1. Chapter 7 Cholinoceptor-Blocking Drugs
Zhang Bin
Institute of Pharmacology
School of Medicine,
Shandong University

2. Section 1 Muscarinic cholinoceptor -blocking drugs
Atropine and atropine-like alkaloids
Synthetic atropine substitutes

3. atropine-like alkaloids and their resources
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

4. 阿托品（atropine） 叔胺

5. pharmacological actions
Atropine
pharmacological actions
block M-R: Competitive and Nonselective block NN-R : in large dose
Organ sensitivity:
Gland ＞eye ＞ splanchnic smooth muscle ＞cardiovascular system ＞CNS

6. 1. glands: secretion↓ salivary, sweat > lacrimal, respiratory >
gastric acid > pancreatic, intestinal juice
十二指肠粘膜G细胞
迷走神经
其他胃肠道激素及非胆碱能递质

7. (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

8. (2) salivary glands:
Actions: ↓salivary secretion markedly
Side reactions: dry mouth, swallowing and talking difficultly
Uses: salivation

9. (3) Respiratory tract glands
Uses:
pre-anaesthetic agent to avoid asphyxia (窒息)
asthma (ipratropium)
(4) Lacriminal glands

10. (5) gastic glands:
Actions:
Large dose, ↓gastric acid, pepsin secretion
Uses: peptic ulcer (pirenzepine)

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

12. (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

13. normal
patient
Hospital
(使用阿托品)
Glasses shop
(不用阿托品)
optometry
glasses

14. 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

15. 4. heart: (1) HR (2) A-V conduction: 
small dose: temporary  (presynaptic M1blockade)
large dose: 
(block vagal effect on M2 –R of sinoatrial node)
(2) A-V conduction: 

16. 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

17. 6. CNS: In clinical doses, minimal stimulant effects on CNS
In toxic doses
Excited (excitement, anxiety, delirium, hallucinations, convulsions) →depression (coma)

19. Clinical Uses 1. Anti-smooth muscle spasm
2.  Pre-anaesthesia medication
3.  Ophthalmological use
(1) iridocyclitis; (2) optometry(验光)
(3) examination of ocular fundus (眼底检查)
4. Bradyarrhythmias
5. Shock (caution)
6. Intoxication of organophosphate or mushroom

20. 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

21. 2. inhibiting secretion of glands
Pre-anaesthesia medication
combined use with conventional sedatives: Diazepam — elimination of tension; transient amnesia
hyperhidrosis (多汗) and salivation

22. 3.  Ophthalmological Use
iritis, iridocyclitis
funduscopic examination (眼底镜检查)
diopter examination(屈光度检查)
For adult: homatropine
For younger children: atropine

23. Treatment of bradyarrhythmias caused by acute myocardial infarction
Treatment of depression of sinoatrial or atrioventricular node function (bradycardia)
Treatment of bradyarrhythmias caused by acute myocardial infarction
注意剂量

24. 5. Shock
very large dose of atropine, most common used to treat infectious intoxicated shock
contraindication:
shock with high fever or tachycardia

25. Adverse reactions 1. Common Side Effects blurred vision tachycardia
dry mouth, dryness of skin and flush
difficulty in urination, constipation
dizziness, confusion

26. 2. Acute Poisoning Prevention
Hyperthermia
Tachypnea (呼吸急促)
Restlessness, delirium, hallucination, convulsion, coma
Respiratory paralysis
minimal lethal dose:
adults –80~130mg
children-- 10mg
Prevention
1. Decontamination: prevent further absorption
2. Antidotes:
Parasympathomimetics (physostigmine iv repeatly)
3. Symptomatic treatment (diazepam)
Maintenance of vital signs

27. Contraindication: Glaucoma
Prostatic hypertrophy

28. Anisodamine (654-2, 山莨菪碱) [Characteristic of Actions]
人工合成的消旋品
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

29. Scopolamine(东莨菪碱) [Characteristics] 1.CNS actions: depression (strong)
euphoria
excitation similar to atropine
2.peripheral actions: (VS Atropine)
glands: stronger
others: weaker
Rapidly & fully distributed into CNS, greater CNS effects

