Drugs Affecting the Central Nervous System

中枢神经系统药理

卢韵碧 yunbi@zju.edu.cn

浙江大学医学院药理学系

Neurons and glia in the CNS

SNAREs

GPCR

NT (ligand)-gated Ion Channel

The Synapse

The basic functioning of neurons is similar.

The circuitry of the CNS is much more complex.

The number of synapses in the CNS is far greater.

The CNS contains powerful networks of inhibitory

neurons.

The CNS communicates through the use of multiple

neurotransmitters.

NEUROTRANSMISSION in the CNS

兴奋性神经元 抑制性神经元

谷氨酸能

DA能

5-HT能

NE能

影响神经递质的合成、储存、释放和灭活（如再摄取）；影响神经递质的受体

（突触前、突触后）；影响神经传递和神经元兴奋性，如离子通道调节剂，等。

Hierarchical pathways in the CNS.

ACh NE

DA 5-HT

Diffuse neurotransmitter pathways in the CNS.

中枢神经系统用药的特点

作用于CNS的药物分为两大类：中枢兴奋药和

中枢抑制药；

作用于CNS的药物易产生各种不良反应；

有些药物不是直接作用于神经细胞而产生作用

Classification of CNS drugs

Antipsychotic drugs 抗精神病药 Anti-depression－mania 抗抑郁-躁狂药 Anti-dementia 抗痴呆药

Sedative-hypnotics 镇静催眠药 Anti-epilepsy 抗癫痫药 Anti-convulsion 抗惊厥药 Anti-Parkinson disease 抗帕金森病药 Analgesics 镇痛药 解热镇痛抗炎药 （NSAIDs） 麻醉药（局部、全身）

Neurological（general and special）

Psychological

第一次课的内容

1、中枢神经系统药理简介

2、镇静催眠药★

3、抗癫痫药和抗惊厥药★

4、局部麻醉药

第二次课的内容

1、抗帕金森病药★

2、治疗阿尔茨海默病药

3、抗精神失常药★

1) 抗精神病药

2) 抗躁狂药

3) 抗抑郁药

4) 抗焦虑药

Sedative-Hypnotic Drugs （镇静催眠药）

Anxiolytic and Hypnotic Agents （抗焦虑和催眠药）

Sedatives （镇静药）：

能缓和激动，消除躁动，恢复安静情绪的药物

Hypnotics （催眠药）：

能促进和维持近似生理睡眠的药物

中枢抑制药多数随剂量增加而出现镇静、催眠等中枢抑制作用，故合称为镇静催眠药

（sedative-hypnotics）

-----prescribed to cause sedation (for patients with anxiety)

-----prescribed to encourage sleep (for patients with insomnia)

Sleep histogram shows a normal pattern of sleep in a young adult.

Molecular Neuropharmacology

Stage 3 & 4, 统称为慢波睡眠

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略

Benzodiazepines

(BZ / BDZ, 苯二氮卓类)

Barbiturates (巴比妥类)

Newer nonbenzodiazepine

hypnotics

Others

Sedative-Hypnotic Drugs

艹

1. Pharmacological effects and clinical uses (1) Anxiolytic effects 抗焦虑 at small doses acting on BZ receptor at limbic system（边

缘系统） (2) Sedative-hypnotic effects at relatively larger doses, no anesthetic effect; not remarkably affect on REM used for insomnia （失眠） and pre-anesthetic

medication （麻醉前给药）

A. Benzodiazepines Diazepam 地西泮（安定）

(3) Antiepileptic and anticonvulsant effects（抗癫痫、抗惊厥）

Convulsion due various causes; status epilepticus (i.v.)

(4) Centrally acting muscle relaxant effect（中枢性肌肉松弛作用）

Relaxing the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord.

Used for the treatment of skeletal muscle spasms caused by central or peripheral diseases.

(5) Others Amnesia (短暂性记忆缺失, i.v.） Respiratory （呼吸比较急促的患者） and CVS effects

A. Benzodiazepines

2. Mechanisms of actions (2) Interaction with GABAA receptor Benzodiazepines bind to specific, high affinity sites on the cell

membrane, which are separate from but adjacent to the receptor

for γ-aminobutyric acid (GABA).

The binding of benzodiazepines enhances the affinity of GABA

receptor for this neurotransmitter, resulting in a more frequent

opening of adjacent chloride channels. - coagonist

This in turn results in enhanced hyperpolarization（超极化）and

further inhibition of neuronal firing.

A. Benzodiazepines

2. Mechanisms of actions (2) Interaction with GABAA receptor

Co-agonist

Centrally acting muscle relaxant effect: increasing presynaptic inhibition in the spinal cord

3. Adverse effects (1) Central depression Most common: drowsiness (嗜睡) and confusion

(potentiated by ethanol or other central depressants).

