Download 神经系统药理3 2014-10

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、抗精神病药和抗抑郁药
4、局部麻醉药
张纬萍
[email protected]
药理学系
2014.10.13
Antiepileptic and Anticonvulsant
Drugs
抗癫痫及抗惊厥药
Local excitatory 
Abnormal high frequency discharging
发病率高；
Abnormal spreading
突发性，不可预测；
不可根治，需终身服药
Brain malfunction
Accompanied with abnormal EEG
Classification 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
•
Partial seizures with
dyscognitive features
Partial Seizures with
secondary generalization
•
Partial seizures
without dyscognitive
features
限性）

（局限性发作继发全身强直阵挛性发
作）
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
表面脑电图
阵挛性发作
发作后抑制
细胞外记录
细胞内记录
PDS：paroxysmal depolarization shift
阵发性去极化漂移
 Seizures are generated by
groups of neurons which
depolarizing synchronously
 Epileptic neurons generate
Paroxysmal Depolarizing Shift
(阵发性去极化飘移, PDS)
 During a PDS, there is the
repetitive activation of key ion
channels.
 These ion channels represent
opportunities to prevent or
terminate seizures.
Surface Spike
PDS
Sodium Influx
Calcium Influx
Chloride Influx
K efflux
Mechanisms of antiepileptic drugs
Electrophysiological
 Inhibiting excessive discharges
 Inhibiting spread of discharges
Molecular
 Potentiating GABA neuronal functions
 Inhibiting excitatory neuronal functions
 Modulating Na+, Ca2+, K+, Cl- channel
fuctions
兴奋性
Molecular targets
for anti-seizure
drugs at the
excitatory,
glutamatergic
synapse.
抑制性
Molecular
targets for antiseizure drugs at
the inhibitory,
GABAergic
synapse.
Imbalance of excitation and inhibitory
Na+、Ca2+、NMDA 、K+ 、Cl-、GABA
Antiepileptic
drugs
Focus formation and epileptic attack
Focus shift
Spreading
Refractory epilepsy
A. Antiepileptic drugs
Phenytoin Sodium
苯妥英钠, 大仑丁
1. Pharmacological effects and the mechanism
(1) Effects
— Inhibiting spread of abnormal discharges
— Not on the happening of abnormal discharge
苯妥英钠
A. Antiepileptic drugs
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)
—  Calmodulin kinase activity 
 Neurotransmitter release (NE, 5-HT, DA etc.)
— Block post-tetanic potentiation (PTP) formation
A. Antiepileptic drugs
2. Clinical uses
(1) Anti-epilepsy
 Grand mal, status epilepticus;
 Partial seizures (simple and complex);
 Ineffective for petit mal (absence seizures)
失神小发作
(2) Trigeminal (三叉神经疼) and related
neuralgia (神经疼)
(3) Anti-arrhythmia
A. Antiepileptic drugs
3. ADME
 Larger doses: non-linear
kinetics（> 10 g/ml）
 Half life = 24 hours
 Therapeutic range = 10-20
ug/ml

Levels above 20 cause
ataxia (共济失调) and
nystagmus（眼球震颤）
 Hepatic metabolism

CYP3A enzyme pathway

CYP3A antagonists will
raise phenytoin levels
 Necessary to monitor plasma
concentrations
Initially linear
Psuedo first order
A. Antiepileptic drugs
4. Adverse effects
(1) Local reactions
 GI reactions; gingival hyperplasia
(2) CNS reactions
 Particularly in the cerebellum and vestibular systems:
nystagmus (眼球震颤), ataxia (共济失调), etc.
 Behavioral changes: confusion, hallucination, coma
(3) Hemological reactions
 Megaloblastic anemia (affect the metabolism of folic
acid)
A. Antiepileptic drugs
(4) Allergic reactions
 Skin reactions; blood cell abnormality (including
thrombocytopenia, agranulocytosis);
 hepatic toxicity; ect.
(5) Skeletal reactions
 Osteomalacia (骨质疏松) by increase vitamin D
metabolism and calcium absorption (inducer)
(6) Others
 Birth defects, hirsutism（多毛）, etc
A. Antiepileptic drugs
5. Drug interactions（蛋白结合、代谢）
(1) Increases plasma concentrations of drugs by
displacement of plasma protein binding (salicylates)
(2) Drug metabolizing enzyme inhibitor decrease the
metabolism of phenytoin (isoniazid异烟肼,
chloramphenicol氯霉素)
(3) Drug metabolizing enzyme inducer increase the
metabolism of phenytoin (phenobarbital,
carbamazepine)
(4) Phenytoin enhances the metabolism of corticosteroids
and vitamin D
A. Antiepileptic drugs
Phenobarbital
NH
O
CO
C
C2H5
C
NH




