神经系统药理课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,13 神经系统药理4,13 神经系统药理4,1,Seizure,Epilepsy is not a single entity; it is a family of different recurrent seizure disorders that have in common the sudden, excessive and disorderly discharge of central neurons.,This results in abnormal movement or perceptions that are of short duration but that tend to recur.,Seizure,2,Local excitatory,Abnormal high frequency discharging,Abnormal spreading,Brain malfunction,Accompanied with abnormal EEG,发病率高；,突发性，不可预测；,不可根治，需终身服药,Local excitatory Abnormal hi,3,Classification of epilepsy,Classification of epilepsy,4,International Classification of Epileptic Seizures:,Partial Onset Seizures,（,局限性发作,）,Simple Partial,（,单纯局限性,）,Complex Partial,（,复合性局限性,）,Partial Seizures with secondary generalization,（,局限性发作继发全身强直阵挛性发作,）,Partial seizures with dyscognitive features,Partial seizures without dyscognitive features,International Classification o,5,International Classification of Epileptic Seizures:,Primary Generalized Seizures,Absence (Petit Mal),（,失神性发作,/,小发作,）,Myoclonic,（,肌阵挛性发作,）,Generalized Tonic+Clonic,（,全身强直阵挛性发作,）,http:/www.uwo.ca/cns/resident/pocketbook/pictures/3-hz-s-w.jpg,International Classification o,6,The pathways for seizure propagation in partial seizures and primary generalized seizures,The pathways for seizure propa,7,Origin of a surface epileptic discharge,强直性发作,阵挛性发作,发作后抑制,表面脑电图,细胞外记录,细胞内记录,PDS,：,paroxysmal depolarization shift,阵发性去极化漂移,Origin of a surface epileptic,8,Sodium Influx,Calcium Influx,Chloride Influx,PDS,Surface Spike,K efflux,Seizures are generated by groups of neurons which depolarizing synchronously,Epileptic neurons generate Paroxysmal Depolarizing Shift (,阵发性去极化飘移,PDS),During a PDS, there is the repetitive activation of key,ion channels.,These ion channels represent opportunities to prevent or terminate seizures.,Sodium InfluxCalcium InfluxChl,9,Mechanisms of antiepileptic drugs,Electrophysiological,Inhibiting excessive discharges,Inhibiting spread of discharges,Molecular,Potentiating GABA neuronal functions,Inhibiting excitatory neuronal functions,Modulating Na,+, Ca,2+, K,+, Cl,-,channel fuctions,Mechanisms of antiepileptic dr,10,Molecular targets for anti-seizure drugs at the excitatory,glutamatergic,synapse.,兴奋性,Molecular targets for anti-sei,11,Molecular targets for anti-seizure drugs at the inhibitory,GABAergic,synapse.,抑制性,Molecular targets for anti-sei,12,Antiepileptic,drugs,Focus formation and epileptic attack,Focus shift,Refractory epilepsy,Imbalance of excitation and inhibitory,Na,+,、,Ca,2+,、,NMDA,、,K,+,、,Cl,-,、,GABA,Spreading,AntiepilepticFocus formation a,13,A.,Antiepileptic drugs,Special drugs,Phenytoin Sodium,苯妥英钠,大仑丁,A. Antiepileptic drugsSpecial,14,1.,Pharmacological effects and the mechanism,(1) Effects, Inhibiting spread of,abnormal discharges, Not on the happening of abnormal discharge,A.,Antiepileptic drugs,1. Pharmacological effects and,15,苯妥英钠,苯妥英钠,16,1.,Pharmacological effects and the mechanism,(2) Mechanism, Blocking Na,+,channel in inactive state, Inhibiting L- and N-type Ca,2+,channel,(but not T-type Ca,2+,channel ), Calmodulin kinase activity , Neurotransmitter release (NE, 5-HT, DA etc.), B,lock posttetanic potentiation (PTP) formation,A.,Antiepileptic