Pharmacology of the nervous system

1. Pharmacology of the nervous system Shi-Hong Zhang (张世红), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn

2. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division Autonomic System (ANS) Somatic System Parasympathetic Sympathetic Enteric Organization of the nervous system Sensory Motor

3. Rest or digest Fight or flight

5. Pharmacology of efferent nervous system • Cholinergic Pharmacology • M/N receptor agonists/antagonists • Drugs affecting metabolism and release of ACh • Adrenergic Pharmacology • //DA receptor agonists/antagonists • Drugs affecting metabolism and release of epinephrine/norepinephrine

6. Cholinergic pharmacology Cholinergic nerve terminal

7. Acetylcholine Release Regulation - by autoreceptors ACh acting on presynaptic M2 receptors - by heteroreceptors NE acting on presynaptic alpha2 receptors - by metabolism (extraneuronal)

8. ACh inactivation Acetylcholinesterase (AChE)乙酰胆碱酯酶is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine琥珀酰胆碱), high efficacy (105 molecules/min). Pseudocholinesterase假性胆碱脂酶(plasmacholinesterase or butyrylcholinesterase丁酰胆碱脂酶) occurs mainly in plasma, liver and in glia (hydrolyzes succinylcholine)

9. Cholinergic Receptors • Muscarinic receptors (M receptors) End organs M1, 3, 5 (smooth muscles, CNS); M2, 4 (heart, CNS) G-protein coupled • Nicotinic receptors (N receptors) NN (N1) receptors (adrenal medulla & ganglia) NM (N2 )receptors (NMJ) Ligand-gated ion (cation) channels

10. M receptors: • M2: Depression of the heart(heart rate, conduction) • M1, 3: Contraction of smooth muscles sensitive: GI tract, bronchial, urinary bladder; less sensitive: uterine, blood vascular • M3: Exocrine glands(sensitive: sweat, tear, salivary; less sensitive: GI tract); • M3: Eye(contraction of sphincter muscle of iris: miosis 缩瞳; contraction of ciliary muscle睫状肌: contraction for near vision)

11. N receptors • NN receptors(N1 receptors) - Sympathetic and parasympathetic ganglia - Adrenal medulla • NM receptors (N2 receptors) - The Neuromuscular Junction (NMJ) (Contraction of skeletal muscles)

12. Drug Classification • Cholinergic mimetics拟似药 • Receptor agonists M, N receptor agonists: acetylcholine Mreceptor agonists: pilocarpine 匹鲁卡品 Nreceptor agonists: nicotine • Cholinesterase inhibitors Reversible:neostigmine 新斯的明 Irreversible:organophosphates 有机磷酸酯类

13. Drug classification • Cholinergic antagonists • Mcholinoceptor antagonists：atropine阿托品 • Ncholinoceptor antagonists： • NNcholinoceptor antagonists:mecamylamine美加明 • (Ganglionic blocking drugs) • NMcholinoceptor antagonists: succinylcholine 琥珀酰胆碱, tubocurarine筒箭毒碱 (neuromuscular blocking drugs) • Cholinesterase reactivators: pralidoxime chloride • 氯解磷定 • Botulinum Toxin (肉毒毒素, Botox, blocks ACh release)

14. 1. Cholinoceptor agonists Choline esters (胆碱酯类) Natural muscarinic agonists (生物碱类M受体激动剂) Nicotinic receptor agonists (N受体激动剂)

15. ACh Derivatives Bond cleaved by AChE 氨基甲酰基 乙酰基 乙酰胆碱 卡巴胆碱 醋甲胆碱 贝胆碱 Resistant to AChE

16. Choline esters *local application Bethanechol贝胆碱 is commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention.

17. Natural Muscarinic Agonists 槟榔碱 毛果芸香碱 毒蕈碱 Nicotinic potency • Arecoline: areca or betal nuts (India, E. Indies) • Pilocarpine: pilocarpus (S. Amer. shrub) • Muscarine: amanita muscaria (mushroom)

18. Pilocarpine 1. Pharmacological effects and clinical uses (1) Effects on eyes • Miosis (缩瞳): induces contraction of sphincter muscle of iris • Spasm of accommodation (调节痉挛): ciliary muscle contraction, zonular relaxation悬韧带松弛, causing clear near vision • Lowering intraocular pressure:enlarges the angle of anterior chamber, increases drainage of aqueous humor

19. (Pilocarpine) (Atropine)

