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CHAPTER 19CHAPTER 19

ANTIPARKINSONISM ANTIPARKINSONISM DRUGS AND DRUG THERAPY DRUGS AND DRUG THERAPY IN ALZHEIMER’S DISEASE IN ALZHEIMER’S DISEASE

CNS degenerative diseaseCNS degenerative disease Parkinson’s disease (PD)Parkinson’s disease (PD) 帕金森病帕金森病 Alzheimer’s disease (AD)Alzheimer’s disease (AD) 阿尔茨海默阿尔茨海默病病

Huntington disease (HD)Huntington disease (HD) 亨廷顿病亨廷顿病 Amyotrophic lateral sclerosis(ALS)Amyotrophic lateral sclerosis(ALS)

肌萎缩侧索肌萎缩侧索硬化症硬化症

MechanismsMechanisms

ExcitotoxicityExcitotoxicity ApoptosisApoptosis Oxidative stressOxidative stress

Parkinson’s diseaseParkinson’s disease

Parkinson’s disease (PD)Parkinson’s disease (PD) Paralysis Paralysis agitansagitans(( 震颤麻痹）震颤麻痹） ClassificationClassification

Primary PDPrimary PD

Parkinsonism Parkinsonism ccerebral arteriosclerosiserebral arteriosclerosis(( 脑动脉硬脑动脉硬化化 ))

encephalitisencephalitis(( 脑炎脑炎 ))

drug poisondrug poison(( 药物中毒药物中毒 ))

Typical symptomTypical symptom1.1. resting tremor(resting tremor( 静止震颤静止震颤 ))

2.2. rigidity(rigidity( 肌肉僵直肌肉僵直 ))

3.3. bradykinesia(bradykinesia( 运动迟缓运动迟缓 ))

4.4. ataxia(ataxia( 共济失调共济失调 ) )

dopaminedopamine

tyrosine dopa dopamine tyrosine dopa dopamine

(( 酪氨酸酪氨酸 ))

noradrenalin and adrenalinnoradrenalin and adrenalin

Pathogenesis (dopamine theory)Pathogenesis (dopamine theory)

DA neuronal degenerationDA neuronal degeneration

Nigro-Nigro-striatalstriatal (caudate nucleus, putamen(caudate nucleus, putamen ， ， pallidum)pallidum)

Dopaminergic neuron activity↓Dopaminergic neuron activity↓

Cholinergic neuron activity↑Cholinergic neuron activity↑

EvidenceEvidence

Oxidative stress theoryOxidative stress theory

Nervous degeneration by oxygen free Nervous degeneration by oxygen free

radical: Hradical: H22OO22, ·O, ·O22--, Fe, Fe2+2+

Dopamine receptorsDopamine receptors

five main subtypes: Dfive main subtypes: D11 ~D ~D55..

DD11 receptor receptor D D11 and D and D55

cAMP excitationcAMP excitation

DD22 receptor receptor DD22~D~D44

cAMP inhibitioncAMP inhibition

Dopaminomimetic Dopaminomimetic

Drugs DrugsTherapeutic Therapeutic Drugs Drugs Central anti-cholinergic Central anti-cholinergic

Drugs Drugs

I. Dopaminomimetic DrugsI. Dopaminomimetic Drugs

LevodopaLevodopa （（ L-dopaL-dopa ））

the immediate precursor of the immediate precursor of

dopamine. penetrates into the brain, dopamine. penetrates into the brain,

where it is decarboxylated to DA.where it is decarboxylated to DA.

corrects dopamine deficiency in corrects dopamine deficiency in

nigra-striatum .nigra-striatum .

