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Autonomic Pharmacology 张纬萍 浙江大学医学院药理 [email protected] 2013.10.11 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 Nervous System 神经系统 Nervous System Peripheral Nervous System (PNS) 神经系统 Central Nervous System (CNS) Nervous System Peripheral Nervous System (PNS) Efferent Division 神经系统 Central Nervous System (CNS) Afferent Division Nervous System Peripheral Nervous System (PNS) Efferent Division Central Nervous System (CNS) Afferent Division Somatic motor Nervous System 神经系统 Nervous System Peripheral Nervous System (PNS) Efferent Division Central Nervous System (CNS) Afferent Division Autonomic nervous System (ANS) 神经系统 Somatic motor Nervous System Nervous System Peripheral Nervous System (PNS) Efferent Division Central Nervous System (CNS) Afferent Division Autonomic nervous System (ANS) Somatic motor Nervous System Parasympathetic副交感 Sympathetic 交感 Enteric 肠神经系统 神经系统 交感和副交感神经系统 thoracolumbar craniosacral 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 Absorptive cell 吸收细胞 Enterochromaffin cell 肠噬铬细胞 The Enteric Nervous System肠神经系统 (+SNS/PSNS) 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 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 Nervous System Peripheral Nervous System (PNS) Central Nervous System (CNS) Drugs that produce their primary therapeutic effect by mimicking or Efferent Division Afferent Division altering the functions of autonomic nervous system are called autonomic drugs. Autonomic nervous System (ANS) Somatic motor Nervous System Parasympathetic Sympathetic (Enteric) 神经系统 Neurotransmitters drugs Receptors Neurotransmitters •Synthesis •Storage •Release •Inactivation Receptors •Activation 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 Agonists激动剂 Antagonists 拮抗剂 Receptors Antagonists Direct-acting: receptor antagonists Indirect-acting: decreasing amounts and/or effects of transmitters 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 Agonists激动剂 Antagonists 拮抗剂 Receptors Antagonists Direct-acting: receptor antagonists Indirect-acting: decreasing amounts and/or effects of transmitters Cholinergic Pharmacology Adrenergic Pharmacology Cholinergic Terminal 1. Choline Uptake 2. ACh Synthesis Choline acetyltransferase(ChAT) Choline + AcCoA → ACh ChAT 3. ACh Storage 4. ACh Release 5. ACh Effects a) Postsynaptic b) Presynaptic 6. ACh Metabolism Acetylcholinesterase(AChE) ACh → Choline + Acetate AChE 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) Cholinesterases 胆碱酯酶 Acetylcholinesterase is 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) 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 M receptors : G-protein Coupled Muscarinic Receptor Signaling Pathways Smooth Muscle contraction cAMP↓ (first, second, third messenger) Heart rate↓ 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 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 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 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) N receptors : Ligand-gated Ion Channels • At the NMJ, N receptors Pentameric 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 The Neuromuscular Junction (NMJ) A B 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) 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 Cholinomimetics: Direct-acting drugs ACh Derivatives Bond cleaved by AChE 卡巴胆碱 乙酰胆碱 氯贝胆碱 乙酰甲胆碱 AChE Resistant Cholinomimetics: Direct-acting drugs Bethanechol is most commonly used, particularly postoperation for the treatment of paralytic ileus(麻痹性肠梗 阻) and urinary retention(尿储留) Natural Muscarinic Agonists 槟榔碱 areca or betal nuts (India,E. Indies) 匹鲁卡品 毛果云香硷 pilocarpus (S. Amer. shrub) 毒蕈碱 amanita muscaria (mushroom) (Most to least nicotinic) “Food” Poisoning Amanita muscaria => muscarine Pilocarpus=> Pilocarpine Atropa belladonna => atropine Deadly Nightshade, 癫茄 Areca nuts=> Arecoline “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 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)- or wide (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) light 巩膜窦 小梁网 睫状肌 睫状体上皮细胞 paralysis of accommodation Ciliary muscle (dilation) Canal of Schlemm mydriasis zonule posterior chamber Anterior chamber lens far sight atropine spasm of accommodation iris 悬韧带 miosis zonule Anterior chamber Ciliary muscle (contraction) near sight pilocarpine 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 Medical Conditions of the Eye • Cataracts - Clouding of the lens • Glaucoma - Loss of peripheral or “side” vision Medical Conditions of the Eye • Macular Degeneration - Loss of central or “straight ahead” vision • Diabetic Retinopathy - Blurring of central vision to blindness 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 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 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 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 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. 