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Welcome to Pharmacology
CHAPTER 19
ANTIPARKINSONISM
DRUGS AND DRUG THERAPY
IN ALZHEIMER’S DISEASE
CNS degenerative disease




Parkinson’s disease (PD)帕金森病
Alzheimer’s disease (AD)阿尔茨海默病
Huntington disease (HD)亨廷顿病
Amyotrophic lateral sclerosis(ALS)
肌萎缩侧索硬化症
Mechanisms
 Excitotoxicity
 Apoptosis
 Oxidative stress
Parkinson’s disease
 Parkinson’s disease (PD)
 Paralysis agitans(震颤麻痹）
 Classification
Primary PD
Parkinsonism cerebral arteriosclerosis(脑动脉硬化)
encephalitis(脑炎)
drug poison(药物中毒)
Typical symptom
1.
2.
3.
4.
resting tremor(静止震颤)
rigidity(肌肉僵直)
bradykinesia(运动迟缓)
ataxia(共济失调)
dopamine
 tyrosine
dopa
dopamine
(酪氨酸)
noradrenalin and adrenalin
Pathogenesis (dopamine theory)
DA neuronal degeneration
Nigro-striatal (caudate nucleus, putamen，
pallidum)
Dopaminergic neuron activity↓
Cholinergic neuron activity↑
Evidence
Oxidative stress theory
 Nervous degeneration by oxygen free
radical: H2O2, ·O2-, Fe2+
Dopamine receptors
 five main subtypes: D1 ~D5.
 D1 receptor
D1 and D5
cAMP
excitation
 D2 receptor
cAMP
D2~D4
inhibition
Dopaminomimetic
Drugs
Therapeutic
Drugs
Central anti-cholinergic
Drugs
I. Dopaminomimetic Drugs
Levodopa（L-dopa）
the immediate precursor of
dopamine. penetrates into the brain,
where it is decarboxylated to DA.
corrects dopamine deficiency in
nigra-striatum .
Pharmacokinetics
1. Absorption
Ready from small intestine, tmax 0.52 hrs, affected by gastric emptying,
gastric acid and amino acids
Pharmacokinetics
2. Distribution and metabolism
 uptake，metabolized by COMT
and MAO
3. Elimination kidney, t1/2 1-3 hrs.
Pharmacokinetics
Decarboxylase
Levodopa
DA
Liver 99%
1%
Decarboxylase
Blood-brain
Barrier
DA
Brain
Pharmacological Actions and Uses
1. Parkinson’s disease
Levodopa is widely used for treatment of
all type of Parkinsonism except that
associated with antipsychotic drug
therapy.
Properties
(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 Parkinson’s
syndrome caused by phenothiazines.
Actions and Uses
2. Hepatic coma
false neurotransmitter theory：正常机体蛋白
质代谢产物苯乙胺和酪胺都在肝内被氧化解毒。
肝功能障碍时，血中苯乙胺和酪胺升高，在神经
细胞内经β-羟化酶分别生成伪递质——苯乙醇胺
和羟苯乙醇胺（鱆胺），它们取代了正常递质去
甲肾上腺素，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。
Levodopa metabolized to noradrenaline
to replace octopamine(鱆胺)
Adverse Reactions
1. Early reactions
Gastrointestinal reaction（early）—
domperidone
Cardiovascular effects （early） —
tachycardia, arrhythmias, orthostatic
hypotension— blocker
Adverse Reactions
2. long-term reactions
a. Hyperkinesia: involuntary
movement
b. on-off response
c. Psychic disorders and epilepsy
Drug Interactions
Carbidopa
VitB6
MAOI (unselective)
(-)
(-)
L-dopa
(+) MAO
DA DA+R
excretion
Effects
Decarboxylase
(-)
Antipsychotic drugs
1.AADC inhibitors