苯巴比妥
CO
C6H5
Sedative and hypnotic effect
Inhibiting both formation and spread of discharges.
Postsynaptic Cl- influx
Presynaptic  Ca2+ influx   neurotransmitter
release (NE, ACh, Glu, etc.)
 Effective for grand mal , status epilepticus, partial
simple seizures.
A. Antiepileptic drugs
Drugs acting at the
chloride channel
Benzodiazepines 苯二氮卓类

Binds to specific
receptors
Phenobarbital 苯巴比妥
Binds to barbiturate
specific receptor
Valproate 丙戊酸钠
 Decreases GABA
degradation in
presynaptic terminal

A. Antiepileptic drugs
Ethosuximide





乙琥胺
Block T-type Ca2+ channel
Block Na+-K+-ATPase
Inhibit cerebral metabolism and GABA transaminase
Effective for peptit mal（小发作）
Combined with phenobarbital
A. Antiepileptic drugs
Valproate sodium
丙戊酸钠
 Broad spectrum
 Inhibiting spread of
discharges but not formation
 Increases GABA levels via
inhibiting GABA transaminase,
GABA transport, Glutamate
decarboxylase
 Inhibit Na+ and L-type Ca2+
 Enhance K+ ?





GI side effects
Tremor
Hepatitis
Pancreatitis
Serious neural tube and
cardiac defects in fetus in
1%
A. Antiepileptic drugs
Carbamazepine
 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!
卡马西平
N
CONH 2
 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
A. Antiepileptic drugs
Other antiepileptic drugs（略）
Primidone 扑米酮：analogues of phenobarbital, used for
phenobarbital- and phenytoin-ineffective patients
Mephenytoin 美芬妥英, Ethotoin 乙苯妥英： analogues of
phenytoin
Diazepam 地西泮: status epilepticus (i.v.)
Nitrozepam 硝西泮, Clonazepam 氯硝西泮：peptit mal
Lamotrigine 拉莫三嗪
A. Antiepileptic drugs
Other antiepileptic drugs（略）
Oxarbazepine（奥卡西平）：similar as carbamazepine but
weaker
Antiepilepsirine（抗痫灵）: broad spectrum, esp. grand mal
Lamotrigine 拉莫三嗪： Na+ channel antagonist. Effective
against both partial and generalized epilepsy
Flunarizine 氟桂利嗪: Inhibit L- and T-type Ca2+ channel.
broad spectrum
Topiramate托吡酯： Blocks AMPA+kainate receptors
Also blocks Na+ and Ca2+ channels
卡马西平
苯妥英钠
拉莫三嗪
丙戊酸钠
丙戊酸钠
二甲双酮
乙琥胺
丙戊酸钠
苯二氮卓类
巴比妥类
A. Antiepileptic drugs
Common toxicity of antiepileptic drugs:
CNS reactions
Hemological reactions
Hepatic toxicity
Teratogenicity（致畸）
Teratogenicity
 All AED's cause fetal
malformations in at least 6%
of infants.
 Highest risk with phenytoin,
valproate, phenobarbital,
and carbamazepine (Class D
drugs)
 Folate supplementation
prevents neural tube defects.
A. Antiepileptic drugs
Principals of antiepileptic drug uses
1. Choice of drugs
(1) Grand mal / Partial：

Phenytoin, Carbamazepine, Phenobarbital

Primidone, Valproate sodium
(2) Peptit mal: Ethosuximide

Clonazepam, Valproate sodium
(3) Psychomotor：Carbamazepine, Phenytoin
(4) Status epilepticus：Diazepan (i.v.)

