医学课件帕金森及其药物治疗
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pallidum) Dopaminergic neuron activity↓ Cholinergic neuron activity↑
Evidence
2020/9/25
Oxidative stress theory
• Nervous degeneration by oxygen free radical: H2O2, ·O2-, Fe2+
2020/9/25
dopamine
• tyrosine
dopa
dopamine
(酪氨酸)
noradrenalin and adrenalin
2020/9/25
Pathogenesis (dopamine theory)
DA neuronal degeneration Nigro-striatal (caudate nucleus, putamen，
2020/源自文库/25
Pharmacokinetics
1. Absorption 2. Ready from small intestine, tmax 0.53. 2 hrs, affected by gastric emptying, 4. gastric acid and amino acids 5.
CHAPTER 19
ANTIPARKINSONISM DRUGS AND DRUG THERAPY IN ALZHEIMER’S DISEASE
2020/9/25
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)
Primary PD Parkinsonism cerebral arteriosclerosis(脑动脉硬化)
encephalitis(脑炎) drug poison(药物中毒)
2020/9/25
Typical symptom
1. resting tremor(静止震颤) 2. rigidity(肌肉僵直) 3. bradykinesia(运动迟缓) 4. ataxia(共济失调)
肌萎缩侧索硬化症
2020/9/25
Mechanisms
• Excitotoxicity • Apoptosis • Oxidative stress
2020/9/25
Parkinson’s disease
• Parkinson’s disease (PD) • Paralysis agitans(震颤麻痹） • Classification
2020/9/25
Properties
(1)Most effective for mild and younger patients
(2)More effective for rigidity and akinesia, less effective for tremor
2020/9/25
Properties
Therapeutic Drugs
Central anti-cholinergic Drugs
2020/9/25
2020/9/25
I. Dopaminomimetic Drugs
2020/9/25
Levodopa（L-dopa）
the immediate precursor of dopamine. penetrates into the brain, where it is decarboxylated to DA. corrects dopamine deficiency in nigra-striatum .
(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.
2020/9/25
Actions and Uses
2020/9/25
Dopamine receptors
• five main subtypes: D1 ~D5. • D1 receptor D1 and D5
cAMP excitation
• D2 receptor D2~D4
cAMP inhibition
2020/9/25
Dopaminomimetic Drugs
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)
2020/9/25
Pharmacokinetics
2. Distribution and metabolism • uptake，metabolized by COMT
and MAO 3. Elimination kidney, t1/2 1-3 hrs.
2020/9/25
Pharmacokinetics
Decarboxylase
Levodopa
DA
Liver 99%
1%
Decarboxylase
Blood-brain
DA
Barrier
Brain
2020/9/25
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.
Evidence
2020/9/25
Oxidative stress theory
• Nervous degeneration by oxygen free radical: H2O2, ·O2-, Fe2+
2020/9/25
dopamine
• tyrosine
dopa
dopamine
(酪氨酸)
noradrenalin and adrenalin
2020/9/25
Pathogenesis (dopamine theory)
DA neuronal degeneration Nigro-striatal (caudate nucleus, putamen，
2020/源自文库/25
Pharmacokinetics
1. Absorption 2. Ready from small intestine, tmax 0.53. 2 hrs, affected by gastric emptying, 4. gastric acid and amino acids 5.
CHAPTER 19
ANTIPARKINSONISM DRUGS AND DRUG THERAPY IN ALZHEIMER’S DISEASE
2020/9/25
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)
Primary PD Parkinsonism cerebral arteriosclerosis(脑动脉硬化)
encephalitis(脑炎) drug poison(药物中毒)
2020/9/25
Typical symptom
1. resting tremor(静止震颤) 2. rigidity(肌肉僵直) 3. bradykinesia(运动迟缓) 4. ataxia(共济失调)
肌萎缩侧索硬化症
2020/9/25
Mechanisms
• Excitotoxicity • Apoptosis • Oxidative stress
2020/9/25
Parkinson’s disease
• Parkinson’s disease (PD) • Paralysis agitans(震颤麻痹） • Classification
2020/9/25
Properties
(1)Most effective for mild and younger patients
(2)More effective for rigidity and akinesia, less effective for tremor
2020/9/25
Properties
Therapeutic Drugs
Central anti-cholinergic Drugs
2020/9/25
2020/9/25
I. Dopaminomimetic Drugs
2020/9/25
Levodopa（L-dopa）
the immediate precursor of dopamine. penetrates into the brain, where it is decarboxylated to DA. corrects dopamine deficiency in nigra-striatum .
(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.
2020/9/25
Actions and Uses
2020/9/25
Dopamine receptors
• five main subtypes: D1 ~D5. • D1 receptor D1 and D5
cAMP excitation
• D2 receptor D2~D4
cAMP inhibition
2020/9/25
Dopaminomimetic Drugs
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)
2020/9/25
Pharmacokinetics
2. Distribution and metabolism • uptake，metabolized by COMT
and MAO 3. Elimination kidney, t1/2 1-3 hrs.
2020/9/25
Pharmacokinetics
Decarboxylase
Levodopa
DA
Liver 99%
1%
Decarboxylase
Blood-brain
DA
Barrier
Brain
2020/9/25
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.