Ataxia (共济失调); cognitive impairment (认知障碍)

Antagonized by BZ receptor antagonist

flumazenil（氟马西尼）

A. Benzodiazepines

3. Adverse effects

(2) Tolerance （耐受） Dependence（依赖） Withdrawal syndrome: 戒断综合征 central excitation 短期、间断用药

A. Benzodiazepines

(3) Others local pain, respiratory and

CVS reactions (i.v.); teratogenic effects（致畸效应）

(4) Contraindications Myasthenia gravis（重症肌无力） Infants < 6 months Pregnancy and lactation mothers Elderly, heart/lung/liver/kidney

dysfunction

A. Benzodiazepines

有镇静作用的药物安全性

氯氮卓

A. Benzodiazepines Other benzodiazepines

According to the metabolisms

三唑仑 奥沙西泮

地西泮 氟西泮

夸西泮

劳拉西泮 阿普唑仑

B. Benzodiazepines Phenobarbital 苯巴比妥

1. ADME Inducing hepatic enzymes（诱导肝药酶）

Alkalining urine: excretion ↑

脂溶性高，血浆蛋白结合率高；

苯巴比妥脂溶性低，不易在肝脏代谢;

硫喷妥钠脂溶性极高，故易通过BBB，易发生再分布。

B. Barbiturates

2. Pharmacological effects and clinical uses

(1) Sedative-hypnotic effects 可缩短REM，反跳明显； (2) Preanesthetic medication (3) Antiepileptic and anticonvulsant effects

B. Barbiturates

3. Adverse effects

(1) Central depression: including residual effect (后遗效应，hangover “宿醉”)

(2) Tolerance and dependence: long-term uses

(3) Acute poisoning supporting therapies alkalizing urine hemodialysis

B. Barbiturates

C. Newer nonbenzodiazepine hypnotics

唑吡坦

扎来普隆

Chloral hydrate 水合氯醛 Sedative-hypnotic effects Anticonvulsant effect: usually used in children

Meprobamate 甲丙氨酯（眠尔通）

Methaqualone 安眠酮

Buspirone 丁螺环酮，抗焦虑，但无镇静作用，激

动突触前5-HT1A受体，反馈抑制5-HT释放而产生抗焦虑作用。

D. Others

阿普唑仑 丁螺环酯

Antihistamines 抗组胺药 （H1 受体阻断药）

Ethanol 乙醇

Melatonin 褪黑素

D. Others

略

Antiepileptic drugs and anticonvulsant drugs

抗癫痫药和抗惊厥药

Key facts Epilepsy is a chronic disorder of the brain that affects people of all ages.

Approximately 50 million people worldwide have epilepsy, making it one of

the most common neurological diseases globally.

Nearly 80% of the people with epilepsy live in low- and middle-income

countries.

People with epilepsy respond to treatment approximately 70% of the time.

Epilepsy is a chronic disorder of the brain.

It is characterized by recurrent seizures, which are brief episodes of

involuntary movement that may involve a part of the body (partial) or the entire

body (generalized)

The recurrent seizures are sometimes accompanied by loss of consciousness

and control of bowel or bladder function.

One seizure does not signify epilepsy (up to 10% of people worldwide have

one seizure during their lifetime). Epilepsy is defined as having 2 or more

unprovoked seizures.

Causes: idiopathic epilepsy 6/10, secondary epilepsy

Epilepsy

Seizure episodes are a result of

excessive electrical discharges in a

group of brain cells.

Different parts of the brain can be

the site of such discharges.

Seizures can vary from the

briefest lapses of attention or muscle

jerks to severe and prolonged

convulsions.

Seizures can also vary in

frequency, from less than 1 per year

to several per day.

Seizure

强直-阵挛性发作(大发作) 失神性发作(小发作) 肌阵挛性发作

失张力发作

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

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

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International Classification of Epileptic Seizures: Primary Generalized Seizures

原发性全身性发作

– Absence (Petit Mal) （失神性发作/小发作）

– Myoclonic （肌阵挛性发作）

– Generalized

Tonic+Clonic （强直阵挛性发作）

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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

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 (阵发性去极化漂移, PDS)

• During a PDS, there is the repetitive activation of key ion channels.

• These ion channels represent opportunities to prevent or terminate seizures.

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

functions

Molecular targets for anti-seizure drugs at the excitatory, glutamatergic synapse.

兴奋性

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Molecular targets for anti-seizure drugs at the inhibitory, GABAergic synapse.