PharmacokineticsPharmacokinetics

1.1. AbsorptionAbsorption

Ready from small intestine, tReady from small intestine, tmax max 0.5-0.5-

2 hrs, affected by gastric emptying,2 hrs, affected by gastric emptying,

gastric acid and amino acidsgastric acid and amino acids

PharmacokineticsPharmacokinetics

2. Distribution and metabolism2. Distribution and metabolism uptakeuptake ，， metabolized by COMT metabolized by COMT

and MAOand MAO

3. Elimination kidney, t3. Elimination kidney, t1/21/2 1-3 hrs. 1-3 hrs.

PharmacokineticsPharmacokinetics

DecarboxylaseDecarboxylase Levodopa DA Levodopa DA

Liver 99%Liver 99%

1% 1%

DecarboxylaseDecarboxylase

Blood-brain DA Blood-brain DA

Barrier BrainBarrier Brain

Pharmacological Actions and UsesPharmacological Actions and Uses

1. Parkinson’s disease1. Parkinson’s disease

Levodopa is widely used for treatment of Levodopa is widely used for treatment of

all type of Parkinsonism except that all type of Parkinsonism except that

associated with antipsychotic drug associated with antipsychotic drug

therapy.therapy.

Properties Properties

(1)Most effective for mild and (1)Most effective for mild and

younger patientsyounger patients

(2)More effective for rigidity and (2)More effective for rigidity and

akinesia, less effective for tremorakinesia, less effective for tremor

PropertiesProperties

(3)Onset slow, 2-3 weeks to effect,(3)Onset slow, 2-3 weeks to effect,

1-6 months to E1-6 months to Emax. max. therapeutic effect therapeutic effect

(4)No effective for Parkinson’s (4)No effective for Parkinson’s

syndrome caused by phenothiazines.syndrome caused by phenothiazines.

Actions and UsesActions and Uses 2. Hepatic coma2. Hepatic coma

false neurotransmitter theoryfalse 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 β-β- 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 noradrenalineLevodopa metabolized to noradrenaline

to replace octopamineto replace octopamine(( 鱆胺 ))

Adverse ReactionsAdverse Reactions1. Early reactions1. Early reactions

Gastrointestinal reactionGastrointestinal reaction （（ earlyearly ））——domperidonedomperidone

Cardiovascular effectsCardiovascular effects （（ earlyearly ） ） ——

tachycardia, arrhythmias, tachycardia, arrhythmias, orthostatic

hypotension— blocker

Adverse ReactionsAdverse Reactions

2. long-term reactions2. long-term reactions

a. Hyperkinesia: involuntary movement a. Hyperkinesia: involuntary movement

b. on-off responseb. on-off response

c. Psychic disorders and epilepsyc. Psychic disorders and epilepsy

Drug InteractionsDrug Interactions

Carbidopa VitBCarbidopa VitB6 6 MAOI (unselective)MAOI (unselective)

(-) (+) (-) (+) MAOMAO

L-dopa DA L-dopa DA DA+R DA+R EffectsEffects

Decarboxylase (-)Decarboxylase (-)

Antipsychotic drugsAntipsychotic drugs

excretion

(-)(-)

1.AADC inhibitors1.AADC inhibitors

CarbidopaCarbidopa （卡比多巴）（卡比多巴） BenserazideBenserazide （苄丝肼）（苄丝肼）Compound PreparationsCompound Preparations

SinemetSinemet （息宁，心宁美）（息宁，心宁美） Levodopa : Carbidopa (10 : 1)Levodopa : Carbidopa (10 : 1) MadoparMadopar （美多巴）（美多巴） Levodopa : Benserazide (4 : 1)Levodopa : Benserazide (4 : 1)

2.2.MAO-BMAO-B inhibitorsinhibitors SelegilineSelegiline ((司来吉兰司来吉兰 ))

MechanismMechanism ：： MAO-B inhibitor (MAO-B—in Nigrostriatal)MAO-B inhibitor (MAO-B—in Nigrostriatal) low doselow dose （＜（＜ 10mg/d10mg/d ）） — —only inhibit MAO-B only inhibit MAO-B high dose high dose （＞（＞ 10mg/d10mg/d ）） — —inhibit MAO-A tooinhibit MAO-A tooMAO: MAO-A: IntestinesMAO: MAO-A: Intestines MAO-B: CNSMAO-B: CNS