drugs,1. Pharmacological effects and,17,2.,Clinical uses,(1) Anti-epilepsy,Grand mal, status epilepticus;,Partial seizures (simple and complex);,Ineffective for petit mal (absence seizures),失身小发作,(2) Trigeminal (,三叉神经疼,) and related neuralgia (,神经疼,),(3) Anti-arrhythmia,A.,Antiepileptic drugs,2. Clinical usesA. Antiepilep,18,Larger doses: non-linear kinetics,（, 10,g/ml,）,Half life = 24 hours,Therapeutic range = 10-20 ug/ml,Levels above 20 cause ataxia (,共济失调,) and nystagmus,（,眼球震颤,）,Hepatic metabolism,CYP3A enzyme pathway,CYP3A antagonists will raise phenytoin levels,Necessary to monitor plasma concentrations,Initially linear,Psuedo first order,A.,Antiepileptic drugs,3.,ADME,Larger doses: non-linear kinet,19,神经系统药理课件,20,4.,Adverse effects,(1) Local reactions,GI reactions; gingival hyperplasia,(2) CNS reactions,Particularly in the cerebellum and vestibular systems: nystagmus (,眼球震颤,), ataxia (,共济失调,),etc.,Behavioral changes: confusion, hallucination, coma,(3) Hemological reactions,Megaloblastic anemia (affect the metabolism of folic acid),A.,Antiepileptic drugs,4. Adverse effectsA. Antiepil,21,(4) Allergic reactions,Skin reactions; blood cell abnormality (including thrombocytopenia, agranulocytosis);,hepatic toxicity;,ect.,(5) Skeletal reactions,Osteomalacia (,骨质疏松,) by increase vitamin D metabolism and calcium absorption (inducer),(6) Others,Birth defects,hirsutism, etc,A.,Antiepileptic drugs,A. Antiepileptic drugs,22,5.,Drug interactions,（蛋白结合、代谢）,(1) Increases plasma concentrations of drugs by displacement of plasma protein binding,(salicylates),(2) Drug metabolizing enzyme,inhibitor,decrease the metabolism,of phenytoin,(isoniazid,异烟肼, chloramphenicol,氯霉素,),(3) Drug metabolizing enzyme,inducer,increase the metabolism,of phenytoin,(phenobarbital, carbamazepine),(4) Phenytoin enhances the metabolism of corticosteroids and vitamin D,A.,Antiepileptic drugs,5. Drug interactions（蛋白结合、代谢）A,23,Phenobarbital,苯巴比妥,A.,Antiepileptic drugs,Sedative and hypnotic,effect,Inhibiting both formation and spread of discharges.,Postsynaptic ,Cl,-,influx,Presynaptic ,Ca,2+,influx, neurotransmitter release (NE, ACh, Glu, etc.),Effective for grand mal , status epilepticus, partial simple seizures.,Phenobarbital 苯巴比妥A. Antiep,24,Drugs acting at the chloride channel,Benzodiazepines,Binds to specific receptors,Phenobarbital,Binds to barbiturate specific receptor,Valproate,Decreases GABA degradation in presynaptic terminal,A.,Antiepileptic drugs,苯巴比妥,苯二氮卓类,丙戊酸钠,Drugs acting at the chloride c,25,Block T-type Ca,2+,channel,Block Na,+,-K,+,-ATPase,Inhibit cerebral metabolism and GABA t,ransaminase,Effective for peptit mal,Combined with phenobarbital,Ethosuximide,乙琥胺,A.,Antiepileptic drugs,Block T-type Ca2+ channel Etho,26,Valproate sodium,丙戊酸钠,A.,Antiepileptic drugs,Broad spectrum,Inhibiting spread of discharges but not formation,Increases GABA levels via,inhibiting,GABA t,ransaminase,GABA transport,Glutamate decarboxylase,Inhibit Na,+,and L-type Ca,2+,Enhance K,+,?,GI side effects,Tremor,Hepatitis,Pancreatitis,Serious neural tube and cardiac defects in fetus in 1%,Valproate sodium 丙戊酸钠A. Ant,27,Blocks Na,+,and Ca,2+,channels,Enhance GABA,Effective against psychomotor seizures, and grand mal,Effective for mania, depression, and