神经系统药理 3 1 、抗癫痫药 2 、抗帕金森病药及抗老年性痴呆药 3 2...

神经系统药理 3

1 、抗癫痫药

22 、抗帕金森病药及抗老年性痴呆药、抗帕金森病药及抗老年性痴呆药

33 、抗精神病药和抗抑郁药4 、局部麻醉药

2014.10.13

张纬萍[email protected]

药理学系

Antiepileptic and Anticonvulsant Antiepileptic and Anticonvulsant DrugsDrugs

抗癫痫及抗惊厥药抗癫痫及抗惊厥药

Local excitatory

Abnormal high frequency discharging

Abnormal spreading

Brain malfunctionAccompanied with abnormal EEG

发病率高；

突发性，不可预测；

不可根治，需终身服药

Classification of epilepsyClassification of epilepsy

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

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 InfluxCalcium 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.

Mechanisms of antiepileptic drugsMechanisms of antiepileptic drugs

ElectrophysiologicalElectrophysiological Inhibiting excessive dischargesInhibiting excessive discharges Inhibiting spread of dischargesInhibiting spread of discharges

MolecularMolecular Potentiating GABA neuronal functionsPotentiating GABA neuronal functions Inhibiting excitatory neuronal functionsInhibiting excitatory neuronal functions Modulating NaModulating Na++, Ca, Ca2+2+, K, K++, Cl, Cl- - channel fuctichannel fucti

onsons

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

兴奋性

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

抑制性

AntiepilepticAntiepilepticdrugsdrugs

Focus formation and epileptic attackFocus formation and epileptic attack

Focus shiftFocus shift

Refractory epilepsyRefractory epilepsy

Imbalance of excitation and inhibitoryImbalance of excitation and inhibitory NaNa++ 、、 CaCa2+2+ 、、 NMDANMDA 、、 KK+ + 、、 ClCl-- 、、 GABAGABA

SpreadingSpreading

1. 1. Pharmacological effects and the mechanismPharmacological effects and the mechanism

(1) Effects(1) Effects

— — Inhibiting Inhibiting spreadspread of of abnormal discharges abnormal discharges

— — Not on the happening of abnormal dischargeNot on the happening of abnormal discharge

A.A. Antiepileptic drugsAntiepileptic drugs

Phenytoin Sodium Phenytoin Sodium 苯妥英钠苯妥英钠 , , 大仑大仑丁丁

苯妥英钠苯妥英钠

1. Pharmacological effects and the mechanism

(2) Mechanism

— Blocking Na+ channel in inactive state

— Inhibiting L- and N-type Ca2+ channel

(but not T-type Ca2+ channel ，失神发作无效失神发作无效 )

— Calmodulin kinase activity

Neurotransmitter release (NE, 5-HT, DA etc.)

— Block post-tetanic potentiation (PTP) formation


2. Clinical uses

(1) Anti-epilepsyGrand 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


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 linearPsuedo first order

A.A. Antiepileptic drugsAntiepileptic drugs3. 3. ADMEADME

4. 4. Adverse effectsAdverse effects

(1) Local reactions(1) Local reactions GI reactions; gingival hyperplasiaGI reactions; gingival hyperplasia

(2) CNS reactions(2) CNS reactions Particularly in the cerebellum and vestibular systems: Particularly in the cerebellum and vestibular systems:

nystagmus (nystagmus ( 眼球震颤眼球震颤 ), ataxia (), ataxia ( 共济失调共济失调 ), ), etc.etc.

Behavioral changes: confusion, hallucination, comaBehavioral changes: confusion, hallucination, coma

(3) Hemological reactions(3) Hemological reactions Megaloblastic anemia (affect the metabolism of folic Megaloblastic anemia (affect the metabolism of folic

acid)acid)


(4) Allergic reactions(4) Allergic reactions Skin reactions; blood cell abnormality (including Skin reactions; blood cell abnormality (including

thrombocytopenia, agranulocytosis);thrombocytopenia, agranulocytosis); hepatic toxicity; hepatic toxicity; ect.ect.

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

metabolism and calcium absorption (inducer)metabolism and calcium absorption (inducer)

(6) Others(6) Others Birth defects, Birth defects, hirsutismhirsutism （多毛）（多毛） , etc, etc


5.5. Drug interactions Drug interactions （蛋白结合、代谢）（蛋白结合、代谢）

(1) Increases plasma concentrations of drugs by (1) Increases plasma concentrations of drugs by displacement of plasma protein binding displacement of plasma protein binding (salicylates)(salicylates)

(2) Drug metabolizing enzyme (2) Drug metabolizing enzyme inhibitorinhibitor decrease the decrease the metabolismmetabolism of phenytoin of phenytoin (isoniazid(isoniazid 异烟肼异烟肼 , , chloramphenicolchloramphenicol 氯霉素氯霉素 ))

(3) Drug metabolizing enzyme (3) Drug metabolizing enzyme inducer inducer increase the increase the metabolismmetabolism of phenytoin of phenytoin (phenobarbital, (phenobarbital, carbamazepine)carbamazepine)

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


Phenobarbital Phenobarbital 苯巴比妥苯巴比妥


C2H5

CO

NH

NH

CO

CO

C

C6H5

Sedative and hypnoticSedative and hypnotic effect effect Inhibiting both formation and spread of discharges.Inhibiting both formation and spread of discharges. Postsynaptic Postsynaptic ClCl-- influx influx Presynaptic Presynaptic Ca Ca2+2+ influx influx neurotransmitter release neurotransmitter release

(NE, ACh, Glu, etc.) (NE, ACh, Glu, etc.) Effective for grand mal , status epilepticus, partial Effective for grand mal , status epilepticus, partial

simple seizures.simple seizures.

