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. Organization of the nervous system Sympathetic Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division Autonomic System (ANS) Somatic System Parasympathetic Enteric Drugs that produce their primary therapeutic effect by mimicking or altering the functions of autonomic nervous system are called autonomic drugs.

4. Sympathetic stimulation causes: stimulates heartbeat raises blood pressure dilates the pupils dilates the trachea and bronchi stimulates the conversion of liver glycogen into glucose shunts blood away from the skin and viscera to the skeletal muscles, brain, and heart inhibits peristalsis （蠕动） in the gastrointestinal (GI) tract inhibits contraction of the bladder and rectum

5. Parasympathetic stimulation causes: slowing down of the heartbeat lowering of blood pressure constriction of the pupils increased blood flow to the skin and viscera peristalsis of the GI tract

7. Drug actions and classification (1) Mimetics - direct-acting: receptor agonists - indirect-acting: increasing amounts and/or effects of transmitters (2) Antagonists - direct-acting: receptor antagonists - indirect-acting: decreasing amounts and/or effects of transmitters

8. Cholinergic Pharmacology Adrenergic Pharmacology Pharmacology of efferent nervous system

9. Cholinergic Terminal

10. Regulation - by autoreceptors ACh acting on presynaptic M 2 -cholinergic receptors - by heteroreceptors NE acting on presynaptic alpha 2 -adrenergic receptors - by metabolism (extraneuronal) Acetylcholine Release

11. ACh inactivation Cholinesterases Acetylcholinesterase is located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine) Pseudocholinesterase ( synonyms: plasmacholinesterase or butyrylcholinesterase 丁酰胆碱脂酶 ) occurs mainly in plasma, liver and in glia (hydrolyzes succinylcholine)

12. Cholinergic Receptors Muscarinic receptors (M receptors) M 1, 3, 5 (smooth muscles); M 2, 4 (heart) G-protein Coupled End Organs Nicotinic receptors (N receptors) N N (N 1 ) receptors; N M (N 2 ) receptors Ligand-gated Ion Channels NMJ & Ganglia

13. M 2 : Depression of the heart (heart rate, conduction) M 1, 3 : Contraction of smooth muscles sensitive: GI tract, bronchial, urinary bladder; insensitive: uterine, blood vascular M 3 : Exocrine glands (sensitive: sweat, tear, salivary; insensitive: GI tract); M 3 : Eye (contraction of sphincter muscle of iris: miosis 缩瞳 ; contraction of ciliary muscle 睫状肌 : contraction for near vision) M receptors:

14. N N receptors （ N 1 receptors ） - Sympathetic and parasympathetic ganglia - Adrenal medulla N M receptors （ N 2 receptors ） - The Neuromuscular Junction (NMJ) (Contraction of skeletal muscles) N receptors

15. 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists: acetylcholine M receptor agonists: pilocarpine 匹鲁卡品 N receptor agonists: nicotine (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases) Reversible: neostigmine 新斯的明 Irreversible: organophosphates 有机磷酸酯类 Cholinesterase reactivators: pralidoxime chloride 氯解磷定 Drug classification

16. 2 Cholinergic antagonists (1) Cholinoceptor antagonists M cholinoceptor antagonists atropine (Antimuscarinic drugs) N cholinoceptor antagonists N N cholinoceptor antagonists: mecamylamine 美加明 (Ganglionic blocking drugs, rarely used) N M cholinoceptor antagonists: succinylcholine 琥珀酰胆碱 (Neuromuscular blocking drugs ) (2) Botulinum Toxin ( 肉毒毒素, Botox, blocks ACh release) Drug classification

17. Cholinomimetics Ach derivatives （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 ) Direct-acting drugs

18. AChE resistant Bond cleaved by AChE 醋甲胆碱 氯贝胆碱 卡巴胆碱乙酰胆碱 ACh Derivatives

19. Bethanechol 氯贝胆碱 is commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention.

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

21. (1) Eyes Miosis ( 缩瞳 ): contraction of sphincter muscle of iris Lowing intraocular pressure: enlarging angle of anterior chamber, increasing drainage of aqueous humor Spasm of accommodation ( 调节痉挛 ): contraction of ciliary muscle, contraction for near vision Ophthalmological 眼科 uses Glaucoma 青光眼 : narrow (closed)- or wide (open)-angle - used for the emergency, lowering intraocular pressure Iritis 虹膜炎 : combination of miotics 缩瞳药 /mydriatics 扩瞳药 Pilocarpine