Phenytoin (i.v.), Phenobrbital (i.m.)
A. Antiepileptic drugs
2. Dosage：

small  larger doses, titration up;


dose individualization;
plasma concentration monitoring if necessary
3. Usage： drug combination
4. Withdrawal：gradually and slowly
B. Anticonvulsant drugs
Magnesium Sulfate
硫酸镁
1. Effects：central depression;


vasodilatation, BP ;
relaxing skeletal muscles
2. Uses：convulsion；hypertension crisis
3. Adverse effects：
 depression of respiratory and vasomotor centers,
antagonized by calcium preparations (i.v.)
B. Anticonvulsant drugs
 Other anticovulsant drugs
 Sedative-hypnotic drugs
Drugs which primarily affect K+ channel
 Levetiracetam
左乙拉西坦
 Few side effects except:


 High Potency->75%
reduction in seizures in
over 20% of refractory
patients

Fatigue
Depression and Psychosis
leading to discontinuation
in 7%.
White et al Neurology 2003
Drugs which affect Kainate
and AMPA receptors
 Topiramate
 Mechanism -Multiple
 Blocks AMPA+kainate
receptors
 Also blocks sodium and
CA channels
 Potentiate GABA
transmission
 Effective against both partial
and generalized epilepsy
 Excreted primarily in urine
 Start at 25 mg/day…titrate to
300-500/day
 Behavioral /Cognitive
problems common
 Low risk of rash
 Causes weight loss
 Relatively safe, Class C in
pregnancy
 High Potency

> 75% reductions in over
20% of refractory patients
 Zonisamide
Anti-epileptics (AEDs)
Note: All of the following drugs have multiple mechanisms of action (primary mechanisms
include blockade of voltage gated Na+ channels, enhancement of GABAergic
neurotransmission, and inhibition of glutamatergic neurotransmission)
Older AED’s
 phenytoin voltage gated Na+ channel blocker
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)



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
Anti-Epileptic Drug’s Effective as
Monotherapy (Single Agent)
Partial
(Localization Related)
Generalized







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
Valproate （丙戊酸钠）


Topiramate（托吡酯）


(GTC and absence)
(GTC)
Lamotrigine （拉莫三嗪）

(absence)

French et al Neurology 2004
New AED’s effective as adjunctive
treatment for refractory epilepsy
Partial





Topiramate
Levetiracetam
Pregabalin
Zonisamide
Oxcarbazepine
 Lamotrigine
 Gabapentin
 Tiagabine
Above all have level I, randomized clinical
trials, or A or B evidence, AAN
guidelines 2004
Generalized
 Topiramate
 Levetiracetam
 Lamotrigine