Drugs acting at the chloride channel

Benzodiazepines Binds to specific

receptors

Phenobarbital Binds to barbiturate

specific receptor

Valproate Decreases GABA

degradation in presynaptic terminal


苯巴比妥

苯二氮卓类

丙戊酸钠

Block T-type CaBlock T-type Ca2+2+ channel channel Block NaBlock Na++-K-K++-ATPase-ATPase Inhibit cerebral metabolism and GABA tInhibit cerebral metabolism and GABA transaminaseransaminase Effective for peptit malEffective for peptit mal （小发作）（小发作） Combined with phenobarbitalCombined with phenobarbital

Ethosuximide Ethosuximide 乙琥胺乙琥胺


Valproate sodium Valproate sodium 丙戊酸钠丙戊酸钠


Broad spectrum

Inhibiting spread of discharges but not formation

Increases GABA levels via

inhibiting GABA tGABA transaminase,ransaminase,

GABA transport,GABA transport, Glutamate Glutamate decarboxylasedecarboxylase

Inhibit Na+ and L-type Ca2+

Enhance K+ ?

GI side effects Tremor Hepatitis Pancreatitis Serious neural tube and

cardiac defects in fetus in 1%

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 （共济失调） rash 5-10%

rare marrow suppression

rare hepatitis

frequent hyponatremia/Water intoxication (Dose dependence)

fetal malformations

Carbamazepine Carbamazepine 卡马西平卡马西平


N

CONH2

Other antiepileptic drugsOther antiepileptic drugs （略）（略）Primidone Primidone 扑米酮扑米酮：： analogues of phenobarbital, used analogues of phenobarbital, used for phenobarbital- and phenytoin-ineffective patientsfor phenobarbital- and phenytoin-ineffective patients

Mephenytoin Mephenytoin 美芬妥英美芬妥英 ,, Ethotoin Ethotoin 乙苯妥英乙苯妥英：： analogues analogues of phenytoinof phenytoin

Diazepam Diazepam 地西泮地西泮 : : status epilepticus (status epilepticus (i.v.i.v.))Nitrozepam Nitrozepam 硝西泮硝西泮 ,, Clonazepam Clonazepam 氯硝西泮氯硝西泮：： peptit malpeptit mal

Lamotrigine Lamotrigine 拉莫三嗪拉莫三嗪


Other antiepileptic drugsOther antiepileptic drugs （略）（略）OxarbazepineOxarbazepine （奥卡西平）：（奥卡西平）： similar as carbamazepine but similar as carbamazepine but weakerweaker

AntiepilepsirineAntiepilepsirine （抗痫灵）（抗痫灵） : : broad spectrum, esp.broad spectrum, esp. grand mal

Lamotrigine Lamotrigine 拉莫三嗪：拉莫三嗪： NaNa++ channel antagonist. Effective channel antagonist. Effective against both partial and generalized epilepsyagainst both partial and generalized epilepsy

FlunarizineFlunarizine 氟桂利嗪氟桂利嗪 : Inhibit L- and T-type Ca: Inhibit L- and T-type Ca2+2+ channel. channel. broad spectrumbroad spectrum

TopiramateTopiramate 托吡酯：托吡酯： Blocks AMPA+kainate receptorsBlocks AMPA+kainate receptors

Also blocks Also blocks NaNa++ and Ca and Ca2+2+ channelschannels


卡马西平

苯妥英钠丙戊酸钠

拉莫三嗪

丙戊酸钠

乙琥胺

二甲双酮

丙戊酸钠

苯二氮卓类

巴比妥类

Common toxicity of antiepileptic drugs:Common toxicity of antiepileptic drugs:

CNS reactionsCNS reactions

Hemological reactionsHemological reactions

Hepatic toxicityHepatic toxicity

TeratogenicityTeratogenicity （致畸）（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.

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Principals of antiepileptic drug usesPrincipals of antiepileptic drug uses1. Choice of drugs1. Choice of drugs

(1) Grand mal / Partial(1) Grand mal / Partial ：： Phenytoin, Carbamazepine, PhenobarbitalPhenytoin, Carbamazepine, Phenobarbital Primidone, Valproate sodium

(2) Peptit mal:(2) Peptit mal: EthosuximideEthosuximide

Clonazepam, Valproate sodium

(3) Psychomotor(3) Psychomotor ：： Carbamazepine, PhenytoinCarbamazepine, Phenytoin

(4) Status epilepticus(4) Status epilepticus ：： Diazepan (i.v.)Diazepan (i.v.)

Phenytoin (i.v.), Phenobrbital (i.m.)


2. Dosage2. Dosage ：： small small larger doses, titration up; larger doses, titration up; dose individualization; dose individualization; plasma concentration monitoring if necessaryplasma concentration monitoring if necessary

3. Usage3. Usage ：： drug combinationdrug combination

4. Withdrawal4. Withdrawal ：： gradually and slowlygradually and slowly


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.B. Anticonvulsant drugsAnticonvulsant drugs

Other anticovulsant drugsOther anticovulsant drugs

Sedative-hypnotic drugsSedative-hypnotic drugs

B.B. Anticonvulsant drugsAnticonvulsant 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

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

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 TiagabineAbove 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 Increased expression of ABC transport in epilepsyepilepsy

TransportersTransporters

耐药癫痫大鼠耐药癫痫大鼠 P-gpP-gp 表达增加表达增加

抗癫痫药敏感大鼠抗癫痫药敏感大鼠抗癫痫药耐药大鼠抗癫痫药耐药大鼠

ControlControl 耐药癫痫大鼠耐药癫痫大鼠

P-gpP-gp 抑制剂增强抗癫痫药抑制剂增强抗癫痫药 OxarbazepineOxarbazepine （（ OXC, OXC, 奥奥卡西平）作用及延长癫痫病人入院间隔时间卡西平）作用及延长癫痫病人入院间隔时间

