Part 3.Cholinoceptor Blocking Drugs

( 胆碱受体阻断药 )

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Cholinoceptor Blocking Drugs:(A)Muscarinic cholinoceptor blocking drugs:Ⅰ. Atropine-like alkaloids: Atropine, et al.Ⅱ. Synthetic substitutes for Atropine: Homatropine( 后马托品 ), et al.(B)Nicotinic cholinoceptor blocking drugs:Ⅰ. NN cholinoceptor blocking drugs, —— Ganglionic blocking drugs( 神经节阻

断药 ): Mecamylamine( 美卡拉明 )Ⅱ. NM cholinoceptor blocking drugs, —— Skeletal muscle relaxants ( 骨骼肌松弛

药 ): (A) Depolarizing agents ( 除极化肌松药 ): Succinylcholine( 琥珀胆碱 ) (B) Nondepolarizing agents ( 非除极化 ): Tubocurarine( 筒箭毒碱 )2

(A)Muscarinic cholinoceptor blocking drugs

Ⅰ. Atropine-like alkaloids:

Atropine( 阿托品 ) It for M-receptor with affinity( 亲和力 ), and without intrinsic activity ( 内在活性 ), thus it can block M-receptor, but it is no selectivity to M1, M2, M3, M4, and M5

receptor.3

1. Pharmacological effects: exocrine glands ＞ eyes ＞ GI ＞heart and blood vessel ＞ CNS.(1)exocrine glands: secretion , salivary gland ( 唾液腺 ) and sweat gland ( 汗腺 ) are very sensitive.(2)Eyes: ▲ mydriasis( 扩瞳 ): strong, 7-10 days; ▲ rise in intraocular pressure; ▲ paralysis of accommodation ( 调节麻痹 ), 2-3 days.

Atropine

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Atropine

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(3)Smooth muscle: relaxation Sensitivity: GI ＞ bladder ＞ biliary

tract ( 胆道 ) ＞ bronchus ＞ ureter ( 输尿管 ).

(4)Heart: ①heart rate: 0.4 ～ 0.6 mg: heart rate blocking M1 receptor of presynaptic

membrane ( 突触前膜 ) Ach release heart rate

＞ 1 mg: heart rate blocking M2 receptor heart rate ②atrioventricular conduction ( 房室传导 )

Atropine

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(5)Blood vessel: larger dose: vasodilatation ( 血管扩

张 )

(6)CNS: when dose: 1 ～ 2 mg: exciting; ＞ 5 mg: exciting clearly; ＞ 10 mg: excitinginhibition

Atropine

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2. Clinical uses:(1)Relieving spasm of smooth muscle of

viscera( 解除内脏平滑肌痉挛 ).(2)Pre-anesthetic medication( 麻醉前给

药 )(3)Ophthomological uses( 眼科的应用 )(4)Bradycardia( 心动过缓 )(5)Treatment of septic shock( 治疗中毒性

休克 )(6)Antidote for organophosphate

poisoning( 解救有机磷酸酯类中毒 )

Atropine

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3. Pharmacokinetics: (1)Absorption: fast, after oral administration(PO); Bioavailability = 50 % (2)Distribution: wide, it can pass through Blood-brain-barrier and Placental-barrier.

(3)Elimination: ≥85% eliminated from kidney; t 1/2=4 hr, effective period: 3 ～ 4 hr.

Atropine

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4. Adverse reactions: (1)Side effects: more ! (2)Toxic reaction: CNS exciting respiratory failure

dead Maximal dose: 1mg Minimal lethal dose: Adult: 80-130 mg; Child: 10 mg 5. Contraindication( 禁忌证 ): glaucoma; prostatauxe ( 前列腺肥大 ).

Atropine

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Scopolamine( 东莨菪碱 )

1. Pharmacological effects (1)Central depression ▲ sedative effect( 镇静作用 ) ▲ anticholingeric effect.

(2)Peripheral effects similar to atropine.

Atropine-like alkaloids

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2. Clinical uses (1)Preanesthetic medication( 麻醉前给

药 ) (2)Prevention of motion sickness( 预防

晕动病 ) (3)Parkinson’s disease( 巴金森氏病 )

3. Adverse reaction Similar to atropine, but central depression.

Scopolamine

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Anisodamine( 山莨菪碱 )1. Characteristics of effects: Selectivity to smooth muscle of GI & blood vessel ＞ exocrine glands and eyes.

