Antiepileptic and Anticonvulsant Drugs 张纬萍 Dept. of Pharmacology, School of Medicine, Zhejiang University weiping601@zju.edu.cn

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.

Local excitatory  Abnormal high frequency discharging 发病率高； 突发性，不可预测； 不可根治，需终身服药 Abnormal spreading Brain malfunction Accompanied with abnormal EEG

Classification of epilepsy

Simple Partial（单纯局限性） Complex Partial （复合性局限性） 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 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

The pathways for seizure propagation in partial seizures and primary generalized seizures

Origin of a surface epileptic discharge 强直性发作 阵挛性发作 表面脑电图 发作后抑制 The extracellular recording was made through a high-pass filter. Note the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal depolarization shift (PDS). (Modified with permission from Ayala et al., 1973.) 细胞外记录 细胞内记录 PDS：paroxysmal depolarization shift 阵发性去极化漂移

During a PDS, there is the repetitive activation of key ion channels. 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. Surface Spike PDS Sodium Influx Calcium Influx Chloride Influx K efflux A paroxysmal depolarizing shift (PDS) is a cellular manifestation of epilepsy. First, there is a Ca2+ mediated depolarization, which causes voltage gated Na+ to open, resulting in action potentials. This depolarization is followed by a period of hyper-polarization mediated by Ca2+-dependent K+ channels or GABA-activated Cl- influx.

Mechanisms of antiepileptic drugs Electrophysiological Inhibiting excessive discharges Inhibiting spread of discharges Molecular Potentiating GABA neuronal functions Inhibiting excitatory neuronal functions Modulating Na+, Ca2+, K+, Cl- channel fuctions

兴奋性 Molecular targets for anti-seizure drugs at the excitatory, glutamatergic synapse. Molecular targets for antiseizure drugs at the excitatory, glutamatergic synapse. Presynaptic targets diminishing glutamate release include 1, voltage-gated (VG) Na+ channels (phenytoin, carbamazepine, lamotrigine, and lacosamide); 2, VG-Ca2+ channels (ethosuximide, lamotrigine, gabapentin, and pregabalin); 3,K+ channels (retigabine); synaptic vesicle proteins, 4, SV2A (levetiracetam); and 5, CRMP-2, collapsin-response mediator protein-2 (lacosamide). Postsynaptic targets include 6, AMPA receptors (blocked by phenobarbital, topiramate, and lamotrigine) and 7, NMDA receptors (blocked by felbamate). EAAT, excitatory amino acid transporter. Red dots represent glutamate.

抑制性 Molecular targets for anti-seizure drugs at the inhibitory, GABAergic synapse. Molecular targets for antiseizure drugs at the inhibitory, GABAergic synapse. These include "specific" targets: 1, GABA transporters (especially GAT-1, tiagabine); 2, GABA-transaminase (GABA-T, vigabatrin); 3, GABAA receptors (benzodiazepines); and potentially, 4, GABAB receptors. Effects may also be mediated by "nonspecific" targets such as by voltage-gated (VG) ion channels and synaptic proteins. IPSP, inhibitory postsynaptic potential. Blue dots represent GABA.

Refractory epilepsy Antiepileptic drugs Focus shift Spreading Imbalance of excitation and inhibitory Na+、Ca2+、NMDA 、K+ 、Cl-、GABA Antiepileptic drugs Focus formation and epileptic attack Focus shift Spreading Refractory epilepsy

Phenytoin Sodium 苯妥英钠, 大仑丁 A. Antiepileptic drugs Special drugs Phenytoin Sodium 苯妥英钠, 大仑丁

A. Antiepileptic drugs 1. Pharmacological effects and the mechanism — Inhibiting spread of abnormal discharges — Not on the happening of abnormal discharge “but not T-type Ca2+ channel”可能与治疗失神发作无效有关；

苯妥英钠

A. Antiepileptic drugs 1. Pharmacological effects and the mechanism — Blocking Na+ channel in inactive state — Inhibiting L- and N-type Ca2+ channel (but not T-type Ca2+ channel ) —  Calmodulin kinase activity   Neurotransmitter release (NE, 5-HT, DA etc.) — Block posttetanic potentiation (PTP) formation “but not T-type Ca2+ channel”可能与治疗失神发作无效有关； posttetanic potentiation (PTP)：突触传递的强直后增强，指反复高频电刺激突触前神经纤维后，引起突触传递易化，使突触后纤维反应增强的现象。