P-gpP-gp 基因敲除及其抑制剂增加脑内抗癫痫药浓度基因敲除及其抑制剂增加脑内抗癫痫药浓度

Contribution of CYPs to drug metabolism

CYP Enzymes

(from Guengerich 2003)

抑制剂

诱导剂

底物

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 rateof metabolism of the affected drug

Inhibition – competition at the enzyme site that results in a decrease in metabolismof the affected drug

Drugs Treating Parkinson Disease Drugs Treating Parkinson Disease and Alzheimer Diseaseand Alzheimer Disease

Parkinson’s disease (PD)Parkinson’s disease (PD)

RigidityTremorBradykinenesiaPostural instability(propulsion, retropulsion).

Tremor:Tremor: one of the one of the common symptoms of PDcommon symptoms of PD

黑质黑质 -- 纹状体通路纹状体通路

中脑中脑 -- 边缘边缘 // 皮层通皮层通路路

结节结节 -- 漏斗通漏斗通路路 Substantia nigro -Substantia nigro -

striatum dopaminergic striatum dopaminergic pathwaypathway is involved in is involved in PD pathogenesisPD pathogenesis

Parkinson diseaseParkinson disease

Dopaminergic neuron Dopaminergic neuron degeneration in degeneration in substantia nigro and substantia nigro and striatumstriatumNormalNormal

NormalNormal

Parkinson diseaseParkinson disease

(-)

injuredinjured

relatively relatively potentiatedpotentiated

(-) (-)

DopamineDopamine

AcetylcholineAcetylcholine

Abnormal balance of DA/ACh neuronal functions Abnormal balance of DA/ACh neuronal functions in extrapyramidal system of Parkinson diseasein extrapyramidal system of Parkinson disease

LevodopaLevodopa

Muscarinic Muscarinic antagonistsantagonists

Tyrosine

TH

DOPA

Dopamine Decarboxylase

Dopamine

DBH

Norepinephrine

MAO-Bmetabolisms

MAO-Ametabolisms

DA receptors

Treatment I: Increase dopamine

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 Parkinson’s disease?

Note: All therapies treat the symptoms of the disease; none are neuroprotective and none slow the progression of the disease

NH2

OH

OH

O

OH

OH

OH

NH2

Dopamine

L-DOPA decarboxylase

L-Dopa

B6

• Striatal dopamine levels are low in PD.

• Dopamine does not pass BBB, 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 drugsLevodopa and related drugsDrugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease

(( 左旋多巴左旋多巴 ))

(( 多巴胺多巴胺 ))

Carbidopa ( 卡比多巴卡比多巴 )The combination of L-DOPA & carbidopa, is called Sinemet™. (L-DOPA t1/2 ~ 1.5 h)

HO

O

CH3

NH NH2

OH

OH

Carbidopa

3-O-methyl- DOPA

Periphery CNS

L-DOPA

dopamine

BBB

COMT

AAAD

L-DOPA

dopamine

AAAD

MAO

Pyridoxal 5- phosphate

Levodopa aloneLevodopa alone

Levodopa Levodopa

++

CarbidopaCarbidopa

LevodopaLevodopa1. ADME1. ADME Penetrating into the brain, transformed to DA or NE Penetrating into the brain, transformed to DA or NE

((lessless)) Distributed in peripheral tissue (Distributed in peripheral tissue (mostmost))2. Effects and uses2. Effects and uses Parkinson disease:Parkinson disease: decreases the rigidity, tremors, and decreases the rigidity, tremors, and

other symptomsother symptoms

Drugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease

LevodopaLevodopa3. Adverse effects3. Adverse effectsEarly: (1)(1)GI:GI: nausea, vomiting, nausea, vomiting, etcetc..(2)(2)CVS:CVS: hypotension, arrhythmia, hypotension, arrhythmia, etcetc. . (3)(3)CNS:CNS: emotional depression/ psychosis; abnormal emotional depression/ psychosis; abnormal involuntary; hallucinations; involuntary; hallucinations; etcetc..Late :(1) (1) fluctuation of response: end of dose/“wearing off” periods; fluctuation of response: end of dose/“wearing off” periods;

on/off periods (sudden loss of symptom control, akinesia)on/off periods (sudden loss of symptom control, akinesia) ..(2) (2) dyskinesia (dyskinesia ( 运动障碍，运动障碍， after years of chronic L-DOPA, up after years of chronic L-DOPA, up

to 80%, Involuntary movements: to 80%, Involuntary movements: chorea( 舞蹈症 ), ballismus( 投掷症 ), athetosis( 手足徐动症 ), dystonia( 肌张力失常 ), myooclonus( 肌阵挛 ), and tremor


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。


Other drugsOther drugs

1. DA1. DA receptor agonist receptor agonistss1st generation agonists: (ergot derivatives, 麦角衍生物 )

bromocriptine* ( 溴隐亭溴隐亭 , , D2 agonist) (t1/2 ~ 12 h)

pergolide* ( 培高利特培高利特 ,, D2/D3 agonist)(t1/2 ~ 24 h)

2nd generation agonists: ropinirole (t1/2 ~ 6 h) ( 普拉克索普拉克索 ,, D2/D3 agonist)pramipexole (t1/2 ~ 8 -12 h) ( 罗平尼咯罗平尼咯 , , 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.

