1、 CHAPTER 19 ANTIPARKINSONISM DRUGS AND DRUG THERAPY IN ALZHEIMERS DISEASE CNS degenerative diseaselParkinsons disease(PD)帕金森病帕金森病lAlzheimers disease (AD)阿尔茨海默病阿尔茨海默病lHuntington disease (HD)亨廷顿病亨廷顿病lAmyotrophic lateral sclerosis(ALS)肌萎缩侧索硬化症肌萎缩侧索硬化症 MechanismslExcitotoxicitylApoptosislOxidative stres
2、s Parkinsons diseaselParkinsons disease(PD)lParalysis agitans(震颤麻痹）震颤麻痹）lClassification Primary PDParkinsonism cerebral arteriosclerosis(脑动脉硬化脑动脉硬化)encephalitis(脑炎脑炎)drug poison(药物中毒药物中毒)Typical symptom1.resting tremor(静止震颤静止震颤)2.rigidity(肌肉僵直肌肉僵直)3.bradykinesia(运动迟缓运动迟缓)4.ataxia(共济失调共济失调)dopaminel
3、tyrosine dopa dopamine (酪氨酸酪氨酸)noradrenalin and adrenalin Pathogenesis(dopamine theory)DA neuronal degeneration Nigro-striatal(caudate nucleus,putamen，pallidum)Dopaminergic neuron activity Cholinergic neuron activityEvidence Oxidative stress theorylNervous degeneration by oxygen free radical:H2O2,O2
4、-,Fe2+Dopamine receptorslfive main subtypes:D1 D5.lD1 receptor D1 and D5 cAMP excitationlD2 receptor D2D4 cAMP inhibition Dopaminomimetic DrugsTherapeutic Drugs Central anti-cholinergic Drugs I.Dopaminomimetic Drugs Levodopa（L-dopa）the immediate precursor of dopamine.penetrates into the brain,where
5、it is decarboxylated to DA.corrects dopamine deficiency in nigra-striatum.Pharmacokinetics1.Absorption Ready from small intestine,tmax 0.5-2 hrs,affected by gastric emptying,gastric acid and amino acids Pharmacokinetics2.Distribution and metabolismluptake，metabolized by COMT and MAO3.Elimination kid
6、ney,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(
7、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
8、neurotransmitter theory：正常机体蛋白正常机体蛋白质代谢产物质代谢产物苯乙胺苯乙胺和和酪胺酪胺都在肝内被氧化解毒。都在肝内被氧化解毒。肝功能障碍时，血中肝功能障碍时，血中苯乙胺苯乙胺和和酪胺酪胺升高，在神经升高，在神经细胞内经细胞内经-羟化酶分别生成羟化酶分别生成伪递质伪递质苯乙醇胺苯乙醇胺和和羟苯乙醇胺羟苯乙醇胺（鱆胺鱆胺），它们取代了正常递质去），它们取代了正常递质去甲肾上腺素，甲肾上腺素，为兴奋性递质，如兴奋冲动不能传为兴奋性递质，如兴奋冲动不能传递，则可出现意识障碍和昏迷。递，则可出现意识障碍和昏迷。Levodopa metabolized to noradren
9、aline to replace octopamine(鱆胺鱆胺)Adverse Reactions1.Early reactions Gastrointestinal reaction（early）domperidone Cardiovascular effects（early）tachycardia,arrhythmias,orthostatic hypotension blocker Adverse Reactions2.long-term reactions a.Hyperkinesia:involuntary movement b.on-off response c.Psychic
10、disorders and epilepsy Drug Interactions Carbidopa VitB6 MAOI(unselective)(-)(+)MAO L-dopa DA DA+R Effects Decarboxylase (-)Antipsychotic drugs excretion1.AADC inhibitorsl Carbidopa（卡比多巴）（卡比多巴）l Benserazide（苄丝肼）（苄丝肼）Compound Preparationsl Sinemet（息宁，心宁美息宁，心宁美）Levodopa:Carbidopa(10:1)l Madopar（美多巴）（美
11、多巴）Levodopa:Benserazide(4:1)2.MAO-B inhibitors Selegiline(司来吉兰司来吉兰)Mechanism：l MAO-B inhibitor(MAO-Bin Nigrostriatal)low dose（10mg/d）only inhibit MAO-B high dose（10mg/d）inhibit MAO-A tooMAO:MAO-A:Intestines MAO-B:CNSlAntioxidants DATATOP 3.COMT inhibitorsl Nitecapone（硝替卡朋硝替卡朋）：）：only inhibit periphe
