Part 5. Adrenoceptor antagonists

( 肾上腺素受体阻断药 )

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Classification of adrenoceptor blocking drugs

① receptor blocking drugs phentolamine ( 酚妥拉明 )

② receptor blocking drugs propranolol ( 普萘洛尔 )

③, receptor blocking drugs: labetalol ( 拉贝洛尔 )

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Ⅰ. Adrenoceptor blocking drugs Classification of adrenoceptor blocking drugs: 1 , 2 receptor blocking drugs: short-acting drug: Phentolamine( 酚妥拉明 ) long-acting drug: Phenoxybenzamine( 酚苄明 ) 1 receptor blocking drug: Prazosin( 哌唑嗪 ) 2 receptor blocking drug: Yohimbine( 育亨宾 ) 3

1, 2 receptor blocking drugs:

Phentolamine( 酚妥拉明 )

1. Pharmacological effects: It can block 1 & 2 receptor. The results of -blockade of peripheral nerve:

▲ 1 receptor blockade: 1 receptor is located in blood vessel, when 1receptor of vessel is blocked, vasodilatation.

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▲ 2 receptor blockade: 2 receptor is located in presynaptic membrane of peripheral nerve terminal: negative feedback regulation When 2 receptor of presynaptic membrane of peripheral nerve terminal is activated, the release of NA can be inhibited. When 2 receptor is blocked, the negative feedback of NA release is cancelled, the release of NA increase.5

(1)Vasodilatation: lead to Bp, ①1 receptor of vessel is blocked, vasodilatation. ②direct relaxation on vascular smooth muscle. (2)Heart stimulation: ①Bp, reflexly heart stimulating; ②presynaptic 2-blockade, cancel negative feedback, to promot NA release, and NA activate 1-receptor of heart. (3)Other action: ①cholinomimetic ②promoting histamine release.

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2. Clinical uses: (1)Peripheral angiospastic disease ( 外周血管痉挛性疾病 ): Raynaud’s disease( 雷诺氏病 , 或 acr

ocyanosis, 肢端青紫症 ). (2)Vasoconstructor extravasation ( 血管收缩剂外漏 ): local infiltration injection. (3)Pheochromacytoma( 嗜铬细胞瘤 ) pre-operational administration, to

prevent Bp .

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(4)Antishock: especially septic shock ( 脓毒性休克 ).

(5)Acute myocardial infarction ( 心肌梗死 ) and congestive cardiac failure ( 充血性心力衰竭 ):

●Venous dilatation: preload ●arterial dilatation: afterload

(6)To diagnose and treat impotence ( 阳痿 ).

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3. Adverse reactions: (1)Orthostatic hypotension( 体位性低血压 , or 直立性低血压 )

(2)Heart stimulation Palpitation( 心悸 ), Tachycardia( 心动过速 ) (3)Gastrointestinal effects: abdominal pain; diarrhea; nausea ( 恶心 ); vomit; and inducing or worsening of peptic ulcer.

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Tolazoline( 妥拉苏林 )1. Effects are similar to phentolamine, but ▲ weaker, ▲ effective by po, ▲ adverse reaction is more.2. Clinical uses: ● Peripheral angiospastic disease ( 外

周血管痉挛性疾病 ): po. ● Pheochromacytoma( 嗜铬细胞瘤 ), to control symptoms.3. Adverse reaction: more than phentolamine.

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Phenoxybenzamine( 酚苄明 )1. Pharmacological effects: blocking 1 and 2 receptor, but slowly, powerful and lasting. 2. Clinical uses: (1)Peripheral angiospastic disease ( 外周血管痉挛性疾病 ) (2)Pheochromacytoma( 嗜铬细胞瘤 )

3. Adverse reaction: Orthostatic hypotension( 直立性低血压 )

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1 adrenoceptor blocking drugs

Prazosin( 哌唑嗪 )

It selectively block 1receptor of artery and vein, the blockade to 2 receptor is very weak.

It can antagonize BP↑of NA, but can’t promote NA release, so that it can’t cause heart rate↑.

used to treat hypertension.12

2 adrenoceptor blocking drugs

Yohimbine( 育亨宾 ) It can selectively block 2 receptor in peripheral & central nerve system, to elevate BP and heart rate .

Its uses: ▲ a tool agent in laboratory; ▲ other uses: male sexual disfunction.