22. pilocarpine atropine lens miosis mydriasis paralysis of accommodation near sight spasm of accommodation far sight iris Ciliary muscle (contraction) Anterior chamber zonule Posterior chamber Anterior chamber Ciliary muscle (dilation) Canal of Schlemm

23. Circulation of aqueous humor Pilocarpine causes the contraction of longitudinal fibers of the ciliary muscles inserted into the scleral spur

24. Glaucoma

25. （ 2 ） Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands Systemic use Antidote 解毒剂 for atropine poisoning Adverse effects M-like syndrome Pilocarpine

26. 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. N receptor agonists: Nicotine

27. 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists: acetylcholine M receptor agonists: pilocarpine N receptor agonists: nicotine (2) Indirect-acting drugs: Cholinesterase inhibitors (Anticholinesterases) Reversible: neostigmine 新斯的明 Irreversible: organophosphates 有机磷酸酯类 Cholinesterase reactivators: pralidoxime chloride 氯解磷定 Drug classification

28. Acetylcholinesterase (AChE) Activity

29. A.Simple alcohols with quaternary ammonium group (reversible) B.Carbamic acid esters (carbamates, 氨甲酰类, slowly reversible) C. Organophosphates (irreversible) AChE Inhibitors neostigmine Reversible agents are used medically (glaucoma or MG) Irreversible agents are used as pesticides or for glaucoma 毒扁豆碱 新斯的明 依酚氯铵 异氟磷

30. Acetylcholinesterase Inhibitors: Carbamates Inhibitory Effects are slowly reversible Representative Drugs neostigmine (quaternary amine 季铵 ) pyridostigmine (quaternary amine) physiostigmine (tertiary amine 叔胺 ) quaternary amines effective in periphery only tertiary amines effective in periphery and CNS （ fat-soluble ）

31. Pharmacological effects AChE(-), ACh release↑, stimulating N M R stronger effect on skeletal muscles effective on GI tract and urinary bladder more polar and can not enter CNS relatively weak effects on CVS, glands, eye Neostigmine 新斯的明

32. 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.Paroxysmal supraventricular tachycardia （ rarely use ） 4.Antidote for tubocurarine 筒箭毒碱 and related drug poisoning 5.Glaucoma Neostigmine

33. 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 ) Neostigmine

34. Acetylcholinesterase Inhibitors: Reversible Edrophonium ( 依酚氯铵 ) Rapidly absorbed; A short duration of action (5-15min); Competitive (reversible) Used in diagnosis of myasthenia gravis. Excess drug may provoke a cholinergic crisis, atropine is the antidote. Other reversible ACHEI: tacrine 他克林, donepezil 多奈哌齐

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

36. (1) Toxic symptoms Acute intoxication 急性中毒 Muscarinic symptom: eye, exocrine glands, respiration, GI tract, urinary tract, CVS Nicotinic symptoms: N N : elevation of BP, increase of HR; N M : tremor of skeletal muscles CNS symptoms: excitation, convulsion; depression (advanced phase) Organophosphates

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

38. (2) Detoxication Elimination of poison; Supportive therapy Antidotes Atropine － antagonizing muscarinic effects; early, large dose, and repeated use Cholinesterase reactivators － reactivation of phosphated AChE; moderate-severe patients, early use (more effective on tremor), combined with atropine – Pyraloxime methoiodide (PAM ，碘解磷定 ) – Pralidoxime chloride （ PAM-CL 氯解磷定） : safer than PAM Organophosphates

39. Pralidoxime can restore AChE activity if administered soon after toxin exposure. Conjugating with organophosphate by oxime group; Conjugating with free organophasphates

40.  glaucoma (e.g. physiostigmine 毒扁豆碱, echothiophate 乙磷硫胆碱 )  myasthenia gravis (e.g. Edrophonium, neostigmine, pyridostigmine )  reverse neuromuscular blockade from competitive antagonists ( neostigmine )  Alzheimer’s disease ( tacrine & donepezil, galanthamine )  chemical warfare agents  insecticides Summary: ACHEI Applications Pharmacological Actions: Increases ACh concentrations at cholinergic synapses, thereby increasing cholinergic activity.

