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第三次课的内容
1、肾上腺素能神经系统
（2）肾上腺素受体拮抗药
2、镇静催眠药
Adrenergic Receptor Antagonists
antagonists of NE at either a or b receptors.
- competitive antagonists (reversible), blocking
endogenous norepinephrine
- irreversible antagonists
Antagonist characteristics:
- receptor occupancy (binding affinity)
- no receptor activation (no efficacy)
- nonselective and selective drugs available for both
the a or b receptors.
Drug actions and classification
Adrenoceptor antagonists
（1）a receptor antagonists
• a1a2 receptor antagonists:
short-acting: phentolamine（酚妥拉明）
long-acting: phenoxybenzamine（酚苄明）
• a1 receptor antagonists: prazosin（哌唑嗪）
• a2 receptor antagonists: yohimbine（育亨宾）
Drug actions and classification
Adrenoceptor antagonists
（2）b receptor antagonists
• b1b2 receptor antagonists: propranolol （普萘洛尔）
• b1 receptor antagonists: atenolol（阿替洛尔）
• b2 receptor antagonists: butoxamine（布他沙明）
（3）a, b receptor antagonists
•
labetalol（拉贝洛尔）
epinephrine
a antagonist epinephrine
BP
Epinephrine reversal
（adrenaline reversal）
Phentolamine （酚妥拉明）
• competitive, nonselective (a1, a2 receptor
antagonists)
CH 3
N
N
CH2
N
H
Pharmacological effects
HO
(1) Vasodilatation
Blocking a1 receptor: vasodilation in both arteriolar
resistance vessels and veins
(2) Cardiac Stimulation
Reflex；blocking a2 receptor ～NE release 
(3) Cholinergic and histamine-like effects
Contraction of GI smooth muscles,
Gastric acid secretion 
Phentolamine
Clinical uses
(1) • Hypertension from pheochromocytoma
(short term use).
• pre- and post-operation of
pheochromocytoma
• Diagnostic test for pheochromocytoma
(2) Peripheral vascular diseases
• Acrocyanosis, Raynaud’s disease
(3) Local vasoconstrictor extravasation
Major Adverse effects– postural hypotension, reflex
tachycardia, arrhythmia, angina pectoris, GI reactions
Pheochromocytoma is a rare
catecholamine-secreting tumor derived
from chromaffin cells of the adrenal
medulla that produces excess epinephrine.
• Hypertension & Crises
• Elevated Metabolic Rate
-heat intolerance
-excessive sweating
-weight loss
• Temporarily manage with
-adrenergic antagonists (a1 & ±b)
Pheochromocytoma
Phenoxybenzamine (酚苄明)
• Irreversible,
nonselective
( a1 and a2
antagonists )
• Long-acting
• Similar to
phentolamine in
actions and
clinical uses
a1 receptor antagonists
• prazosin（哌唑嗪）
treatment for hypertension
a2 receptor antagonists
•
yohimbine（育亨宾）
for research use only
b receptor antagonists
ADME
• First-pass elimination,
low bioavailability: propranolol
• Hepatic metabolism and renal excretion,
hepatic and renal functions alter the
effects of the drugs and result in large
individual variation
• So, dose individualization is necessary.
Effects of an b AR Antagonist
b receptor antagonists
Pharmacological effects
(1) b receptor blockade
A. Cardiovascular effects：
• Depressing heart: reduction in HR, A-V
conduction, automaticity, cardiac output,
oxygen consumption
•
Hypotension: peripheral blood flow ,
hypotensive
effects
in
hypertensive
patients
b receptor antagonists
(1) b receptor blockade
B. Bronchial smooth muscles
• induces bronchial smooth muscle contraction
in asthmatic patients
C. Metabolism
• lipolysis  , glycogenolysis  , potentiating
insulin effects ~ hypoglycemia
D. Renin secretion
• decreasing secretion of renin
b receptor antagonists
(2) Intrinsic sympathomimetic effects
• Partial agonists: e.g. pindolol, acebutolol
(3) Membrane-stabilizing effects
• Larger doses of some drugs: quinidine-like
effects, Na+ channel block
(4) Others
• Lowering intraocular pressure;
• Inhibiting platelet aggregation
Circulation of Aqueous humor
b receptor antagonists
Clinical uses
(1) Arrhythmia：supraventricular, sympathetic
activity 
(2) Hypertension
(3) Angina pectoris and myocardial infarction
(4) Chronic heart failure
(5) Others: hyperthyroidism, migraine headache,
glaucoma（timolol）...