20. Circulation of aqueous humor 巩膜窦 Pilocarpine

21. Glaucoma青光眼

22. Pilocarpine 1. Pharmacological effects and clinical uses • Ophthalmological uses 眼科应用 • Glaucoma 青光眼:narrow (closed)- orwide (open)-angle • - used for the emergency, lowering intraocular pressure • Iritis 虹膜炎:combination of miotics缩瞳药/mydriatics扩瞳药 (2)Promoting secretion of exocrine glands especially sweat, salivary and tear glands (3) Antidote解毒剂for atropine poisoning 2. Adverse effects: M-like syndrome

23. N receptor agonists: Nicotine Actions at ganglia, NMJ, brain are complex and frequently unpredictable, because of the variety of neuroeffector sites and because nicotine both stimulates and desensitizes effectors. Periphery:HR, BP,  GI tone & motility CNS:stimulation, tremors,  respiration, emetic effects The addictive power of cigarettes is directly related to their nicotine content.

24. CASE STUDY • In mid-afternoon, a coworker brings 43-year-old Laowang to the emergency department. His gait is unsteady and he walks with support from his colleague. He has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker tells that Laowang was working in a field that had been sprayed malathion (马拉硫磷) early in the morning. Within 3 hours after starting his work, Laowang complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.

25. AChE Inhibitors • Reversible agents (edrophonium, carbamates氨甲酰类) • B. Irreversible agents (organophosphates有机磷酸酯类) Reversible agents Irreversible agents 依酚氯铵 氨甲酰类 有机磷酸酯类 新斯的明 异氟磷 滕喜龙 neostigmine 毒扁豆碱

26. AChE Inhibitors

27. AChE Inhibitors Carbamates氨甲酰类 Quaternary ammonium 季铵 • neostigmine (新斯的明) • pyridostigmine (吡斯的明) • ambestigmin (安贝氯铵) • Tertiary ammonium 叔胺 • physostigmine (毒扁豆碱) • galantamine (加兰他敏) • rivastigmine (利斯的明) • donepezil (多奈哌齐) Unable to enter CNS, act in the periphery. Able to enter CNS, can be used for Alzheimer's disease.

28. Neostigmine 新斯的明 • 1. Pharmacological effects * • AChE inhibition, ACh release↑, stimulates NMR • stronger effect on skeletal muscles • effective on GI tract and urinary bladder • relatively weak effects on CVS, glands, eye • highly polar and can not enter CNS

29. Neostigmine 2. Clinical uses* 1) Myasthenia gravis (MG): symptomatic treatment overdose: cholinergic crisis 胆碱能危象 (大量出汗，大小便失禁，瞳孔缩小，睫状肌痉挛，心动过缓，低血压，肌无力，呼吸困难) 2) Paralytic ileus 麻痹性肠梗阻 and urinary retention: post- operative abdominal distension and urinary retention 3) Antidote for non-depolarizing skeletal muscle relaxants (e.g. tubocurarine筒箭毒碱) 4) Paroxysmal supraventricular tachycardia(rare use) 5) Glaucoma

30. Neostigmine Adverse effects* • Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic) • Contraindications： mechanical ileus（机械性肠梗阻） urinary obstruction bronchial asthma poisoning of depolarizing skeletal muscle relaxants (e.g. succinylcholine, 琥珀酰胆碱)

31. AChE Inhibitors:Reversible Edrophonium (依酚氯铵，滕喜龙) • Rapidly absorbed; • A short duration of action (5-15min); • Used in diagnosis of myasthenia gravis (试验性注射); • Overdose may provoke a cholinergic crisis, atropine is the antidote.

32. AChE Inhibitors: Irreversible Bond is hydrolyzed in binding to the enzyme 梭曼 乙磷硫胆碱 For ophthalmic use Dichlorvos敌敌畏 对硫磷 对氧磷 Dimethoate 乐果 马拉硫磷 马拉氧磷

33. Organophosphates (1) Toxic symptoms Acute intoxication 急性中毒 • Muscarinic symptom: eye, exocrine glands, respiration, GI tract, urinary tract, CVS (BP and HR) • Nicotinic symptoms: NN: decrease in BP and HR; NM: tremor of skeletal muscles • CNS symptoms: excitation, convulsion; depression (advanced phase)

34. Organophosphates (1) Toxic symptoms Chronic intoxication 慢性中毒 • usually occupational poisoning • plasma ChE activity ↓ • weakness, restlessness, anxiety, tremor, miosis, ……

35. Organophosphates • (2) Detoxication • Elimination of poison (洗胃/导泻); supportive therapy • Antidotes • Atropine: antagonizes muscarinic effects (early, large dose, and repetitive use, 2 mg every 5-10 min, lasting at least 48 h) • Cholinesterase reactivators: for moderate to severe patients, early use (more effective on tremor), combined with atropine • - Pralidoxime iodide (PAM，碘解磷定) • - Pralidoxime chloride (PAM-CL 氯解磷定): safer than PAM

