医学课件帕金森及其药物治疗
合集下载
相关主题
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
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）
cAMP excitation
D2 receptor D2~D4
cAMP inhibition
Therapeutic Drugs
Dopaminomimetic Drugs
Central anti-cholinergic Drugs
I. Dopaminomimetic Drugs
Levodopa（L-dopa）
(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。
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.”
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
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.
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
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.
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
(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
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
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
the immediate precursor of dopamine. penetrates into the brain, where it is decarboxylated to DA. corrects dopamine deficiency in nigra-striatum .
Pharmacokinetics
dBiblioteka Baidupamine
(酪氨酸)
noradrenalin and adrenalin
Pathogenesis (dopamine theory)
DA neuronal degeneration Nigro-striatal (caudate nucleus, putamen，
pallidum) Dopaminergic neuron activity↓ Cholinergic neuron activity↑
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.
1. Parkinson’s disease Levodopa is widely used for treatment of all type of Parkinsonism except that associated with antipsychotic drug therapy.
Properties
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)
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)
encephalitis(脑炎) drug poison(药物中毒)
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)
dopamine
tyrosine
dopa
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）
and MAO
3. Elimination kidney, t1/2 1-3 hrs.
Pharmacokinetics
Decarboxylase
Levodopa
DA
Liver 99%
1%
Decarboxylase
Blood-brain
DA
Barrier
Brain
Pharmacological Actions and Uses
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
(-) L-dopa
VitB6 MAOI (unselective)
(-)
(+) MAO
excretion
DA DA+R Effects
Decarboxylase
(-)
Antipsychotic drugs
1.AADC inhibitors
Carbidopa（卡比多巴） Benserazide（苄丝肼）
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
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)
cAMP excitation
D2 receptor D2~D4
cAMP inhibition
Therapeutic Drugs
Dopaminomimetic Drugs
Central anti-cholinergic Drugs
I. Dopaminomimetic Drugs
Levodopa（L-dopa）
(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。
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.”
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
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.
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
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.
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
(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
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
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
the immediate precursor of dopamine. penetrates into the brain, where it is decarboxylated to DA. corrects dopamine deficiency in nigra-striatum .
Pharmacokinetics
dBiblioteka Baidupamine
(酪氨酸)
noradrenalin and adrenalin
Pathogenesis (dopamine theory)
DA neuronal degeneration Nigro-striatal (caudate nucleus, putamen，
pallidum) Dopaminergic neuron activity↓ Cholinergic neuron activity↑
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.
1. Parkinson’s disease Levodopa is widely used for treatment of all type of Parkinsonism except that associated with antipsychotic drug therapy.
Properties
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)
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)
encephalitis(脑炎) drug poison(药物中毒)
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)
dopamine
tyrosine
dopa
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）
and MAO
3. Elimination kidney, t1/2 1-3 hrs.
Pharmacokinetics
Decarboxylase
Levodopa
DA
Liver 99%
1%
Decarboxylase
Blood-brain
DA
Barrier
Brain
Pharmacological Actions and Uses
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
(-) L-dopa
VitB6 MAOI (unselective)
(-)
(+) MAO
excretion
DA DA+R Effects
Decarboxylase
(-)
Antipsychotic drugs
1.AADC inhibitors
Carbidopa（卡比多巴） Benserazide（苄丝肼）
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
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)