A. Antiepileptic drugs 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 3. ADME 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 呈碱性，有刺激性，不宜肌注，口服吸收不规则，剂型、颗粒大小及添加剂均可影响吸收的速率和程度，血浆蛋白结合率高达85-90%，经肝脏羟化再加葡萄糖醛酸结合后经肾脏排出

Nonlinear relationship of phenytoin dosage and plasma concentrations Nonlinear relationship of phenytoin dosage and plasma concentrations. Five patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage.

A. Antiepileptic drugs 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) Allergic reactions (5) Skeletal 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 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 Phenobarbital 苯巴比妥 Sedative and hypnotic effect Inhibiting both formation and spread of discharges. Postsynaptic Cl- influx Presynaptic  Ca2+ influx   neurotransmitter release (NE, ACh, Glu, etc.) Effective for grand mal , status epilepticus, partial simple seizures. Cl- influx (突触前) and  Ca2+ influx（突触后，导致NE、Ach和谷氨酸释放减少） 对小发作和婴儿痉挛效果差 起效快，疗效好，价格低、毒性低（嗜睡、精神萎靡、共济失调，偶见巨幼细胞贫血、血小板减少、白细胞减少等）

Drugs acting at the chloride channel A. Antiepileptic drugs Drugs acting at the chloride channel Benzodiazepines Binds to specific receptors Phenobarbital Binds to barbiturate specific receptor Valproate Decreases GABA degradation in presynaptic terminal 苯二氮卓类 苯巴比妥 丙戊酸钠

A. Antiepileptic drugs Ethosuximide 乙琥胺 Block T-type Ca2+ channel Block Na+-K+-ATPase Inhibit cerebral metabolism and GABA transaminase Effective for peptit mal Combined with phenobarbital T-type Ca2+ channel电流 被认为是丘脑神经元的起搏电流，导致失神发作中产生有节律的皮层放电，抑制磁电流可用以解释乙琥胺特殊的治疗作用。 疗效不及氯硝西泮，但副作用及耐受性的产生较少，故为小发作首选。 GI responses， CNS（头疼、头晕、嗜睡等）、精神异常（精神病史患者）、贫血、可导致癫痫大发作。

A. Antiepileptic drugs Valproate sodium 丙戊酸钠 Broad spectrum Inhibiting spread of discharges but not formation Increases GABA levels via inhibiting GABA transaminase, GABA transport, Glutamate decarboxylase Inhibit Na+ and L-type Ca2+ Enhance K+ ? GI side effects Tremor Hepatitis Pancreatitis Serious neural tube and cardiac defects in fetus in 1% GABA合成增加，抑制降解、摄取，增强对GABA的反应性 对小发作的作用优于乙琥胺，但由于其肝脏毒性作用，不做首选。

A. Antiepileptic drugs Carbamazepine 卡马西平 Blocks Na+ and Ca2+ 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 Rash、marrow suppression为特异质反应

Other antiepileptic drugs A. Antiepileptic drugs 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 扑米酮：体内转化为苯巴比妥和苯乙基丙二酰胺，用药期间定期查血象，肝肾功能不全者禁用； 美芬妥英：体内容易蓄积、不良反应重，仅用于其他药物不能控制的患者。 乙苯妥英钠：作用和毒性均弱，仅用于辅助用药。 氯硝西泮:对小发作的疗效较地西泮强

Other antiepileptic drugs A. Antiepileptic drugs 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 Ca2+ channel. broad spectrum Topiramate托吡酯： Blocks AMPA+kainate receptors Also blocks Na+ and Ca2+ channels 奥卡西平：过敏反应少，对肝药酶的诱导作用弱。 抗痫灵：桂皮酰胺类药，系我国合成的抗癫痫药物，厌食、恶心头晕嗜睡等，无肝毒性、造血系统损伤； 氟桂利嗪:对电惊厥引起的癫痫有效，但对戊四唑引起的癫痫无效，安全，主要有困倦、镇静、体重增加

卡马西平 拉莫三嗪 丙戊酸钠 苯妥英钠

丙戊酸钠 二甲双酮 乙琥胺

丙戊酸钠 苯二氮卓类 巴比妥类

A. Antiepileptic drugs Common toxicity of antiepileptic drugs: CNS reactions Hemological reactions Hepatic toxicity Teratogenicity（致畸）

Teratogenicity All AED's 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.

