chapter 7 cholinoceptor-blocking drugs zhang bin institute of pharmacology school of medicine,...

Chapter 7

Cholinoceptor-Blocking DrugsZhang Bin

Institute of PharmacologySchool of Medicine, Shandong University

Section 1 Muscarinic cholinoceptor -blocking drugs

Atropine and atropine-like alkaloids

Synthetic atropine substitutes

atropine and atropine-like alkaloids

atropine-like alkaloids and their resources

植物 主要生物碱

颠茄 (atropa belladonna) 莨菪碱 (hyoscyamine )

曼陀罗 (datura stramonium) 莨菪碱洋金花 (datura sp) 东莨菪碱 (scopolamine)

莨菪 (hyoscyamus niger) 莨菪碱 唐古特莨菪 (scopolia tangutica) 山莨菪碱 (anisodamine) 樟柳碱 (anisodine)

阿托品为消旋莨菪碱

well from gut, well into the eye conjunctiva ( 眼结膜 ), scopolamine: skin

Widely distribution, high levels achieved in CNS, especially scopolamine

Atropine: t1/2 = 4h, 60% unchanged in urine, others as hydrolysis and conjugation products

Atropine: effects about 3-4h, but in eye, effects on the iris & ciliary muscle persist for 72h or longer

pharmacological actions

block M-R: competitive and nonselective block NN-R : in large dose

Organ sensitivity: Gland ＞ eye ＞ splanchnic smooth

muscle ＞ cardiovascular system ＞CNS

Atropine

1. glands: secretion↓salivary, sweat > lacrimal, respiratory >

gastric acid > pancreatic, intestinal juice

(1) Sweat glands Actions:

↓secretion of the sweat glands—dry skin. In adult, large dose cause T ↑; In ℃infants& children ordinary dose cause “atropine fever”

Uses: night sweat

elimination

generationContraction of skeletal muscle

Metabolism of body

evaporation （ sweating）

conduction; convection; radiation

respiratory; gastrointestinal tract; urine

temperature

elimination

generationContraction of skeletal muscle

Metabolism of body

(2) salivary glands: Actions: ↓salivary secretion markedly Side reactions: dry mouth, swallowing and

talking difficultly Uses: salivation

(3) Respiratory tract glands Uses:

pre-anaesthetic agent to avoid asphyxia (窒息 )

asthma (ipratropium)

(4) Lacriminal glands

(5) gastic glands: Actions:

Large dose, ↓gastric acid, pepsin secretion Uses: peptic ulcer (pirenzepine)

2. eyes (1) mydriasis (2) increase intraocular pressure (3) paralysis of accommodation

(1) Mydriasis Uses: iritis, iridocyclitis, funduscopic examination ( 眼底镜检查 )

Side reactions: photophobia (afraid of light)(2) Intraocular pressure↑ Side reactions ： induce glaucoma(3) Paralysis of accommodation (cycloplegia, 睫状肌麻痹 ) Uses: diopter examination ( 屈光度检查 ) Side reactions: near vision blurred

hospital Glasses shop

optometry

normal

glasses

3. spasmodic smooth muscle: relaxation GI tract : significant

relax walls of the viscera, both tone & propulsive ↓ Detrusor muscle of bladder: significant Ureter (输尿管 ), Bronchial: weak Biliary tract, Uterus: no significant effect

(spasmodic)

4. heart:

(1) HR temporary decrease (presynaptic M1blockade)

increase (block vagal effect on M2 –R of sinoatrial

node)

(2) A-V conduction: increase

5.vessels: At normal dose: little effect At large dose: dilate Mechanism:

(1) Direct effect (2) Compensative reaction by T℃ rise

Uses: infective shock Side reactions: flush skin

6. CNS: excited In clinical doses, minimal stimulant

effects on CNS In toxic doses

Excited (excitement, anxiety, delirium, hallucinations, convulsions) →depression (coma )

Clinical Uses

1. Anti-smooth muscle spasm

2.  Pre-anaesthesia medication agent

3.  Ophthalmological use(1) iridocyclitis; (2) optometry(验光 )

(3) examination of ocular fundus (眼底检查 )

4. Bradyarrhythmias

5. Shock

6. Intoxication of organophosphate or mushroom

1. Anti-smooth Muscle Spasm

Visceral colic pain ( 绞痛 ), especially GI colic pain Urinary urgency caused by inflammaion or tumor;

enuresis( 遗尿症 )

biliary colic and renal colic pain, often combined

with an opioid drug

2. inhibiting secretion of glands Pre-anaesthesia medication

combined use with conventional sedatives: Diazepam — elimination of tension; transient amnesia

hyperhidrosis ( 多汗 ) and salivation

3.  Ophthalmological Use iritis, iridocyclitis funduscopic examination diopter examination

For adult: homatropine

For younger children: atropine

4. Bradyarrhythmias Treatment of depression of sinoatrial or

atrioventricular node function (bradycardia) Treatment of bradyarrhythmias caused by

acute myocardial infarction

注意剂量

5. Shock very large dose of atropine, most common used

to treat infectious intoxicated shock

contraindication:

shock with high fever or tachycardia

adverse reactions

1. Common Side Effects

a. Dry mouth, blurred visionb. Tachycardiac. Dryness of skin and flushd. Difficulty in urination, constipatione. Dizziness, confusion