neuralgia,Like phenytoin, metabolized by CYP3A pathway (an inducer),Need titration up!,Safety and Toxicity,Dose dependence-double vision, ataxia,rash 5-10%,rare marrow suppression,rare hepatitis,frequent hyponatremia/,Water intoxication,(Dose dependence),fetal malformations,Carbamazepine,卡马西平,A.,Antiepileptic drugs,Blocks Na+ and Ca2+ channelsSa,28,Other antiepileptic drugs,Primidone,扑米酮,：,analogues of phenobarbital, used for phenobarbital- and phenytoin-ineffective patients,Mephenytoin,美芬妥英,Ethotoin,乙苯妥英,：,analogues of phenytoin,Diazepam,地西泮,:,status epilepticus (,i.v.,),Nitrozepam,硝西泮,Clonazepam,氯硝西泮,：,peptit mal,Lamotrigine,拉莫三嗪,A.,Antiepileptic drugs,Other antiepileptic drugsA. A,29,Other antiepileptic drugs,Oxarbazepine,（奥卡西平）：,similar as carbamazepine but weaker,Antiepilepsirine,（抗痫灵）,:,broad spectrum, esp.,grand mal,Lamotrigine,拉莫三嗪：,Na,+,channel antagonist. Effective against both partial and generalized epilepsy,Flunarizine,氟桂利嗪,: Inhibit L- and T-type Ca,2+,channel. broad spectrum,Topiramate,托吡酯：,Blocks AMPA+kainate receptors,Also blocks,Na,+,and Ca,2+,channels,A.,Antiepileptic drugs,Other antiepileptic drugsA. A,30,卡马西平,苯妥英钠,丙戊酸钠,拉莫三嗪,卡马西平苯妥英钠丙戊酸钠拉莫三嗪,31,丙戊酸钠,乙琥胺,二甲双酮,丙戊酸钠乙琥胺二甲双酮,32,丙戊酸钠,苯二氮卓类,巴比妥类,丙戊酸钠苯二氮卓类巴比妥类,33,Common toxicity of antiepileptic drugs:,CNS reactions,Hemological reactions,Hepatic toxicity,Teratogenicity,（致畸）,A.,Antiepileptic drugs,Common toxicity of antiepilept,34,Teratogenicity,All AEDs cause fetal malformations in at least 6% of infants.,Highest risk with phenytoin, valproate, phenobarbital, and carbamazepine (Class D drugs),Folate supplementation prevents neural tube defects.,TeratogenicityAll AEDs cause,35,Principals of antiepileptic drug uses,1. Choice of drugs,(1) Grand mal / Partial,：,Phenytoin, Carbamazepine, Phenobarbital,Primidone, Valproate sodium,(2) Peptit mal:,Ethosuximide,Clonazepam, Valproate sodium,(3) Psychomotor,：,Carbamazepine, Phenytoin,(4) Status epilepticus,：,Diazepan (i.v.),Phenytoin (i.v.), Phenobrbital (i.m.),A.,Antiepileptic drugs,Principals of antiepileptic dr,36,2. Dosage,：,small,larger doses;,dose individualization;,plasma concentration monitoring if necessary,3. Usage,：,drug combination,4. Withdrawal,：,gradually and slowly,A.,Antiepileptic drugs,2. Dosage：A. Antiepileptic dr,37,1.,Effects,：,central depression;,vasodilatation, BP,;,relaxing skeletal muscles,2.,Uses,：,convulsion,；,hypertension crisis,3.,Adverse effects,：,depression of respiratory and vasomotor centers, antagonized by calcium preparations (,i.v.,),Magnesium Sulfate,硫酸镁,B.,Anticonvulsant drugs,1. Effects：central depression;,38,Other anticovulsant drugs,Sedative-hypnotic drugs,B.,Anticonvulsant drugs,Other anticovulsant drugsB. A,39,Drugs which primarily affect K,+,channel,Levetiracetam,左乙拉西坦,High Potency-75% reduction in seizures in over 20% of refractory patients,Few side effects except:,Fatigue,Depression and Psychosis,leading to discontinuation in 7%.,W,hite et al Neurology 2003,Drugs which primarily affect K,40,Mechanism -Multiple,Blocks AMPA+kainate receptors,Also blocks sodium and CA channels,Potentiate GABA transmission,Effective against both partial and generalized epilepsy,Excreted primarily in urine,Start at 25 mg/day,titrate to 300-500/day,Behavioral /Cognitive problems common,Low risk of rash,Causes weight loss,Relatively safe, Class C in pregnancy,High Potency, 75% reductions in over 20% of refractory patients,Drugs which affect Kainate and AMPA receptors,Zonisamide,Topiramate,Mechanism -MultipleBehavioral,41,Anti-epileptics (AEDs,),Note: All of the following drugs have multiple mechanisms of action (primary mechanisms include blockade of voltage gated Na,+,channels, enhancement of GABAergic neurotransmission, and inhibition of glutamatergic neurotransmission),Older AEDs,phenytoin,voltage gated,Na,+,channel blocker,carbamazepine,voltage gated,Na,+,channel blocker,valproate/valproic acid,GABA metabolism inhibitor,phenobarbital,allosteric GABA A agonist,Newer AEDs,oxcarbazepine,voltage gated,Na,+,channel blocker,lamotrigine,voltage gated,Na,+,channel blocker,topiramate,glutamate receptor antagonist; voltage gated,Na,+,channel blocker,levetiracetam multiple actions,gabapentin,Ca,2+,channel blocker,zonisamide,glutamate receptor antagonist; Na,+,and T-type Ca,+2+,channel blocker,lorazepam (I.V.) for status epilepticus,allosteric GABA A agonist,inhibition is use-dependent; limits ability of neurons to fire at high frequency. . maintains Na+ channel in inactivated state and slows rate of recovery; no change in spontaneous activity or firing at slow rate),Anti-epileptics (AEDs) inhib,42,A,nti-,E,pileptic,D,rugs Effective as Monotherapy (Single Agent),Partial,(Localization Related),Older AED,s,Phenytoin (,苯妥英钠,),Carbamazepine,（卡马西平）,Valproate,（丙戊酸钠）,Newer AED,s,Oxcarbazepine,（奥卡西平）,Lamotrigine,（拉莫三嗪）,Topiramate,（托吡酯）,French et al Neurology 2004,Bold= new generation AED,Generalized,Valproate,（丙戊酸钠）,(GTC and absence),Topiramate,（托吡酯）,(GTC),Lamotrigine,（拉莫三嗪）,(absence),French et al Neurology 2004,Anti-Epileptic Drugs Effectiv,43,New AED,s effective as,adjunctive,treatment for refractory epilepsy,Partial,Topiramate,Levetiracetam,Pregabalin,Zonisamide,Oxcarbazepine,Lamotrigine,Gabapentin,Tiagabine,Above all have level I, randomized clinical trials, or A or B evidence, AAN guidelines 2004,Generalized,Topiramate,Levetiracetam,Lamotrigine,Data from randomized placebo controlled trials,Drugs in red are generally considered high potency,New AEDs effective as adjunc,44,Increased expression of ABC transport in epilepsy,Transporters,Increased expression of ABC tr,45,耐药癫痫大鼠,P-gp,表达增加,抗癫痫药敏感大鼠,抗癫痫药耐药大鼠,Control,耐药癫痫大鼠,耐药癫痫大鼠P-gp表达增加抗癫痫药敏感大鼠抗癫痫药耐药大鼠,46,P-gp,抑制剂增强抗癫痫药,Oxarbazepine,（,OXC,奥卡西平）,作用及延长癫痫病人入院间隔时间,P-gp,基因敲除及其抑制剂增加脑内抗癫痫药浓度,P-gp抑制剂增强抗癫痫药Oxarbazepine（OXC,47,Contribution of CYPs to drug metabolism,Contribution of CYPs to drug m,48,CYP Enzymes,(from Guengerich 2003),抑制剂,诱导剂,底物,CYP Enzymes(from Guengerich 20,49,AEDs and Hepatic CYP450 Interactions,Valproic acid,CYP2C inhibitor,(inhibits phenobarbital, phenytoin metabolism),Phenytoin,CYP inducer,(3A4 and 2C); metabolized by 2C9,Carbamazepine,CYP inducer,(CYP inducer (3A4 and 2C); metabolized by 3A4. . . induces its own metabolism,Phenobarbital,CYP inducer,(3A4 and 2C),Induction, increase in amount of enzyme protein, resulting in an increase in the rate,of metabolism of the affected drug,Inhibition, competition at the enzyme site that results in a decrease in metabolism,of the affected drug,AEDs and Hepatic CYP450 