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Nervous System

Pharmacology for Autonomic Drugs Shi-Hong Zhang ( 张世红 ), PhD Dept. of Pharmacology, School of Medicine, Zhejiang University shzhang713@zju.edu.cn. Nervous System. Peripheral Nervous System (PNS). Central Nervous System (CNS). Organization of the nervous system. Peripheral Nervous

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Nervous System

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  1. Pharmacology for Autonomic DrugsShi-Hong Zhang (张世红), PhDDept. of Pharmacology, School of Medicine, Zhejiang Universityshzhang713@zju.edu.cn

  2. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Organization of the nervous system

  3. Peripheral Nervous System (PNS) Efferent Division Afferent Division Autonomic System (ANS) Somatic System Parasympathetic Sympathetic Enteric

  4. The Enteric Nervous System (+SNS/PSNS)

  5. The release of noradrenalin 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

  6. 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 （蠕动）of the GI tract

  7. Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Efferent Division Afferent Division Autonomic System (ANS) Somatic System 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

  8. Neurotransmitters • Synthesis • Storage • Release • Degradation • Receptors • Activation

  9. Drug actions and classification Autonomic drugs: mimetics and antagonists (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

  10. Cholinergic Pharmacology Adrenergic Pharmacology

  11. CASE STUDY • In mid-afternoon, a coworker brings 43-year-old JM to the emergency department because he is unable to continue picking vegetables. His gait is unsteady and he walks with support from his colleague. JM has difficulty speaking and swallowing, his vision is blurred, and his eyes are filled with tears. His coworker notes that JM was working in a field that had been sprayed early in the morning with a material that had the odor of sulfur. Within 3 hours after starting his work, JM complained of tightness in his chest that made breathing difficult, and he called for help before becoming disoriented.

  12. Cholinergic Terminal • Choline Uptake→ • ACh Synthesis • Choline + AcCoA → ACh • ChAT • ACh Storage • ACh Release • ACh Effects • - Postsynaptic • - Presynaptic • ACh inactivation • ACh→ Choline + Acetate • AChE

  13. Acetylcholine Release Regulation - by autoreceptors ACh acting on presynaptic m2-cholinergic receptors - by heteroreceptors NE acting on presynaptic alpha2-adrenergic receptors - by metabolism (extraneuronal)

  14. Cholinesterases Acetylcholinesteraseis 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)

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

  16. M receptors : G-protein Coupled MuscarinicReceptorSignalingPathways

  17. M receptors: • Depression of the heart(heart rate, conduction) • Contraction of smooth muscles(sensitive: GI tract, bronchial, urinary bladder; insensitive: uterine, blood vascular) • 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)

  18. Cholinergic Vasodilation • 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

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

  20. 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

  21. Ganglionic Neurotransmission EPSP = Excitatory Postsynaptic Potential IPSP = Inhibitory Postsynaptic Potential N = Nicotinic AChR M = Muscarinic AChR

  22. The Neuromuscular Junction (NMJ) A B

  23. Myasthenia Gravis • 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)

  24. 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 Cholinesterase reactivators: pralidoxime iodide

  25. Drug classification 2 Cholinergic antagonists (1) Cholinoceptor antagonists M cholinoceptor antagonists atropine (Antimuscarinic drugs) N cholinoceptor antagonists NN cholinoceptor antagonists:mecamylamine (Ganglionic blocking drugs, rarely used) NM cholinoceptor antagonists: succinylcholine (Neuromuscular blocking drugs ) (2) Botulinum Toxin(blocks ACh release)

  26. Cholinomimetics Direct-acting drugs Ach derivatives （胆碱酯类） Natural Muscarinic agonists (生物碱类M受体激动剂) N受体激动剂

  27. Bond cleaved by AChE 乙酰胆碱 卡巴胆碱 醋甲胆碱 氯贝胆碱 AChE resistant

  28. ACh Derivatives Bethanechol is most commonly used, particularly post-op for the treatment of paralytic ileus and urinary retention

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

  30. “Food” Poisoning • Poisoning causes muscarinic overstimulation： - salivation, lacrimation, visual disturbances; - abdominal colic and diarrhea - bronchospasm and bradycardia - hypotension; shock • Treatment is with atropine Amanita muscaria 伞形毒蕈 Atropa belladonna 颠茄

  31. Pilocarpine • (1) Eyes • Miosis: contraction of sphincter muscle of iris • Lowing intraocular pressure: enlarging angle of anterior chamber, increasing drainage of aqueous humor • Spasm of accommodation: contraction of ciliary muscle, contraction for near vision • Ophthalmological uses • Glaucoma:narrow (closed)- orwide (open)-angles • used for the emergency lowering of intraocular pressure • Iritis:miotics缩瞳药/mydriatics扩瞳药

  32. Circulation of aqueous humor

  33. 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

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

  35. Glaucoma • Glaucoma management involves lowering IOP by - Decreasing aqueous production by the ciliary body - Increasing aqueous outflow through the trabecular meshwork and uveal outflow paths

  36. pilocarpine:parasympathomimetics increase aqueous outflow by contraction of the ciliary muscle to increase tone and alignment of the trabecular network

  37. Pilocarpine • （2） Promoting secretion of exocrine glands, especially in sweat, salivary and tear glands • Systemic use • Antidotefor atropine poisoning • Adverse effects • M -like syndrome

  38. 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 Irreversible:organophosphates Cholinesterase reactivators: pralidoxime iodide

  40. Acetylcholinesterase (AChE) Activity

  41. Cholinomimetics-Indirect Agents: AChE Inhibitors A. Competitive (reversible) B. Carbamates (氨甲酰类slowly reversible) C. Organophosphates (irreversible) 新斯的明 依酚氯铵 These agents are irreversible and are used as pesticides or for glaucoma neostigmine These agents are reversible and are used medically (glaucoma or MG) 毒扁豆碱

  42. Acetylcholinesterase Inhibitors:Reversible Edrophonium 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.

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

  44. Neostigmine 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 ineffective on CVS, glands, eye

  45. Neostigmine Clinical uses • Myasthenia gravis: symptomatic treatment • overdose: cholinergic crisis • Paralytic ileus and bladder: post operative abdominal distension and urinary retention • Paroxysmal superventricular 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（肠梗阻） • urinary obstruction • bronchial asthma • poisoning of depolarizing skeletal muscle relaxants • (e.g. succinylcholine, 琥珀酰胆碱)

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