神经系统药理教学 讲义.pptVIP

Levodopa 1. ADME Penetrating into the brain, transformed to DA or NE (less) Distributed in peripheral tissue (most) 2. Effects and uses Parkinson disease: decreases the rigidity, tremors, and other symptoms 3. Adverse effects Early (1) GI: nausea, vomiting, etc.(2) CVS: hypotension, arrhythmia, etc. -(1) CNS: emotional depression/ psychosis; abnormal involuntary; hallucinations; etc. Late (1) fluctuation of response: end of dose/“wearing off” periods; on/off periods (sudden loss of symptom control, akinesia) .(2) dyskinesia (运动障碍，after years of chronic L-DOPA, up to 80%, Involuntary movements: chorea(舞蹈症), ballismus(投掷症), athetosis(手足徐动症), dystonia(肌张力失常), myoclonus(肌阵挛), and tremor Drugs for treatment of Parkinson disease Carbidopa (卡比多巴) a peripheral decarboxylase inhibitor reduces peripheral metabolism of L-DOPA, increases L-DOPA bioavailability, can not cross BBB; decreases its adverse effects by allowing lower L-DOPA dosages to be used. The combination of L-DOPA carbidopa, is called Sinemet?. (L-DOPA t1/2 ~ 1.5 h) 3-O-methyl- DOPA Periphery CNS L-DOPA dopamine BBB COMT AAAD L-DOPA dopamine AAAD MAO Pyridoxal 5- phosphate Levodopa alone Levodopa + Carbidopa Dopamine Synthesis and Storage Without With COMT Inhibitor FDOPA -/+ COMT Inhibitor: 2 FDOPA PET Studies - one individualSame dose of FDOPA, iv; plus carbidopa, po FDOPA Uptake Conclusion: COMT inhibitor increased brain bioavailability of FDOPA by inhibiting peripheral metabolism of FDOPA to 3-O-methyl FDOPA FDOPA fluorodopamine AAAD COMT In periphery: 3-O-methylFDOPA FDOPA fluorodopamine AAAD COMT 一般情况下，对L-dopa制剂的反应可分为3个阶段： ①良好反应阶段（2～5年），为用药的最初阶段，每6～8小时或更长时间服药1次，可使全部症状得到平稳的缓解或改善。 ②中间反应阶段（2～3年），此阶段中每次服药仅可引起短时间的症状改善，每个剂量的后期与下一个剂量前，有1个药物无作用期，称为剂末现象，此外，还可出现开关现象和反常性运动不能；这种疗效下降与黑质DA能神经元逐渐衰退，DA合成、贮存进一步下降，及DA受体反应能力降低有关。 ③反应衰退阶段，对L-dopa制剂反应明显下降或根本不起反应；运动困难与致残程度更为严重；同时治疗中的一些不良反应更为明显。 Drugs for treatment of Parkinson disease Other drugs 1. DA receptor agonists 1st generation agonists: (ergot deriva