2.    Acute Poisoning

a. Hyperthermiab. Tachypnea ( 呼吸急促 )

c. Restlessness, delirium, hallucination, convulsion, coma

d. Respiratory paralysis

minimal lethal dose: adults –80~130mg children-- 10mg

Prevention

1. Decontamination:

to prevent further absorption

2. Antidotes:

Parasympathomimetics (physostigmine iv repeatly)

3. Symptomatic treatment (diazepam)

Maintenance of vital signs

Contraindication: Glaucoma Prostatic hypertrophy

Anisodamine (654-2, 山莨菪碱 )

[Characteristic of Actions] 1.high selectivity (smooth muscle and vessels)

2.little side effect (not pass through BBB, other effects are weaker than Atropine)

[Clinical Uses] 1. Septic Shock 2. visceral colic

人工合成的消旋品

Scopolamine( 东莨菪碱 )

[Characteristics] 1.CNS actions: depression (strong)

2.peripheral actions: (VS Atropine)

glands: stronger

others: weaker

Rapidly & fully distributed into CNS, greater CNS effects than others

[Clinical Uses] 1. pre-anaesthesia medication: better 2. prevention of motion

sickness, vomiting of pregnancy or

radiation disease 3. Parkinson disease 4. traditional medicine anaesthesia

抑制前庭神经内耳功能或大脑皮层功能

motion sickness 晕动病，是晕车、晕船、晕机等的总称。指乘坐交通工具

时，人体内耳前庭平衡感受器受到过度运动刺激，前庭器官产生过量生物电，影响神经中枢而出现的出冷汗、恶心、呕吐、头晕等症状群。

防治： 1. 镇静止吐药，如乘晕宁、东莨菪碱、安定等，抑制中枢

兴奋，缓解消化道痉挛。 2. 耳后皮肤贴剂，为东莨菪缓释剂可经皮肤渗透吸收。 3. 其它：贴肚脐、压内关穴、开窗通风向前注视、前庭锻

炼方法（如同飞行员训练，在相当一段时间内反复刺激前庭，如：旋转椅、秋千、俯虎、荡船等，使前庭产生适应，可以达到减轻晕动病症状的目的）

Synthetic atropine substitutes

Synthetic Mydriatics

Synthetic Antispasmodics

Selective M1 Antagonists

Synthetic Mydriatics

Homatropine( 后马托品 ) Tropicamide( 托吡卡胺 ) Cyclopentolate( 环喷托酯 ) Eucatropine( 尤卡托品 )

Comparison of some mydriatics

drugsconcentration(%)

mydriasis paralysis of accommodation

peak(m) duration(d)

peak(h) duration(d)

atropine 1.0 30~40 7~10 1~3 7~12

homatropine 1.0~2.0 40~60 1~2 0.5~1 1~2

tropicamide 0.5~1.0 20~40 0.25 0.5 <0.25

cyclopentolate 0.5 30~50

1 1 0.25~1

eucatropine 2.0~5.0 30 1/12~1/4 noUses: iridocyclitis, optometry, examination of retina

Synthetic Antispasmodics

Quaternary amines ( 季胺类 ) ：Propantheline bromide ( 溴丙胺太林，普鲁本辛 )1. low BBB permeability2. Low absorption orally (take before meal)3. Used in ulceration, GI spasm, bladder stimulation,

prevention of enuresis and vomiting from the cause of pregnancy

4. NM-R blockadge at toxic dose

Ipratropium bromide( 异丙托溴胺 )1. low BBB permeability2. Relieve bronchospasm by inhalation3. Uses: chronic obstructive pulmonary disease4. ganglionic block action stronger than atropine

Quaternary amines ( 季胺类 )– propantheline bromide ( 普鲁本辛 )

– Ipratropium bromide ( 异丙托溴铵 )

– Tiotropiumbromide ( 噻托溴铵 )

– Glycopyrronium bromide ( 格隆溴铵 )

– Oxyphenonium bromide ( 奥芬溴铵 )

– Valethamate bromide ( 戊沙溴铵 )

– Diponium bromide ( 奥芬溴铵 )

