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1、Drugs forDrugs forParkinsonParkinson s Diseases DiseaseAnd AlzheimerAnd Alzheimer s diseases diseaseParkinsons disease, PD 帕金森病帕金森病(paralysis agitants 震颤麻痹震颤麻痹) tremor ragidity bradykinesia Progressive neurologic disorder of muscle movement, characterized by: Resting tremors; Muscular rigidity; Brad
2、ykinesia Postural and gait abnormalities Memory interruption and dementia 痴呆 Muhammad Ali, the greatest boxer who suffers from parkinsonism, lit the Olympic flame at the 1996 Summer games in Atlanta .degeneration and loss in brain and /or spinal neuron Parkinsons disease, PDAlzheimers disease, ADHun
3、tington disease, HDAmyotrophic lateral sclerosis, ALSEtiology: exitotoxicity, apoptosis, oxidative stressParkinsonismParkinsons syndromeEtiology Loss of dopaminergic neurons in substantia nigra Imbalance between the excitatory cholinergic neurons and the greatly diminished number of inhibitory dopam
4、inergic neuronsDopamineDopamineAcetylcholineAcetylcholineAcetylcholineAcetylcholineAChDAAChDAAChDADA-ACh平衡平衡帕金森帕金森症候群症候群舞蹈病舞蹈病运动机能正常运动机能正常正常正常帕金森症帕金森症候群候群多巴胺多巴胺AChGABA黒质黒质纹状体纹状体StrategyDA + drugdrugAChImprove DAImprove DAAChDAdrugdrugAntagonism AChAntagonism AChDA + drugdrugAChdrugdrugCombinationCom
5、binationDrugsL-dopacarbidopabromocriptineselegilineamantadine Trihexyphenidyl /benzhexolDA： (DA replacement therapy/ DA agonist therapy)ACh：(Anticholinergic therapy) Tyrosine L-dopa Dopamine NA Dopaminergic agents 拟多巴胺药拟多巴胺药 levodopa, (L-dopa) 左旋多巴左旋多巴tyrosine hydroxylasedopa decarboxylasedopamine -
6、hydroxylaseLevodopa Mechanism PharmacokineticsAdministered orally and rapidly absorbed from small intestine (food delays absorption)Only about 1%- 3% of administered levodopa actually enters the brain unaltered, the remainder being metabolized extracerebrally, predominantly by decarboxylation to dop
7、amine, which dose not penetrate the blood-brain barrier. Levodopa Clinical useParkinsonismpThe best results are obtained in the first few years of treatment. pThe benefits of levodopa treatment often begin to diminish after 3 or 4 years of therapy.pgiven in combination with carbidopa. Hepatic comaDo
8、pamine NA Adverse Effects Gastrointestinal effects Orthostatic hypotension 体位性低血压体位性低血压 arrhythmia 心律不齐心律不齐 Abnormal involuntary movements hyperkinesia 运动过多症运动过多症 on-off phenomena “开关现象开关现象” Psychogenia 精神障碍精神障碍Early stageLate stage Interactions VB6 increases peripheral breakdown of levodopa MAO inh
9、ibitors decrease dopamine inactivation and produce a hypertensive crisisAntipsychotic drugs block dopamine receptors and produce a parkinsonian syndrome by themselvesContraindications: psychotic diseases, glaucoma, melanomaNot cross the blood-brain barrierinhibits decarboxylases in peripherydecrease
10、s dose of Levodopa by 75%; reduces or prevents the side effects of levodopa increases the availability of levodopa to the CNSDecarboxylases inhibitor Carbidopa 卡比多巴卡比多巴 Bromocriptine 溴隐亭溴隐亭D2-R agonist, across the blood-brain barrier easilyCombination with levodopa Have an important role as first-li
11、ne therapy Lower incidence of the adverse effects with long-term levodopa therapy nitecapone 硝替卡朋硝替卡朋COMT儿茶酚氧位甲基转移酶儿茶酚氧位甲基转移酶 inhibitorCOMT inhibitor in periphery and increase availability of L-dopa in brain, no effect on COMT in CNS AADCL-dopaDA3-OMDCOMTinhibitorCOMTCNSperipheralCOMT抑制剂作用机制抑制剂作用机制A
12、ADC：amino decarboxylase；3-OMD：3-O-methyldopacarrierselegiline 司来吉兰司来吉兰MAOI 单胺氧化酶抑制剂单胺氧化酶抑制剂 , selective inhibitor of monoamine oxidase B (MAO-B) retards the breakdown of dopamine, increases therapeutic effects of levodopadecreases the dose of levodopa , reduces the adverse effects. DopamineH2O2，O2-O
13、xidativestressremovalFe3+MAOselegilineAmantadine 金刚烷胺金刚烷胺enhance the release of dopamine from the surviving neuronsside effects are fewCentral anticholinergic drug 中枢抗胆碱药中枢抗胆碱药 trihexyphenidyl 苯海索苯海索（Artane 安坦）安坦）nBlockage of cholinergic transmission produces similar to augmentation of dopaminergic
14、transmissionn Peripheral side effects like atropineCOMT抗帕金森病药物效价抗帕金森病药物效价临床用药倾向于在临床用药倾向于在PDPD早期应用低效价药物（司早期应用低效价药物（司来吉兰，金刚烷胺，抗胆碱能药），后期应用来吉兰，金刚烷胺，抗胆碱能药），后期应用左旋多巴与卡比多巴复方，多巴胺能激动剂左旋多巴与卡比多巴复方，多巴胺能激动剂左旋多巴左旋多巴Levodopa 溴溴隐亭亭Bromocriptine 金金刚烷胺胺Amantadine抗胆碱能抗胆碱能药ArtaneAlzheimer disease ( AD)阿尔茨海默病阿尔茨海默病 CNS
15、degenerative disease cognitive disorder in progress 进行性进行性认知障碍认知障碍memory impairment 记忆力损害记忆力损害Main course: cholinergic insufficiencyCholinesterase inhibitor drug 胆碱酯酶抑制药胆碱酯酶抑制药 Tacrine 他克林他克林 best choice for AD at presentMechanism：inhibiting cholinesterase stimulating M and N receptors directlypromo
16、ting Ach releaseAdverse effects: hepatotoxicityCholinergic receptor agonist胆碱受体激动药胆碱受体激动药 xanomeline 占诺美林占诺美林 stimulating M1 receptor selectively Nerve cell GF potentiator 神经细胞生长因子增强剂神经细胞生长因子增强剂 neotrofin（AIT 082）:improve neuron function, increase axon growing, neurotrophy, improve memory.Review questionsThe etiology of parkinsons diseaseThe mechanism and actions of L-dopaActions of carbidopaThe advantages of combination of L-dopa and carbidopaThanks
