Drugs forDrugs for

Parkinson’s Parkinson’s

DiseaseDisease

Drugs forDrugs for

Parkinson’s Parkinson’s

DiseaseDisease

Chapter 24 Chapter 24

Parkinson’s disease, PD 帕金森病(paralysis agitants 震颤麻痹 )

T

Dopamine: Inhibitory

Ach: Excitatory

GABA: Inhibitory

DA neuron generated

Cause

Loss of dopaminergic neurons in substantia nigra

Imbalance between the excitatory cholinergic

neurons and the greatly diminished number of

inhibitory dopaminergic neurons

DopamineDopamine

AcetylcholineAcetylcholineAcetylcholineAcetylcholine

Treatment strategy

To regain balance of dopamine and ACh

Dopaminergic agents 拟多巴胺药Promote activation of dopamine receptors

Levodopa 左旋多巴

Antioxidant

Selegiline 司来吉兰 Anticholinergic agents 抗胆碱药

Prevent activation of cholinergic receptors

Trihexyphenidyl 苯海索

Tyrosine

L-dopa

Dopamine

NA

Dopaminergic agents Dopaminergic agents 拟多巴胺药拟多巴胺药 levodopa, (L-dopa) levodopa, (L-dopa) 左旋多巴左旋多巴

tyrosine hydroxylase

dopa decarboxylase

dopamine β-hydroxylase

Levodopa Mechanism

Pharmacokinetics Administered 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 dopamine, which dose

not penetrate the blood-brain barrier.

Clinical use Parkinsonism

The best results are obtained in the first few years of treatment.

The benefits of levodopa treatment often begin to diminish after 3 or 4 years of therapy.

given in combination with carbidopa.

Hepatic coma

Adverse Effects

Gastrointestinal effects

Orthostatic hypotension 体位性低血压 arrhythmia 心律不齐 Abnormal involuntary movements

hyperkinesia 运动过多症 on-off phenomena “ 开－关现象” Psychogenia 精神障碍

Interactions VB6 increases peripheral breakdown of

levodopa

MAO inhibitors decrease dopamine

inactivation and produce a hypertensive

crisis

Antipsychotic drugs block dopamine

receptors and produce a parkinsonian

syndrome by themselves

Not cross the blood-brain barrier

inhibits decarboxylases in periphery

decreases dose of Levodopa by 75%;

reduces or prevents the side effects of

levodopa

increases the availability of levodopa to the

CNS

Decarboxylases inhibitorDecarboxylases inhibitor

Carbidopa Carbidopa 卡比多巴

selegiline 司来吉兰 MAOI 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 levodopa

decreases the dose of levodopa , reduces the

adverse effects.

nitecapone 硝替卡朋 COMT 儿茶酚氧位甲基转移酶 inhibitor

Bromocriptine 溴隐亭 D2-R agonist, across the blood-brain barrier

easily Combination with levodopa Have an important role as first-line therapy Lower incidence of the adverse effects with

long-term levodopa therapy

Amantadine 金刚烷胺 enhance the release of dopamine from the

surviving neurons side effects are few

Central anticholinergic drug

中枢抗胆碱药

trihexyphenidyl 苯海索（ Artane 安坦）

Blockage of cholinergic transmission

produces similar to augmentation of

dopaminergic transmission

Peripheral side effects like atropine

Alzheimer’ disease ( AD)

阿尔茨海默病

CNS degenerative disease

cognitive disorder in progress 进行性认知障碍

memory impairment 记忆力损害

Main course: cholinergic insufficiency

Cholinesterase inhibitor drug 胆碱酯酶抑制药

Tacrine 他克林 best choice for AD at present

Mechanism ： inhibiting cholinesterase

stimulating M and N receptors directly

promoting Ach release

Adverse effects: hepatotoxicity

Cholinergic receptor agonist胆碱受体激动药

xanomeline 占诺美林 stimulating M1 receptor selectively

Nerve cell GF potentiator

神经细胞生长因子增强剂 neotrofin （ AIT 082 ）