Most of others are used as the auxiliary medicine in ulcers

Tertiary amines ( 叔胺类 ) ：Benactyzine ( 贝那替嗪，胃复康）1. high BBB permeability

2. high absorption orally

3. Antianxiety

4. Used in ulceration, GI spasm, bladder stimulation

Tertiary amines Benactyzine （贝那替秦） Benzatropine mesylate ( 甲磺酸苯扎托品 ) trihexyphenidyl hydrochloride （盐酸苯海

索） Dicyclomine hydrochloride （双环维林） Oxyphencyclimine （羟苄利明） Oxybutynin （奥昔布宁）

Selective M1 Antagonists

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

Inhibit secretion of gastric acid and pepsin Clinical use: peptic ulcer Not into CNS

Section 2 Nicotinic cholinoceptor- blocking drugs

NN-R antagonists

(ganglionic blocking drugs)

NM-R antagonists

(neuromuscular blocking drugs)(skeletal muscular relaxants)

Ⅰ NN-R antagonists

(ganglionic blocking drugs)

Mecamylamine ( 美卡拉明，美加明 )

Trimethaphan ( 樟磺咪芬，阿方那特 )

NN-R antagonists

[Characteristics] Co-innervation and dominant theory CVS: vasodilation, peripheral resistance , blood pressure

， tachycardia Glands, eye, GI, bladder: dry mouth, mydriasis,

constipation, urinary retention

[Clinical use] HBP Control BP in Anesthesia, decrease hemorrhage aortic aneurysm surgery 主动脉瘤手术

×

Ⅱ NM-R antagonists （ Skeletal muscular relaxants ）(neuromuscular blocking drugs )

Depolarizing muscular relaxants

— succinylcholine ( 琥珀胆碱 )

Nondepolarizing muscular relaxants

— D-tubocurarine ( 筒箭毒碱 )

Depolarizing muscular relaxants(noncompetitive muscular relaxants) Mechanism: Two-phase block

durable depolarizing blockNM receptor desensitization

[Mechanism of Action]

Combined with Nm-R→ long-lasting depolarization →

refractory to Ach → relaxation of skeletal muscle

Two-phase block

Phase 1: durable depolarizing block

Phase 2: N2 receptor desensitization

[Characteristics of Action]

（ 1 ） Muscle fasciculation

（ 2 ） Techyphylaxis( 快速耐受性 )

（ 3 ） Can’t be antagonized by ChEI

（ 4 ） have no ganglionic blocking actions at therapeutic dose

（ 5 ） rapid onset and short duration

order of muscle relaxation:

head, neck→ scapular( 肩胛 ), abdomen, limbs

neck, limbs ＞ face, tongue, throat, masticatory muscle( 咀嚼肌 ) ＞ respiratory muscle

(Strong effect on laryngeal and tracheal muscle)

succinylcholine (scoline, 司可林 )

[Pharmacokinetics] (1) Onset rapid (1’), Emax (2’), short duration (5’)

(2) pseudocholinesterase

[Uses]

1. assistant agents of anesthetics (ivd)

2. bronchial cannulation, bronchoscopy and oesophagoscop ( 食管镜 )

Adverse reactions (1)  asphyxy(窒息 ): respiratory muscle paralysis: genetic pseudo-ChE low patients anti-AChE agents aminoglycosides

(2) Muscle fasciculation (3) Elevation of extracellular K+

(4) cardiovascular effects (bradycardia, hypotention): activate

NN-receptor at large dose

(5) malignant hyperpyrexia—idiosyncrasy( 特异质反应 )

(6) increase histamine release

Nondepolarizing muscular relaxants (competitive muscular relaxants)

Mechanisms:

NM-R competitive antagonist

Characteristics of Action (1) no fasciculation (2) synergism with aminoglycosides (3) antagonized by ChEI (4) long duration

d-tubocurarine ( 筒箭毒碱 )

[Pharmacokinetics] onset 4-6min iv duration 80-120min

[Actions] muscle relaxant NN blockade

histamine release

[Uses] assistant agents of anesthetics

hypotension

[Contradictions] Myasthenia gravis bronchial asthma severe shock

Other drugsbenzylisoquinolines ( 苄基异喹啉类 ) Atracurium （阿曲库铵 ） Doxacurium （多库溴铵 ） Mivacurium （米库溴铵 ）ammoniosteroids （类固醇铵类） Pancuronium （泮库溴铵 ） Pipecuronium （哌库溴铵 ） Rocuronium （罗库溴铵 ） Vecuronium （维库溴铵 ）

注射死刑 配方：

大剂量巴比妥 ( 硫喷妥钠 ) 肌肉松弛剂 ( 泮库溴铵 ) 高浓度氰化钾

先给速效巴比妥类药物，可使人先处于镇静和深睡眠状态，否则，直接用肌松药的话死刑犯会感到窒息难受，不人道，加用钾类药物，是使心脏加快停搏，让犯人在数十秒内就得到解脱直至死亡。

糯康，成克杰，袁宝璟