Data from randomized
placebo controlled trials
Drugs in red are generally
considered high potency
Increased expression of ABC transport in
epilepsy
Transporters
抗癫痫药敏感大鼠
Control
耐药癫痫大鼠
耐药癫痫大鼠P-gp表达增加
抗癫痫药耐药大鼠
P-gp基因敲除及其抑制剂增加脑内抗癫痫药浓度
P-gp抑制剂增强抗癫痫药Oxarbazepine（OXC, 奥卡
西平）作用及延长癫痫病人入院间隔时间
Contribution of CYPs to drug metabolism
CYP Enzymes
底物
抑制剂
诱导剂
(from Guengerich 2003)
AEDs and Hepatic CYP450 Interactions
Induction – increase in amount of enzyme protein, resulting in an increase in the rate
of metabolism of the affected drug
Inhibition – competition at the enzyme site that results in a decrease in metabolism
of the affected drug
 Valproic acid CYP2C inhibitor (inhibits phenobarbital, phenytoin metabolism)
 Phenytoin CYP inducer (3A4 and 2C); metabolized by 2C9
 Carbamazepine CYP inducer (CYP inducer (3A4 and 2C); metabolized by 3A4. . .
induces its own metabolism
 Phenobarbital CYP inducer (3A4 and 2C)
Drugs Treating Parkinson Disease
and Alzheimer Disease
Parkinson’s disease (PD)
Rigidity
Tremor
Bradykinesia
Postural instability
(propulsion,
retropulsion).
Tremor: one of the
common symptoms of PD
黑质-纹状体通路
结节-漏斗通路
中脑-边缘/皮层通路
Substantia nigro striatum dopaminergic
pathway is involved in
PD pathogenesis
Parkinson disease
Normal
Dopaminergic neuron
degeneration in
substantia nigro and
striatum
Normal
(-)
Parkinson disease
relatively
potentiated
injured
(-) 
Abnormal balance of DA/ACh neuronal functions
in extrapyramidal system of Parkinson disease
Acetylcholine
Muscarinic
antagonists
Levodopa
Dopamine
Treatment I: Increase dopamine
Tyrosine
TH
DOPA
DA receptors
Dopamine Decarboxylase
MAO-B
Dopamine
metabolisms
DBH
Norepinephrine
MAO-A
metabolisms
What is the desired goal of pharmacological
therapies for Parkinson’s disease?
Different approaches include:
I.
increases in dopamine synthesis capacity
II. direct activation of post-synaptic receptors
III. inhibition of dopamine metabolism
IV. alteration of the interaction/balance with other
neurotransmitters
V. dopamine releasers
VI. L-DOPA metabolism inhibitors
Note: All therapies treat the symptoms of the disease;
none are neuroprotective and none slow the progression of the disease
Drugs for treatment of Parkinson disease
Levodopa and related drugs
OH
OH
OH
Rationale for L-Dopa
Precursor Loading:
OH
L-DOPA decarboxylase
B6
O
NH2
OH
L-Dopa
(左旋多巴)
NH2
Dopamine
(多巴胺)
• 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.
Carbidopa (卡比多巴)
The combination of L-DOPA & carbidopa, is called Sinemet™.
(L-DOPA t1/2 ~ 1.5 h)
BBB
Periphery
3-O-methylDOPA
CNS
L-DOPA
COMT
L-DOPA
AAAD
OH
OH
CH3
Pyridoxal 5phosphate
dopamine
AAAD
dopamine
NH NH2
HO
O
Carbidopa
MAO
Levodopa alone
Levodopa
+
Carbidopa
Drugs for treatment of Parkinson disease
Levodopa
1. ADME
 Penetrating into the brain, transformed to DA or NE
(less)
 Distributed in peripheral tissue (most)
2. Effects and uses
 Parkinson disease: decreases the rigidity, tremors, and
other symptoms
Drugs for treatment of Parkinson disease
Levodopa
3. Adverse effects
Early:
(1)GI: nausea, vomiting, etc.
(2)CVS: hypotension, arrhythmia, etc.
(3)CNS: emotional depression/ psychosis; abnormal
involuntary; hallucinations; etc.
Late :
(1) fluctuation of response: end of dose/“wearing off” periods;
on/off periods (sudden loss of symptom control, akinesia) .
(2) dyskinesia (运动障碍，after years of chronic L-DOPA, up
to 80%, Involuntary movements: chorea(舞蹈症),
ballismus(投掷症), athetosis(手足徐动症), dystonia(肌张力失
常), myoclonus(肌阵挛), and tremor
一般情况下，对L-dopa制剂的反应可分为3个阶段：
①良好反应阶段（2～5年），为用药的最初阶段，每6～8小时
或更长时间服药1次，可使全部症状得到平稳的缓解或改善。
②中间反应阶段（2～3年），此阶段中每次服药仅可引起短时
间的症状改善，每个剂量的后期与下一个剂量前，有1个药物
无作用期，称为剂末现象，此外，还可出现开关现象和反常性
运动不能；这种疗效下降与黑质DA能神经元逐渐衰退，DA合
成、贮存进一步下降，及DA受体反应能力降低有关。
③反应衰退阶段，对L-dopa制剂反应明显下降或根本不起反应；
运动困难与致残程度更为严重；同时治疗中的一些不良反应更
为明显。
Drugs for treatment of Parkinson disease
 Other drugs
1. DA receptor agonists
1st generation agonists: (ergot derivatives, 麦角衍生物)
bromocriptine* (溴隐亭, D2 agonist) (t1/2 ~ 12 h)
pergolide* (培高利特, D2/D3 agonist)(t1/2 ~ 24 h)
2nd generation agonists:
ropinirole (t1/2 ~ 6 h) (普拉克索, D2/D3 agonist)
pramipexole (t1/2 ~ 8 -12 h) (罗平尼咯, D2 agonist)
Can be used as monotherapy for mild parkinsonism, or
combined with levodopa for advanced disease,
permitting the dose of levodopa to be reduced and
smoothing out response fluctuations.
the major adverse effects of DA receptor agonists
• Lower incidence of dyskinesia and response fluctuation
• Some individuals develop a troubling sleep disorder, with
sudden attacks of sleep (突然昏睡) during ordinary
daytime activities
• Postural hypotension
• Dose-related psychiatric side effects (similar to L-DOPA
but may occur more frequently, especially in elderly)
•
Nausea or vomiting (drugs active at chemotrigger zone
(CTZ) )
Drugs for treatment of Parkinson disease
2. MAO-B inhibitors （ Peripheral metabolism of
catecholamines (mostly MAO-A) is unaffected.）
 decreasing DA metabolism in the CNS
 Selegiline
 Rasagiline
司来吉兰
雷沙吉兰
3. COMT inhibitors (decreasing DA metabolism)
CNS COMT inhibitor: ：itecapone 硝替卡朋
peripheral COMT inhibitor: entacapone恩他卡朋
Drugs for treatment of Parkinson disease
4. Amantadine 金刚烷胺
 Used for mild Parkinson’s disease, as an early
monotherapy
 Mechanisms of action may include: release of
dopamine, block DA reuptake, actions on glutamate
receptors (as an NMDA-receptor antagonist)
 The dose should be reduced with renal impairment.
 Potential adverse effects:
 - CNS reactions (dizziness, anxiety, impaired
coordination)
 - hyperkinesias(运动亢进)
 - nausea, vomiting
 - others
Drugs for treatment of Parkinson disease
Muscarinic antagonists
 Trihexyphenidyl (苯海索，artane, 安坦)
 Benzatropine (苯扎托品)
 Decreasing CNS cholinergic functions
 Adjuvant of Parkison disease treatment
DRUG THERAPY - Summary
• Main Line Agents:
