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Introduction to Autonomic Pharmacology in the Nervous System

This lecture covers the basics of the autonomic nervous system, including the parasympathetic and sympathetic divisions. Topics include cholinergic and adrenergic pharmacology, neurotransmitters, receptors, and the effects of autonomic drugs.

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Introduction to Autonomic Pharmacology in the Nervous System

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  1. Autonomic Pharmacology张纬萍 浙江大学医学院药理weiping601@zju.edu.cn 2013.10.11

  2. 第一次课的内容 1、传出神经系统简介 2、胆碱能神经系统 （1）胆碱受体激动药 （2）胆碱酯酶抑制药

  3. Nervous System 神经系统

  4. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) 神经系统

  5. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division 神经系统

  6. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division Somatic motor Nervous System 神经系统

  7. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division Autonomic nervous System (ANS) Somatic motor Nervous System 神经系统

  8. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division Parasympathetic副交感 Sympathetic 交感 Enteric 肠神经系统 Autonomic nervous System (ANS) Somatic motor Nervous System 神经系统

  9. 交感和副交感神经系统

  10. thoracolumbar craniosacral

  11. The Enteric Nervous System肠神经系统 (+SNS/PSNS) longitudinal muscle layer 纵行肌 Myenteric plexus 肌间神经丛 Circular muscle layer 环行肌 Submucosal plexus 粘膜下神经丛 Secretory cell 分泌细胞 Enterochromaffin cell 肠噬铬细胞 Absorptive cell 吸收细胞

  12. The release of noradrenaline has the following effects • 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 in the gastrointestinal (GI) tract • inhibits contraction of the bladder and rectum

  13. 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

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

  15. drugs • Neurotransmitters • Receptors • Neurotransmitters • Synthesis • Storage • Release • Inactivation • Receptors • Activation

  16. Neurotransmitters Mimetics Indirect actions • Synthesis • Transport and storage • Release • Inactivation • Direct-acting: receptor agonists • Indirect-acting: increasing amounts and/or effects of transmitters drugs Direct actions Antagonists Agonists激动剂 • Direct-acting: receptor • antagonists • Indirect-acting: decreasing amounts and/or effects of transmitters Antagonists 拮抗剂 Receptors

  17. Neurotransmitters Mimetics Indirect actions • Synthesis • Transport and storage • Release • Inactivation • Direct-acting: receptor agonists • Indirect-acting: increasing amounts and/or effects of transmitters drugs Direct actions Antagonists Agonists激动剂 • Direct-acting: receptor • antagonists • Indirect-acting: decreasing amounts and/or effects of transmitters Antagonists 拮抗剂 Receptors

  18. Cholinergic Pharmacology Adrenergic Pharmacology

  19. 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

  20. Acetylcholine Release by exocytosis Regulation - by auto-receptors ACh acting on presynaptic M2-cholinergic receptors - by hetero-receptors NE acting on presynaptic a2-adrenergic receptors - by metabolism (extra-neuronal)

  21. Cholinesterases 胆碱酯酶 Acetylcholinesteraseis located at cholinergic synapses and in erythrocytes (does not hydrolyze succinylcholine) Pseudocholinesterase(假性胆碱酯酶，synonyms: plasma cholinesterase or butyrylcholinesterase丁酰胆碱酯酶) exists mainly in plasma, liver and in glia (hydrolyzes succinylcholine)

  22. 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

  23. Smooth Muscle contraction cAMP↓ Heart rate↓ M receptors : G-protein Coupled MuscarinicReceptorSignalingPathways (first, second, third messenger)

  24. M receptors : end organs and effect of activation • 血管平滑肌：收缩或舒张 • The response of an isolated blood vessel to ACh depends on whether the endothelium is intact (unrubbed) or missing • When the endothelium is present, ACh causes smooth muscle relaxation by stimulating the production of nitric oxide (NO)in the endothelium • In the absence of the endothelium, a small amount of vasoconstriction is observed ——Fred Murad, 1998

  25. M receptors : end organs and effect of activation • 心脏：Depression of the heart — 负性肌力：NE释放 — 负性频率：open K+ channel，depolarization — 负性传导：AV node and Purkinje fibers — 缩短心房不应期：  AP duration

