Understanding Muscarinic Receptor Agonists and Antagonists

1. Muscarinic receptor agonists

2. A Muscarinic receptor agonists • 1. Choline esters (胆碱酯类) • Acetylcholine 乙酰胆碱 • Carbachol 卡巴胆碱 • Methacholine 醋甲胆碱 • Bethanechol chloride 氯贝胆碱 • 2. Natural alkaloids (生物碱类) • Pilocarpine毛果芸香碱（匹罗卡品） • Muscarine 毒蕈碱

3. Muscarinic receptor agonists Pilocarpine 毛果芸香碱（匹罗卡品） Pilocarpine 毛果芸香碱

4. Muscarinic receptor agonists • 1. Pharmacological effects • （1）Eyes • Miosis（缩瞳）:contraction ofsphincter muscle of iris • Lowing intraocular pressure（降低眼内压）:enlarging angle of anterior chamber, increasing drainage of aquous humor • Spasm of accommodation（调节痉挛）:contraction of ciliary muscle, contraction for near vision

5. Iris, cilliary muscles, and Schelemm canal

6. Aqueous humor drainage

8. Atropine Pilocarpine

9. Muscarinic receptor agonists • （2） Promoting secretion of exocrine glands（外分泌腺体） • especially in sweat, salivary and tear glands

10. Muscarinic receptor agonists • 2. Clinical uses • （1）Ophthamological uses • Glaucoma:narrow- orwide-angles • Iritis:miotics/mydriatics • BOXGlaucoma • Acute congestive glaucoma（narrow-angle） • Chronic simple glaucoma（wide-angle）

11. Muscarinic receptor agonists • （2）Systemic use • Dry mouth: radiotherapy • Antidote for atropine poisoning

12. Muscarinic receptor agonists • 3. Adverse effects • （1）Local (eye): pain, tears • （2）Systemic: secretion of exocrine glands, treated with atropine

13. Cholinoceptor antagonists

14. Muscarinic receptor antagonists

15. Action sites of cholinoceptor antagonist

16. N M Action sites of cholinoceptor antagonist

17. Atropine-like alkaloids Atropine阿托品 Scopolamine东莨菪碱 Anisodamine 山莨菪碱

18. Muscarinic receptor antagonists Atropine 阿托品 • 1. Pharmacological effects • (1) Inhibition of exocrine gland secretion • salivary, sweat glands • tear, respiratory tract glands • relatively ineffective: GI tract • (2) Eyemydriasis • rise in intraocular pressure • paralysis of accommodation

20. atropine pilocarpine

21. Durations of the action atropine-like drugs on eye

22. Muscarinic receptor antagonists • (3) Antispamodic action on smooth muscle • sensitive: GI, urinary bladder (spasmodic state) • relatively insensitive: bile duct, urinary tract, bronchial tract • insensitive: uterus • (4) HeatHR↓: because of M1 blockade; • HR↑:if vagal tone ↑ • A-V conduction:if vagal tone ↑

23. Muscarinic receptor antagonists • (5) Blood vessels and blood pressure • Therapeutic doses: no remarkable effect • Larger doses:vasodilatation in the skin (indirect) • and in septic shock • (6) Central stimulation • Larger doses

24. Muscarinic receptor antagonists • 2. Clinical uses • (1) Spasms of smooth muscles • GI, biliary or renal colic, enuresis • (2) Inhibiting exocrine gland secretion • Preanesthetic medication, over-secretion • (3) Ophthalmology • Acute iritis or iridocyclitis: mydriatics/miotics • Measurement of the refraction: children

25. Muscarinic receptor antagonists • (4) Bradyarrhythmia • sinus or nodal bradycardia, A-V block • (5) Septic shock • (6) Antidote for organophosphate poisoning

26. Muscarinic receptor antagonists • 3. Adverse effects • (1) Side effects • (2) Central toxicity • Lethal dose: 80~130 mg (adults), 10 mg (child) • but not including the case of treating • organophosphate toxication

27. Muscarinic receptor antagonists • (3) Detoxication • Symptomatic treatment: diazepam, etc. • Physostigmine (毒扁豆碱) or pilocarpine (毛果芸香碱) • (4) Contraindications • glaucoma, prostatauxe, fever

28. Muscarinic receptor antagonists Scopolamine 东莨菪碱 • Actions and clinical uses • Peripheral effects are similar to atropine; but has stronger central effects (depression) • Pre-anesthetic medication, prevention of motion sickness, Parkinson’s disease