• L-DOPA plus carbidopa (Sinemet®)
• Dopamine receptor agonists (ropinirole)
• Lower Efficacy/Second Line or Adjuvant Agents:
• Anticholinergics
• Reuptake Inhibitor or releaser (amantadine)
• COMT Inhibitor (entacapone)
• MAO B Inhibitors (rasagiline, selegiline)
Drug-Induced Parkinsonism
• Reserpine, which depletes brain catecholamines,
induces Parkinson’s disease symptoms
• Antipsychotics (neuroleptics), that block DA receptors,
ie, dopamine receptor antagonists.
• N-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP).
MPTP first came to medical attention because it
produced symptoms similar to Parkinson’s disease.
3、Drugs for treatment of dementia
(Alzheimer and related diseases)
 Anticholinesterase drugs
 Cholinoceptor agonists
 Neurotrophic factor-like drugs
Pathological characteristics of AD
Atrophy of the brain
Senile plaques
Neurofibrillary
tangles
Pathophysiologic Hypothesis of AD
Glutamate
-Amyloid
Excitotoxicity
Neurofibrillary
Tangles
Other Factors
Cell Damage/
Loss (ACh deficit)
Dementia
Inflammation
Mitochondrial
Dysfunction
Normal Cholinergic Function
Presynaptic
neuron
Glial cell
Acetyl
CoA
+
Choline
Choline
BuChE
ChAT
MR
ACh
NR
BuChE
Synaptic cleft
ACh
AChE
Postsynaptic
neuron
Acetate
MR NR
ACh = acetylcholine; AChE = acetylcholinesterase;
BuChE = butyrylcholinesterase; ChAT = choline acetyltransferase;
CoA = coenzyme A; MR = muscarinic receptor; NR = nicotinic receptor.
Adapted from Adem, 1992.
Choline
+
AChE
ACh
Drugs for treatment of dementia
 Anticholinesterase drugs
 Tarcrine 他克林:
Easy to pass BBB; Decrease AChE 70%; activate M and
N receptors (especially M receptor); Enhance the release
of ACh (throught M receptor). Induce hepatic toxicity.
 Galantamine 加兰他敏: similar to tarcrine, except
without hepatic toxicity and high specific to neuron
AChE.
 Huperzine 哈伯因（石杉碱甲）: a high selective AChE
inhibitor; improve memory and recognization.
 Metrifonate 美曲磷脂: the first AChE inhibitor; Increase
central DA and NE; Decrease the red blood cell AChE
52%.
Drugs for treatment of dementia
 Cholinoceptor agonists
 Xanomeline 占诺美林: selective to M1 receptor; high
concentration in cortex and striatum; Has GI and CVS
side effects.
 Sabcomedine hydrochloride: selective to M1 receptor;
safe.
 Neurotrophic factor enhancer
 AIT 082: increase the release of neurotrophins in injured
neurons
 ALCAR（盐酸乙酰L肉碱）: protect synapse and
increase nurotrophins
 Propentofylline 丙戊茶碱: inhibit adrenaline reuptake
and cAMP metabolize; neuroprotective effects;
Pathophysiologic Hypothesis of AD
Glutamate
-Amyloid
Future treatment
•K+channel blocker
•Glutamate receptor regulator
•5-HT receptor blocker
Excitotoxicity
Cell Damage/
Loss (ACh deficit)
Neurofibrillary
Tangles
Other Factors
Inflammation
Dementia
Mitochondrial
Dysfunction
4、抗精神病药和抗抑郁药
 Antidepressant and antimanic drugs
抗抑郁和抗躁狂药
 Anxiolytics / antianxietics
抗焦虑药
 Antipsychotic drugs
抗精神分裂药
Disorders of Mood
Disorders of mood (affective disorders 情感障碍) are
extremely common in medical practice. The severity
of these conditions covers an extraordinarily broad
range, from normal grief(悲伤) reactions and
dysthymia(心境恶劣) to severe, incapacitating illness
that may result in death.
Emotion（情绪）refers to transient responses to
environmental, internal, and cognitive stimuli, while
mood （心境）refers to the predominant emotional
state over time.
Disorders of Mood
The symptoms of depression are intense feelings of
sadness, hopelessness, despair, and inability to
experience pleasure in usual activity.
Mania is characterized by the opposite behavior,
that is, enthusiasm, rapid thought and speech
patterns, and extreme self-confidence and impaired
judgment.
Anxiety, a state characterized by arousal, vigilance,
physiologic preparedness, and negative subjective
states, may share certain critical circuits with fear.
Monoamine hypothesis of Depression
（单胺假说）
5-HT  — genetic basis of depression & mania
NE  — depression
NE  — mania
Modulation of monoamines in the synaptic space
and/or the related post-synaptic receptors is of
therapeutic importance
Long-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
hypothesis of
antidepressant treatments and
stress-related disorders
A. Antidepressant Drugs
Tricyclic Antidepressants (TCAs)
Imipramine
丙米嗪（米帕明）
Tricyclic
structure
N
CH 3
CH 2CH 2CH 2N
CH 3
临床应用
阿米替林
氯丙咪嗪
多塞平
丙咪嗪
副作用
Imipramine
丙米嗪（米帕明）
1. Pharmacological effects
(1) Central effects
 Inhibiting reuptake of monoamine transmitters
 Improving patient’s mood after 2 weeks
 Sedative effects in normal subjects (antihistaminergic
or
a-adrenergic
blocking
properties)
(2) Autonomic effects
 Muscarinic blocking effects
(3) Cardiovascular effects
 Hypotension, tachycardia, arrhythmia
Imipramine
丙米嗪（米帕明）
2. Clinical uses
(1) Depression
Endogenous, melancholic, etc.
(2) Enuresis (遗尿)
(3) Anxiety (焦虑) and panic disorder (惊恐症)
Imipramine
丙米嗪（米帕明）
3. Adverse effects
(1) Antimuscarinic effects
dry mouth, constipation(便秘), intraocular pressure increase,
blurred vision, urinary retention, etc.
Contraindicated in prostatauxe and glaucoma
(2) CNS reactions
Confusion or delirium(谵妄), depression-mania (bipolar
patients)
(3) CVS reactions
Postural hypotension, sinus tachycardia, potential of
arrhythmia
Imipramine
丙米嗪（米帕明）
4. Drug interactions
(1) Plasma protein binding
displacement by phenytoin, aspirin, scopolamine(东莨菪碱),
phenothiazines (吩噻嗪类), etc.
(2) MAO inhibitors
potentiating the effects of TCA,
contraindicated for combination with MAOIs
(3) Potentiating the effects of CNS depressant drugs
Interaction of TCA with other types of drugs
A. Antidepressant Drugs
 Monoamine oxidase inhibitors
(MAOIs)
 Selective for central MAO-B, less selective for enteric
MAO-A;
 Used in treatments of depression (non-sensitive to
TCAs) and Parkinson disease


