The document discusses drug therapies for Parkinson's disease and Alzheimer's disease. It first covers dopaminergic drugs like levodopa that are used to treat Parkinson's disease. It then discusses central anticholinergic drugs that can help treat tremors and rigidity caused by Parkinson's. Finally, it outlines therapies for Alzheimer's disease, including cholinesterase inhibitors to potentiate cholinergic function and drugs that may improve neuronal growth factors or microcirculation in the brain.

1. Welcome to Pharmacology 张岫美 山东大学医学院 药理学研究所 Welcome to Pharmacology

2. 药 理 学 PHARMACOLOGY 张岫美 山东大学医学院 药理学研究所 [email_address]

3. CHAPTER 16 ANTIPARKINSONISM DRUGS AND DRUG THERAPY IN ALZHEIMER’S DISEASE

4. Parkinson’s disease Parkinson’s disease (PD) Features( paralysis agitants ) Tremor, rigidity, akinesia and bradykinesia(ataxia) Parkinson’s syndrome

5. Pathogenesis(dopamine theory) Nigro-striatal(caudate nucleus, putamen and pallidum) DA neuronal degeneration Dopaminergic neuron activity↓ Cholinergic neuron activity↑ Oxidative stress theory

7. Dopaminomimetic Drugs Therapeutic Drugs Central anti-cholinergic Drugs

8. Section 1 Dopaminomimetic Drugs Levodopa （ L-dopa, 左旋多巴） Levodopa could penetrates into the brain, where it is decarboxylated to dopamine.

9. Pharmacokinetics Absorption Ready from small intestine, t max 0.5- 2 hrs, affected by gastric emptying, gastric acid and amino acids

10. 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.

11. Pharmacokinetics Decarboxylase Levodopa DA Liver 99% 1% Decarboxylase Blood-brain DA Barrier Brain

12. 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.

13. Properties (1)Most effective for mild and younger patients (2)More effective for rigidity and akinesia, less effective for tremor

14. 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.

15. Actions and Uses 2. Hepatic coma Levodopa metabolized to noradrenaline to replace octopamine( false neurotransmitter theory)

16. Adverse Reactions 1. Gastrointestinal Effects 2. Cardiovascular Effects 3. Abnormal involuntary movement “on-off” phenomena 4. Psychic disorders and epilepsy

17. Drug Interactions Carbidopa VitB 6 (-) (+) L-dopa DA+R Effects Decarboxylase (-) Antipsychotic drugs

18. 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)

19. Amantadine ( 金刚烷胺 ) Mechanism of Action 1.↑release DA from dopaminergic terminals. 2.↓reuptake of DA. 3. dopamine receptor agonism

20. 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.

21. Adverse Reactions Livedo reticularis Psychotic disorders

22. 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

23. Selegiline MAO-B inhibitor and antioxidants

24. Section 2 Central Anticholinergic Drugs

25. 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 .

26. Drug Therapy in Alzheimer’s Disease Alzheimer’s disease （ AD ） 3/4 Vascular dementia （ VD ） 1/4

27. Incidence >65y 3.0%~5.0% 65~70y 3.0% 75~84y 19% >85y 47% Course of disease: 3~20y

28. 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.”

29. 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.

30. 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。

31. 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

32. SEE You !

33. Thank You !