2. Main clinical uses: (1)GI colic ( 绞痛 ) (owing to spasm of smooth muscle);

(2)Septic shock ( 感染性休克 )

Atropine-like alkaloids

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Ⅱ. Synthetic substitutes for Atropine

1. Synthetic mydriatics:

Homatropine( 后马托品 ) Mydriasis and paralysis of accom-modation with a short duration of action(1-2 days). 扩瞳、调节麻痹

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2. Synthetic antispasmotics:Propantheline bromide( 溴丙胺太

林 , probanthine, 普鲁本辛 )

Characteristics: ▲ quaternary amine compound, it is absorbed difficultly by oral administration.

▲ use only in antispasmodics and anti-ulcer therapy in GI system.

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Benactyzine

( 贝那替嗪 , 胃复康 ) Characteristics: (1)tertiary amine compound It can be absorbed easily. (2)pharmacological effect: ①antispasmodic effect; ②inhibiting of secretion of gastric acid; ③sedative effect ( 镇静 ). It can be used to anti-ulcer therapy, especially the patients with anxiety.

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3. Selective M1 receptor blocking agents:

Pirenzepine( 哌仑西平 )& Telenzepine( 替仑西平 )

Characteristics: ▲ selectively block M1receptor,

reducing secretion of gastric acid; ▲ be used to treat peptic ulcer ( 消化性

溃疡 ).17

(B)Nicotinic cholinoceptor blocking drugs

Ⅰ. NN cholinoceptor blocking drug —— Ganglionic blocking drugs

( 神经节阻断药 ):

Mecamylamine( 美卡拉明 ) Trimethaphan( 樟磺咪吩 )

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Ⅱ. NM cholinoceptor blocking drugs (NM 受体阻滞药 )

—— Neuromuscular blocking agents ( 神经肌肉阻滞药 ) or Skeletal muscle relaxants ( 骨骼肌松弛药 ): According to the mechanism of action, they can be divided into two kinds: (A)Depolarizing agents (B)Nondepolarizing agents

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(A)Depolarizing agents ( 除极化型肌松药 )

H3C

Succinylcholine( 琥珀胆碱 , Scoline, 司可林 )

H3C O H3C N+-CH2-CH2-O-C-CH3

H3C 乙酰胆碱 H3C O O CH3 H3C N+-CH2-CH2-O-C-CH2-CH2-C-O-CH2-CH2-N+ CH3 H3C CH3

琥珀胆碱20

Succinylcholine( 琥珀胆碱 , Scoline, 司可林 )

1. Characteristics of pharmacology: (1)Depolarization—desensitization; (2)Short-acting: after iv, 1 min go into effect; 2 min to max; 5 min the effect vanish, because it is destroyed by plasma esterase fast.

(3)muscle bundle tremle( 肌束颤动 ).21

2. Clinical Uses

▲ Surgery;

▲ Insertion of endoscopes;

Succinylcholine

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3. Adverse reactions (1)Muscular pain (2)Respiratory paralysis/overdose, this ADR can be rescued by artificial

respirator(iron lung ), but the patients can not be injected by neostigmine ! ! !

(3)Hyperpotassemia; (4)Malignant high fever.

Contraindication: Glaucoma, a tendency to hyperpotassemia.

Succinylcholine

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(B)Non-depolarizing agents ( 非除极化型肌松药 )

Tubocurarine( 筒箭毒碱 ) Characteristics compared with Scoline: (1)competitive neuromuscular blockade;(2)longer action: iv, 3 ～ 6 min go into effect,

80 ～ 120 min later the effects vanish. (3)can block ganglion ( 神经节 ) & induce

histamine releasing, Bp , and asthma attack

(4)respiratory paralysis/overdose: can be rescued by injection of neostigmine and artificial respirator.

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Contraindication: (1)myasthnia gravis ( 重症肌无力 ); (2)bronchial asthma, because of histamine release; (3)shock, because of Bp ; (4)child (< 10 years old), hyperreactivity of child to this drug.

Other nondepolarizing agents: Pancuronium( 泮库胺 ): long-acting, 2-3h; Atracurium( 阿曲库胺 ): intermediate -acting, 30-40 min; Mivacurium( 米库胺 ): short-acting, 12-18 min,

Tubocurarine

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Part 4.Adrenoceptor agonists

( 肾上腺素受体激动药 )

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•Ⅲ. -Adrenoceptor agonists

Ⅰ . Chemical structure and the relationship between structure and effects

•Ⅱ. , -Adrenoceptor agonists

•Ⅳ. -Adrenoceptor agonists

•Contents

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Ⅰ . Chemical structure and the relationship between str

ucture and effects

CH2-CH2-NH2 -phenylethylamine(- 苯乙胺 )

HO HO catechol( 儿茶酚 ) 28

HO CH-CH2-NH2 HO catecholamine ( 儿茶酚胺 )

HO CH-CH2-NH2 HO OH noradrenaline( 去甲肾上腺素 )

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According to the selectivity of drugs to or adrenoceptor, they can be divided into 3 kinds:

, -adrenoceptor agonist;

-adrenoceptor agonist;

-adrenoceptor agonist.