phenelzine (苯乙肼): non-selective
selegiline (司来吉兰): 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. Antidepressant Drugs
 NE reuptake inhibitors (NRIs)
 Selective norepinephrine reuptake inhibits

rapid actions

weaker sedative, anticholinergic and hypotensive effects





desipramine (地昔帕明)
maprotiline (马普替林)
nortriptyline (去甲替林)
protriptylin (普罗替林)
amoxapine (阿莫沙平)
A. Antidepressant Drugs
 Selective 5-HT reuptake inhibitors
 Selective serotonin reuptake inhibits (SSRIs)





weaker sedative effects
with anti-anxiety effects
fluoxetine (氟西汀，百忧解)：抑郁症、神经性贪食症
paroxetine (帕罗西汀)
sertraline (舍曲林)
A. Antidepressant Drugs
 5-HT/NE reuptake inhibitors
 Mixed serotonin/norepinephrine reuptake inhibits
(SNRIs)

rapid action

less affinity with receptors

higher safety



venlafaxine (文拉法辛)
milnacipram (米那普仑)
lofepramine (洛夫帕明)
A. Antidepressant Drugs
Noradrenergic and specific serotonergic
antidepressant (NaSSA) mirtezapine (米氮平)
 blocking presynaptic (auto- or hetero-) a2 receptor
on both
norepinephrine and serotonin (5-HT) pre-synaptic axons


