can lower the seizure threshold in a dose-dependent manner. The drug represents a significant advancement in the treatment of mental illness.
氯氮平是一种抗精神病药物，其结构由带有哌嗪基侧链的二苯并二氮䓬衍生物组成。由于其独特的神经药理学特性，它被归类为非典型抗精神病药物。氯氮平对多巴胺D-1和D-2受体的结合亲和力较弱，对D-1受体的偏好略高，D-1:D-2受体结合率为1.3。由于该药物对5-羟色胺受体5-HT1A和5-HT2具有强大的结合亲和力，因此其他神经受体也参与其中。氯氮平还具有抗组胺、抗胆碱能和α-肾上腺素能拮抗特性。电生理学研究表明，它与其他典型抗精神病药物不同，其作用似乎对皮质-边缘多巴胺A-10束具有特异性。在动物实验中，与典型抗精神病药物相比，氯氮平不会产生僵住症，并且在拮抗其他多巴胺激动剂方面只有短暂的效果。该药物口服后吸收迅速，生物利用度为0.27。单次口服给药后消除半衰期约为8-10小时，但多次给药后增加到14.1小时。该药物通过肝脏微粒体酶广泛代谢，形成N-去甲基和N-氧化物代谢产物。它是一种有效的抗精神病药物，已在短期和长期临床试验以及多中心试验中进行了研究。在治疗对先前抗精神病治疗无反应的难治性精神分裂症方面，氯氮平优于氯丙嗪。锥体外系副作用的报告极少，且尚未发表迟发性运动障碍的病例报告。实际上，氯氮平已被用于治疗迟发性运动障碍和其他运动障碍。粒细胞缺乏症是主要的不良反应，其发生率在不同种族群体中似乎有所不同。报告的其他不良反应包括流涎过多、体位性低血压和便秘。氯氮平可剂量依赖性地降低癫痫阈值。该药物代表了精神疾病治疗方面的重大进展。
