Drugs for CNS degenerative disorders治疗中枢神经系统退行性疾病药物（可编辑）

Drugs for CNS degenerative disorders治疗中枢神经系统退行性疾病药物（可编辑） Drugs for CNS degenerative disorders治疗中枢神经 系统退行性疾病药物 Drugs Used for Neurodegenerative Diseases of CNS 治疗中枢神经系统 退行性疾病药物 Neurodegenerative Diseases Associated with progressive loss of neurons and their functionsParkinson’s disease帕金森病Alzheimer’s disease阿尔茨海默病Huntington’s disease亨廷顿病,舞蹈病 Amyotrophic lateral sclerosis 肌萎缩侧索硬化症 Common Mechanisms of NeurodegenerationMisfolded and aggregated proteins?-synuclein in PD; ?-amyloid and tau in AD; huntingtin in HD; SOD and TDP-43 in ALS? Excess glutamate in the brain Impairment in the capacity of neurons for oxidative metabolism Parkinsonism Parkinson’s syndrome not resulted from neurodegenerative disease used to describe the syndrome Parkinson's disease the second most prevalent neurodegenerative disease after Alzheimer's diseasethe most common cause of parkinsonism Parkinson’s disease Symptoms:Resting tremorMuscle rigidity ---- increased tone, akinesia运动不能 Bradykinesia运动徐缓-----difficulty in initiating movements and controlling fine movementsPostural instability Parkinson’s disease Background: 1. Neuronal circuits involved in movements:cortical regions, thalamus丘脑 , cerebellum小 脑 , and basal ganglia基底节 substantia nigra黑质, striatum纹状体, globus pallidus苍 白球 and subthalamus下丘脑 striatum: caudate nucleus 尾核and putamen壳 核 2. The basal ganglia play an important part in the initiation and scaling of movement Dopamine pathways Parkinson’s disease Background: 3. Dopamine neurons in the substantia nigra project to the striatum纹状体caudate nucleus and putamen and exert an inhibitory influence on motoneurons4. Cholinergic interneurons in the striatum 纹状体 promote motoneuronal excitation Parkinson’s disease Pathophysiologic basis:Degeneration of dopaminergic neurons in the substantia nigraNigrostriatal pathway黑质纹状体通路 Dopaminergic nerve Cholinergic nerve Treatment strategies:Restore dopamine functionInhibit Ach within striatum Drugs for Parkinson’s disease Groups of DrugsQuasi-Dopamine drugs拟多巴胺类药 ----levodopa(左旋多巴), carbidopa(卡比多巴), selegiline(司来吉兰)Central anticholinergic drugs 中枢抗胆碱 药 ----benzhexol苯海索, benzatropine苯扎托品Others ----amantadine金刚烷胺, ropinirole, pramipexole bromocriptine溴隐亭, pergolide培高利特 LevodopaL-dopaDopamine can not be administered directly, as it does not cross the blood brain barrier Levodopa is the biosynthetic precursor of dopamine. L-dopa can cross the blood-brain barrier. Levodopa Pharmacokinetics:Absorbed by the small intestine by an active transport systemFirst pass effect:Metabolised in peripheral tissues by LAADL- Amino Acid Decarboxylase, MAO and COMT ?Extracerebral dopamine causes unwanted effects Short half-life Treatment with L-Dopa L-dopa taken up by dopaminergic neurons in the substantia nigra and converted to dopamine by LAADL-dopa therapy can have a dramatic effect on all the signs and symptoms of PDImprovement in rigidity, tremor, depressionGood functional mobility can be maintained for many years Life expectancy is increased substantiallyHowever,disease progresses and may get worse Treatment with L-Dopa L-dopa therapy can’t block the progresse of PD "buffering" capacity is lost after long-term therapy of L-dopa"wearing off" phenomenon "on/off " phenomenon L-Dopa Side Effects 1. Gastrointestinal reactions, induction of peptic ulcer 2. Cardiovascular reactions: postural hypotension, arrhythmia. 