Antioxidants DATATOPAntioxidants DATATOP

3.COMT inhibitors3.COMT inhibitors NitecaponeNitecapone （（硝替卡朋硝替卡朋）：）： only inhibit only inhibit

peripheral COMTperipheral COMT

TocaponeTocapone （（托卡朋托卡朋）：）： inhibit COMT both inhibit COMT both

peripheral and CNSperipheral and CNS

Prolonged the duration of of levodopa by Prolonged the duration of of levodopa by

diminishing in peripheral metabolismdiminishing in peripheral metabolism

May be helpful in patients receiving May be helpful in patients receiving

levodopa who have developed response levodopa who have developed response

fluctuation.fluctuation.

DA-R agonistsDA-R agonists

Not produce free radicalNot produce free radical Long tLong t1/21/2 ----long stimulus on receptor ----long stimulus on receptor

Possible have neural protection effectPossible have neural protection effect

DA-R agonistsDA-R agonists

BromocriptineBromocriptine(( 溴隐亭溴隐亭 ))

1. Small dose 1. Small dose ：： stimulate Dstimulate D22 receptor in receptor in

tuberoinfundibular, reduce PRL and GH tuberoinfundibular, reduce PRL and GH

releaserelease

2. Large dose2. Large dose ： ： stimulate Dstimulate D22 receptor in receptor in

substantia nigro-striatalsubstantia nigro-striatal

Used to treat PD and hyperprolactinemiaUsed to treat PD and hyperprolactinemia （（高催乳素血症）

DA-R agonistsDA-R agonists

LisurideLisuride （利修来得）：（利修来得）： stronger than stronger than

BromocriptineBromocriptine

PergolidePergolide(( 培高利特培高利特 )) ：： stronger than Lisuridestronger than Lisuride

RopiniroleRopinirole （罗匹尼罗）和（罗匹尼罗）和 pramipexolepramipexole （普拉（普拉克索）克索）

1.only agonist on D1.only agonist on D22 receptor receptor ，，

no effect on Dno effect on D11

2.on-off response is few2.on-off response is few

ApomorphineApomorphine （阿扑吗啡）（阿扑吗啡）

Drugs enhancing DA releaseDrugs enhancing DA release

AmantadineAmantadine(( 金刚烷胺金刚烷胺 ))

1.↑release DA from dopaminergic 1.↑release DA from dopaminergic

terminals.terminals.

2.↓reuptake of DA.2.↓reuptake of DA.

3. dopamine receptor agonism3. dopamine receptor agonism

Clinical UsesClinical Uses

Parkinson’s disease, less effective than Parkinson’s disease, less effective than

levodopa, and more effective than levodopa, and more effective than

anticholinergic agents. anticholinergic agents.

Onset rapidly; synergised by L-dopa.Onset rapidly; synergised by L-dopa.

II.Central Anticholinergic DrugsII.Central Anticholinergic Drugs

ActionsActions

Blocking the M-R ,↓cholinergic Blocking the M-R ,↓cholinergic

neurons in the nigrostriatal.neurons in the nigrostriatal.

TrihexyphenidylTrihexyphenidyl(( 苯海索苯海索 ))

BenzatropineBenzatropine(( 苯扎托品苯扎托品 ))

Improve the tremor and rigidity of PD, Improve the tremor and rigidity of PD,

little effect on bradykinesia.little effect on bradykinesia.

Drug Therapy in Drug Therapy in Alzheimer’s Disease Alzheimer’s Disease

Alzheimer’s diseaseAlzheimer’s disease （（ ADAD ） ） 3/43/4 Vascular dementiaVascular dementia （（ VDVD ） ） 1/4 1/4

Dr.Alois Alzheimer, a German doctor,

diagnosed Alzheimer’s disease in 1906

IncidenceIncidence

65y 5.0% 65y 5.0%

75y 19% 75y 19%

85y 47%85y 47%

95y 90%95y 90%

Course of disease: 3~20yCourse of disease: 3~20y

International Symposium for International Symposium for

Alzheimer’s DiseaseAlzheimer’s Disease 2000 2000

“If the effective methods for AD “If the effective methods for AD

treatment is not found, the AD treatment is not found, the AD

patients will be 22 000 000 in 2025; 45 patients will be 22 000 000 in 2025; 45

000 000 in 2050 in whole world.”000 000 in 2050 in whole world.”

