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Welcome to Pharmacology

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.

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Welcome to Pharmacology

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  1. Welcome to Pharmacology

  2. CHAPTER 19 ANTIPARKINSONISM DRUGS AND DRUG THERAPY IN ALZHEIMER’S DISEASE

  3. 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

  4. Mechanisms • Excitotoxicity • Apoptosis • Oxidative stress

  5. 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)

  6. Typical symptom • resting tremor(静止震颤) • rigidity(肌肉僵直) • bradykinesia(运动迟缓) • ataxia(共济失调)

  7. dopamine • tyrosine dopa dopamine (酪氨酸) noradrenalin and adrenalin

  8. Pathogenesis (dopamine theory) DA neuronal degeneration Nigro-striatal(caudate nucleus, putamen， pallidum) Dopaminergic neuron activity↓ Cholinergic neuron activity↑ Evidence

  9. Oxidative stress theory • Nervous degeneration by oxygen free radical: H2O2, ·O2-, Fe2+

  10. Dopamine receptors • five main subtypes: D1 ~D5. • D1 receptor D1 and D5 cAMP excitation • D2 receptor D2~D4 cAMP inhibition

  11. Dopaminomimetic DrugsTherapeutic DrugsCentral anti-cholinergic Drugs

  12. I. Dopaminomimetic Drugs

  13. Levodopa（L-dopa） the immediate precursor of dopamine. penetrates into the brain, where it is decarboxylated to DA. corrects dopamine deficiency in nigra-striatum .

  14. Pharmacokinetics • Absorption Ready from small intestine, tmax 0.5- 2 hrs, affected by gastric emptying, gastric acid and amino acids

  15. Pharmacokinetics 2. Distribution and metabolism • uptake，metabolized by COMT and MAO 3. Elimination kidney, t1/2 1-3 hrs.

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

  17. 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.

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

  19. 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.

  20. 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)

  21. Adverse Reactions 1. Early reactions Gastrointestinal reaction（early）—domperidone Cardiovascular effects（early） —tachycardia, arrhythmias, orthostatic hypotension— blocker

  22. Adverse Reactions 2. long-term reactions a. Hyperkinesia: involuntary movement b. on-off response c. Psychic disorders and epilepsy

  23. Drug Interactions Carbidopa VitB6 MAOI (unselective) (-) (+) MAO L-dopa DA DA+R Effects Decarboxylase (-) Antipsychotic drugs (-) excretion

  24. 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)

  25. 2.MAO-BinhibitorsSelegiline(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

  26. 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.

  27. DA-R agonists • Not produce free radical • Long t1/2 ----long stimulus on receptor • Possible have neural protection effect

  28. 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）

  29. 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）

  30. Drugs enhancing DA release • Amantadine(金刚烷胺) 1.↑release DA from dopaminergic terminals. 2.↓reuptake of DA. 3. dopamine receptor agonism

  31. Clinical Uses Parkinson’s disease, less effective than levodopa, and more effective than anticholinergic agents. Onset rapidly; synergised by L-dopa.

  32. II.Central Anticholinergic Drugs

  33. 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.

  34. 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

  35. Incidence 65y 5.0% 75y 19% 85y 47% 95y 90% Course of disease: 3~20y

  36. International Symposium for Alzheimer’s Disease2000 “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.”

  37. Clinical Features Dementia, cognition dysufficiency, memory damage

  38. 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.

  39. Pathological Features • 1.Neuron toxication ofamyloidβ-protein(Aβ) 。 • Aβ cholinergic function • AchE Aβ

  40. Pathological Features • 2.Neurotransmittor activity Ach and Glu Cholinergic neurons regress

  41. 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)

  42. 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

  43. 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）

  44. 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

  45. M-R agonist • Xanomeline（占诺美林） • Sabcomedine（沙可美林） selective M1-R agonist

  46. Thank You !

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