A. Antiepileptic drugs 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 2. Dosage： small  larger doses; dose individualization; plasma concentration monitoring if necessary 3. Usage： drug combination 4. Withdrawal：gradually and slowly

B. Anticonvulsant drugs Magnesium Sulfate 硫酸镁 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.)

B. Anticonvulsant drugs Other anticovulsant drugs Sedative-hypnotic drugs

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%. White et al Neurology 2003

Topiramate Zonisamide Drugs which affect Kainate and AMPA receptors 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 Zonisamide

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 AED’s phenytoin voltage gated Na+ channel blocker carbamazepine voltage gated Na+ channel blocker valproate/valproic acid GABA metabolism inhibitor phenobarbital allosteric GABA A agonist Newer AED’s 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 Ca2+ 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-Epileptic Drug’s 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

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

Increased expression of ABC transport in epilepsy Transporters

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

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, 奥卡西平）作用及延长癫痫病人入院间隔时间

Contribution of CYPs to drug metabolism

CYP Enzymes 底物 抑制剂 诱导剂 (from Guengerich 2003)

AEDs and Hepatic CYP450 Interactions 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 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)

Drugs Treating Parkinson Disease and Alzheimer Disease

Parkinson’s disease (PD) Rigidity Tremor Bradykinesia Postural instability (propulsion, retropulsion).

Tremor: one of the common symptoms of PD

黑质-纹状体通路 结节-漏斗通路 中脑-边缘/皮层通路 Substantia nigro -striatum dopaminergic pathway is involved in PD pathogenesis 中脑-边缘/皮层通路

Parkinson disease Dopaminergic neuron degeneration in substantia nigro and striatum Normal

Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson disease Acetylcholine Muscarinic antagonists Levodopa Dopamine

Normal (-) Parkinson disease relatively potentiated injured (-) 

Treatment I: Increase dopamine Tyrosine TH DOPA Dopamine Decarboxylase MAO-B DA receptors Dopamine metabolisms DBH MAO-A Norepinephrine metabolisms

What is the desired goal of pharmacological therapies for Parkinson’s disease? 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 Note: All therapies treat the symptoms of the disease; none are neuroprotective and none slow the progression of the disease

Drugs for treatment of Parkinson disease Levodopa and related drugs Rationale for L-Dopa Precursor Loading: • 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. (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.

L-DOPA peripheral metabolism

Drugs for treatment of Parkinson disease 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), myoclonus(肌阵挛), and tremor

Periphery CNS 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 t1/2 ~ 1.5 h) BBB Periphery CNS L-DOPA L-DOPA 3-O-methyl- DOPA COMT AAAD AAAD Pyridoxal 5- phosphate dopamine dopamine MAO

Levodopa alone Levodopa + Carbidopa

Dopamine Synthesis and Storage

FDOPA -/+ COMT Inhibitor: 2 FDOPA PET Studies - one individual Same dose of FDOPA, iv; plus carbidopa, po FDOPA Uptake Without With COMT Inhibitor Conclusion: COMT inhibitor increased brain bioavailability of FDOPA by inhibiting peripheral metabolism of FDOPA to 3-O-methyl FDOPA In periphery: 3-O-methylFDOPA FDOPA fluorodopamine AAAD COMT AAAD COMT fluorodopamine FDOPA

一般情况下，对L-dopa制剂的反应可分为3个阶段： ①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。 ②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。 ③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。