- increasing NE and 5-HT release;
stimulating postsynaptic a1 receptors on serotonergic cell bodies

- increasing the firing rate of serotonergic neurons

potently blocking postsynaptic 5-HT2A, 5-HT2C and 5-HT3
receptors – attenuating 5-HT2C-mediated anxiety
 The net outcome of these effects is：
increased noradrenergic activity
increased serotonergic activity, esp. 5-HT1A receptors
B. Antimanic Drugs
 Lithium carbonate
 Carbamazepine
 Chlorpromazine
 Other related antiepileptic
and antipsychotic drugs
B. Antimanic Drugs
Lithium carbonate
碳酸锂
1. Pharmacological effects and clinical uses
 Mood-stabilizing agent
(1) Inhibiting NE and DA release
(2) Interfering phosphatidylinositol (PI) metabolism
(3) Substitute for sodium in generating action potentials and
in Na+-K+ exchange across the membrane.
B. Antimanic Drugs
2. Adverse effects
Related to the serum concentration of Li+



0.8 – 1.5 mmol/L: therapeutic level
1.6 – 2.0 mmol/L: GI reactions
> 2.0 mmol/L: CNS toxicity
 Monitoring serum concentration of Li+ if
possible
B. Antimanic Drugs
(1) Side effects
 Nausea, vomiting, abdominal pain, diarrhea, sedation,
finger tremor, polyuria, etc.
(2) Acute intoxication
 Mental confusion, coma, hyperreflexia(反射亢进),
gross tremor, dysarthria(构音困难), seizures, etc.
(3) Others
 Benign thyroid enlargement, renal damage
C. Anxiolytic drugs
1. Benzodiazepines see details in Sedative-Hypnotic Drugs
2. Buspirone（丁螺环酮）
 5-HT1A receptor selective partial agonist, lowering
5-HT release
 Fewer sedative, hypnotic, memory-deficient effects
 No cross tolerance to benzodiazepines, and less
potential 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)
Signs & Symptoms

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 )
D. Antipsychotic drugs
Classified according to chemical structures
1. Phenothiazines（吩噻嗪类）
 Chlorpromazine 氯丙嗪
 perphenazine 奋乃静； fluphenazine 氟奋乃静
 trifluoperazine 三氟拉嗪；thioridazine 硫利达嗪
• Typical
2. Thioxanthenes (硫杂蒽类)
 Chlorprothixene 氯普噻吨（泰尔登）
3. Butyrophenones（丁酰苯类）
 Haloperidol 氟哌啶醇
 Droperidol 氟哌利多（氟哌啶）
Typical antipsychotic drugs are dopamine D2 receptor antagonists
 Others
 Penfluridol
 Sulpride
五氟利多
舒必利
Longer duration of action, taking once weekly
selectively acts on mesolimbic D2 receptors
few extrapyramidal reactions
 Clozapine
 Risperidone
氯氮平
Blocking D4 and 5-HT receptors
利培酮
Blocking D2 and 5-HT2 receptors
• Atypical
Actions of some
secondary generation
drugs
D. Antipsychotic drugs
High potency
Low potency
普马嗪
氟哌利多
三氟哌啶醇
苯哌利多
螺环哌啶酮
D. Antipsychotic drugs
•
The dopamine hypothesis of schizophrenia
•
The serotonin hypothesis of schizophrenia
•
The glutamate hypothesis of schizophrenia
D. Antipsychotic drugs
 Phenothiazines（吩噻嗪类）
Chlorpromazine
氯丙嗪
S
N
(CH 2)3
Cl
N(CH3)2
D. Antipsychotic drugs
1. Pharmacological effects
(1)Central effects:Blocking central D2 dopamine receptors
a) Antipsychotic effects (neuroleptic effects)
 for treatment of schizophrenia
 controlling excitation and then hallucinations (weeks to months)
b) Antiemetic effects(镇吐作用)
 inhibiting chemoreceptor trigger zone (CTZ) dopaminergic
function
c) Poikilothermic effects (体温调节作用)
 hypothermic anesthesia
 artificial hibernation (人工冬眠)
d) Extrapyramidal effects
 primary adverse effects
e) Potentiating the effects of central depressants