30. [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

31. Synthetic atropine substitutes
Synthetic Mydriatics
Synthetic Antispasmodics
Selective M1 Antagonists

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

33. Comparison of some mydriatics
drugs
concentration(%)
mydriasis
paralysis of accommodation
peak(m)
duration(d)
peak(h)
atropine
1.0
30~40
7~10
1~3
7~12
homatropine
1.0~2.0
40~60
1~2
0.5~1
tropicamide
0.5~1.0
20~40
0.25
0.5
<0.25
cyclopentolate
30~50 1
0.25~1
eucatropine
2.0~5.0 30
1/12~1/4 no
Uses:
iridocyclitis, optometry, examination of retina

34. Synthetic Antispasmodics
Quaternary amines (季胺类)：
Propantheline bromide (溴丙胺太林，普鲁本辛)
1. low BBB permeability
2. Low absorption orally (take before meal)
3. Uses: ulceration, GI spasm, bladder stimulation, prevention of enuresis and vomiting from the cause of pregnancy
4. NM-R blockade at toxic dose
Ipratropium bromide(异丙托溴胺)
1. low BBB permeability
2. low absorption orally 气雾给药aerosol administration
3. Relieve bronchospasm by inhalation
4. Uses: chronic obstructive pulmonary disease
5. NN-R blockade stronger than atropine

35. 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

36. 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

37. Tertiary amines (叔胺类) 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）

38. 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

39. Section 2 Nicotinic cholinoceptor- blocking drugs
NN-R antagonists
(ganglionic blocking drugs)
NM-R antagonists
(neuromuscular blocking drugs)
(skeletal muscular relaxants)

40. Ⅰ NN-R antagonists (ganglionic blocking drugs)
Mecamylamine (美卡拉明, 美加明)
Trimetaphan Camsilate (樟磺咪芬, 阿方那特)

41. NN-R antagonists
[Characteristics] Co-innervation and dominant theory
CVS: vasodilation, 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 ×

42. 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)

43. Schematic representation of the neuromuscular junction
Schematic representation of the neuromuscular junction. (V, transmitter vesicle; M, mitochondrion; ACh, acetylcholine; AChE, acetylcholinesterase; JF, junctional folds.)

44. Depolarizing muscular relaxants (noncompetitive muscular relaxants) Mechanism: Two-phase block
durable depolarizing block
NM receptor desensitization

45. Ⅰ相阻断
复极后进入Ⅱ相阻断
动作电位

46. [Characteristics of Action]
（1）Muscle fasciculation
（2）Can’t be antagonized by ChEI
（3）have no ganglionic blocking actions
（4）rapid onset and short duration
（5）Techyphylaxis(快速耐受性)
succinylcholine (scoline,司可林)

47. succinylcholine (scoline,司可林)
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)

48. 1. assistant agents of anesthetics (ivd)
[Pharmacokinetics]
(1) Onset rapid (1’), Emax (2’), short duration (5’)
(2) pseudocholinesterase (BChE)
[Uses]
1. assistant agents of anesthetics (ivd)
2. bronchial cannulation, bronchoscopy and oesophagoscop (食管镜)

49. Adverse reactions genetic pseudo-ChE low patients anti-AChE agents
(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, BPor): activate NN-receptor at large dose
(5) malignant hyperpyrexia—idiosyncrasy(特异质反应)
(6) increase histamine release

50. Nondepolarizing muscular relaxants (competitive muscular relaxants)
Mechanisms:
NM-R competitive antagonist
Characteristics of Action
no fasciculation
antagonized by ChEI
have ganglionic blocking actions
long duration

51. d-tubocurarine (筒箭毒碱)
[Pharmacokinetics]
onset 4-6min iv
duration min
[Actions]
muscle relaxant
NN blockade
histamine release
[Uses] assistant agents of anesthetics
hypotension
[Contradictions]
Myasthenia gravis
bronchial asthma
severe shock

52. Other drugs benzylisoquinolines (苄基异喹啉类) ammoniosteroids（类固醇铵类）
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 ）

53. 注射死刑
大剂量巴比妥
肌肉松弛剂 (泮库溴铵)
高浓度氰化钾

54. 下课了，真开心！！！