哈尔滨医科大学药理学6课件.ppt

抗中枢退行性疾病药;抗帕金森病药;The normally high concentration of dopamine in the basal ganglia of the brain is reduced in parkinsonism, and pharmacologic attempts to restore dopaminergic activity with levodopa and dopamine agonists have been successful in alleviating many of the clinical features of the disorder. An alternative but complementary approach has been to restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs. The pathophysiologic basis for these therapies is that in idiopathic parkinsonism, dopaminergic neurons in the substantia nigra that normally inhibit the output of γ-aminobutyric acid (GABA)ergic cells in the corpus striatum are lost.;Schematic representation of the sequence of neurons involved in parkinsonism. Top: Dopaminergic neurons (color) originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons (gray) exert an excitatory effect. Middle: In parkinsonism, there is a selective lossof dopaminergic neurons (dashed, color). ;; Fate of orally administered levodopa and the effect of carbidopa, estimated from animal data. The width of each pathway indicates the absolute amount of the drug present at each site, while the percentages shown denote the relative proportion of the administered dose. The benefits of coadministration of carbidopa include reduction of the amount of levodopa diverted to peripheral tissues and an increase in the fraction of the dose that reaches the brain.;一、左旋多巴及其增效剂 1.左旋多巴（L-dopa) 药理作用与机制 左旋多巴可使 80% PD 病人症状明显改善。其中20%的病人可恢复到正常运动状态。起病初期用药疗效更为显著，用药后患者感觉良好，抑制和淡漠症状改善，服药后先改善肌强直和运动迟缓，后改善肌震颤，由于情绪好转，能关心周围环境，思维清晰敏捷，听觉口语学习能力明显改善，生活质量明显提高。;特点 ① 奏效慢，用药2 ~ 3周后才出现体征的改善， 1~6个月后获得最大疗效。 ② 对轻症及年轻患者疗效好，对重症及年老患 者疗效差。 机制 L-dopa属DA的前体药，本身无药理活性，脑内转化为DA，补充了纹状体中DA的不足，提高中枢DA神经功能，抑制胆碱能神经功能，产生抗震颤麻痹的作用。; 体内过程 口服后主要在小肠经主动转运系统而迅速吸收。进入中枢量不到1%，99%在外周经脱羧换化为DA