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    chapter 16 chapter 16 Presentation Transcript

    • Welcome to Pharmacology   张岫美 山东大学医学院 药理学研究所 Welcome to Pharmacology
    • 药 理 学 PHARMACOLOGY   张岫美 山东大学医学院 药理学研究所 [email_address]
    • CHAPTER 16
      • ANTIPARKINSONISM DRUGS
      • AND DRUG THERAPY IN
      • ALZHEIMER’S DISEASE
    • Parkinson’s disease
      • Parkinson’s disease (PD)
      • Features( paralysis agitants )
      • Tremor, rigidity, akinesia and
      • bradykinesia(ataxia)
      • Parkinson’s syndrome
    • Pathogenesis(dopamine theory)
      • Nigro-striatal(caudate nucleus,
      • putamen and pallidum)
      • DA neuronal degeneration
      • Dopaminergic neuron activity↓
      • Cholinergic neuron activity↑
      • Oxidative stress theory
    •  
    • Dopaminomimetic Drugs Therapeutic Drugs Central anti-cholinergic Drugs
    • Section 1 Dopaminomimetic Drugs
      • Levodopa ( L-dopa, 左旋多巴) Levodopa could penetrates into the brain, where it is decarboxylated to dopamine.
    • Pharmacokinetics
      • Absorption
      • Ready from small intestine, t max 0.5-
      • 2 hrs, affected by gastric emptying,
      • gastric acid and amino acids
    • Pharmacokinetics
      • 2. Distribution and metabolism
      • about 1% through blood brain barrier by dopa decarboxylase to dopamine.
      • 99% peripheral transfore to dopamine.
      • a little to melonnin, most metabolized
      • by COMT and MAO
      • 3. Elimination kidney, t 1/2 1-3 hrs.
    • Pharmacokinetics Decarboxylase Levodopa DA Liver 99% 1% Decarboxylase Blood-brain DA Barrier 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 wks to effect,
      • 1-6 months to E max
      • (4)No effective for Parkinson’s syndrome caused by phenothiazines.
    • Actions and Uses
      • 2. Hepatic coma
      • Levodopa metabolized to noradrenaline
      • to replace octopamine( false neurotransmitter theory)
    • Adverse Reactions
      • 1. Gastrointestinal Effects
      • 2. Cardiovascular Effects
      • 3. Abnormal involuntary movement “on-off” phenomena
      • 4. Psychic disorders and epilepsy
    • Drug Interactions
      • Carbidopa VitB 6
      • (-) (+)
      • L-dopa DA+R Effects
      • Decarboxylase
      • (-)
      • Antipsychotic drugs
    • Other dopaminomimetics
      • Decarboxylase inhibitors
      • Carbidopa (卡比多巴)
      • Benserazide (苄丝肼)
      • Compound Preparations
      • Sinemet (息宁 )
      • Levodopa : Carbidopa (10 : 1)
      • Madopar (美多巴)
      • Levodopa : Benserazide (4 : 1)
    • Amantadine ( 金刚烷胺 )
      • Mechanism of Action
      • 1.↑release DA from dopaminergic
      • terminals.
      • 2.↓reuptake of DA.
      • 3. dopamine receptor agonism
    • Amantadine
      • Clinical Uses
      • Parkinson’s disease, less effective than levodopa, and more effective than anticholinergic agents. Effective for Parkinson’s syndrome caused by phenothiazines, synergized by l-dopa. Onset rapidly, 2 wks; Last short about
      • 4-8 wks.
    • Adverse Reactions
      • Livedo reticularis
      • Psychotic disorders
    • Bromocriptine ( 溴隐亭 ) Pergolide ( 培高利特 )
      • Large dose stimulate D 2 receptor in
      • substantia nigro-striatal
      • Small dose stimulate D 2 receptor in
      • tubero-infundibular, reduce PRL and GH
      • release
      • Used to treat PD and hyperprolactinemia
    • Selegiline
      • MAO-B inhibitor and antioxidants
      • Section 2 Central Anticholinergic Drugs
      • Actions
      • Blocking the M-R ,↓cholinergic neurons in the basal ganglia.
      • Benzatropine ( 苯扎托品 )
      • Trihexyphenidyl ( 苯海索 )
      • 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
    • Incidence
      • >65y 3.0%~5.0%
      • 65~70y 3.0%
      • 75~84y 19%
      • >85y 47%
      • 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, behavioral disorder
      • Pathological Features
      • Senile plaque (SP, 老年斑 ) was found in brain , Neurofibrillary tangles (NFT, 神经元纤维缠结 ) and selective death of neuron.
    • Pathogenesis
      • Neuron toxication of amyloidβ-protein(Aβ,β- 淀粉样蛋白 ) 。
      • Aβ 可能是胆碱能神经系统高强度、高选择性的负性调节物 , AChE 对 Aβ 的神经毒性起重要的加强和易化作用。
    • Therapy for AD
      • 1.Potentiate cholinergic function AChEI 、 M-R agonists
      • 2.Potentiator of neuronal nutrition factor and neuron cell growth factor
      • 3.Activator brain metabolism 吡拉西坦
      • 4.Drugs improving microcirculation 麦角类衍生物、都可喜等
      • 5.Calcium antagonists
    • SEE You !
    • Thank You !