Carbidopa（卡比多巴）
Benserazide（苄丝肼）
Compound Preparations

Sinemet（息宁，心宁美）
Levodopa : Carbidopa (10 : 1)
 Madopar（美多巴）
Levodopa : Benserazide (4 : 1)
2.MAO-B inhibitors
Selegiline (司来吉兰)
Mechanism：
 MAO-B inhibitor (MAO-B—in Nigrostriatal)
low dose（＜10mg/d）
—only inhibit MAO-B
high dose （＞10mg/d）
—inhibit MAO-A too
MAO: MAO-A: Intestines
MAO-B: CNS
 Antioxidants
DATATOP
3.COMT inhibitors
 Nitecapone（硝替卡朋）：only inhibit
peripheral COMT
 Tocapone（托卡朋）：inhibit COMT both
peripheral and CNS
Prolonged the duration of of levodopa by
diminishing in peripheral metabolism
 May be helpful in patients receiving
levodopa who have developed response
fluctuation.
DA-R agonists
 Not produce free radical
 Long t1/2 ----long stimulus on receptor
 Possible have neural protection effect
DA-R agonists
Bromocriptine(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
乳素血症）
DA-R agonists
 Lisuride（利修来得）：stronger than
Bromocriptine
 Pergolide(培高利特)：stronger than Lisuride
 Ropinirole（罗匹尼罗）和pramipexole（普拉
克索）
1.only agonist on D2 receptor ，
no effect on D1
2.on-off response is few
 Apomorphine（阿扑吗啡）
Drugs enhancing DA release
 Amantadine(金刚烷胺)
1.↑release DA from dopaminergic
terminals.
2.↓reuptake of DA.
3. dopamine receptor agonism
 Clinical Uses
Parkinson’s disease, less effective than
levodopa, and more effective than
anticholinergic agents.
Onset rapidly; synergised by L-dopa.
II.Central Anticholinergic
Drugs
 Actions
Blocking the M-R ,↓cholinergic
neurons in the nigrostriatal.
Trihexyphenidyl(苯海索)
Benzatropine(苯扎托品)
Improve the tremor and rigidity of PD,
little effect on bradykinesia.
Drug Therapy in
Alzheimer’s Disease
 Alzheimer’s disease（AD） 3/4
 Vascular dementia（VD） 1/4
Dr.Alois Alzheimer, a
German doctor,
diagnosed Alzheimer’s
disease in 1906
Incidence
65y 5.0%
75y 19%
85y 47%
95y 90%
Course of disease: 3~20y
 International Symposium for
Alzheimer’s 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 Features
Dementia, cognition dysufficiency,
memory damage
Pathological Features
 Brain atrophy (脑萎缩)
 Senile plaque (SP, 老年斑)
 Neurofibrillary tangles (NFT, 神经元纤维
缠结)
 Selective death of neuron.
Pathological Features
 1.Neuron toxication of amyloidβprotein(Aβ) 。
 Aβ
 AchE
cholinergic function
Aβ
Pathological Features
 2.Neurotransmittor activity
Ach and Glu
Cholinergic neurons regress
Therapy for AD
1.Potentiate cholinergic function :AChEI、M-R
agonists
2.Potentiator of neuronal nutrition factor and
neuron cell growth factor
3. brain metabolism activator吡拉西坦(脑复康)
4.Drugs improving microcirculation 麦角类衍生物、
都可喜等
5.Calcium antagonists(尼莫地平)
AChE-inhibitors
 Tacrine(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-inhibitors
 donepezil （多奈哌齐）——second
generation
inhibit AChE（selectivity is high）
 Rivastigmine（利凡斯的明）—second
generation
inhibit AChE（mainly to cortex and
hippocamp）
AChE-inhibitors
 galanthamine —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 agonist
 Xanomeline（占诺美林）
 Sabcomedine（沙可美林）
selective M1-R agonist
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 disease
 世界帕金森病日
从１９９７年开始，每年的４月１１
日被确定为“世界帕金森病日”(World
Parkinson's 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。