41. 2 Cholinergic antagonists (1) Cholinoceptor antagonists M cholinoceptor antagonists atropine (Antimuscarinic drugs) N cholinoceptor antagonists N N cholinoceptor antagonists: mecamylamine 美加明 (Ganglionic blocking drugs, rarely used) N M cholinoceptor antagonists: succinylcholine 琥珀酰胆碱 (Neuromuscular blocking drugs ) (2) Botulinum Toxin ( 肉毒毒素, Botox, blocks ACh release) Drug classification

42. Muscarinic Antagonists (Antimuscarinic drugs) Tertiary amines （叔铵） Quaternary amines （季铵） 异丙托铵 噻托溴铵 东莨菪碱

43. Atropa belladonna 颠茄 Datura stramonium 曼陀罗 Datura metel 洋金花 山莨菪 Henbane Seed

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

45. pilocarpine atropine lens miosis mydriasis paralysis of accommodation near sight spasm of accommodation far sight iris Ciliary muscle (contraction) Anterior chamber zonule Posterior chamber Anterior chamber Ciliary muscle (dilation) Canal of Schlemm

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

47. 1.Pharmacological effects (4) Cardiovascular system: dose dependent Lower doses: HR↓ (bradycardia); blood vessels and blood pressure: no effect Moderate to high doses / high vagal tone: HR↑ (tachycardia); A-V conduction ↑ Large doses: cutaneous vasodilatation (5) CNS stimulation ： sedation, memory loss, psychosis (high dose) Atropine

48. 2. Clinical uses (1) Ophthalmology 眼科 Measurement of the refractive errors ( 屈光不正 ): children Acute iritis or iridocyclitis: mydriatics/miotics (2) Antispasmodic agent GI, biliary or renal colic, enuresis (3) Inhibiting 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 Atropine

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

50. 3. Adverse effects (3) Detoxication Supportive treatment Symptomatic treatment: e.g. diazepam. Antidote: Physostigmine or pilocarpine (4) Contraindications glaucoma, prostatauxe 前列腺肥大, fever Atropine

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

52. Anisodamine (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 smooth muscles)

53. Tropicamide 托吡卡胺 : mydriatic, cycloplegic shorter duration (1/4 day) Propantheline 丙胺太林，普鲁本辛 poor absorption (po) and BBB penetration antispasmodic effects in GI, treatment of peptic ulcer Ipratropium 异丙托铵 : asthma Benztropine 苯托品 : Parkinson’s disease Trihexyphenidyl 苯海索 Pirenzepine 哌仑西平： M1 selective, peptic ulcer, asthma Synthesized surrogates

54. Acting on sympathetic and parasympathetic ganglionic cells; reducing blood pressure by inhibiting sympathetic ganglia ( have been abandoned for clinical use, due to their lack of selectivity) Short-acting; tachyphylaxis ( 快速抗药反应 ) Used for treatment of hypertension ─Trimethaphan( 咪噻芬 ) –Mecamylamine ( 美加明 ) N N receptor antagonists (Ganglionic blocking drugs)

55. Two classes: Depolarizing: succinylcholine 琥珀酰胆碱 Non-depolarizing: drugs act as competitive antagonists d-tubocurarine 筒箭毒碱 Note: Belong to Skeletal Muscle Relaxants. It is important to realize that muscle relaxation does not ensure unconsciousness, amnesia, or analgesia. N M receptor antagonists ( Neuromuscular blocking drugs )

