医学课件帕金森及其药物治疗

CHAPTER 19 ANTIPARKINSONISM DRUGS AND DRUG THERAPY IN ALZHEIMERS DISEASE CNS degenerative disease lParkinsons disease (PD)帕金森病 lAlzheimers disease (AD)阿尔茨海默 病 lHuntington disease (HD)亨廷顿病 lAmyotrophic lateral sclerosis(ALS) 肌萎缩侧索硬化 症 Mechanisms lExcitotoxicity lApoptosis lOxidative stress Parkinsons disease lParkinsons disease (PD) lParalysis agitans(震颤麻痹） lClassification Primary PD Parkinsonism cerebral arteriosclerosis(脑动脉硬 化) encephalitis(脑炎) drug poison(药物中毒) Typical symptom resting tremor(静止震颤) rigidity(肌肉僵直) bradykinesia(运动迟缓) ataxia(共济失调) dopamine l tyrosine dopa dopamine (酪氨酸) noradrenalin and adrenalin Pathogenesis (dopamine theory) DA neuronal degeneration Nigro-striatal (caudate nucleus, putamen， pallidum) Dopaminergic neuron activity Cholinergic neuron activity Evidence Oxidative stress theory lNervous degeneration by oxygen free radical: H2O2, O2-, Fe2+ Dopamine receptors lfive main subtypes: D1 D5. lD1 receptor D1 and D5 cAMP excitation lD2 receptor D2D4 cAMP inhibition Dopaminomimetic Drugs Therapeutic Drugs Central anti-cholinergic Drugs I. Dopaminomimetic Drugs Levodopa（L-dopa） the immediate precursor of dopamine. penetrates into the brain, where it is decarboxylated to DA. corrects dopamine deficiency in nigra-striatum . Pharmacokinetics Absorption Ready from small intestine, tmax 0.5- 2 hrs, affected by gastric emptying, gastric acid and amino acids Pharmacokinetics 2. Distribution and metabolism luptake，metabolized by COMT and MAO 3. Elimination kidney, t1/2 1-3 hrs. Pharmacokinetics Decarboxylase Levodopa DA Liver 99% 1% Decarboxylase Blood-brain DA Barrier Brain Pharmacological Actions and Uses 1. Parkinsons disease Levodopa is widely used for treatment of all type of Parkinsonism except that associated with antipsychotic drug therapy. Properties (1)Most effective for mild and younger patients (2)More effective for rigidity and akinesia, less effective for tremor Properties (3)Onset slow, 2-3 weeks to effect, 1-6 months to Emax. therapeutic effect (4)No effective for Parkinsons syndrome caused by phenothiazines. Actions and Uses 2. Hepatic coma false neurotransmitter theory：正常机体蛋 白质代谢产物苯乙胺和酪胺都在肝内被氧化解 毒。肝功能障碍时，血中苯乙胺和酪胺升高， 在神经细胞内经-羟化酶分别生成伪递质 苯乙醇胺和羟苯乙醇胺（鱆胺），它们取代了 正常递质去甲肾上腺素，为兴奋性递质，如兴 奋冲动不能传递，则可出现意识障碍和昏迷。 Levodopa metabolized to noradrenaline to replace octopamine(鱆胺) Adverse Reactions 1. Early reactions Gastrointestinal reaction（early） domperidone Cardiovascular effects （early） tachycardia, arrhythmias, orthostatic hypotension blocker Adverse Reactions 2. long-term reactions a. Hyperkinesia: involuntary movement b. on-off response c. Psychic disorders and epilepsy Drug Interactions Carbidopa VitB6 MAOI (unselective) (-) (+) MAO L-dopa DA DA+R Effects Decarboxylase (-) Antipsychotic drugs excretion (-)(-) 1.AADC inhibitors lCarbidopa（卡比多巴） lBenserazide（苄丝肼） Compound Preparations lSinemet（息宁，心宁美） Levodopa : Carbidopa (10 : 1) lMadopar（美多巴） Levodopa : Benserazide (4 : 1) 2.MAO-B inhibitors Selegiline (司来吉兰) Mechanism： l MAO-B inhibitor (MAO-Bin Nigrostriatal) low dose（10mg/d） only inhibit MAO-B high dose （10mg/d） inhibit MAO-A too MAO: MAO-A: Intestines MAO-B: CNS lAntioxidants DATATOP 3.COMT inhibitors lNitecapone（硝替卡朋）：only inhibit peripheral COMT lTocapone（托卡朋）：inhibit COMT both peripheral and CNS vProlonged the duration of of levodopa by diminishing in peripheral metabolism v May be helpful in patients receiving levodopa who have developed response fluctuation. DA-R agonists lNot produce free radical lLong t1/2 -long stimulus on receptor lPossible have neural protection effect DA-R agonists Bromocriptine(溴隐亭) 1. Small dose ：stimulate D2 receptor in tuberoinfundibular, reduce PRL and GH release 2. Large dose： stimulate D2 receptor in substantia nigro-striatal Used to treat PD and hyperprolactinemia（高 催乳素血症） DA-R agonists lLisuride（利修来得）：stronger than Bromocriptine lPergolide(培高利特)：stronger than Lisuride lRopinirole（罗匹尼罗）和pramipexole（普拉 克索） 1.only agonist on D2 receptor ， no effect on D1 2.on-off response is few lApomorphine（阿扑吗啡） Drugs enhancing DA release lAmantadine(金刚烷胺) 1.release DA from dopaminergic terminals. 2.reuptake of DA. 3. dopamine receptor agonism lClinical Uses Parkinsons disease, less effective than levodopa, and more effective than anticholinergic agents. Onset rapidly; synergised by L-dopa. II.Central Anticholinergic Drugs lActions Blocking the M-R ,cholinergic neurons in the nigrostriatal. Trihexyphenidyl(苯海索) Benzatropine(苯扎托品) Improve the tremor and rigidity of PD, little effect on bradykinesia. Drug Therapy in Alzheimers Disease lAlzheimers disease（AD） 3/4 lVascular dementia（VD） 1/4 Dr.Alois Alzheimer, a German doctor, diagnosed Alzheimers disease in 1906 Incidence 65y 5.0% 75y 19% 85y 47% 95y 90% Course of disease: 320y lInternational Symposium for Alzheimers Disease 2000 “If the effective methods for AD treatment is not found, the AD patients will be 22 000 000 in 2025; 45 000 000 in 2050 in whole world.” Clinical Features Dementia, cognition dysufficiency, memory damage Pathological Features lBrain atrophy (脑萎缩) lSenile plaque (SP, 老年斑) lNeurofibrillary tangles (NFT, 神经元纤维 缠结) lSelective death of neuron. Pathological Features l1.Neuron toxication of amyloid- protein(A) 。 lA cholinergic function lAchE A Pathological Features l2.Neurotransmittor activity Ach and Glu Cholinergic neurons regress Therapy for AD 1.Potentiate cholinergic function :AChEI、M-R agonists 2.Potentiator of neuronal nutrition factor and neuron cell growth factor 3. brain metabolism activator吡拉西坦(脑复康) 4.Drugs improving microcirculation 麦角类衍生物 、都可喜等 5.Calcium antagonists(尼莫地平) AChE-inhibitors lTacrine(他克林)first generation 1. inhibit AChE（selectivity is low） 2. excite M-R, N-R 3. promote glucose use adverse reaction: hepatotoxicity AChE-inhibitors ldonepezil （多奈哌齐）second generation inhibit AChE（selectivity is high） lRivastigmine（利凡斯的明