chapter 7 cholinoceptor-blocking drugs zhang bin institute of pharmacology school of medicine,...
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Chapter 7
Cholinoceptor-Blocking DrugsZhang Bin
Institute of PharmacologySchool of Medicine, Shandong University
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Section 1 Muscarinic cholinoceptor -blocking drugs
Atropine and atropine-like alkaloids
Synthetic atropine substitutes
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atropine and atropine-like alkaloids
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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
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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
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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
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1. glands: secretion↓salivary, sweat > lacrimal, respiratory >
gastric acid > pancreatic, intestinal juice
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(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
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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
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(2) salivary glands: Actions: ↓salivary secretion markedly Side reactions: dry mouth, swallowing and
talking difficultly Uses: salivation
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(3) Respiratory tract glands Uses:
pre-anaesthetic agent to avoid asphyxia (窒息 )
asthma (ipratropium)
(4) Lacriminal glands
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(5) gastic glands: Actions:
Large dose, ↓gastric acid, pepsin secretion Uses: peptic ulcer (pirenzepine)
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2. eyes (1) mydriasis (2) increase intraocular pressure (3) paralysis of accommodation
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(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
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hospital Glasses shop
optometry
normal
glasses
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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)
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4. heart:
(1) HR temporary decrease (presynaptic M1blockade)
increase (block vagal effect on M2 –R of sinoatrial
node)
(2) A-V conduction: increase
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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
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6. CNS: excited In clinical doses, minimal stimulant
effects on CNS In toxic doses
Excited (excitement, anxiety, delirium, hallucinations, convulsions) →depression (coma )
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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
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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
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2. inhibiting secretion of glands Pre-anaesthesia medication
combined use with conventional sedatives: Diazepam — elimination of tension; transient amnesia
hyperhidrosis ( 多汗 ) and salivation
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3. Ophthalmological Use iritis, iridocyclitis funduscopic examination diopter examination
For adult: homatropine
For younger children: atropine
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4. Bradyarrhythmias Treatment of depression of sinoatrial or
atrioventricular node function (bradycardia) Treatment of bradyarrhythmias caused by
acute myocardial infarction
注意剂量
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5. Shock very large dose of atropine, most common used
to treat infectious intoxicated shock
contraindication:
shock with high fever or tachycardia
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adverse reactions
1. Common Side Effects
a. Dry mouth, blurred visionb. Tachycardiac. Dryness of skin and flushd. Difficulty in urination, constipatione. Dizziness, confusion
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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
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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
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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
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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
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[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
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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)
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Synthetic atropine substitutes
Synthetic Mydriatics
Synthetic Antispasmodics
Selective M1 Antagonists
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Synthetic Mydriatics
Homatropine( 后马托品 ) Tropicamide( 托吡卡胺 ) Cyclopentolate( 环喷托酯 ) Eucatropine( 尤卡托品 )
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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
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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
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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
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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
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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)
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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
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Section 2 Nicotinic cholinoceptor- blocking drugs
NN-R antagonists
(ganglionic blocking drugs)
NM-R antagonists
(neuromuscular blocking drugs)(skeletal muscular relaxants)
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Ⅰ NN-R antagonists
(ganglionic blocking drugs)
Mecamylamine ( 美卡拉明,美加明 )
Trimethaphan ( 樟磺咪芬,阿方那特 )
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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
×
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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 )
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Depolarizing muscular relaxants(noncompetitive muscular relaxants) Mechanism: Two-phase block
durable depolarizing blockNM receptor desensitization
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[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
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[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
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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 )
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[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 )
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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
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Nondepolarizing muscular relaxants (competitive muscular relaxants)
Mechanisms:
NM-R competitive antagonist
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Characteristics of Action (1) no fasciculation (2) synergism with aminoglycosides (3) antagonized by ChEI (4) long duration
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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
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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 )
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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