Intera,50,Drugs Treating Parkinson Disease and Alzheimer Disease,Drugs Treating Parkinson Disea,51,Parkinsons disease (PD),Rigidity,Tremor,Bradyki,ne,sia,Postural instability,(propulsion,retropulsion).,Parkinsons disease (PD)Rigidi,52,Tremor:,one of the common symptoms of PD,Tremor: one of the common symp,53,黑质,-,纹状体通路,中脑,-,边缘,/,皮层通路,结节,-,漏斗通路,Substantia nigro -striatum dopaminergic pathway,is involved in PD pathogenesis,黑质-纹状体通路中脑-边缘/皮层通路结节-漏斗通路Subst,54,Parkinson disease,Dopaminergic neuron degeneration in substantia nigro and striatum,Normal,Parkinson diseaseNormal,55,神经系统药理课件,56,Dopamine,Acetylcholine,Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson disease,Levodopa,Muscarinic antagonists,DopamineAcetylcholineAbnormal,57,Normal,Parkinson disease,(-),injured,relatively potentiated,(-),NormalParkinson disease(-)inju,58,Tyrosine,TH,DOPA,Dopamine Decarboxylase,Dopamine,DBH,Norepinephrine,MAO-B,metabolisms,MAO-A,metabolisms,DA receptors,Treatment I: Increase dopamine,TyrosineTHDOPA Dopamine Decarb,59,Different approaches include:,I. increases in dopamine,synthesis,capacity,II. direct,activation,of post-synaptic,receptors,III. inhibition of dopamine,metabolism,IV. alteration of the interaction/balance with other neurotransmitters,V. dopamine releasers,VI. L-DOPA metabolism inhibitors,What is the desired goal of pharmacological therapies for Parkinsons disease?,Note,: All therapies treat the symptoms of the disease;,none are neuroprotective and none slow the progression of the disease,Different approaches include:,60,Striatal dopamine levels are low,in PD., Dopamine does not pass BBB,and, hence, has no therapeutic effect in PD., L-Dopa, an amino acid, the immediate precursor to dopamine, is transported across BBB and is an effective drug for PD.,Rationale for L-Dopa Precursor Loading:,Levodopa and related drugs,Drugs for treatment of Parkinson disease,(,左旋多巴,),(,多巴胺,),L-dopa is transformed to DA,by dopa decarboxylase (one of the aromatic L-amino acid decarboxylases,AAAD,左旋芳香氨基酸脱羧酶,) in both the brain and peripheral organs., Striatal dopamine levels are,61,L-DOPA peripheral metabolism,L-DOPA peripheral metabolism,62,Levodopa,1. ADME,Penetrating into the brain, transformed to DA or NE (,less,),Distributed in peripheral tissue (,most,),2. Effects and uses,Parkinson disease:,decreases the rigidity, tremors, and other symptoms,3. Adverse effects,Early,(1) GI:,nausea, vomiting,etc,.,(2) CVS:,hypotension, arrhythmia,etc,.,-,(1) CNS:,emotional depression/ psychosis; abnormal involuntary; hallucinations;,etc,.,Late,(1),fluctuation of response: end of dose/“wearing off” periods; on/off periods (sudden loss of symptom control, akinesia),.,(2),dyskinesia (,运动障碍，,after years of chronic L-DOPA, up to 80%, Involuntary movements:,chorea(,舞蹈症,), ballismus(,投掷症,), athetosis(,手足徐动症,), dystonia(,肌张力失常,), my,o,clonus(,肌阵挛,), and tremor,Drugs for treatment of Parkinson disease,LevodopaDrugs for treatment of,63,Carbidopa (,卡比多巴,),a peripheral decarboxylase inhibitor reduces peripheral metabolism of L-DOPA, increases L-DOPA bioavailability, can not cross BBB;,decreases its adverse effects by allowing lower L-DOPA dosages to be used.,The combination of L-DOPA & carbidopa, is called Sinemet,.,(L-DOPA t,1/2, 1.5 