• 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

2. MAO-B2. MAO-B inhibitor inhibitors s （（ Peripheral metabolism of catecholamines (mostly MAO-A) is unaffected. ））

decreasing DA metabolism in the CNSdecreasing DA metabolism in the CNSSelegilineSelegiline 司来吉兰司来吉兰

RasagilineRasagiline 雷沙吉兰雷沙吉兰

3. COMT inhibitors (3. COMT inhibitors (decreasing DA metabolismdecreasing DA metabolism))

CNSCNS COMT inhibitor: COMT inhibitor: ：： itecaponeitecapone 硝替卡朋硝替卡朋

peripheral COMT inhibitor:peripheral COMT inhibitor: entacaponeentacapone 恩他卡朋恩他卡朋


Drugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease 4. 4. Amantadine Amantadine 金刚烷胺金刚烷胺

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

Muscarinic antagonistsMuscarinic antagonists

Trihexyphenidyl (Trihexyphenidyl ( 苯海索，苯海索， artaneartane,, 安坦安坦 ))Benzatropine (Benzatropine ( 苯扎托品苯扎托品 ))

Decreasing CNS cholinergic functionsDecreasing CNS cholinergic functionsAdjuvant of Parkison disease treatmentAdjuvant of Parkison disease treatment


DRUG THERAPY - Summary - 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)

• 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). MPTP first came to medical attention because it produced symptoms similar to Parkinson’s disease.

Drug-Induced Parkinsonism

33 、、 Drugs for treatment of Drugs for treatment of dementia dementia (Alzheimer and related (Alzheimer and related diseases)diseases)

Anticholinesterase drugsAnticholinesterase drugsCholinoceptor agonistsCholinoceptor agonistsNeurotrophic factor-like drugsNeurotrophic factor-like drugs

Pathological characteristics of ADPathological characteristics of AD

Atrophy of the brainAtrophy of the brain

Senile plaquesSenile plaques

Neurofibrillary Neurofibrillary tanglestangles

Mitochondrial Mitochondrial DysfunctionDysfunction

InflammationInflammation

Other FactorsOther Factors

-Amyloid-Amyloid

GlutamateGlutamate

ExcitotoxicityExcitotoxicity

Cell Damage/Cell Damage/Loss (ACh deficit)Loss (ACh deficit)

DementiaDementia

NeurofibrillaryNeurofibrillaryTanglesTangles

Pathophysiologic Hypothesis of AD

AChE

AcetylCoA

CholineACh

Presynaptic neuron

Synaptic cleft

Postsynapticneuron Acetate

CholineCholine+

+

ACh

AChE

ChAT

Normal Cholinergic Function

MR NR

MR NR

Glial cell

BuChE

BuChE

ACh

ACh = acetylcholine; AChE = acetylcholinesterase;BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase; CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor.

Adapted from Adem, 1992.

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 dementiaDrugs 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;

Drugs for treatment of dementiaDrugs for treatment of dementia

Mitochondrial Mitochondrial DysfunctionDysfunction

InflammationInflammation

Other FactorsOther Factors

-Amyloid-Amyloid

GlutamateGlutamate

ExcitotoxicityExcitotoxicity

Cell Damage/Cell Damage/Loss (ACh deficit)Loss (ACh deficit)

DementiaDementia

NeurofibrillaryNeurofibrillaryTanglesTangles

Pathophysiologic Hypothesis of AD

Future treatment•K+channel blocker•Glutamate receptor regulator•5-HT receptor blocker

4、抗精神病药和抗抑郁药 Antidepressant and antimanic drugsAntidepressant and antimanic drugs

抗抑郁和抗躁狂药抗抑郁和抗躁狂药 Anxiolytics / antianxieticsAnxiolytics / antianxietics

抗焦虑药抗焦虑药 Antipsychotic drugsAntipsychotic drugs

抗精神分裂药抗精神分裂药

Disorders of mood Disorders of mood ((affective disordersaffective disorders 情感障碍情感障碍 )) are are extremely common in medical practice. The severity extremely common in medical practice. The severity of these conditions covers an extraordinarily broad of these conditions covers an extraordinarily broad range, from normal grief(range, from normal grief( 悲伤悲伤 ) reactions and ) reactions and dysthymia(dysthymia( 心境恶劣心境恶劣 ) to severe, incapacitating illness ) to severe, incapacitating illness that may result in death.that may result in death.

EmotionEmotion （情绪）（情绪） refers to transient responses to refers to transient responses to environmental, internal, and cognitive stimuli, while environmental, internal, and cognitive stimuli, while moodmood （心境）（心境） refers to the predominant emotional refers to the predominant emotional state over time.state over time.

Disorders of MoodDisorders of Mood

The symptoms of The symptoms of depressiondepression are intense feelings of are intense feelings of sadness, hopelessness, despair, and inability to sadness, hopelessness, despair, and inability to experience pleasure in usual activity.experience pleasure in usual activity.

ManiaMania is characterized by the opposite behavior, is characterized by the opposite behavior, that is, enthusiasm, rapid thought and speech that is, enthusiasm, rapid thought and speech patterns, and extreme self-confidence and impaired patterns, and extreme self-confidence and impaired judgment.judgment.

AnxietyAnxiety, a state characterized by arousal, vigilance, , a state characterized by arousal, vigilance, physiologic preparedness, and negative subjective physiologic preparedness, and negative subjective states, may share certain critical circuits with states, may share certain critical circuits with fearfear..