29. Muscarinic receptor antagonists Anisodamine 山莨菪碱, 654-2 • Actions and clinical uses • Primarily acts on the smooth muscles of peripheral organs; weak in CNS, glands, eye • Septic shock, spasms of smooth muscles of GI and biliary duct

30. Muscarinic receptor antagonists Synthetic Substitutes for atropine • Synthetic mydriatics • Homatropine 后马托品 • shorter duration (1~2 days) • Examination of eyes generally • Tropicamide托吡卡胺 （1/4 day）

31. Muscarinic receptor antagonists • Synthetic Antispasmadics • Airway • Ipratropine bromide 异丙托溴铵 (溴化异丙托品) • poor absorption and BBB penetration; antispasmodic effects in bronchial smooth muscle • treatment of bronchial asthma and chronic bronchitis; injection or aerosol

32. Muscarinic receptor antagonists • G.I. • Propantheline bromide 溴化丙胺太林 (普鲁本辛) • poor absorption (po) and BBB penetration • antispasmodic effects in GI, treatment of peptic ulcer disease • Benactyzine 贝那替秦 (胃复康) • peptic ulcer disease with anxiety, GI and urinary bladder spasms

33. Muscarinic receptor antagonists • M1 receptor antagonists • Pirenzepine 哌仑西平 • inhibition of gastric acid and pepsin secretion • weak in salivary glands and eye, poor penetration into CNS • used in treatment of peptic ulcer disease

34. Nicotinic receptor antagonists

35. Nicotinic receptor antagonists • Ganglion Blockers (NN receptor antagonists) • Acting on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibiting sympathetic ganglia • Short-acting; tachyphylaxis • Used for controlled hypotension

36. Nicotinic receptor antagonists neuromuscular blockers

37. Nicotinic receptor antagonists • 1. Depolarizing neuromuscular blockers • (depolarizing skeletal muscle relaxants) • Binding to NM receptors, initial excitation action, then persisting depolarization and resistance to ACh • initially transient fasciculations • tachyphylaxis after repeated uses • anti-AChE potentiates their effects • no ganglion-blocking effects at therapeutic doses

38. Nicotinic receptor antagonists Succinylcholine 琥珀胆碱, Scoline

39. Nicotinic receptor antagonists • 1.1 Pharmacological effects • Transient excitation (fasciculations), and then inhibition (relaxation) • neck, limbs > face, tongue, throat; less effective on breath muscles at therapeutic doses • Short-acting (5 min), degradation by plasma pseudocholinesterases

40. Nicotinic receptor antagonists • 1.2 Clinical uses • An adjuvant in anesthesia or operation • Intubation of trachea, esophagus, etc. • Prevention of trauma during electroshock therapy • Contraindicated in awake patients, should be used under anesthesia

41. Nicotinic receptor antagonists • 1.3 Adverse effects • (1) Apnea (respiratory paralysis) • overdose or hypersensitive patients; • neostigmine potentiates the toxic effects • (2) Muscle spasm • muscular pain after operation

42. Nicotinic receptor antagonists • (3) Elevation of K+ in plasma • contraindicated in patients with a tendency of hyperkalemia • (4) Malignant hyperthermia • genetic abnormality • (5) Others • rise in intraocular pressure (glaucoma) • histamine release

43. Nicotinic receptor antagonists • 1.4 Drug interactions • Thiopental • ChE inhibitors: • AChE inhibitors, cyclophosphamide, procaine, etc. • Some antibiotics: • kanamycin, polymyxins, etc. (synergism in neuromuscular blocking)

44. Nicotinic receptor antagonists • 2. Nondepolarizing neuromuscular blockers • (nondepolarizing skeletal muscle relaxants) • 2.1 Effects: competitive blockade of NM receptors • 2.2 Uses: adjuvant treatment of anesthesia or operations Tubocurarine 筒箭毒碱

45. Nicotinic receptor antagonists • 2.3 Adverse effects • Respiratory paralysis:can be reversed by neostigmine • Enhancing histamine release:BP , bronchoconstriction, salivery secretion • Blocking ganglion:BP  • Contraindications:myasthenia gravis, bronchial asthma, shock, child (< 10 y)

46. Nicotinic receptor antagonists Other nondepolarizing neuromuscular blockers • Benzylisoquinolines （苄基异喹啉类） • atracurium 阿曲库铵doxacurium 多库铵 • mivacurium 米库铵 • Ammonio steroids（类固醇铵类） • pancuronium 泮库铵vecuronium 维库铵 • pipecuronium 哌库铵rocuronium 罗库铵