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1. , - adrenoceptor agonist: • Adrenaline( 肾上腺素 ), Ephedrine( 麻黄碱 )

•2. - adrenoceptor agonist: • (1) 1, 2 receptor agonist:• Noradrenaline( 去甲肾上腺素 )• (2) 1 receptor agonist:• Phenylephrine( 去氧肾上腺素 )• (3) 2 receptor agonist: • Oxymetazoline( 羟甲唑啉 )•3. - adrenoceptor agonist: • (1) 1, 2 receptor agonist• Isoprenaline( 异丙肾上腺素 )• (2) 1 receptor agonist:• Dobutamine( 多巴酚丁胺 )• (3) 2 receptor agonist:• Salbutamol( 沙丁胺醇 )

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Ⅱ. , -Adrenoceptor agonists:

Adrenaline( 肾上腺素 , AD)

HO CH-CH2-NH-CH3

HO OH

Activating and receptors directly.

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1. Phamacological effects: (1)Heart stimulation: very strong, activating 1 & 2 receptor. ●Force of myocardial contraction ( 心肌收

缩 ) (1 receptor); ●A-V conduction(1 receptor); ●Heart rate(1& 2 receptor); ●Cardiac output( 心输出量 ); ●Automaticity( 自律性 ); ●Oxygen consumption( 氧耗量 ), so that the

work efficiency.

•Adrenaline

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(2)Blood vessel: ●vessel of skin, mucosa, visera: vasoconstriction, by activating

receptor; ●vessel of skeletal muscle: vasodilation, by activating 2 receptor; ●coronary artery ( 冠状动脉 ): vasodilation, by activating and 2

receptor; ●renal artery: vasoconstriction, by activating receptor,

the volume of renal blood flow .

•Adrenaline

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(3)Blood pressure: Therapeutic doses: by activating 1, 2 receptor and receptor:

systolic pressure: diastolic pressure: or pulse pressure

( 脉压差 ): Large doses: systolic pressure: diastolic pressure: pulse pressure:

•Adrenaline

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(4)Smooth muscle: ①Bronchus: ▲ 2 receptor activated: ● bronchodilatation; ● inhibiting mast cell( 肥大细胞 )

releasing histamine( 组胺 ) & other anaphylactic mediators( 过敏介质 ).

▲ receptor activated: ● relieving congestion & edema of the

bronchial mucosa. ( 消除支气管粘膜水肿 )

•Adrenaline

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②Gastrointestinal tract: , receptor activated, inhibiting

smooth muscle of GI. ③Bladder: 2 receptor activated, inhibiting

bladder pubovesical muscle( 膀胱逼尿肌 )—— retention of urine( 尿潴留 ).

④Eyes: ▲ mydriasis is unclear; ▲ reducing aqueous humor( 房水 ),

intraocular pressure .37

(5)Metabolism: ①glycogenolysis ( 糖原分解 ): by activating and 2 receptor of liver cell;

②insulin: by activating 2 receptor of islet cell; ( 抑制胰岛素释放 )

① + ② blood sugar . ③lipolysis: by activating 2 and 3 receptor of fat cell.

(6)CNS: ①small dose: unclear; ②large dose: CNS excited.

•Adrenaline

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2. Clinical uses: (1)Cardiac arrest( 心脏骤停 ); (2)Anaphylactic shock( 过敏性休克 ); (3)Bronchial asthma( 支气管哮喘 ); (4)Local use: ●prolonging anesthetic time of local anesthetics( 延长局麻药麻醉时间 ):

1/250 000 (4 g/ml) total dose ＜ 0.3 mg. ●local hemostasis( 局部止血 ): 0.1%

•Adrenaline

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3. Adverse reactions: (1)Bp / overdose, cerebral hemorrhage( 脑出血 ); (2)Arrhythmia( 心律失常 ).

Contraindication: ▲ hypertension( 高血压 ); ▲ diabetes( 糖尿病 ); ▲ cerebral arteriosclerosis( 脑动脉硬化 ); ▲ organic heart disease( 器质性心脏病 ); ▲ hyperthyroidism( 甲亢 ), etc.

•Adrenaline

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Ephedrine( 麻黄碱 )

CH-CH-NH-CH3

OH CH3

Direct action: weak activating , receptor

Indirect action: promoting NA release.

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1. Pharmacokinetics: (1)Absorption: po: fast and wholly, Tmax=1 hr; sc: faster. (2)Distribution: whole body, can pass through BBB. (3)Elimination: The most excreting from kidney, T ½=3 ～ 6 hr, The effective period: 3 ～ 6 hr/ once

dosage.