b receptor antagonists
Adverse effects
(1) Heart depression: contraindicated in heart
failure, severe A-V block, sinus bradycardia
(2) Worsening of asthma: contraindicated in
bronchial asthmatic patients
(3) Withdrawal syndrome：up-regulation of the
receptors
(4)
Worsening
constriction
of
peripheral
vascular
(5) Others：central depression, hypoglycemia,
etc.
Propranolol （普萘洛尔）
• b1, b2 receptor blocking
• no intrinsic activity
• first-elimination after oral administration,
individual variation of bioavailability
Timolol （噻吗洛尔）
• For treatment of glaucoma (wide-angle)
Atenolol （阿替洛尔）
Metoprolol（美托洛尔）
• b1receptor antagonists, no
intrinsic activity
•
• atenolol : longer t1/2, once daily
• usually used for treatment of
hypertension
b受体阻断剂的药理学特性
NO, b2 agonist,
a1 blocker Ca2+ blocker Antioxidation
a1 blocker
NO
α, b receptor antagonists
Labetalol （拉贝洛尔）
•
•
α, β receptor blocking, β> α
usually used for treatment of
hypertension
Therapeutic Uses of a1 (±b) AR Agonists
1. Hypotension
-To preserve adequate blood perfusion to heart, brain or kidneys in cases of
hemorrhage, overdose of antihypertensive drugs or spinal cord injuries.
-Short duration of treatment: NE, phenylephrine, methoxamine, ephedrine
(a1 AR agonists).
2. Shock
-Inadequate perfusion to tissues as a consequence of hypovolemia, cardiac
failure, or altered vascular resistance.
-Usually associated with hypotension.
-Use of a1-adrenergic agonists to increase peripheral vascular resistance,
and b1-adrenergic agonists to improve cardiac function.
3. Cardiogenic Shock
-Massive myocardial infarction.
-Stimulation of cardiac b1-adrenergic receptors is needed: isoproterenol,
norepinephrine, epinephrine, dobutamine, dopamine.
Therapeutic Uses of a1 (±b) AR Agonists
4. Local Vascular Effects
-Reduction of regional blood flow in surgery (nose, throat, larynx) to improve
visualization by limiting hemorrhage.
-Epinephrine retards the absorption of local anesthetics and increases the
duration of anesthesia (vasoconstrictor effect of epinephrine)
5. Nasal Decongestion
-a1-Adrenergic agonists are used as nasal decongestants.
-These drugs decrease the volume of the nasal mucosa and therefore
reduce the resistance to airflow.
-Oxymetazoline, phenylephrine and ephedrine are commonly used.
6. Allergic Reactions
-Epinephrine (s.c.) is used in acute hypersensitivity reactions.
-Activation of b-adrenergic receptors on mast cells suppresses the release
of histamine and leukotrienes.
Therapeutic Uses of b2 AR Agonists
1. Asthma
-Asthma is a condition of overreactive airways. Asthma attacks can make it
very difficult to breath because of excess bronchoconstriction.
-b2 AR agonists such as albuterol, metaproterenol and terbutaline are used.
-The drugs are administered by inhalation and are absorbed slowly, limiting
their systemic side effects, and b2 selectivity reduces cardiac stimulation.
2. Premature Labor
-When labor occurs prematurely (before 37 weeks), it is a risk to the fetus.
- b2 AR agonists relax the smooth muscle of the uterus and help prevent
premature delivery. The goal is to reach at least 37 weeks when the fetal
lungs have matured.
Therapeutic Uses of a1 & b AR Antagonists
1. Pheochromocytoma
2. Hypertension
-While not commonly used anymore, a1 blockers can be use to treat
hypertension.
-Somewhat more common is the use of b blockers. These work centrally
(the most important effect – the mechanism is not completely understood)
and peripherally (decrease heart rate some).
3. Heart Failure
-After a myocardial infarction, the SNS will be activated to increase the
cardiac output from the remaining good heart tissue. This is good in the
short-term, but long-term changes lead to cardiac hypertrophy and failure.