12、ral COMTl Tocapone（托卡朋托卡朋）：）：inhibit COMT both peripheral and CNSvProlonged the duration of of levodopa by diminishing in peripheral metabolismv May be helpful in patients receiving levodopa who have developed response fluctuation.DA-R agonistslNot produce free radicallLong t1/2-long stimulus on rec
13、eptorlPossible have neural protection effect DA-R agonists Bromocriptine(溴隐亭溴隐亭)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（高催高催乳素血症）乳素血症）DA-R agonistsl Lisu
14、ride（利修来得）：（利修来得）：stronger than Bromocriptinel Pergolide(培高利特培高利特)：stronger than Lisuridel Ropinirole（罗匹尼罗）和（罗匹尼罗）和pramipexole（普拉（普拉克索）克索）1.only agonist on D2 receptor，no effect on D1 2.on-off response is fewl Apomorphine（阿扑吗啡）（阿扑吗啡）Drugs enhancing DA releaselAmantadine(金刚烷胺金刚烷胺)1.release DA from do
15、paminergic terminals.2.reuptake of DA.3.dopamine receptor agonism l Clinical 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 ni
16、grostriatal.Trihexyphenidyl(苯海索苯海索)Benzatropine(苯扎托品苯扎托品)Improve the tremor and rigidity of PD,little effect on bradykinesia.Drug Therapy in Alzheimers DiseaselAlzheimers disease（AD）3/4lVascular dementia（VD）1/4 Dr.Alois Alzheimer,a German doctor,diagnosed Alzheimers disease in 1906 Incidence 65y 5.0
17、%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 FeaturesDementia,cognition dysufficiency,memory damage Path
18、ological FeatureslBrain atrophy(脑萎缩脑萎缩)lSenile plaque(SP,老年斑老年斑)lNeurofibrillary tangles(NFT,神经元纤维缠神经元纤维缠结结)lSelective death of neuron.Pathological Featuresl1.Neuron toxication of amyloid-protein(A)。lA cholinergic functionlAchE A Pathological Featuresl2.Neurotransmittor activity Ach and Glu Choliner
19、gic neurons regress Therapy for AD1.Potentiate cholinergic function:AChEI、M-R agonists2.Potentiator of neuronal nutrition factor and neuron cell growth factor3.brain metabolism activator吡拉西坦吡拉西坦(脑复康脑复康)4.Drugs improving microcirculation 麦角类衍生物、麦角类衍生物、都可喜等都可喜等5.Calcium antagonists(尼莫地平尼莫地平)AChE-inhib
20、itorslTacrine(他克林他克林)first generation 1.inhibit AChE（selectivity is low）2.excite M-R,N-R 3.promote glucose use adverse reaction:hepatotoxicity AChE-inhibitorsldonepezil（多奈哌齐）（多奈哌齐）second generation inhibit AChE（selectivity is high）lRivastigmine（利凡斯的明利凡斯的明）second generation inhibit AChE（mainly to cor
21、tex and hippocamp）AChE-inhibitorslgalanthamine second generation 1)high selectivity for AChE In CNS.2)have no hepatotoxicity.3)mild and moderate AD 4)nausea,vomitting,diarrhea,dizzy M-R agonistlXanomeline（占诺美林）（占诺美林）lSabcomedine（沙可美林）（沙可美林）selective M1-R agonist Thank You!Thank You!英国的内科医生JamesParkinson于1871年最早系统描述该病.“震颤麻痹”。后来，人们对该病进行了更为细致的观察，发现除了震颤外，尚有肌肉僵直、写字越写越小等其它症状，但是四肢的肌肉的力量并没有受损，认为称麻痹并不合适，所以建议将该病命名为“帕金森病”。Dr.Alois Alzheimer,a German doctor,diagnosed Alzheimers disease in 1906 Parkinsons diseasel世界帕金森病日 从年开始，每年的月日被确定为“世界帕金森病日”(World Parkinsons Disease Day)。这一天是帕金森病的发现者英国内科医生詹姆斯帕金森博士的生日。
