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Part 3 . Cholinoceptor Blocking Drugs (胆碱受体阻断药)

Part 3 . Cholinoceptor Blocking Drugs (胆碱受体阻断药). 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.

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Part 3 . Cholinoceptor Blocking Drugs (胆碱受体阻断药)

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  1. Part 3. Cholinoceptor Blocking Drugs (胆碱受体阻断药)

  2. 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)

  3. (A)Muscarinic cholinoceptor blocking drugs Ⅰ. Atropine-like alkaloids: Atropine(阿托品) It for M-receptorwithaffinity(亲和力),andwithoutintrinsic activity (内在活性), thus it can block M-receptor, but it is no selectivity to M1, M2,M3, M4, andM5 receptor.

  4. Atropine 1. Pharmacological effects: exocrine glands ＞eyes ＞GI ＞heart andblood 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.

  5. Atropine

  6. Atropine (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)

  7. Atropine (5)Blood vessel: larger dose:vasodilatation (血管扩张) (6)CNS: when dose: 1～2 mg: exciting; ＞ 5 mg: exciting clearly; ＞10 mg: excitinginhibition

  8. Atropine 2. Clinical uses: (1)Relieving spasmofsmooth 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)

  9. Atropine 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.

  10. Atropine 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).

  11. Atropine-like alkaloids 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.

  12. Scopolamine 2. Clinical uses (1)Preanesthetic medication(麻醉前给药) (2)Preventionofmotionsickness(预防晕动病) (3)Parkinson’s disease(巴金森氏病) 3. Adverse reaction Similar to atropine, but central depression.

  13. Atropine-like alkaloids 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)

  14. 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

  15. 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.

  16. 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.

  17. 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; ▲ beused to treat peptic ulcer (消化性溃疡).

  18. (B)Nicotinic cholinoceptor blocking drugs Ⅰ.NNcholinoceptorblockingdrug —— Ganglionic blocking drugs (神经节阻断药): Mecamylamine(美卡拉明) Trimethaphan(樟磺咪吩)

  19. 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

  20. Depolarizing agents (除极化型肌松药)H3C Succinylcholine(琥珀胆碱, Scoline, 司可林) H3CO H3C N+-CH2-CH2-O-C-CH3 H3C 乙酰胆碱 H3CO O CH3 H3C N+-CH2-CH2-O-C-CH2-CH2-C-O-CH2-CH2-N+ CH3 H3C CH3 琥珀胆碱

  21. Succinylcholine(琥珀胆碱, Scoline, 司可林) 1. Characteristics of pharmacology: (1)Depolarization—desensitization; (2)Short-acting: after iv, 1min go into effect; 2min to max; 5min the effect vanish, because it is destroyed by plasma esterase fast. (3)muscle bundle tremle(肌束颤动).

  22. Succinylcholine 2. Clinical Uses ▲Surgery; ▲Insertion of endoscopes;

  23. Succinylcholine 3.Adverse reactions (1)Muscular pain (2)Respiratory paralysis/overdose, this ADR can be rescued by artificialrespirator(iron lung ),but the patients can not be injected by neostigmine ! ! ! (3)Hyperpotassemia; (4)Malignant high fever. Contraindication: Glaucoma, a tendency to hyperpotassemia.

  24. (B)Non-depolarizing agents (非除极化型肌松药) Tubocurarine(筒箭毒碱) Characteristicscompared withScoline: (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 asthmaattack (4)respiratory paralysis/overdose: can be rescued by injection ofneostigmine and artificial respirator.

  25. Tubocurarine 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,

  26. Part 4. Adrenoceptor agonists (肾上腺素受体激动药)

  27. Contents Ⅰ.Chemical structure and the relationshipbetweenstructure and effects • Ⅱ. , -Adrenoceptor agonists • Ⅲ. -Adrenoceptor agonists • Ⅳ. -Adrenoceptor agonists

  28. Ⅰ.Chemical structure and the relationshipbetween structure and effects CH2-CH2-NH2 -phenylethylamine(-苯乙胺) HO HO catechol(儿茶酚)

  29. HO CH-CH2-NH2 HO catecholamine (儿茶酚胺) HO CH-CH2-NH2 HO OH noradrenaline(去甲肾上腺素)

  30. Accordingtotheselectivityof drugs to  or  adrenoceptor, they canbedivided into3kinds: , -adrenoceptor agonist; -adrenoceptor agonist; -adrenoceptor agonist.

  31. 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) 1. ,  - adrenoceptor agonist: • 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)

  32. Ⅱ. , -Adrenoceptor agonists: Adrenaline(肾上腺素, AD) HOCH-CH2-NH-CH3 HO OH Activating and receptors directly.

  33. Adrenaline 1. Phamacological effects: (1)Heart stimulation:very strong, activating1&2 receptor. ●Force of myocardial contraction (心肌收缩) (1receptor); ●A-V conduction(1receptor); ●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.

  34. Adrenaline (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 .

  35. Adrenaline (3)Blood pressure:  Therapeutic doses:byactivating 1, 2 receptor and  receptor: systolic pressure:  diastolic pressure:  or  pulse pressure (脉压差):  Large doses: systolic pressure:  diastolic pressure:  pulse pressure: 

  36. Adrenaline (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)

  37. 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 .

  38. Adrenaline (5)Metabolism: ①glycogenolysis (糖原分解): by activating and 2 receptor of liver cell; ②insulin:byactivating2receptor of islet cell; (抑制胰岛素释放) ① + ② blood sugar . ③lipolysis: byactivating2and 3 receptor of fat cell. (6)CNS: ①small dose: unclear; ②large dose: CNS excited.

  39. Adrenaline 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%

  40. Adrenaline 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.

  41. Ephedrine(麻黄碱) CH-CH-NH-CH3 OH CH3 Direct action: weak activating ,  receptor Indirect action: promoting NA release.

  42. Ephedrine 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.

  43. Ephedrine 2. Pharmacological effects: Comparing withAdrenaline, 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)

  44. Ephedrine 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.

  45. Dopamine(多巴胺, DA) HO CH2CH2NH2 HO It can activat 1, and DA receptor.

  46. Dopamine 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

  47. Dopamine 2. Clinical uses: (1)Antishock; (2)Acute renal failure, used withdiuretics(利尿药). 3. Adverse reaction:less. (1)Arrhythmia (心律失常); (2)reducing renal functionwhen overdose, or iv fast.

  48. 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 receptoralso) (2)Stimulating heart: activating 1 receptoralso. “ large  and small  effect” (3)Blood pressure .

  49. Noradrenaline 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.

  50. Metaraminol(间羟胺, Aramine, 阿拉明) CH-CH-NH2 HO OHCH3 Direct action: activating receptor; Indirect action: promotingNArelease.

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