-Ironically, b blockers reduce the incidence of sudden death from heart
failure.
Other Important Catecholamine Drugs
• TH Inhibitor – a-methyl-p-tyrosine
• DBH Inhibitors – (no good selective ones)
• VMAT Inhibitors – reserpine & amphetamine
• False Transmitters – tyramine &
a-methyl-DOPA (  a-methyl-NE)
• MAO Inhibitors – pargyline (nonselective),
chlorgyline (MAOA), deprenyl (MAOB)
• NET Inhibitors – desipramine, reboxetine
• Neurotoxin – 6-hydroxydopamine, DSP-4
Classification of CNS drugs
Sedative-hypnotics
Epilepsy and
convulsion
Parkinson disease
Analgesics
Central stimulants
Antipsychotic drugs
depression－mania
Dementia
Neurological
（general and special）
Psychological
Sedative-Hypnotic Drugs
Sedatives （镇静药）：
能缓和激动，消除躁动，恢复安静情绪的药物
-----prescribed to cause sedation (for patients with anxiety)
Hypnotics （催眠药）：
能促进和维持近似生理睡眠的药物
-----prescribed to encourage sleep (for patients with insomnia)
中枢抑制药多数随剂量增加而出现镇静、催眠
等中枢抑制作用，故合称为镇静催眠药
（sedative-hypnotics）
Stage 3 & 4, 统称为慢波睡眠
Molecular Neuropharmacology
Sleep histogram shows a normal pattern of sleep in a
young adult.
A schematic drawing showing key components of the
ascending reticular activating system (ARAS)
Circadian rhythm & Circadian control
SCN: suprachiasmatic nucleus
视交叉上核
Sedative-Hypnotic Drugs
 Benzodiazepines
(BZ / BDZ, 苯二氮卓类)
 Barbiturates (巴比妥类)
 Others
A. Benzodiazepines
Diazepam
地西泮（安定）
R1
CH 3
O
R2
N
Cl R7
R3
N
R4
A. Benzodiazepines
1. Pharmacological effects and clinical uses
(1) Antianxiety
at small doses
acting on limbic system（边缘系统，杏仁核、
海马）
(2) Sedative-hypnotic effects（作用于脑干）
at relatively larger doses, no anesthetic
effect;
not remarkably affect on REM
used
for
insomnia （ 失 眠 ）
and
A. Benzodiazepines
(3) Antiepileptic and anticonvulsant
effects
Convulsion due various causes; status epilepticus (i.v.)
(4) Centrally acting muscle relaxant effect
Relaxing the spasticity of skeletal muscle, probably by increasing
presynaptic inhibition in the spinal cord.
Used for the treatment of skeletal muscle spasms caused by central or
peripheral diseases.
(5) Others
Amnesia (短暂性记忆缺失, i.v.）
Respiratory and CVS effects
A. Benzodiazepines
2. Mechanisms of actions
(1) Sites of action:
mainly acts on limbic system and midbrain
reticular formation.
(2) Interaction with GABAA receptor
Benzodiazepines bind to specific, high affinity sites on the cell membrane,
which are separate from but adjacent to the receptor for -aminobutyric
acid (GABA).
The binding of benzodiazepines enhances the affinity of GABA
receptor for this neurotransmitter, resulting in a more frequent
opening of adjacent chloride channels. - coagonist
This in turn results in enhanced hyperpolarization（超极化）and
further inhibition of neuronal firing.
Modulation mode of the central inhibitory transmitter GABA and the action
sites of drugs
Action of the central inhibitory transmitter GABA on Cl- influx and the
action sites of benzodiazepines (BDZs)
ACh
DA
NE
5-HT
Centrally acting muscle relaxant effect:
increasing presynaptic inhibition in the spinal cord
A. Benzodiazepines
3. Adverse effects
(1) Central depression
Most common: drowsiness and confusion (potentiated by ethanol or
other central depressants).
