Pharmacology of the nervous system

1. Pharmacology of the nervous system Zhong Chen(陈忠), PhD，Professor Dept. of Pharmacology, School of Medicine, Zhejiang Universitychenzhong@zju.edu.cn，88208228 医学院科研楼B402-416

2. 1、传出神经系统简介（自学） 2、胆碱能神经系统药理 （1）胆碱受体激动药 （2）胆碱酯酶抑制药

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

4. The Neuron • The neuron is the basic unit of the nervous system that permits integration of information and transmits this info to other cells • The dendrites receive info from other neurons (or sensory endings) • The cell body integrates the dendritic input and determines whether an action potential is fired • The axon is the cable that transmits the action potential • The synaptic terminal is where the action potential is converted into neurotransmitter release that is sensed by the postsynaptic cell

5. Synapse The synapse converts the electrical signals of action potentials into the chemical signals of neurotransmitter (NT) release. NTs are packaged at high concentration in synaptic vesicles via transporters. Action potential depolarization of the terminal activates voltage-dependent Ca++ channels, causing an influx of Ca++. SNAREs GPCR NT (ligand)-gated Ion Channel

9. 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

10. 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

11. Neurotransmitters • Synthesis • Storage • Release • Inactivation • Receptors • Activation Drug actions and classification Efferent neurons of ANS

12. Drug actions and classification 1. Mechanisms of drug actions 1.1 Direct actions on the receptors Agonists Antagonists 1.2 Indirect actions via affecting transmitters Synthesis Transport and storage Release Inactivation 1.3 Mimetics（拟似药） and antagonists（拮抗剂） (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

13. Pharmacology of efferent nervous system • Cholinergic Pharmacology • Adrenergic Pharmacology

14. Cholinergic Terminal • Choline Uptake • ACh Synthesis • Choline acetyltransferase(ChAT) • Choline + AcCoA → ACh • ChAT • ACh Storage • ACh Release • ACh Effects • Postsynaptic • Presynaptic • ACh Metabolism • Acetylcholinesterase(AChE) • ACh→ Choline + Acetate • AChE

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

16. ACh inactivation Cholinesterases Acetylcholinesteraseis located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine琥珀胆碱)

17. Cholinergic Receptors (cholinoceptors, acetylcholine receptors) Muscarinic receptors (M receptors) M1, 3, 5 ; M2, 4 G-protein Coupled End Organs Nicotinic receptors (N receptors) NN (N1) receptors; NM(N2 )receptors Ligand-gated Ion Channels NMJ & Ganglia

18. M receptors : G-protein Coupled MuscarinicReceptorSignalingPathways Smooth Muscle contraction cAMP↓ Heart rate↓

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

20. Depression of the heart (heart rate, conduction) Contraction of smooth muscles (sensitive:GI tract, bronchial, urinary bladder;insensitive:uterine, blood vascular) Mostly smooth muscle contraction - heart being the main exception Exocrine glands (sensitive: sweat, tears, salivary; insensitive: GI tract); Eye (contraction of sphincter muscle of iris: miosis; contraction of ciliary muscle: contraction for near vision) CNS M receptors : end organs and effect of activation

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

22. N receptors : Ligand-gated Ion Channels • At the NMJ, N receptorsPentameric with four types of subunits, two a subunits bind ACh for ligand gating • All other nAChRs, including those at the peripheral ganglia, have 2 a’s and 3 b’s

23. The Neuromuscular Junction (NMJ) B A

24. Myasthenia Gravis（重症肌无力） This means “serious disorder the NMJ” This is an autoimmune disease Antibodies against the a subunit of the nAChR The ability of ACh to activate the nAChRs is blocked by the antibodies As for many autoimmune diseases, stress can make the symptoms worse Treatment is to potentiate cholinergic signaling and to remove the antibodies (blood dialysis)

25. Drug classification 1. Cholinomimetics (1) Direct-acting drugs: Cholinoceptor agonists M, N receptor agonists:acetylcholine（乙酰胆碱） M receptor agonists:pilocarpine （毛果芸香碱） N receptor agonists:nicotine（烟碱） (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

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

27. ACh Derivatives Bond cleaved by AChE 乙酰胆碱 卡巴胆碱，不易被水解 醋甲胆碱 氯贝胆碱，不易被水解 AChE resistant Bethanechol氯贝胆碱is commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention.

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

29. Poisoning causes muscarinic overstimulation - salivation（流涎）, lacrimation（流泪）, visual disturbances; - abdominal colic and diarrhea - bronchospasm and bradycardia - hypotension; shock Treatment is with atropine （阿托品） Atropa belladonna => atropine “Food” Poisoning Amanita muscaria => muscarine

30. Pilocarpine • Eyes • Miosis (缩瞳): contraction of sphincter muscle of iris • Lowing intraocular pressure （减低眼内压）: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)- orwide (open)-angle • - used for the emergency, lowering intraocular pressure • Iritis 虹膜炎:combination of miotics缩瞳药/mydriatics扩瞳药

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

32. Glaucoma • 乙酰唑胺：减少房水生成，降低眼内压，治疗各种青光眼（开角和闭角）

33. field of vision  Normal Glaucoma

34. Pilocarpine • （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

35. 1 Cholinomimetics (Parasympathomimetics) (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 Irreversible: organophosphates Drug classification

36. 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.

39. Drug classification 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碘解磷定；氯解磷定

40. Cholinomimetics-Indirect Agents: AChE Inhibitors

41. Acetylcholinesterase (AChE) Activity

42. AChE Inhibitors • Edrophonium (reversible, competitive) • Carbamic acid esters (carbamates, 氨甲酰类, slowly reversible) • C. Organophosphates (irreversible) 新斯的明 依酚氯铵 异氟磷 neostigmine Reversible agents are used medically (glaucoma or MG) Excess drug may provoke a cholinergic crisis(胆碱能危象), Atropine is the antidote. Irreversible agents are used as pesticides or for glaucoma 毒扁豆碱

43. Acetylcholinesterase Inhibitors:Reversible Edrophonium chloride (依酚氯铵) Rapidly absorbed; A short duration of action (5-15min); Competitive (reversible) Used in diagnosis of myasthenia gravis (重症肌无力). Excess drug may provoke a cholinergic crisis(胆碱能危象), Atropine is the antidote.

44. Neostigmine 新斯的明 Inhibitory Effects are slowly reversible • Pharmacological effects • AChE(-), ACh release↑, stimulating NMR • 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

45. Neostigmine Clinical uses 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 Paralytic ileus 麻痹性肠梗阻 and urinary retention: post operative abdominal distension and urinary retention Paroxysmal supraventricular tachycardia（rarely use） Antidote for tubocurarine筒箭毒碱 and related drug poisoning Glaucoma

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

47. Other reversible AChE inhibitors Pyridostigmine 吡斯的明 • Similar as neostigmine, slow but longer duration Physostigmine毒扁豆碱 • Stronger than neostigmine • No direct action on M and N receptor • Can enter CNS, 先兴奋后抑制 • Stimulate N receptor of sympathetic nervous node  complex effects on cardiovascular system • Stimulate N receptor of skeletal muscle  肌束震颤 • 主要用于急性青光眼，抗胆碱药中毒，但其本身的毒性较大。

48. Other reversible AChE inhibitors Galanthamine加兰他敏 • Similar as neostigmine, can enter CNS and treat for AD Dihydrogalanthamine二氢加兰他敏 • Ambenonium chloride安贝氯胺 • Demecarium bromide地美溴铵 • Distigmine bomide溴地斯的明 • Eseridine依舍立定 • Eptastigmine依斯的明

49. Acetylcholinesterase 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

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