Disorders of MoodDisorders of Mood

Monoamine hypothesis of DepressionMonoamine hypothesis of Depression （单胺假说）（单胺假说）

5-HT 5-HT — genetic basis of depression & mania — genetic basis of depression & mania

NE NE — — depressiondepression

NE NE — — maniamania

Modulation of monoamines in the synaptic space Modulation of monoamines in the synaptic space and/or the related post-synaptic receptors is of and/or the related post-synaptic receptors is of therapeutic importancetherapeutic importance

Long-term adaptations to antidepressant treatmentLong-term adaptations to antidepressant treatment

支持

不支持

Classes of Antidepressants

Tricyclic Antidepressants (TCAs)

Monoamine Oxidase Inhibitors (MAOIs)

Norepinephrine Reuptake Inhibitors (NARIs)

Selective Serotonin Reuptake Inhibitors (SSRIs)

Serotonin and Norepinephrine Reuptake

Inhibitors (SNRIs)

Noradrenergic and specific serotonergic

antidepressants (NaSSAs)

Model of the neurotrophic Model of the neurotrophic hypothesis ofhypothesis ofantidepressant treatments and antidepressant treatments and stress-related disordersstress-related disorders

Imipramine Imipramine 丙米嗪丙米嗪（米帕明）（米帕明）

N

CH2CH2CH2NCH3

CH3

Tricyclic Tricyclic structurestructure

A.A. Antidepressant Drugs Antidepressant Drugs

Tricyclic Antidepressants (TCAs)

丙咪嗪

阿米替林

氯丙咪嗪

多塞平

临床应用副作用

1. 1. Pharmacological effectsPharmacological effects

(1) Central effects(1) Central effects Inhibiting reuptake of monoamine transmittersInhibiting reuptake of monoamine transmitters Improving patient’s mood after 2 weeksImproving patient’s mood after 2 weeks Sedative effects in normal subjects (anti-Sedative effects in normal subjects (anti-

histaminergic or histaminergic or -adrenergic blocking -adrenergic blocking properties)properties)

(2) Autonomic effects(2) Autonomic effects Muscarinic blocking effectsMuscarinic blocking effects

(3) Cardiovascular effects(3) Cardiovascular effects Hypotension, tachycardia, arrhythmiaHypotension, tachycardia, arrhythmia


2. 2. Clinical usesClinical uses

(1) Depression(1) Depression

Endogenous, melancholic, Endogenous, melancholic, etc.etc.

(2) Enuresis(2) Enuresis (( 遗尿遗尿 ))

(3) Anxiety (3) Anxiety (( 焦虑焦虑 )) and panic disorder and panic disorder (( 惊恐惊恐症症 ))



(1) Antimuscarinic effects(1) Antimuscarinic effects dry mouth, constipation(dry mouth, constipation( 便秘便秘 ), intraocular pressure ), intraocular pressure

increase, blurred vision, urinary retention, increase, blurred vision, urinary retention, etc.etc.

Contraindicated in prostatauxe and glaucomaContraindicated in prostatauxe and glaucoma

(2) CNS reactions(2) CNS reactions Confusion or delirium(Confusion or delirium( 谵妄谵妄 ), depression-mania (bipolar ), depression-mania (bipolar

patients)patients)

(3) CVS reactions(3) CVS reactions Postural hypotension, sinus tachycardia, potential of Postural hypotension, sinus tachycardia, potential of

arrhythmiaarrhythmia


4. 4. Drug interactionsDrug interactions

(1) Plasma protein binding(1) Plasma protein binding displacement by phenytoin, aspirin, scopolamine(displacement by phenytoin, aspirin, scopolamine( 东莨菪东莨菪

碱碱 ), phenothiazines (), phenothiazines ( 吩噻嗪类吩噻嗪类 ), ), etc. etc.

(2) MAO inhibitors(2) MAO inhibitors potentiating the effects of TCA,potentiating the effects of TCA,

contraindicated for combination with MAOIscontraindicated for combination with MAOIs

(3) Potentiating the effects of CNS depressant drugs(3) Potentiating the effects of CNS depressant drugs


Interaction of TCA with other types of drugs Interaction of TCA with other types of drugs


Monoamine oxidase inhibitors Monoamine oxidase inhibitors ((MAOIsMAOIs))

Selective for central MAO-B, less selective for enteric Selective for central MAO-B, less selective for enteric MAO-A; MAO-A;

Used in treatments of depression (non-sensitive to Used in treatments of depression (non-sensitive to TCAs) and Parkinson diseaseTCAs) and Parkinson disease

phenelzinephenelzine (( 苯乙肼苯乙肼 ): non-selective): non-selective

selegilineselegiline (( 司来吉兰司来吉兰 ): also used in Parkinson disease): also used in Parkinson disease

•MAOIs and Dietary Interactions

Tyramine(酪胺 ) is normally metabolized by MAO

Tyramine is sympathomimetic (it acutely displaces NE from terminals to activate receptors)

Ingesting tyramine during MAO inhibition results in hypertension, headache, palpitations, nausea, vomiting

Tyramine is present in a number of foodstuffs, such as aged cheese, red wine, etc.


NE reuptake inhibitors NE reuptake inhibitors ((NRIsNRIs)) Selective norepinephrine reuptake inhibitsSelective norepinephrine reuptake inhibits rapid actionsrapid actions weaker sedative, anticholinergic and hypotensive effectsweaker sedative, anticholinergic and hypotensive effects

desipramine desipramine (( 地昔帕明地昔帕明 ))

maprotiline maprotiline (( 马普替林马普替林 ))

nortriptyline nortriptyline (( 去甲替林去甲替林 )) protriptylin protriptylin (( 普罗替林普罗替林 ))

amoxapine amoxapine (( 阿莫沙平阿莫沙平 ))


