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?