h),3-O-methyl- DOPA,Periphery,CNS,L-DOPA,dopamine,BBB,COMT,AAAD,L-DOPA,dopamine,AAAD,MAO,Pyridoxal 5- phosphate,Carbidopa (卡比多巴)3-O-methyl- D,64,Levodopa alone,Levodopa,+,Carbidopa,Levodopa aloneLevodopa,65,Dopamine Synthesis and Storage,Dopamine Synthesis and Storage,66,Without,With COMT Inhibitor,FDOPA -/,+,COMT Inhibitor:,2 FDOPA PET Studies - one individualSame dose of FDOPA, iv; plus carbidopa, po,FDOPA Uptake,Conclusion:,COMT inhibitor increased brain bioavailability of FDOPA by inhibiting peripheral metabolism of FDOPA to 3-O-methyl FDOPA,FDOPA,fluorodopamine,AAAD,COMT,In periphery:,3-O-methylFDOPA,FDOPA,fluorodopamine,AAAD,COMT,WithoutWith COMT InhibitorFDOP,67,一般情况下，对,L-dopa,制剂的反应可分为,3,个阶段：,良好反应阶段（,2,5,年），,为用药的最初阶段，每,6,8,小时或更长时间服药,1,次，可使全部症状得到平稳的缓解或改善。,中间反应阶段（,2,3,年），,此阶段中每次服药仅可引起短时间的症状改善，每个剂量的后期与下一个剂量前，有,1,个药物无作用期，称为,剂末现象,，此外，还可出现,开关现象,和,反常性运动不能,；这种疗效下降与黑质,DA,能神经元逐渐衰退，,DA,合成、贮存进一步下降，及,DA,受体反应能力降低有关。,反应衰退阶段，,对,L-dopa,制剂反应明显下降或根本不起反应；运动困难与致残程度更为严重；同时治疗中的一些不良反应更为明显。,一般情况下，对L-dopa制剂的反应可分为3个阶段：,68,Drugs for treatment of Parkinson disease,Other drugs,1. DA,receptor agonist,s,1,st,generation agonists: (,ergot derivatives,),bromocriptine*,(,溴隐亭,D,2,agonist),(t,1/2, 12 h),pergolide*,(,培高利特,D,2,/D,3,agonist),(t,1/2, 24 h),2,nd,generation agonists:,ropinirole,(t,1/2, 6 h),(,普拉克索,D,2,/D,3,agonist),pramipexole,(t,1/2, 8 -12 h,),(,罗平尼咯,D,2,agonist),Can be used as monotherapy for mild parkinsonism, or combined with levodopa for advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations,.,Drugs for treatment of Parkins,69,Lower incidence of dyskinesia and response fluctuation,Some individuals develop a troubling sleep disorder, with sudden attacks of sleep (,突然昏睡,) during ordinary daytime activities,Postural hypotension,Dose-related psychiatric side effects (similar to L-DOPA but may occur more frequently, especially in elderly),Nausea or vomiting (drugs active at chemotrigger zone (CTZ) ),the major adverse effects of DA receptor agonists,Lower incidence of dyskinesia,70,2. MAO-B,inhibitor,s,（,Peripheral metabolism of catecholamines (mostly MAO-A) is unaffected.,）,decreasing DA metabolism in the CNS,Selegiline,司来吉兰,Rasagiline,雷沙吉兰,3. COMT inhibitors (,decreasing DA metabolism,),CNS,COMT inhibitor:,：,itecapone,硝替卡朋,peripheral COMT inhibitor:,entacapone,恩他卡朋,Drugs for treatment of Parkinson disease,2. MAO-B inhibitors （ Peripher,71,Drugs for treatment of Parkinson disease,4.,Amantadine,金刚烷胺,Used for mild Parkinsons disease, as an early monotherapy,Mechanisms of action may include: release of dopamine, block DA reuptake, actions on glutamate receptors (as an NMDA-receptor antagonist),The dose should be reduced with renal impairment.,Potential adverse effects:,- CNS reactions (dizziness, anxiety, impaired coordination),- hyperkinesias(,运动亢进,),- nausea, vomiting,- others,Drugs for treatment of Parkins,72,Muscarinic antagonists,Trihexyphenidyl (,苯海索,，,artane,安坦,),Benzatropine (,苯扎托品,),Decreasing CNS cholinergic functions,Adjuvant of Parkison disease treatment,Drugs for treatment of Parkinson disease,Muscarinic antagonistsDrugs fo,73,DRUG THERAPY,- Summary,Main Line Agents:,L-DOPA,plus,carbidopa,(,Sinemet,),Dopamine receptor agonists (ropinirole,),Lower Efficacy/Second Line or Adjuvant Agents:,Anticholinergics,