Clinical FeaturesClinical Features

Dementia, cognition dysufficiencyDementia, cognition dysufficiency, , memory damage memory damage

Pathological FeaturesPathological Features

Brain atrophy (Brain atrophy ( 脑萎缩脑萎缩 ))

Senile plaque (SP, Senile plaque (SP, 老年斑老年斑 ) )

Neurofibrillary tangles (NFT, Neurofibrillary tangles (NFT, 神经元纤维神经元纤维

缠结缠结 ) )

Selective death of neuron.Selective death of neuron.

Pathological FeaturesPathological Features

1.Neuron toxication of1.Neuron toxication of amyloidβ-amyloidβ-

protein(Aβ)protein(Aβ) 。。

Aβ cholinergic functionAβ cholinergic function

AchE Aβ AchE Aβ

Pathological FeaturesPathological Features

2.2.Neurotransmittor activity Neurotransmittor activity

Ach and Glu Ach and Glu

Cholinergic neurons regressCholinergic neurons regress

Therapy for ADTherapy for AD

1.Potentiate cholinergic function1.Potentiate cholinergic function :AChEI:AChEI 、、 M-R M-R agonistsagonists

2.Potentiator of neuronal nutrition factor and 2.Potentiator of neuronal nutrition factor and neuron cell growth factorneuron cell growth factor

3. brain metabolism activator3. brain metabolism activator 吡拉西坦吡拉西坦 (( 脑复康脑复康 ))

4.Drugs improving microcirculation4.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 antagonists5.Calcium antagonists(( 尼莫地平尼莫地平 ))

AChE-inhibitorsAChE-inhibitors

TacrineTacrine(( 他克林他克林 )——)——first generationfirst generation

1. inhibit AChE1. inhibit AChE （（ selectivity is lowselectivity is low ））

2. excite M-R, N-R2. excite M-R, N-R

3. promote glucose use3. promote glucose use

adverse reaction: hepatotoxicityadverse reaction: hepatotoxicity

AChE-inhibitorsAChE-inhibitors

donepezil donepezil （多奈哌齐）（多奈哌齐）———— second second generationgeneration

inhibit AChEinhibit AChE （（ selectivity is highselectivity is high ）） RivastigmineRivastigmine （（利凡斯的明利凡斯的明）— second second

generationgeneration

inhibit AChEinhibit AChE （（ mainly to mainly to cortex and hippocamp ））

AChE-inhibitorsAChE-inhibitors

galanthamine galanthamine —second generationsecond generation

1) 1) high selectivity for AChE In CNS.high selectivity for AChE In CNS.

2) have no hepatotoxicity.2) have no hepatotoxicity.

3) mild and moderate AD3) mild and moderate AD

4) nausea, vomitting, diarrhea, dizzy4) nausea, vomitting, diarrhea, dizzy

M-R agonistM-R agonist

XanomelineXanomeline （占诺美林）（占诺美林）

Sabcomedine （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 Alzheimer’s disease in 1906

Parkinson’s diseaseParkinson’s disease

世界帕金森病日世界帕金森病日 从１９９７年开始，每年的４月１１从１９９７年开始，每年的４月１１

日被确定为“世界帕金森病日”日被确定为“世界帕金森病日” (World (World Parkinson's Disease Day)Parkinson's Disease Day) 。这一天是帕。这一天是帕金森病的发现者金森病的发现者————英国内科医生詹姆斯英国内科医生詹姆斯·· 帕金森博士的生日。 帕金森博士的生日。