•Ephedrine

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2. Pharmacological effects: Comparing with Adrenaline, there are 4 characteristics:

• (1)weaker potency and longer duration of action;

• (2)effective by p.o.;• (3)more pronounced central

action;• (4)tachyphylaxis(快速耐受性 )

•Ephedrine

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3. Clinical uses: (1)Prevention and treatment of

hypotensive state; (2)Nasal congestion; (3)Prevention and treatment of

bronchospasm; (4)Certain allergic disorders.

4. Adverse reaction: (1)Central exciting; (2)BP, contraindicte hypertension.

•Ephedrine

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Dopamine(多巴胺 , DA)

HO CH2 CH2 NH2

HO It can activat 1, and DA receptor.

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1. Pharmacological effect: (1)small doses: ▲ activating 1 receptor, cardiac

output ▲ activating D1 receptor, volume of

renal blood flow ,

(2)large doses: ▲ activating receptor: Bp

•Dopamine

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2. Clinical uses: (1)Antishock; (2)Acute renal failure, used with diureti

cs(利尿药 ).

3. Adverse reaction: less. (1)Arrhythmia ( 心律失常 ); (2)reducing renal function when overd

ose, or iv fast.

•Dopamine

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Ⅲ. - Adrenoceptor agonists: 1, 2-Adrenoceptor agonists

Noradrenaline( 去甲肾上腺素 , NA)1.Pharmacological effects: (1)Vasoconstriction: activating 1 receptor; (activating 2 receptor also) (2)Stimulating heart: activating 1 receptor also. “ large and small effect” (3)Blood pressure . 48

2. Clinical uses: (1)Hypotension and early stage of

shock; (2)Hemorrhage of upper digestive tract.

3. Adverse reaction: (1)Local ischema and necrosis ( 局部组

织缺血坏死 ); (2)Inducing acute renal function failure.

•Noradrenaline

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Metaraminol( 间羟胺 ,Aramine, 阿拉明 )

CH-CH-NH2

HO OH CH3

Direct action: activating receptor;

Indirect action: promoting NA release.

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1-Adrenoceptor agonists

Phenylephrine( 去氧肾上腺素 )

CH-CH2-NH-CH3

HO OH The other name: 苯肾上腺素 , or Neosynephrine(新福林 )

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1. Characteristics of action: Only activating 1 receptor.

2. Clinical uses: (1)Paroxysmal supraventricular ta-

chycardia(阵发性室上性心动过速 ) (2)Mydriasis( 扩瞳 ): eye drops

•Phenylephrine

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2-Adrenoceptor agonists1. 2-receptor agonist of peripheral postsynaptic membrane:

Oxymetazoline(羟甲唑啉 , 氧甲唑啉 ) to treat congestion of nasal mucosa and rhinitis, 0.05% solution.

Apreclonidine( 阿可乐定 ) to treat glaucoma, because of reducing aqueous humor.

2. 2-receptor agonist of CNS: Clonidine( 可乐定 ) & Methyldopa ( 甲基多巴 ): anti-hypertensive drugs.53

Ⅳ. -adrenoceptor agonists:

1, 2 - adrenoceptor agonists

Isoprenaline(异丙肾上腺素 )

CH3

HO CH CH2 NH CH

HO OH CH3

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1. Pharmacological effects: (1)Stimulating heart: activating 1 activation (2)Vasodilation: activating 2 activation (3)Blood pressure: small dose: systolic pressure diastolic pressure pulse pressure large dose: average Bp

•Isoprenaline

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(4)Branchodilation: 2 activation;

(5)Glycogenlysis and lipolysis.

2. Clinical uses: (1)Cardiac arrest ( 心脏骤停 ); (2)A-V conduction blocking ( 房室传导

阻滞 ); (3)Acute attack of asthma; (4)Anti-shock ? ×

•Isoprenaline

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1 - adrenoceptor agonists:

Dobutamine(多巴酚丁胺 ) CH2-CH2- -OH HO CH2-CH2-NH-CH HO CH3 Activating 1 receptor only: Myocardial contraction( heart rate), cardiac output.

can be used to treat myocardial infarction with cardiac failure ( 心肌梗死并发心力衰竭 ).

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2 - adrenoceptor agonists:

Salbutamol(沙丁胺醇 ), Terbutaline(特布他林 ), Clenbuterol( 克仑特罗 ), etc.

They are used to treat asthma mainly, without cardiac reaction. 58

• 应颂敏应颂敏• yings@zju.edu.cnyings@zju.edu.cn 5959

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