Selective 5-HT reuptake inhibitorsSelective 5-HT reuptake inhibitors Selective serotonin reuptake inhibits (SSRIs)Selective serotonin reuptake inhibits (SSRIs) weaker sedative effectsweaker sedative effects with anti-anxiety effectswith anti-anxiety effects

fluoxetine fluoxetine (( 氟西汀，百氟西汀，百忧忧解解 )) ：抑郁症、神经性贪食症：抑郁症、神经性贪食症 paroxetine paroxetine (( 帕罗西汀帕罗西汀 ))

sertraline sertraline (( 舍曲林舍曲林 ))


5-HT/NE reuptake inhibitors5-HT/NE reuptake inhibitors Mixed serotonin/norepinephrine reuptake inhibits Mixed serotonin/norepinephrine reuptake inhibits

(SNRIs)(SNRIs) rapid action rapid action less affinity with receptors less affinity with receptors higher safetyhigher safety

venlafaxine venlafaxine (( 文拉法辛文拉法辛 ))

milnacipram milnacipram (( 米那普仑米那普仑 )) lofepramine lofepramine (( 洛夫帕明洛夫帕明 ))

A.A. Antidepressant Drugs Antidepressant DrugsNoradrenergic and specific serotonergic Noradrenergic and specific serotonergic

antidepressantantidepressant (NaSSA) (NaSSA) mirtezapine mirtezapine (( 米氮平米氮平 ))

blockingblocking presynapticpresynaptic (auto- or hetero-) (auto- or hetero-) 22 receptor receptor on both on both

norepinephrine and serotonin (5-HT) pre-synaptic axonsnorepinephrine and serotonin (5-HT) pre-synaptic axons

- increasing NE and 5-HT release- increasing NE and 5-HT release;; stimulating postsynaptic stimulating postsynaptic 11 receptors receptors on serotonergic cell bodies on serotonergic cell bodies

- increasing the firing rate of serotonergic neurons- increasing the firing rate of serotonergic neurons potently blocking postsynaptic 5-HTpotently blocking postsynaptic 5-HT2A2A, 5-HT, 5-HT2C2C and 5-HT and 5-HT33

receptors receptors – attenuating 5-HT– attenuating 5-HT2C2C-mediated anxiety-mediated anxiety

The net outcome of these effects isThe net outcome of these effects is ：： increased increased noradrenergicnoradrenergic activity activity

increased increased serotonergic activityserotonergic activity, esp. 5-HT, esp. 5-HT1A1A receptors receptors

B.B. Antimanic Drugs Antimanic Drugs

Lithium carbonateLithium carbonateCarbamazepine Carbamazepine ChlorpromazineChlorpromazineOther related antiepileptic Other related antiepileptic

and antipsychotic drugs and antipsychotic drugs


1. 1. Pharmacological effects and clinical usesPharmacological effects and clinical uses

Mood-stabilizing agentMood-stabilizing agent

(1) Inhibiting NE and DA release(1) Inhibiting NE and DA release

(2) Interfering phosphatidylinositol (PI) metabolism(2) Interfering phosphatidylinositol (PI) metabolism

(3) Substitute for sodium in generating action potentials and (3) Substitute for sodium in generating action potentials and in Nain Na++-K-K++ exchange across the membrane. exchange across the membrane.

Lithium carbonate Lithium carbonate 碳酸锂碳酸锂


Related to the serum concentration of LiRelated to the serum concentration of Li++

0.8 – 1.5 mmol/L:0.8 – 1.5 mmol/L: therapeutic leveltherapeutic level 1.6 – 2.0 mmol/L:1.6 – 2.0 mmol/L: GI reactionsGI reactions > 2.0 mmol/L:> 2.0 mmol/L: CNS toxicityCNS toxicity

Monitoring serum concentration of LiMonitoring serum concentration of Li++ if if possiblepossible


(1) Side effects(1) Side effects Nausea, vomiting, abdominal pain, diarrhea, Nausea, vomiting, abdominal pain, diarrhea,

sedation, finger tremor, polyuria, sedation, finger tremor, polyuria, etc.etc.

(2) Acute intoxication(2) Acute intoxication Mental confusion, coma, hyperreflexia(Mental confusion, coma, hyperreflexia( 反射亢进反射亢进 ), ),

gross tremor, dysarthria(gross tremor, dysarthria( 构音困难构音困难 ), seizures, ), seizures, etc.etc.

(3) Others (3) Others Benign thyroid enlargement, renal damageBenign thyroid enlargement, renal damage


C.C. Anxiolytic drugs Anxiolytic drugs

1. Benzodiazepines 1. Benzodiazepines see details in Ssee details in Sedative-Hypnotic Drugsedative-Hypnotic Drugs

2. Buspirone2. Buspirone （丁螺环酮）（丁螺环酮）

5-HT5-HT1A 1A receptor selective partial agonist, lowering receptor selective partial agonist, lowering

5-5-HT releaseHT release Fewer sedative, hypnotic, memory-deficient effectsFewer sedative, hypnotic, memory-deficient effects No cross tolerance to benzodiazepines, and less No cross tolerance to benzodiazepines, and less

potential of dependencepotential of dependence

Schizophrenia(精神分裂症 )

• Neurological Disorder - impairs ability to

perceive, understand & interpret the environment

• Impaired social and occupational function

• Behavioral Syndrome – predictable or not

• Etiology and biology remain unclear- familial

tendency, DA and other neurotransmitters

• History – early dementia, unremitting bad course

Signs & Symptoms

Positive symptoms• Delusions ( 妄想 ) - fixed false belief outside

cultural norm (bizarre vs. non bizarre)• Hallucinations ( 幻觉 ) - perceptual (hearing),

have no outside source • “Like my voice”• Not an illusion (a mistaken perception for which there is

an actual external stimulus)

• Disorganization ( 思维紊乱 ) - pattern of speech or behavior, making up words without a meaning (neologisms)