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 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 reactivators pralidoxime iodide CholinomimeticsIndirect Agents: AChE Inhibitors Acetylcholinesterase (AChE) Activity 酯解部位 阴离子部位 水解 乙酰化AChE 胆碱 Cholinomimetics- Indirect Agents: AChE Inhibitors A. Edrophonium依酚氯铵 (reversible, competitive) B. Carbamates 氨甲酰类(slowly reversible) C. Organophosphates 有机磷类(irreversible) 新斯的明 依酚氯铵 These agents are reversible and are used medically (glaucoma or MG) 氨甲酰酚羟基 异氟磷 neostigmine 毒扁豆碱 These agents are irreversible and are used as pesticides or for glaucoma 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. Acetylcholinesterase Inhibitors: Carbamates Inhibitory Effects are slowly reversible Representative Drugs neostigmine 新斯的明 (quaternary amine) physiostigmine 毒扁豆碱 (tertiary amine) pyridostigmine吡斯的明 (quaternary amine) 二甲氨基甲酰化AChE quaternary amines effective in periphery only tertiary amines effective in periphery and CNS (fat-soluble) Acetylcholinesterase Inhibitors: Carbamates neostigmine (quaternary amine) – Pharmacological effects • AChE(-), Ach ↑, directly 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 Acetylcholinesterase Inhibitors: Carbamates neostigmine (quaternary amine) – Clinical uses • Myasthenia gravis: symptomatic treatment, overdose: cholinergic crisis • Paralytic ileus and bladder: post operative abdominal distension and urinary retention • Paroxysmal superventricular tachycardia(阵发性室上速) • Antidote for tubocurarine (筒箭毒碱) and related drug poisoning Acetylcholinesterase Inhibitors: Carbamates neostigmine (quaternary amine) – Adverse effects • Cholinergic effects: muscarinic and nicotinic effects, treated with atropine (muscarinic) • Contraindications: mechanical ileus 机械性肠梗阻 urinary obstruction 泌尿道梗阻 bronchial asthma 支气管哮喘 poisoning of depolarizing skeletal muscle relaxants (e.g. succinylcholine琥珀胆碱) 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。 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 Acetylcholinesterase Inhibitors: Irreversible Bond is hydrolyzed in binding to the enzyme 乙膦硫胆碱 梭曼 For ophthalmic use 对硫磷 These agents are used as pesticides or for glaucoma. 马拉硫磷 Acetylcholinesterase Inhibitors: Organophosphates 异氟磷 老化 解磷定 Effects of Organophosphates are irreversible (covalent bond formation) 单烷氧基磷酰化AChE Pralidoxime(碘解磷定) can restore AChE activity if administered soon after toxin exposure. •Conjugating with organophosphate by oxime group; •Conjugating with free organophasphates Acetylcholinesterase Inhibitors: Organophosphates (1) Toxic symptoms – Acute intoxication • Muscarinic symptoms eye, exocrine glands, respiration, GI tract, urinary tract, CVS • Nicotinic symptoms NN: elevation of BP, increase of HR; N2: tremor of skeletal muscles • CNS symptoms excitation, convulsion( 抽 搐 ); depression (advanced phase) – Chronic intoxication • usually occupational poisoning • plasma ChE activity ↓,神经衰弱症候群 • weakness, restlessness, anxiety, tremor, miosis, …… Acetylcholinesterase Inhibitors: Organophosphates (2) Detoxication •Elimination of poison; Supportive therapy •Antidotes Atropine-antagonizing muscarinic effects; early, larger dose, and repeated use Cholinesterase reactivators-reactivation of phosphated AChE; moderate-severe patients, early use (More effective on tremor), combined with atropine – Pyraloxime chloride (氯解磷定):saver than PAM – Pralidoxime iodide (PAM) (碘解磷定) – Obidoxime chloride(双复磷): two active oxime groups ACHEI Applications Pharmacological Actions: Increases ACh concentrations at cholinergic synapses, thereby increasing cholinergic activity. glaucoma (e.g. physiostigmine毒扁豆碱) myasthenia gravis (e.g. Edrophonium依酚氯胺, neostigmine 新斯的明, pyridostigmine 吡斯的明) reverse neuromuscular blockade from competitive antagonists (neostigmine) Alzheimer’s disease (tacrine他克林 & donepezil多奈派齐) chemical warfare agents insecticides Summary 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: AChE inhibitors Reversible: neostigmine Irreversible: organophosphates Cholinesterase reactivators:PAM See you next Class!