Drugs for treatment of Parkinson disease Other drugs 1. DA receptor agonists 1st generation agonists: (ergot derivatives) bromocriptine* (溴隐亭, D2 agonist) (t1/2 ~ 12 h) pergolide* (培高利特, D2/D3 agonist)(t1/2 ~ 24 h) 2nd generation agonists: ropinirole (t1/2 ~ 6 h) (普拉克索, D2/D3 agonist) pramipexole (t1/2 ~ 8 -12 h) (罗平尼咯, D2 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. 治疗初期即可使用，较少引发由于长期运用左旋多巴治疗所致的病情反复与运动障碍。 用左旋多巴无效的患者应用多巴胺激动剂. 溴隐亭:不良反应多 普拉克索：与左旋多巴联合用于PD重症治疗

the major adverse effects of DA receptor agonists 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) )

Drugs for treatment of Parkinson disease 2. MAO-B inhibitors （ 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 4. Amantadine 金刚烷胺 Used for mild Parkinson’s 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 Parkinson disease Muscarinic antagonists Trihexyphenidyl (苯海索，artane, 安坦) Benzatropine (苯扎托品) Decreasing CNS cholinergic functions Adjuvant of Parkison disease treatment

DRUG THERAPY - Summary Main Line Agents: L-DOPA plus carbidopa (Sinemet®) Dopamine receptor agonists (ropinirole) • Lower Efficacy/Second Line or Adjuvant Agents: Anticholinergics Reuptake Inhibitor or releaser (amantadine) COMT Inhibitor (entacapone) MAO B Inhibitors (rasagiline, selegiline)

Drug-Induced Parkinsonism • Reserpine, which depletes brain catecholamines, induces Parkinson’s disease symptoms • Antipsychotics (neuroleptics), that block DA receptors, ie, dopamine receptor antagonists. • N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) is a by-product of illicit synthesis of isomeperidine. MPTP first came to medical attention because it produced symptoms similar to Parkinson’s disease.

Drugs for treatment of dementia (Alzheimer and related diseases) Anticholinesterase drugs Cholinoceptor agonists Neurotrophic factor-like drugs

Pathological characteristics of AD Atrophy of the brain

Senile plaques Neurofibrillary tangles

Senile plaques and neurofibrillary tangles

Regions related to neuronal injury Importance of ACh system Regions related to neuronal injury

Pathophysiologic Hypothesis of AD Glutamate -Amyloid Excitotoxicity Neurofibrillary Tangles Mitochondrial Dysfunction Inflammation Other Factors Cell Damage/ Loss (ACh deficit) Dementia

Normal Cholinergic Function Acetyl CoA Glial cell BuChE Presynaptic neuron + Choline Choline ChAT ACh MR NR Synaptic cleft ACh Choline ACh + AChE Postsynaptic neuron Acetate AChE MR NR ACh = acetylcholine; AChE = acetylcholinesterase; BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor. Adapted from Adem, 1992.

Drugs for treatment of dementia Anticholinesterase drugs Tarcrine 他克林: Easy to pass BBB; Decrease AChE 70%; activate M and N receptors (especially M receptor); Enhance the release of ACh (throught M receptor). Induce hepatic toxicity. Galantamine 加兰他敏: similar to tarcrine, except without hepatic toxicity and high specific to neuron AChE. Huperzine 哈伯因（石杉碱甲）: a high selective AChE inhibitor; improve memory and recognization. Metrifonate 美曲磷脂: the first AChE inhibitor; Increase central DA and NE; Decrease the red blood cell AChE 52%.

Drugs for treatment of dementia Cholinoceptor agonists Xanomeline 占诺美林: selective to M1 receptor; high concentration in cortex and striatum; Has GI and CVS side effects. Sabcomedine hydrochloride: selective to M1 receptor; safe. Neurotrophic factor enhancer AIT 082: increase the release of neurotrophins in injured neurons ALCAR（盐酸乙酰L肉碱）: protect synapse and increase nurotrophins Propentofylline 丙戊茶碱: inhibit adrenaline reuptake and cAMP metabolize; neuroprotective effects;

Pathophysiologic Hypothesis of AD Glutamate -Amyloid Excitotoxicity Neurofibrillary Tangles Future treatment K+channel blocker Glutamate receptor regulator 5-HT receptor blocker Cell Damage/ Loss (ACh deficit) Mitochondrial Dysfunction Inflammation Other Factors Dementia

See you next class!