抑制性

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Antiepileptic drugs

Focus formation and epileptic attack

Focus shift

Refractory epilepsy

Imbalance of excitation and inhibitory Na+、Ca2+、NMDA 、K+ 、Cl-、GABA

Spreading

A. Antiepileptic drugs

Special drugs

Phenytoin Sodium 苯妥英钠, 大仑丁

1. Pharmacological effects and the mechanism

(1) Effects

— Inhibiting spread of abnormal discharges — Not on the happening of abnormal

discharge

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

1. Pharmacological effects and the mechanism

(2) Mechanism — Block posttetanic potentiation (PTP) formation

— 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..)

A. Antiepileptic drugs

2. Clinical uses (1) Anti-epilepsy Grand mal, status epilepticus; Partial seizures (simple and complex); Ineffective for petit mal (absence seizures) 失神小发作 (2) Trigeminal (三叉神经疼) and related

neuralgia (神经疼) (3) Anti-arrhythmia

A. Antiepileptic drugs

Larger doses: non-linear kinetics（> 10 µg/ml）

Half life = 24 hours Levels above 20 µg/ml

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

A. Antiepileptic drugs 3. ADME

therapeutic range

4. Adverse effects

(1) Local reactions GI reactions; gingival hyperplasia(齿龈增生)

(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 Skin reactions; blood cell abnormality (including

thrombocytopenia, agranulocytosis); hepatic toxicity; etc.

(5) Skeletal reactions Osteomalacia (骨质疏松) by increase vitamin D metabolism and

calcium absorption (inducer)

(6) Others Birth defects, hirsutism(多毛症), 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) 竞争血浆蛋白结合

(2) Drug metabolizing enzyme inhibitor decrease the metabolism of phenytoin (isoniazid异烟肼, chloramphenicol氯霉素) 抑制代谢

(3) Drug metabolizing enzyme inducer increase the metabolism of phenytoin (phenobarbital, carbamazepine) 加快代谢

(4) Phenytoin enhances the metabolism of corticosteroids and vitamin D

A. Antiepileptic drugs

• Blocks Na+ and Ca2+ channels

• Enhance GABA

• Broad spectrum，effective against psychomotor seizures, and grand mal

• Effective for mania(躁狂), depression(抑郁), and neuralgia(神经痛)

• 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(骨髓抑制)

– rare hepatitis

– frequent hyponatremia/Water intoxication (Dose dependence)

– fetal malformations（致畸）

Carbamazepine 卡马西平

A. Antiepileptic drugs N

CONH2

Phenobarbital 苯巴比妥

A. Antiepileptic drugs

Postsynaptic ↑Cl- influx

Presynaptic ↓ Ca2+ influx → ↓ neurotransmitter release (NE, ACh, Glu, etc.)

Effective for grand mal , status epilepticus, partial simple seizures.

Sedative and hypnotic effect Inhibiting excessive discharges Inhibiting spread of discharges

Block T-type Ca2+ channel Block Na+-K+-ATPase Inhibit cerebral metabolism and GABA

transaminase Effective for peptit mal（失神小发作）

Ethosuximide 乙琥胺

A. Antiepileptic drugs

Valproate sodium 丙戊酸钠

A. Antiepileptic drugs

Inhibiting spread of discharges but not formation

Increases GABA levels via

↓ GABA transaminase, GABA transporter, ↑Glutamate decarboxylase → GABA ↑

Inhibit Na+ and T-type Ca2+

Enhance K+ ?

Broad spectrum（广谱抗癫痫药）

GI side effects Tremor Hepatitis Pancreatitis Serious neural tube and

cardiac defects in fetus in 1%

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

A. Antiepileptic drugs

Other antiepileptic drugs Lamotrigine 拉莫三嗪： Na+ channel antagonist. Effective against

both partial and generalized epilepsy

Topiramate托吡酯： Blocks AMPA+kainate receptors Also blocks Na+ and Ca2+ channels

Oxarbazepine（奥卡西平）：similar as carbamazepine but weaker

Flunarizine 氟桂利嗪: Inhibit L- and T-type Ca2+ channel. broad spectrum

A. Antiepileptic drugs

Common toxicity of antiepileptic drugs: CNS reactions

Hemological reactions

Hepatic toxicity

Teratogenicity（致畸）

A. Antiepileptic drugs

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

Principals of antiepileptic drug uses 1. Choice of drugs

(1) Grand mal / Partial： Phenytoin, Carbamazepine, Phenobarbital Primidone, Valproate sodium (2) Peptit mal: Ethosuximide Clonazepam(氯硝西泮), 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

A. Antiepileptic drugs

1. Effects （im., i.v.gtt） 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. 抗惊厥药

Local Anesthetics

(局麻药)