sedative-hypnotics, analgesics, general anesthetics, ethanol
D. Antipsychotic drugs
(2) Autonomic nervous system effects
a) Hypotensive effects
 a receptor blockade, postural hypotension
b) Anticholinergic effects
 dry mouth, constipation, blurred vision, urinary
retention, etc.
(3) Endocrine effects
 prolactin 
 ACTH, growth hormone 
D. Antipsychotic drugs
2. Clinical uses
(1) Treatment of schizophrenia
(2) Treatments of emesis and hiccough
used for emesis （止吐） and hiccough（呃逆）
but ineffective on motion sickness
(3) Hypothermic anesthesia (combined with lowering room
temperature) and artificial hibernation (combined with
Pethidine 哌替啶 and promethazine异丙嗪)
D. Antipsychotic drugs
3. Adverse effects
(1) Side effects
Central depression
Peripheral effects: postural hypotension,
dry mouth, and other effects resulting from
muscarinic and a receptor blockade
D. Antipsychotic drugs
(2) Extrapyramidal effects
Due to DA receptor block:
a) Parkinsonism
b) Akathisia (静坐不能)
c) Acute dystonia (急性肌张力障碍)
attenuated by central muscarinic antagonists
Due to supersensitive to DA:
Tardive dyskinesia (迟发性运动障碍)
D. Antipsychotic drugs
(3) Other central reactions
 neuroleptic maglinant syndrome (神经阻滞药恶
性综合征）
 psychotic reactions (药源性精神异常)

epilepsy and convulsion: lowering seizure
threshold
(4) Allergic and hemological reactions
skin reactions, leukopenia, obstructive
jaundice, liver damage
D. Antipsychotic drugs
(5) CVS reactions
 arrhythmia


hypotension: treated by a receptor agonists
sudden death (elderly with CVS diseases)
(6) Endocrine reactions
 hyperplasia of mammary glands (乳腺增生),
galactorrhea (溢乳), amenorrhea (闭经 ),
child growth retard(生长抑制)
D. Antipsychotic drugs
(6) Acute intoxication

severe CNS depression, coma, severe hypotension
(7) Contraindications

epilepsy

coma

elderly with CVS disorders

severe hepatic and renal dysfunction
D. Antipsychotic drugs
 Other phenothiazines




perphenazine 奋乃静
fluphenazine 氟奋乃静
trifluoperazine 三氟拉嗪
thioridazine 硫利达嗪
 more potent therapeutic effects and
extrapyramidal effects
D. Antipsychotic drugs
 Thioxanthenes (硫杂蒽类)
Chlorprothixene 氯普噻吨（泰尔登）
Used for the patients with symptoms of
depression and anxiety
D. Antipsychotic drugs
Butyrophenones（丁酰苯类）
 Haloperidol
氟哌啶醇
 Droperidol 氟哌利多（氟哌啶）
 Combined with fentanyl: neuroleptanalgesia（神经
安定 [镇痛] 麻醉术）
D. Antipsychotic drugs
Others
 Penfluridol
五氟利多
 Longer duration of action, taking once weekly
 Sulpride
舒必利
 selectively acts on mesolimbic D2 receptors
 few extrapyramidal reactions
 Clozapine
氯氮平
 Blocking D4 and 5-HT receptors
 Risperidone 利培酮
 Blocking D2 and 5-HT2 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
Structural Classes: Esters (酯类) and Amides（酰胺类）
胺基团
all are weak bases
BH+
B + H+
可卡因
普鲁卡因
丁卡因
苯佐卡因
芳香族环
酯链
芳香族环
利多卡因
甲哌卡因
布比卡因
布比卡因
丙胺卡因
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 Toxicity
 Attributable 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
Pharmacokinetics
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
Distribution
- LAs bind in the blood to a1-glycoprotein and albumin
 Alpha phase (快速吸收相) – rapidly redistributed
to well-perfused tissues
 Beta phase (再分布相) – distribution to less
perfused or slowly equilibrating tissues
 Gamma phase (消除相) – clearance representing
metabolism and excretion
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
蛛网膜下腔
脊神经阻滞
椎旁阻滞
硬膜外阻滞
骶管阻滞
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
1、抗癫痫药：分类，苯妥英钠
2、抗帕金森病药及抗老年性痴呆药
L-DOPA
3、抗精神病药和抗抑郁药
丙咪嗪、氯丙嗪
4、局部麻醉药：利多卡因
药理作用、作用机制、临床应用、不良反应、体内过程及
药物相互作用