1、DRUGS FOR NEURODEGENERATIVE DISORDERObjectives Demonstrate the clinical use and adverse effects of levodopa. Describe the characteristics of dopamine agonists, monoamine oxidase inhibitors, COMT inhibitors and acetylcholine-blocking drugs in the treatment of PD.Parkinsons DiseaseProgressive neurolog
2、ical disorder of muscle movement Postural and gait abnormality BradykinesiaMuscular rigidityTremors http:/ cause of Parkinsons disease is unknown for most patients. Slow TremorRigidFall Etiology for ParkinsonnullsDiseaseDrugs treatment A. Levodopa and carbidopa B. Selegiline and rasagiline C. Catech
3、ol-O-methyltransferase inhibitors D. Dopamine-receptor agonists E. Amantadine F. Antimuscarinic agentsDOPADOPAMINENOREPINEPHRINETYROCINETYROCINE hydroxylaseDopa decarboxylaseDOPAMINE - hydroxylaseCOMT,MAO3-O-METHYLDOPAA. Levodopa and carbidopa Replenish the dopamine deficiency Levodopa: immediate pr
4、ecursor of dopamine Carbidopa: a dopa decarboxylase inhibitor CANT cross BBB“Wear off” Actions and Therapeutic usesDecreases the rigidity, tremors, other symptomsSubstantially reduces the severity of the disease for the first few yearsCombination useAbsorption and metabolismSmall intestine, rapidly,
5、 t1/2: 1-2hrs Large, neutral amino acids (leucine and isoleucine), Meals high in protein absorption Taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual. Adverse effectsPeripheral effectsAnorexia, nausea, and vomiting-chemoreceptor trigger zone of t
6、he medullaTachycardia and ventricular extra systoles-peripheral DAHypotensionMydriasis -receptorBrownish saliva and urine CNS effectsVisual and auditory hallucinations and abnormal involuntary movements (dyskinesias)Mood changes, depression, psychosis,and anxietyhttp:/ effects Motor fluctuations On-
7、off response Short half life Sudden onset of PD symptoms with a usual therapeutic dose of L-dopa that maybe the result of progression of the disease loss of dopamine nerve terminals in the striatum Interactions Increase in intraocular pressure Cardiac arrhythmias Antipsychotic drugs aregenerally con
8、traindicated in PD patients Atypical agents sometimes employed to treat levodopa-induced psychiatric symptomsphenylzineB. Selegiline and rasagiline selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses given at above recommended doses, it loses its selectivity. Reduce
9、s the motor fluctuation caused by levodopa Metabolites: methamphetamine and amphetamine, may produce insomnia if administered later than midafternoon Rasagiline: five times the potency of selegiline. Unlike selegiline, it is not metabolized to an amphetamine-like substance C. Catechol-O-methyltransf
10、erase inhibitors LevodopaEntacapone or tolacapone can reduce the symptoms of“wearing-off” phenomena Prolong the “on” reseponse of PDCompetes with levodopa for activetransport into the CNS Decarboxylase pathwaynullCOMT 3-O-methyldopa: major pathwayCarbidopaPharmacokinetics for COMTIOral absorption oc
11、curs readily, notinfluenced by food.Extensively bound to plasma albumin(98 percent), with limited volumes ofdistributionExtensively metabolized eliminated in thefeces and urineT: longer t1/2 than ET can cross BBB, EcannotAdverse effect Diarrhea, postural hypotension, nausea, anorexia, dyskinesias, h
12、allucinations, and sleep disorders. Tolcapone: fulminating hepatic necrosis used along with appropriate hepatic function monitoring only in patients in whom other modalities have failed. Entacapone does not exhibit this toxicity and has largely replaced tolcapone. D. Dopamine-receptor agonists Bromo
13、criptine, ropinirole, pramipexole, rotigotine and Apomorphine (longer duration than levodopa) Effective in patients exhibiting fluctuations in their response to levodopa Ineffective in patients who have shown no therapeutic response to levodopaBromocriptineA. Hallucinations, confusion, delirium, nau
