Chapter 7 Cholinoceptor-Blocking Drugs

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 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. Atropine pharmacological actions • block M-R: Competitive and Nonselectiveblock 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 迷走神经 其他胃肠道激素及非胆碱能递质 十二指肠粘膜G细胞

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. (spasmodic) 3. spasmodicsmooth 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 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. 4. Bradyarrhythmias • 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 • blurred vision • tachycardia • dry mouth, dryness of skin and flush • difficulty in urination, constipation • dizziness, confusion 1. Common Side Effects

26. 2. Acute Poisoning • 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. 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 throughBBB 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 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. Quaternaryamines (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. ⅡNM-R antagonists （Skeletal muscularrelaxants） (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. (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. 动作电位 Ⅰ相阻断 复极后进入Ⅱ相阻断

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 laryngealandtracheal muscle)

48. [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 (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-Rcompetitive antagonist Characteristics of Action • no fasciculation • antagonized by ChEI • have ganglionic blocking actions • long duration