Drugs for Parkinson ’ s Disease 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 neuronsDopamineAcetylcholineAcetylcholine

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 拟多巴胺药 levodopa, (L-dopa) 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  VB 6 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 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 D 2 -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 M 1 receptor selectively Nerve cell GF potentiator 神经细胞生长因子增强剂 neotrofin （ AIT 082 ）