3. Mental disorders: insomnia失眠 , anxiety, hallucinations幻觉4. Involuntary abnormal movement L-dopa drug interactionsPyridoxine Vitamin B6Coenzyme of decarboxylase and enhances the extracerebral metabolism of L-dopa, then increases side effects of dopamineNon-selective MAOi monoamine oxidase inhibitorSlow metabolism of dopamine and cause a hypertensive crisis in PD patients taking L-dopaAntipsychotics(抗精神 失常药)Block dopamine receptors and exacerbate motor dysfunction CarbidopaAnalog of L-dopaInhibits the conversion of L-dopa to dopamine by LAAD in peripheral tissuesCarbidopa is highly ionized at physiological pH and does not cross the blood-brain barrierCombination therapies of L-dopa and carbidopa allow for a reduction in the amount of L-dopa needed - Carbidopa reduces the peripheral metabolism of L- dopa, and more L-dopa enters into the brain. Carbidopa Selegiline司来吉兰 selective MAO-B inhibitor In CNS L -dopa Dopamine MAO B Reuptake COMTUptake II Uptake I Selegiline 司来吉兰It is a selective MAOB inhibitor----Enhance and prolongs the anti-parkinsonism effect of L-dopa----Reduce the dose of L-dopa----Reduce L-dopa wearing off effect and “on-off” phenomenon Benzhexol Artane 苯海索Central anticholiergic Used in the treatment of early PD or as an adjunct to dopamimetic therapyLess effective than L-dopa and Amantadine金刚烷胺 Effective in Parkinsonism produced by antipsychotic Drugs Adverse effects: sedation, confusion, constipation, urinary retention, and blurred vision? Used with caution in patients with narrow-angle glaucomaAmantadine 金刚烷胺Antiviral agent Mechanism:increases the release of dopamine from the nigrostriatal neurons? has anticholinergic properties blocks NMDA glutamate receptors Better tolerated but less effective than L-dopaHas synergistic action with L-dopa Used as initial therapy of mild PD? Helpful as an adjunct in patients on L-dopa with dose- related fluctuations and dyskinesiasDA-R agonists Ropinirole and pramipexole older agents: Bromocriptine溴隐亭 & Pergolide培高利特 Advantages:enzymatic conversion is not requireddo not depend on the functional capacities of the nigrostriatal neuronshave durations of action substantially longer than that of L-dopa? Directly stimulates D2 receptors Used for patients who can not sustain L-dopa therapy, particularly effective in the treatment of patients who have developed on/off phenomenaAdverse effects: similar to that observed with levodopa, eghallucinosis, nausea and orthostatic hypotension Disease Modifying Drugs Overview Alzheimer’s DiseaseIncurable, degenerative, and terminal disease The most common form of dementia痴呆 SymptomsEarly stages: memory loss, Advances: confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss ?Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions, particularly entorhinal cortex内嗅皮层 and hippocampus海马/memory regions Alzheimer’s DiseaseThe most striking neurochemical disturbance in AD is a deficiency of acetylcholine Atrophy萎缩 and degeneration of subcortical cholinergic neurons Treatment of ADThere is no cure for Alzheimer‘s disease Available treatments offer relatively small symptomatic benefit but remain palliative(治标 药)in natureTreatment of ADThe treatment strategies are based on two biochemical features of ADReduction in the activity of the cholinergic neuronsOverstimulation of glutamate receptors, especially NMDA receptors Classification of drugs 1. Cholinesterase Inhibitors Tacrine cognex他克林 Donepezil Aricept多奈哌齐 Galantamine Reminyl加兰他敏 Huperzine A 石杉碱甲 Metrifonate 美曲膦脂 Exelon 艾斯能 2. M receptor agonists Xanomeline占诺美林 Milameline米拉美林 3. NMDA receptor antagonists Memantine 美金刚 4. Others Questions 1. Carbidopa blocks the conversion of dopa to dompamine, so why doesn’t it abolish the therapeutic effect of levedopa? 2. How do selegiline, benzhexol, amantadine and bromocriptine work respectively?