Ataxia (共济失调); cognitive impairment
Antagonized by BZ
flumazenil（氟马西尼）
receptor
(2) Tolerance and dependence
Withdrawal syndrome: central excitation
antagonist
A. Benzodiazepines
(3) Others
local pain, respiratory and CVS reactions (i.v.)
teratogenic effects（致畸效应）
(4) Contraindications
Myasthenia gravis
Infants < 6 months
Pregnancy and lactation mothers
Elderly, heart/lung/liver/kidney dysfunction
A. Benzodiazepines
Other benzodiazepines
According to the metabolisms
 Long-acting：
diazepam, chlordiazepoxide (氯氮卓),艹
flurazepam (氟西泮)
 Intermediate-acting：
Nitrozepam (硝西泮), flunitrozepam (氯硝西泮),
oxazepam (奥沙西泮), estazolam (艾司唑仑）
 Short-acting：triazolam (三唑仑)
B. Barbiturates
Phenobarbital
NH
O
苯巴比妥
CO
C
C2H5
C
NH
CO
C6H5
B. Barbiturates
1. ADME
 Inducing hepatic enzymes
 Alkalining urine: excretion 
 硫喷妥钠脂溶性极高，故易通过BBB，易
发生再分布；
 苯巴比妥脂溶性低，不易在肝脏代谢；
 脂溶性高，血浆蛋白结合率高。
B. Barbiturates
2. Pharmacological effects and clinical
uses
(1) Sedative-hypnotic effects
可缩短REM，反跳明显；
(2) Preanesthetic medication
(3)
Antiepileptic
effects
and
anticonvulsant
B. Barbiturates
3. Adverse effects
(1) Central depression: including after
effect (hangover “宿醉”)
(2) Tolerance and dependence: longterm uses
(3) Acute poisoning
supporting therapies
alkalizing urine
hemodialysis
C. Others
 Chloral hydrate 水合氯醛
Sedative-hypnotic effects
Anticonvulsant effect: usually used in children
 Hydroxyzine
羟嗪（安泰乐）
 Meprobamate
 Buspirone
甲丙氨酯（眠尔通）
丁螺环酮
 Methaqualone
安眠酮
C. Others
 Antihistamines
 Ethanol
乙醇
 Melatonin
褪黑素
抗组胺药
In her circulation system:
8 % chloral hydrate (3% toxic
level and 10% lethal level)
4.5 % Nembutal
(pentobarbital )
(death level 1.5-4%)
In her stomach and
duodenum:
急性巴比妥中毒！
No drug
crystal found!
自杀可能！
1962年8月5日梦露在洛杉矶布莱登木寓所的卧室内被发现已经去世，终年36岁
Central stimulants
 Psychomotor stimulants
 Respiratory center
stimulants
A Psychomotor stimulants
Psychomotor stimulants
(mainly acting on cerebral cortex)
Xanthines: caffeine 咖啡因
Related drugs
Respiratory center stimulants
Direct stimulation
Indirect stimulation (reflex)
A Psychomotor stimulants
Caffeine
咖啡因
O
N
H3C
O
N
N
CH3?
N
CH3?
A Psychomotor stimulants
1. Pharmacological effects
(1) Central stimulation
(2) CVS effects: cardiac stimulation, dilatation of vessels
(3) Relaxing smooth muscles: airways, GI
(4) Other effects: Gastric acid secretion, diuretic effect
(5) Mechanisms of action：inhibiting PDE- cAMP  ；
antagonizing A1 adenosine receptor & GABA receptor
A Psychomotor stimulants
2. Clinical uses
 Central depression
 Adjuvant of migraine
analgesic drugs
3. Adverse effects
 Central excitation
 Convulsion (overdose)
and
antipyretic-
A Psychomotor stimulants
Methylphenidate 哌甲酯（利他灵）
 used for central depression caused by
drugs or diseases; mild depression; child
hyperactivity; enuresis; etc.
Meclofenoxate
甲氯芬酯（氯酯醒）
 Adjuvant of central depressive diseases;
enuresis; etc.
B Respiratory center stimulants
Nikethamide
尼可刹米
O
C2H5
C
N
C2H5
N
B Respiratory center stimulants
1. Pharmacological effects

Direct
and indirect
chemoreceptor) stimulation
(respiratory centre)
(reflex via
2. Clinical uses

Respiratory failure
3. Adverse effects

Elevation of BP, tachycardia, tremor,
convulsion
B Respiratory center stimulants
Dimefline
二甲弗林 （回苏灵）
 Direct stimulation
Lobeline 洛贝林（山梗菜碱）
 Indirect stimulation