Transcript Dopaminergic agents 拟多巴胺药levodopa, (L

Chapter 24
Drugs for
Parkinson’s
Disease
Parkinson’s disease, PD 帕金森病
(paralysis agitants 震颤麻痹)
Dopamine: Inhibitory
Ach: Excitatory
GABA: Inhibitory
DA neuron generated
T

Cause
Loss of dopaminergic neurons in substantia nigra
Imbalance between the excitatory cholinergic
neurons and the greatly diminished number of
inhibitory dopaminergic neurons
Dopamine
Acetylcholine
Acetylcholine

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
Dopaminergic agents 拟多巴胺药
levodopa, (L-dopa) 左旋多巴
Tyrosine
tyrosine hydroxylase
L-dopa
dopa decarboxylase
Dopamine
dopamine β-hydroxylase
NA
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
Decarboxylases inhibitor
Carbidopa 卡比多巴

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
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）