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...
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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
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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)
A.A. Antiepileptic drugsAntiepileptic drugs
(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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
Phenobarbital Phenobarbital 苯巴比妥苯巴比妥
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
Valproate sodium Valproate sodium 丙戊酸钠丙戊酸钠
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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)
A.A. Antiepileptic drugsAntiepileptic 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.
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.)
A.A. Antiepileptic drugsAntiepileptic drugs
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
A.A. Antiepileptic drugsAntiepileptic drugs
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
Drugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease
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 diseaseDrugs for treatment of Parkinson disease
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
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
Drugs for treatment of Parkinson diseaseDrugs for treatment of Parkinson disease
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
Imipramine Imipramine 丙米嗪丙米嗪(米帕明)(米帕明)
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 ))
Imipramine Imipramine 丙米嗪丙米嗪(米帕明)(米帕明)
3. 3. Adverse effectsAdverse effects
(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
Imipramine Imipramine 丙米嗪丙米嗪(米帕明)(米帕明)
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
Imipramine Imipramine 丙米嗪丙米嗪(米帕明)(米帕明)
Interaction of TCA with other types of drugs Interaction of TCA with other types of drugs
A.A. Antidepressant Drugs Antidepressant 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.
A.A. Antidepressant Drugs Antidepressant Drugs
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 ))
A.A. Antidepressant Drugs Antidepressant Drugs
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 ))
A.A. Antidepressant Drugs Antidepressant Drugs
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
B.B. Antimanic Drugs Antimanic 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
2. 2. Adverse effectsAdverse effects
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
B.B. Antimanic Drugs Antimanic Drugs
(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
B.B. Antimanic Drugs Antimanic Drugs
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
D.D. Antipsychotic drugs Antipsychotic drugs
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
D.D. Antipsychotic drugs Antipsychotic drugs
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
D.D. Antipsychotic drugs Antipsychotic drugs
(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
D.D. Antipsychotic drugs Antipsychotic drugs
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 ))
D.D. Antipsychotic drugs Antipsychotic drugs
3. 3. Adverse effectsAdverse effects
(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
D.D. Antipsychotic drugs Antipsychotic drugs
(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 ))
D.D. Antipsychotic drugs Antipsychotic drugs
(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
D.D. Antipsychotic drugs Antipsychotic drugs
(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 ))
D.D. Antipsychotic drugs Antipsychotic drugs
(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
D.D. Antipsychotic drugs Antipsychotic drugs
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
D.D. Antipsychotic drugs Antipsychotic drugs
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
D.D. Antipsychotic drugs Antipsychotic drugs
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)
D.D. Antipsychotic drugs Antipsychotic drugs
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
D.D. Antipsychotic drugs Antipsychotic drugs
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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