14、sea, and orthostatic hypotension. dyskinesia less prominent. (derivative of ergotamine) B. Worse mental condition/cardiac problems, worsen vasospasm/ulcer.Pulmonary and retroperitoneal fibrosisAction: Similar to levodopaReduce motor fluctuationApomorphine/rotigotine/Pramipexole/ ropiniroleUse: hypom
15、obility “off” phenomenonDelay the need to employ levodopa therapy in early PDDecrease the dose of levodopa in advanced PD. Alleviate the motor deficits in both levodopa-naive patients and patients with advanced PD who are taking levodopa. Rotigotine: used in early stage and once-daily transdermal pa
16、tch that provides even pharmacokinetics over 24 hours inhibitors of the CYP1A2 and to enhance the AUC by 80%. cimetidineincreases its half-life by 40% Fewer Ergotamine-like side effects No peripheral vasospasm worsen, no fibrosis. Side effectsSide effectsMetabolismElimination: renalE. Amantadine Act
17、ion: Increase the release of dopamine, Blockade cholinergic receptors inhibit the NMDA type of glutamate receptors Side effects: restlessness, agitation, confusion, and hallucinations Levodopa amantadine anticholinergics Effective for rigidity and bradykinesiaF. Antimuscarinic agents Adjuvant: Benzt
18、ropine, trihexyphenidyl , procyclidine, biperiden Contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis Adverse effects Pupillary dilation, confusion, hallucination, sinus tachycardia, urinary retention, constipation, and dry mouth Summary Alzheimers disease an irreve
19、rsible, progressive brain disorder that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks.此照片 ，作者: 未知作者，许可证: CC BY-SADrugs Used in Alzheimers Disease Progressive loss of cholinergic neurons(Hippocampus) Cholinergic transmission within the cortex t
20、o the memory loss Improving cholinergic transmission within the CNS or preventing excitotoxic actions resulting from overstimulation of NMDA glutamate receptors in selected brain areas. A. Acetylcholinesterase inhibitors Donepezil, galantamine, rivastigmine, and tacrine Modest reduction in the rate
21、of loss of cognitive functioning Nausea, diarrhea, vomiting, anorexia, tremors, bradycardia, and muscle cramp hepatotoxicity B. NMDA-receptor antagonist Stimulation of glutamate receptors in the CNS appears to be critical for the formation of certain memories Overstimulation are toxic Memantine well
22、 tolerated, with few dose-dependent adverse events. Expected side effects are indistinguishable from the symptoms of AD, such as confusion, agitation, and restlessness, Memantine is often given in combination with an AChE inhibitorComprehension Questions Carbidopa reduces A. dopa-decarboxylase activ
23、ity in the CNS B. The necessary dose of L-dopa to achieve a therapeutic effect C. The severity of L-dopa associated dyskinesias D. The time to onset of L-dopas therapeutic effects Which of the following is the most common limiting adverse effect of L-dopa? A. Depression B. Dyskinesia C. Nausea D. Or
24、thostatic hypotension Entacapone inhibits A. Dopamine D,-receptors B. catechol-o-methyltransferase C. Monoamine oxidase B D. Muscarinic cholinoreceptorsA 66- year-old man comes in to your office for evaluation of a tremor. He has noticed a progressively worsening tremor in his hands for the past 6 m
25、onths. The tremor is worse when he is resting and improves some when he reaches for an object or is using hands. He has also noticed that it is harder to get started” when he stands up to walk. He takes several small, shuffling steps before he can reach his full stride. He has no significant medical history and takes only an aspirin a day. On exam you note that his face is expressionless, he has a pill-rolling type tremor of his hands at rest and has “cogwheel” rigidity of his arms.Questions What is the mechanism of action of L-dopa? Why is L-dopa usually given in combination with carbidopa?