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Ⅱ. adrenoceptor blocking drugs CH3

HO— —CH—CH2—NH—CH HO OH CH3

Isoprenaline blocking drug 与 Isoprenaline 有共同结构 : CH3

—CH—CH2—NH—CH OH CH3

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Classification of blocking drugs1: 1 , 2 receptor blocking drugs: 1A: without intrinsic sympathomimetic

activity(ISA, 内在拟交感神经活性 ): Propranolol( 普萘洛尔 ), Timolol 1B: with ISA: Pindolol( 吲哚洛尔 )2: 1 receptor blocking drugs: 2A: without ISA: Atenolol( 阿替洛尔 ) 2B: with ISA: Acebutolol( 醋丁洛尔 )3: , receptor blocking drugs: Labenolol( 拉贝洛尔 )15

Propranolol( 普萘洛尔 )1. Pharmacological effects 1 , 2 receptor blocking drugs without ISA, belong to 1A. (1) receptor blockade: ①Heart: 1 blockade ▲ Negative inotropic ( 负性肌力 ) effect: cardiac output ▲ Chronotropic effect: heart rate ▲ Oxygen consumption ▲ A-V conduction ▲ Automaticity 16

②Blood vessel and BP: ▲ Normal subjects: peripheral resistance ▲ Hypertensive patients: Bp

③Bronchial effects: 2 blockade ▲ Normal subjects: no problem ▲ Asthmatic subjects (bronchial responsiveness): ●resistance of airway ●inducing and worsening asthma.

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④Renin ( 肾素 ): Owing to 1 receptor blockade of juxtaglomerular cell( 肾小球旁细胞 ).

⑤Metabolism: can block 2 receptor of liver cell, to inhibit glycogenolysis ( 糖原分解 ); can block 3 receptor of fat cell, to inhibit lipolysis ( 脂肪分解 ).

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(2)Membrane-stabilizing effect: at high concentration. (3)Inhibiting platelet-aggregation: reducing viscosity ( 粘性 ) of blood.

2. Pharmacokinetics: ▲ first pass elimination is obvious, 60%

～ 70%, bioavailability is low, about 30%.

▲ large variation between individuals, about 20 times.

dose individualization !19

3. Clinical Uses: (1)Arrhythmia( 心律失常 );

(2)Coronary heart disease and angina pectoris( 冠心病和心绞痛 );

(3)Hypertension( 高血压 );

(4)Hyperthyroidism and thyroid crisis( 甲状腺机能亢进和甲状腺危象 ).

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4. Adverse reactions: (1)Inducing acute heart failure; (2)Inducing and worsening asthma; (3)Withdrawal syndrome ( 戒断综合征 ); (4)Contraindication: heart failure; sinus bradycardia ( 窦性心动过缓 ); high grade A-V block; bronchial asthma.

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Timolol( 噻吗洛尔 )

It is the most powerful receptor blockade, 5~10 times stronger more than propranolol. eyedrops(0.25% solution) used to treat glaucoma. To lower intraocular pressure by reducing the production of aqueous humor( 房水 ).

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Part 6.

Sedative-hypnotics ( 镇静催眠药 )

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Brief Introduction1. History of Sedative-hypnotics 19 century Sedatives: from 1853, Bromide( 溴剂 ): KBr, NaBr, NH4Br; Hypnotics: Chloral hydrate( 水合氯醛 ) 20 century Sedative-hypnotics: from 1903, Barbiturates ( 巴比妥类 ) from 1961, Benzodiazepines ( 苯二氮

卓类 )24

2. Classification: According to the chemical structure, sedative-hypnotics can be divided into 3 kinds:

(1)Benzodiazepines( 苯二氮卓类 );

(2)Barbiturates( 巴比妥类 );

(3)Others( 其他类 ).

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Ⅰ. Benzodiazepines( 苯二氮卓类 , BZ, BDZ):

According to the duration of action, they can be divided into 3 kinds:

▲ Long-acting: diazepam( 地西泮 ) ▲ Intermediate-acting: clonazepam( 氯硝西泮 ) ▲ Short-acting: triazolum( 三唑仑 )

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Diazepam( 地西泮 , Valium, 安定 )

1. Pharmacological effects & Clinical uses:

(1)Anti-anxiety( 抗焦虑 ): Small dose and high effective, to treat anxiety: 2.5 ～ 5 mg, tid, po.

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(2)Sedative-hypnotic effect:

Sedation: 5 mg, tid, po. Hypnotism: 10 mg, qn. The merits of diazepam: ①TI higher, safety of margin larger; ②effect on REM is small; ③don’t induce P450; ④dependence & addiction small; side reaction is light.⑤ Preanesthetic medication: 10mg iv.

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(3)Anti-convulsant and anti-epilepsy effect( 抗惊厥和抗癫痫作用 )

Convulsion( 惊厥 ): 10 mg, iv. Status epilepticus( 癫痫持续状态 ) 10 mg, iv. (4)Centrally acting muscle relaxant ( 中

枢性肌肉松弛 ): Central myotonia( 中枢性肌强直 ) Lumbar muscle strain( 腰肌劳损 ) (5)Other effect and clinical uses: Transient dysmnesia( 暂时性记忆缺失 ) Endoscopy( 内窥镜检查 )

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2. Mechanism of BZ effects:

GABA receipt site

GABAAreceptor

Cl- BZ receptor

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GABA: Gama-Aminobutyric acid ( - 氨基丁酸 )(1)There are GABAergic neuron in CNS,

the terminal release GABA;(2)GABAA receptor is a ligand-gated Cl-

channel( 配体门控性 Cl- 通道 ), which located at post-synaptic membrane of GABAergic neuron.