Negative symptoms• Affective flattening• Avolition / Amotivation (decreased motivation)• Autistic(孤独 ) behaviors (social withdrawal )• Anhedonia (inability to experience pleasure )• Ambivalence (coexistence of opposing attitudes or

feelings，矛盾心态 ) • Anosognosia (疾病感缺失 ) (impaired awareness

of illness )

Signs & Symptoms

1. Phenothiazines1. Phenothiazines （吩噻嗪类）（吩噻嗪类） Chlorpromazine 氯丙嗪氯丙嗪 perphenazine perphenazine 奋乃静；奋乃静； fluphenazine fluphenazine 氟奋乃静氟奋乃静 trifluoperazine trifluoperazine 三氟拉嗪；三氟拉嗪； thioridazine thioridazine 硫利达嗪硫利达嗪

2. Thioxanthenes (2. Thioxanthenes ( 硫杂蒽类硫杂蒽类 )) Chlorprothixene 氯普噻吨（泰尔登）

3. Butyrophenones3. Butyrophenones （丁酰苯类）（丁酰苯类） Haloperidol 氟哌啶醇 Droperidol 氟哌利多（氟哌啶）

Classified according to chemical structures

D.D. Antipsychotic drugs Antipsychotic drugs

Typical antipsychotic drugs are dopamine DTypical antipsychotic drugs are dopamine D22 receptor antagonists receptor antagonists

• Typical

OthersOthers

PenfluridolPenfluridol 五氟利多五氟利多 Longer duration of action, taking once Longer duration of action, taking once weeklyweekly

SulprideSulpride 舒必利舒必利 selectively acts on mesolimbic Dselectively acts on mesolimbic D22 receptors receptors

few extrapyramidal reactions few extrapyramidal reactions

ClozapineClozapine 氯氮平氯氮平 Blocking DBlocking D44 and 5-HT receptors and 5-HT receptors

RisperidoneRisperidone 利培酮利培酮 Blocking Blocking DD22 and 5-and 5-HTHT22 receptors receptors

Actions of some Actions of some secondary generation secondary generation drugsdrugs

• Atypical


High potency Low potency

螺环哌啶酮

苯哌利多三氟哌啶醇

氟哌利多

普马嗪

D.D. Antipsychotic drugs Antipsychotic drugs• The dopamine hypothesis of schizophrenia

• The serotonin hypothesis of schizophrenia

• The glutamate hypothesis of schizophrenia

PhenothiazinesPhenothiazines （吩噻嗪类）（吩噻嗪类）

Chlorpromazine Chlorpromazine 氯丙嗪氯丙嗪

N

S

(CH2)3

Cl

N(CH3)2


1. 1. Pharmacological effectsPharmacological effects

(1)(1)Central effects:Central effects:Blocking central DBlocking central D22 dopamine receptors dopamine receptorsa) Antipsychotic effects (neuroleptic effects)a) Antipsychotic effects (neuroleptic effects) for treatment of for treatment of schizophreniaschizophrenia controlling excitation and then hallucinations (weeks to controlling excitation and then hallucinations (weeks to

months)months)b) Antiemetic effects(b) Antiemetic effects( 镇吐作用镇吐作用 )) inhibiting inhibiting chemoreceptor trigger zonechemoreceptor trigger zone (CTZ) dopaminergic (CTZ) dopaminergic

functionfunctionc) Poikilothermic effects (c) Poikilothermic effects ( 体温调节作用体温调节作用 )) hypothermic anesthesiahypothermic anesthesia artificial hibernation (artificial hibernation ( 人工冬眠人工冬眠 ))d) Extrapyramidal effectsd) Extrapyramidal effects primary adverse effectsprimary adverse effectse) Potentiating the effects of central depressantse) Potentiating the effects of central depressants sedative-hypnotics, analgesics, general anesthetics, ethanolsedative-hypnotics, analgesics, general anesthetics, ethanol


(2) Autonomic nervous system effects(2) Autonomic nervous system effects

a) Hypotensive effectsa) Hypotensive effects receptor blockade, receptor blockade, postural hypotensionpostural hypotension

b) Anticholinergic effectsb) Anticholinergic effects dry mouth, constipation, blurred vision, urinary dry mouth, constipation, blurred vision, urinary

retention, etc.retention, etc.

(3) Endocrine effects(3) Endocrine effects prolactin prolactin ACTH, growth hormone ACTH, growth hormone


2. 2. Clinical usesClinical uses

(1) Treatment of schizophrenia(1) Treatment of schizophrenia

(2) Treatments of emesis and hiccough(2) Treatments of emesis and hiccough

used forused for emesis emesis （止吐）（止吐） andand hiccoughhiccough （呃逆）（呃逆） but ineffective on motion sicknessbut ineffective on motion sickness

(3) Hypothermic anesthesia ((3) Hypothermic anesthesia (combined with lowering room combined with lowering room

temperaturetemperature)) and artificial hibernation ( and artificial hibernation (combined with combined with

Pethidine Pethidine 哌替啶哌替啶 and promethazineand promethazine 异丙嗪异丙嗪 ))



(1) Side effects(1) Side effects

Central depressionCentral depression

Peripheral effects:Peripheral effects: postural hypotensionpostural hypotension, , dry mouth, and other effects resulting from dry mouth, and other effects resulting from muscarinic and muscarinic and receptor blockade receptor blockade


(2) Extrapyramidal effects(2) Extrapyramidal effects

Due to DA receptor block:Due to DA receptor block: a) Parkinsonisma) Parkinsonism

b) Akathisia (b) Akathisia ( 静坐不能静坐不能 ))

c) Acute dystonia (c) Acute dystonia ( 急性肌张力障碍急性肌张力障碍 ))

attenuated by central muscarinic antagonistsattenuated by central muscarinic antagonists