36. Organophosphates • AChE reactivitors can restore AChE activity if administeredsoon after toxin exposure. • Conjugate with organophosphate by oxime group (肟基); • Conjugate with free organophosphates

37. Muscarinic Antagonists (Antimuscarinic drugs) 2. Cholinergic antagonists Tertiary amines（叔铵） Quaternary amines（季胺） 东莨菪碱 异丙托铵 噻托溴铵

38. Atropine Atropa belladonna Datura stramonium 颠茄 曼陀罗，野洋金花 Datura metel Henbane Seed 山莨菪 白曼陀罗， 南洋金花

39. Atropine 1. Pharmacological effects (1) Inhibition of exocrine gland secretion salivary, sweat glands tear, respiratory tract glands less sensitive: GI tract glands (2) Eye mydriasis 瞳孔散大 rise in intraocular pressure 升高眼内压 cycloplegia（paralysis of accommodation，调节麻痹）

40. (Pilocarpine) (Atropine)

41. Atropine 1. Pharmacological effects (3)Antispasmodic解痉 action on smooth muscle • sensitive: GI, urinary bladder (ep. spasmodic state) • less sensitive: bile duct, urinary tract, bronchial tract • insensitive: uterus

42. Atropine • Pharmacological effects • (4) Cardiovascular system: dose dependent • Lower doses: transient HR↓ (bradycardia) [blocking presynaptic M1and ACh release];no effect on blood vessels and blood pressure • Moderate to high doses (esp. high vagal tone): HR↑ (tachycardia); A-V conduction ↑ • Large doses: cutaneous vasodilatation • (5) CNS stimulation： • sedation, memory loss, psychosis(high dose)

43. Atropine 2. Clinical uses (1) Ophthalmological uses 眼科应用 Measurement of the refractive errors (屈光不正): children Acute iritis or iridocyclitis: mydriatics/miotics alternately Comparison of effects of several mydriatics

44. Atropine 2. Clinical uses (1) Ophthalmological uses 眼科应用 Measurement of the refractive errors (屈光不正): children Acute iritis or iridocyclitis: mydriatics/miotics alternatively (2) Antispasmodic uses GI, irritable bladder, enuresis遗尿, weaker for biliary or renal colic (+analgesics) (3) Inhibition of exocrine gland secretion Preanesthetic medication麻醉前用药 (4) Bradycardia: sinus or nodal bradycardia, A-V block (5) Antidote for organophosphate poisoning (6) Septic shock 感染性休克

45. Atropine 3. Adverse effects (1) Side effects dry mouth, blurred vision, “sandy eyes” (0.5 mg) (2) Toxicity Lethal dose: 80~130 mg (adult), 10 mg (child) • Low (1 mg): dry mouth, dry skin, tachycardia • Moderate (2-5 mg): above plus mydriasis, cycloplegia (睫状肌麻痹); difficulty in speaking, swallowing & urinating; hot/red/dry skin • High (10 mg): above plus ataxia, hallucinations幻觉 & delirium谵妄; coma

46. Atropine 3. Adverse effects (3) Detoxication Supportive treatment Symptomatic treatment: e.g. diazepam. Antidote: physostigmine毒扁豆碱 or pilocarpine (4) Contraindications glaucoma, prostatic hyperplasia (前列腺肥大), fever

47. Scopolamine东莨菪碱 • Actions and clinical uses • Peripheral effects are similar to atropine; but has stronger central effects (depression, euphoria, memory impairment, hallucination) • Pre-anesthetic medication (抑制腺体分泌), prevention of motion sickness, Parkinson’s disease

48. Anisodamine (山莨菪碱，654-1,2) • Actions and clinical uses • Peripheral effects, similar to atropine; weak inhibition of glands; lower toxicity • Septic shock and visceral colic (relieve spasm of vascular or visceral smooth muscles)

49. Other M antagonists • Ipratropium 异丙托溴铵/tiotropium噻托溴铵: asthma, COPD • Propantheline 丙胺太林 (普鲁本辛), dicyclomine双环维林, etc: antispasmodic effects in GI, treatment of peptic ulcer • Benztropine 苯托品, trihexyphenidyl 苯海索: PD • Pirenzepine 哌仑西平：M1 selective, peptic ulcer, asthma

50. NN receptor antagonists(Ganglionic blocking drugs) • Act on sympathetic and parasympathetic ganglionic cells; reduce blood pressure by inhibiting sympathetic ganglia (lack of selectivity) • Short-acting • Tachyphylaxis (快速抗药反应) • Used for control of hypertension • Trimethaphan (咪噻芬) • Mecamylamine (美加明)