GABAA receptor consists of 4 groups of , , , , and 14 subunites;

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(3)When GABA combine with GABAA receipt site, the Cl- channel open, Cl- influx, then postsynaptic membrane super-polarization, to produce post-synaptic inhibition;

(4)When BZ combine with BZ receptor, to promote GABA combine with GABAA

receipt site, the frequency of which Cl- channel open increases, more Cl-

influx.32

Mechanism of BZ effects:

GABA receipt site

GABAAreceptor

Cl- BZ receptor

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3. Pharmacokinetics: (1)Absorption: po: fast and wholly, im: slow and irregular: im× (2)Elimination: t1/2= 44 ±13 hr, its metabolites are demethyldiazepam ( 去甲西泮 ) and oxazepam( 奥沙西泮 ), they have pharmacological activity.

Diazepam can be secreted from milk, to inhibit CNS of baby.

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4. Adverse drug reaction(ADR): ADR of Diazepam are less, toxicity low and safety margin large. When overdose, especially taking other CNS inhibitors or drinking at same time, it will lead to intoxication easily. When intoxication, flumazenil( 氟马西尼 ) can be used to first-aid, the latter is an antagonist of BZ receptor. Taking long time: tolerance, dependence, addiction.

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5. Other drugs(1):Chlordiazepoxide( 氯氮卓 , 利眠宁 )

belong to long-acting, t1/2 = 7~13(10 ±3.4) hr,

Clinical uses: ①anxiety, 10 mg began; ②hypnosis, 10~30 mg, qn; ③alcohol abstinence symptoms ( 酒精戒断症状 ).

Nitrozepam( 硝西泮 , 硝基安定 ) belong to intermediate acting (6~8hr). t½=26hr, used to treat convulsion ( 抽 搐 ), clonic seizure( 肌 阵 挛 性 发 作 ), status epilepticus ( 癫痫持续状态 ), preanesthetic medication ( 麻醉前给药 ).

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5. Other drugs(2):Clonazepam( 氯硝西泮 , 氯硝安定 )

belong to intermediate-acting, t1/2=15 hr, used to control Petit mal( 癫痫小发作 ).

Triazolum( 三唑仑 , 三唑安定 ) belong to short-acting, t1/2=2.3±0.4hr, used to treat various isomnia( 各种失眠症 ), 0.25 ~ 0.5 mg, qn.

Estazolam( 艾司唑仑 , 舒乐安定 ) belong to intermediate-acting, t1/2=10 ~30hr, the effects of sedation, hypnosis, anti-anxiety, anti-convulsion are stronger, used to treat various isomnia ( 失眠 ), convulsion, pre-anesthetic medication.37

Part 2. Barbiturates1. Classification: ● Ultrashort-acting: Thiopental sodium( 硫喷妥钠 ), 15’ ● Short-acting: Secobarbital( 司可巴比妥 ), 2-3 hr ● Intermediate-acting: Pentobarbital( 戊巴比妥 ) and Amibarbital( 异戊巴比妥 ), 3-6 hr ● Long-acting: Phenobarbital( 苯巴比妥 , Luminal, 鲁 米

那 ), 6-8 hr38

2. Pharmacological effects: Most drugs: dose from small to large, its effect:

▲ sedation ▲ hypnosis ▲ anesthesia ▲ respiratory inhibition Some drugs: anti-convulsant and anti-epileptic ( 抗癫痫 ) effects

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3. Mechanism of action:

Cl- Barbiturate receptor

GABAA receipt site

GABAAreceptor

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4. Clinical uses: (1)Intravenous anesthesia & induced an

esthesia(Thiopental sodium); (2)Anticonvulsion(phenobarbital); (3)Antiepileptic(phenobarbital); (4)Sedation & hypnotism ? ×

5. Adverse reaction: (1)After effect: hangover( 宿醉 ); (2)Respiratory inhibition /overdose; (3)Allergy; (4)Tolerance and dependence.

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6. Acute barbiturate intoxication: (1)Oral intoxication: gastric lavage promptly ( 及时洗胃 ); (2)Artificial respirator + intravenous infusion ( 静脉滴注 ) + stimulants ( 兴奋剂 ) (3)Alkalinizing the urine + diuretics( 利尿药 ); (4)Hemodialysis( 血液透析 ).

7. Drug interaction: Enzyme inducer — Phenobarbital

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Part 3. Others Chloral hydrate( 水合氯醛 )1. Pharmacological effects and

clinical uses: (1)Hypnosis: 15’, 6-8hr. 5~10 ml(10%),

dilution, po (2)Anticonvulsion: 10-20 ml(10%), pr.

2. Adverse reaction: (1)Irritant action (2)Tolerance, dependence, addiction3. Contraindication: severe heart, liver and kidney disease. 43

Melatonin( 褪黑素 , MT) The other name: “ 美拉托宁” MT is a main hormone secreted from pineal body( 松果体 ), there are many physiological effects. After taking MT, normal subjects fall asleep fast, and the quality of sleep is very good.

Clinical uses: ①hypnosis; ②to get over time difference( 时差 , jet lag), its ADR is less.

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应颂敏yings@zju.edu.cn 4545

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