Due to supersensitive to DA:Due to supersensitive to DA:

Tardive dyskinesiaTardive dyskinesia (( 迟发性运动障碍迟发性运动障碍 ))


(3) Other central reactions(3) Other central reactions neuroleptic maglinant syndrome neuroleptic maglinant syndrome (( 神经阻滞药神经阻滞药恶性综合征）恶性综合征）

psychotic reactions psychotic reactions (( 药源性精神异常药源性精神异常 ))

epilepsy and convulsion: lowering seizure epilepsy and convulsion: lowering seizure thresholdthreshold

(4) Allergic and hemological reactions(4) Allergic and hemological reactions

skin reactions, leukopenia, skin reactions, leukopenia, obstructive obstructive jaundice, jaundice, liver damageliver damage


(5) CVS reactions (5) CVS reactions

arrhythmiaarrhythmia

hypotension: treated byhypotension: treated by receptor agonists receptor agonists sudden death (elderly with CVS diseases)sudden death (elderly with CVS diseases)

(6) Endocrine reactions(6) Endocrine reactions hyperplasia of mammary glands (hyperplasia of mammary glands ( 乳腺增生乳腺增生 ), ),

galactorrhea (galactorrhea ( 溢乳溢乳 ), amenorrhea (), amenorrhea ( 闭经闭经 ),),

child growth retard(child growth retard( 生长抑制生长抑制 ))


(6) Acute intoxication(6) Acute intoxication

severe CNS depression, coma, severe hypotensionsevere CNS depression, coma, severe hypotension

(7) Contraindications(7) Contraindications epilepsyepilepsy comacoma elderly with CVS disorderselderly with CVS disorders severe hepatic and renal dysfunctionsevere hepatic and renal dysfunction


Other phenothiazinesOther phenothiazines

perphenazine perphenazine 奋乃静奋乃静

fluphenazine fluphenazine 氟奋乃静氟奋乃静

trifluoperazine trifluoperazine 三氟拉嗪三氟拉嗪

thioridazine thioridazine 硫利达嗪硫利达嗪

more potent therapeutic effects and more potent therapeutic effects and extrapyramidal effectsextrapyramidal effects


Thioxanthenes Thioxanthenes (( 硫杂蒽类硫杂蒽类 ))

ChlorprothixeneChlorprothixene 氯普噻吨（泰尔登）氯普噻吨（泰尔登）

Used for the patients with symptoms of Used for the patients with symptoms of depressiondepression and and anxietyanxiety


ButyrophenonesButyrophenones （丁酰苯类）（丁酰苯类）

Haloperidol Haloperidol 氟哌啶醇氟哌啶醇

Droperidol Droperidol 氟哌利多（氟哌啶）氟哌利多（氟哌啶）

Combined with fentanyl:Combined with fentanyl: neuroleptanalgesianeuroleptanalgesia （神（神经安定经安定 [[ 镇痛镇痛 ] ] 麻醉术）麻醉术）


OthersOthers Penfluridol Penfluridol 五氟利多五氟利多 Longer duration of action, taking once weeklyLonger duration of action, taking once weekly

Sulpride Sulpride 舒必利舒必利

selectively acts on mesolimbic Dselectively acts on mesolimbic D22 receptors receptors

few extrapyramidal reactions few extrapyramidal reactions

Clozapine Clozapine 氯氮平氯氮平

Blocking DBlocking D44 and 5-HT receptors and 5-HT receptors

Risperidone Risperidone 利培酮利培酮

Blocking Blocking DD22 and 5-and 5-HTHT22 receptors receptors


局部麻醉药

Local Anesthetics (LAs)

Definition: drugs that cause loss of sensation

without loss of consciousness

Reversibly block nerve conduction

Act on every type of nerve fiber

Also act on cardiac muscle, skeletal muscle and the brain

No structural damage to the nerve cell

可卡因

普鲁卡因

丁卡因

苯佐卡因

all are weak basesBH+ B + H+

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

芳香族环酯链

胺基团

利多卡因

甲哌卡因

布比卡因

布比卡因

丙胺卡因

芳香族环酰胺链胺基团

神经纤维末梢、神经节、中枢神经系统的突触较为敏感；细的比粗的神经纤维敏感；有髓鞘的比无髓鞘的敏感；钝痛比锐痛敏感；

Use-dependent Blockade

Actions of LAs

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

CNS Toxicity

Correlation between potency and seizure threshold Bupivacaine

• 2 ug/ml Lidocaine

• 10 ug/ml

Cardiovascular ToxicityAttributable to their direct effect on cardiac muscle

Contractility Negative inotropic effect that is dose-related and

correlates with potency

Interference with calcium signaling mechanisms

Automaticity Negative chronotropic effect

Rhythmicity and Conductivity Ventricular arrhythmias

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

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 equiliibrating tissues

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

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

Pharmacokinetics

Uses of local anesthesia / 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.

• Conduction anesthesia (传导麻醉 ): local injection around the peripheral nerve trunk

• Epidural anesthesia (硬膜下麻醉 ): local injection into the epidural space

• 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

硬膜下

硬膜外

骶管阻滞

蛛网膜下腔

硬膜外阻滞

椎旁阻滞脊神经阻滞

Adverse reactions

Toxicity: CNS, CVS

Allergic Reactions

Metabolite of “ester” LAs Para-aminobenzoic acid （对氨基苯甲酸） Allergen

Allergy to “amide” LAs is extremely rare

Lidocaine （利多卡因）One of the most widely used local anesthetics

Rapid onset, medium duration

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

Other uses: anti-arrhythmic

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