Local Anesthetics (局麻药，LAs)

• Definition: drugs that cause loss of sensation without loss of consciousness • Reversibly block nerve conduction(可逆阻断) • Act on every type of nerve fiber (无选择性) • No structural damage to the nerve cell(无结构

破坏) • Also act on cardiac muscle, skeletal muscle

and the brain

1. Structural Classes: Esters (酯类) and Amides（酰胺类）

酯键

酰胺键

可卡因

普鲁卡因

丁卡因

苯佐卡因

all are weak bases BH+ B + H+

Structural Classes: Esters (酯类) and Amides（酰胺类）

芳香族环 酯键

胺基团

利多卡因

甲哌卡因

布比卡因

依替卡因

丙胺卡因

芳香族环 酰胺键 胺基团

• Ionic gradient and resting membrane potential are unchanged

• Decrease the amplitude of the action potential • Slow the rate of depolarization • Increase the firing threshold • Slow impulse conduction • Prolong the refractory period

2. Pharmacological effects

神经纤维末梢、神经节、中枢

神经系统的突触对局麻药较为

敏感；

细的比粗的神经纤维敏感；

钝痛比锐痛敏感；

2. Pharmacological effects

• LAs blocks action potential generation by blocking voltage-gated Na+ channels.

3. Action mechanism

Onset and duration of action • The ionized form interacts with the Na+ channels to

inhibit its function and, thereby, achieve local anesthesia.

• pH of the tissue • pKa of the drug • lipid solubility

Use-dependent Blockade (使用依赖性/频率依赖性)

4. Modes of Administration • Topical local (surface) anesthesia(表面麻醉): for eye, ear,

nose, and throat procedures and for cosmetic surgery

• Infiltration anesthesia (浸润麻醉): local injection around the region to be operated 手术野或皮下局部注射

• Conduction anesthesia (传导麻醉): local injection around the peripheral nerve trunk 外周神经干附近局部注射

• Epidural anesthesia (硬膜外麻醉): local injection into the epidural space 将药液注入硬膜外腔，阻断神经根

• Subarachnoid anesthesia (蛛网膜下腔麻醉): or Spinal anesthesia (脊髓麻醉，腰麻): local injection into the cerebrospinal fluid in subarachnoid cavity 注入腰椎蛛网膜下腔，麻醉该部位神

经根

• Regional analgesia (区域镇痛) 神经阻滞技术

5. Uses of local anesthesia

• Topical local (surface) anesthesia(表面麻醉): 丁卡因 • Infiltration anesthesia (浸润麻醉): 利多卡因，普鲁卡因 • Conduction anesthesia (传导麻醉):利多卡因，普鲁卡因，

布比卡因 • Epidural ansthesia (硬膜外麻醉):利多卡因，布比卡因，罗

哌卡因 • Subarachnoid anesthesia (蛛网膜下腔麻醉): or Spinal

anesthesia (脊髓麻醉，腰麻):利多卡因，普鲁卡因，丁卡

因 • Regional analgesia (区域镇痛)：布比卡因，罗哌卡因

骶管阻滞

蛛网膜下腔

硬膜外阻滞

椎旁阻滞 脊神经阻滞

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1) CNS Toxicity

Correlation between potency and seizure threshold

– Bupivacaine

• 2 ug/ml

– Lidocaine • 10 ug/ml

布比卡因

利多卡因

6. Adverse effects

2) Cardiovascular Toxicity • Attributable to their direct effect on cardiac muscle

• Contractility

– Negative inotropic (负性肌力) effect that is dose-related and correlates with potency

– Interference with calcium signaling mechanisms

• Automaticity

– Negative chronotropic (负性频率) effect

• Rhythmicity and Conductivity – Ventricular arrhythmias

3) Allergic reactions Esters > Amides

Absorption (injected or topical) - affected by vascularity (血供) - presence of additional vasoconstrictor (血管收缩剂)

- Duration prolonged by vasoconstrictor (epinephrine)

- localizes agent to site of action

- contraindicated in extremities(末梢部位)

- Systemic Toxic Effects: CNS, cardiovascular

7. Pharmacokinetics

• Alpha phase (快速吸收相) – rapidly redistributed to well-perfused tissues

• Beta phase (再分布相) – distribution to less perfused or slowly equilibrating tissues

• Gamma phase (消除相) – clearance representing metabolism and excretion

Distribution - LAs bind in the blood to a1-glycoprotein and albumin

7. Pharmacokinetics

Lidocaine（利多卡因）

• One of the most widely used local anesthetics

• Rapid onset, medium duration

• available in ointment（软膏）, jelly（凝胶）, and aerosol（喷雾剂）

• Other uses: anti-arrhythmic