  26. M receptors : end organs and effect of activation • 平滑肌：收缩(sensitive:GI tract, bronchial, urinary bladder;insensitive:uterine, blood vascular) Mostly smooth muscle contraction - heart being the main exception • 外分泌腺：sensitive: sweat, tears, salivary; insensitive: GI tract; • Eye (contraction of sphincter muscle of iris: miosis缩瞳; contraction of ciliary muscle睫状肌收缩: contraction for near vision) • CNS: activation，yet ACh can hardly pass BBB

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

  28. 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

  29. B A The Neuromuscular Junction (NMJ)

  30. 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)

  31. Drug classification ACh Indirect actions • Cholinesterase inhibitors (Anticholinesterases) • Reversible: neostigmine • 新斯的明 • Irreversible: organophosphates drugs Direct actions • Cholinoceptor agonists • M, N receptor agonists: • acetylcholine，乙酰胆碱 • M receptor agonists: • pilocarpine，匹鲁卡品 • N receptor agonists: • nicotine，尼古丁 Cholinergic antagonists M- and N- Receptors

  32. Cholinomimetics:Direct-acting drugs AChDerivatives Bond cleaved by AChE 卡巴胆碱 乙酰胆碱 氯贝胆碱 AChEResistant 乙酰甲胆碱

  33. Cholinomimetics:Direct-acting drugs Bethanechol is most commonly used, particularly post-operation for the treatment of paralytic ileus（麻痹性肠梗阻）and urinary retention（尿储留）

  34. Natural Muscarinic Agonists 匹鲁卡品 毛果云香硷 毒蕈碱 槟榔碱 pilocarpus (S. Amer. shrub) areca or betal nuts (India,E. Indies) amanita muscaria (mushroom) (Most to least nicotinic)

  35. “Food” Poisoning Amanita muscaria => muscarine Atropa belladonna => atropine Deadly Nightshade, 癫茄 Pilocarpus=> Pilocarpine Areca nuts=> Arecoline

  36. “Food” Poisoning Poisoning causes muscarinic overstimulation or blocking (for belladonna only) - salivation, lacrimation(流泪), visual disturbances; - abdominal colic and diarrhea - bronchospasm and bradycardia - hypotension; shock Treatment is with atropine

  37. Muscarinic Agonists: Parasympathetic Effects & Therapeutic Uses • Pilocarpine • （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 uses • Glaucoma(青光眼): (concentration ≤ 2%) • narrow (closed)- orwide (open)-angles • it is the drug of choice in the emergency lowering of intraocular pressure • Iritis (虹膜炎):miotics（缩瞳）/mydriatics（扩瞳）

  38. light 巩膜窦 小梁网 睫状体上皮细胞 睫状肌

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

  40. Glaucoma • Disease of the aging eye - increased intraocular pressure (IOP), degeneration of the optic head, and restricted visual field typify primary open-angle glaucoma • obstruction of the aqueous drainage leads to elevated IOP, and may result in glaucomatous damage to the optic nerve

  41. Medical Conditions of the Eye • Cataracts - Clouding of the lens • Glaucoma - Loss of peripheral or “side” vision

  42. Medical Conditions of the Eye • Macular Degeneration - Loss of central or “straight ahead” vision • Diabetic Retinopathy - Blurring of central vision to blindness

  43. Glaucoma Glaucoma management involves lowering IOP by - Decreasing aqueous production by the ciliary body - Increasing aqueous outflow through the trabecular meshwork (小梁网) and uveal outflow paths（房水排出通道） - Neuroprotection

  44. Pilocarpine Increase Aqueous Humor Outflow • pilocarpine:parasympathomimetics increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network

  45. Muscarinic Agents: Parasympathetic Effects & Therapeutic Uses Pilocarpine (2) Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands (3) Gastrointestinal tract: increasing tone and motility (4) Urinary tract: contraction of bladder and relax for external sphincter muscles (5) Respiratory system: bronchoconstriction and secretion (5) CNS: cortical arousal or activation

  46. Muscarinic Agents: Parasympathetic Effects & Therapeutic Uses • Other use • (1) Gastrointestinal disorders, like gastroparesis • (2) Urinary bladder disorders, urinary retention • (3) Xerostomia（口腔干燥）, • (4) Antidote for atropine poisoning

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

  48. Drug classification 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

  49. 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 • Irreversible:organophosphates • Cholinergic antagonists：Cholinesterase reactivatorspralidoxime iodide

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