56. 1. Depolarizing neuromuscular blockers ( Non-competitive ) (depolarizing skeletal muscle relaxants) act as acetylcholine (ACh) receptor agonists the depolarized membranes remain depolarized and unresponsive to subsequent impulses (ie, they are in a state of depolarizing block). not metabolized by AChE - diffuse away from the neuromuscular junction and are hydrolyzed in the plasma and liver by pseudocholinesterase (nonspecific cholinesterase, plasma cholinesterase, or butyrylcholinesterase) and elimination by kidney N M receptor antagonists ( Neuromuscular blocking drugs )

57. Succinylcholine (Scoline 司可林 ) Succinylcholine is the only depolarizing agent used clinically (t 1/2 = 2-4 min). Properties of actions: initially transient fasciculations （肌束震颤） anti-AChE potentiates their effects tachyphylaxis after repeated uses no ganglion-blocking effects at therapeutic doses the drugs are highly polar, poor bioavailability; i.v. as quaternary compounds, do not enter CNS acetylcholine succinylcholine

58. Main pharmacological effects –Transient excitation (fasciculations), and then inhibition (relaxation) –Relax skeletal muscles in neck, limbs > face, tongue, throat; less effective on breath muscles at therapeutic doses Succinylcholine (Scoline)

59. Clinical uses –An adjuvant in anesthesia or operation –Intubation of trachea, esophagus, etc. –Prevention of trauma during electroshock therapy （无抽 搐电休克疗法） – Contraindicated in awake patients, should be used under anesthesia Succinylcholine (Scoline)

60. Adverse effects (1) Apnea (respiratory paralysis) overdose or hypersensitive patients; neostigmine potentiates the toxic effects (2) Muscle spasm muscular pain after operation Succinylcholine (Scoline)

61. (3) Elevation of K + in plasma e contraindicated in patients with a tendency of hyperkalemia (4) Malignant hyperthermia genetic abnormality, treated by dantrolene (Ca2+ release inhibitor) (5) Others rise in intraocular pressure (glaucoma); histamine release Succinylcholine (Scoline)

62. Drug interactions - Thiopental （强碱性，可分解 scoline ） - ChE inhibitors: AChE inhibitors, cyclophosphamide, procaine, etc. - Some antibiotics: kanamycin, polymyxins, etc. (synergism in neuromuscular blocking) Succinylcholine (Scoline)

63. 2. Nondepolarizing neuromuscular blockers ( Competitive) (nondepolarizing skeletal muscle relaxants) Tubocurarine ( 筒箭毒碱 ) Reversibly bind to the nicotinic receptor at the neuromuscular junction (competitive antagonists) N M receptor antagonists (Neuromuscular blocking drugs)

64. Effects: competitive blockade of N M receptors Uses: adjuvant medication for anesthesia or operations, eg. tracheal intubation Adverse effects: Respiratory paralysis: can be reversed by neostigmine Enhancing histamine release: BP , bronchoconstriction, salivary secretion Blocking ganglion: BP  Contraindications: myasthenia gravis, bronchial asthma, shock, child (< 10 y) Tubocurarine

65. Benzylisoquinolines （苄基异喹啉类） atracurium （阿曲库铵） doxacurium （多撒库铵） mivacurium （米库铵） Ammonio steroids （类固醇铵类） pancuronium （潘库铵） vecuronium （维库铵） pipecuronium （哌库铵） rocuronium （罗库铵） Other nondepolarizing neuromuscular blockers

66. Botulinum Toxin 肉毒杆菌毒素 - Skeletal muscle relaxants - blocks ACh release from cholinergic terminals - selective for ACh terminals - results in irreversible flaccid paralysis ( 松弛性瘫痪 ) in muscles

67. Acts by cleaving SNAP proteins → inhibits ACh release

68. Applications Strabismus (lack of parallelism of eyes 斜视 ), blepharospasm (eyelid spasm), dystonia (abnormal tonicity). Excessive sweating Cosmetic procedures ( “frown lines” or “crow’s feet” 鱼尾纹 ) Note: effects can last for ~3-6 months. Botulinum Toxin

69. 杨世杰主编《药理学》人民卫生出版社 2010 第二版 Katzung BG, Basic & Clinical Pharmacology (10th edition), 2007. Lipincott’s illustrated reviews— Pharmocology (2nd edition), 2002 参 考 书 目参 考 书 目参 考 书 目参 考 书 目