《基础医学各论3》资料：神经系统药理1

1、Autonomic Pharmacology张纬萍 浙江大学医学院药理,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,神经系统,神经系统,神经系统,Nervous System,Peripheral Nervous System (PNS),Central Nervous System (CNS),Efferent Division,Afferent Division,Autonomic nervous System (ANS),Somatic motor Nervous Sy

2、stem,神经系统,神经系统,Autonomic nervous System (ANS),Somatic motor Nervous System,交感和副交感神经系统,thoracolumbar craniosacral,The Enteric Nervous System肠神经系统 (+SNS/PSNS),Circular muscle layer 环行肌,longitudinal muscle layer 纵行肌,Absorptive cell 吸收细胞,Enterochromaffin cell 肠噬铬细胞,Submucosal plexus 粘膜下神经丛,Myenteric ple

3、xus 肌间神经丛,Secretory cell 分泌细胞,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 musc

4、les, 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

5、 of the GI tract,神经系统,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,Neurotransmitters Receptors,Neurotransmitters Synthesis Storage Release

6、 Inactivation Receptors Activation,Receptors,drugs,Direct actions,Agonists激动剂,Antagonists 拮抗剂,Neurotransmitters,Synthesis Transport and storage Release Inactivation,Indirect actions,Direct-acting: receptor agonists Indirect-acting: increasing amounts and/or effects of transmitters,Direct-acting: rec

7、eptor antagonists Indirect-acting: decreasing amounts and/or effects of transmitters,Mimetics,Antagonists,Receptors,drugs,Direct actions,Agonists激动剂,Antagonists 拮抗剂,Neurotransmitters,Synthesis Transport and storage Release Inactivation,Indirect actions,Direct-acting: receptor agonists Indirect-actin

8、g: increasing amounts and/or effects of transmitters,Direct-acting: receptor antagonists Indirect-acting: decreasing amounts and/or effects of transmitters,Mimetics,Antagonists,Cholinergic Pharmacology Adrenergic Pharmacology,Choline Uptake ACh Synthesis Choline acetyltransferase(ChAT) Choline + AcC

9、oA ACh ChAT ACh Storage ACh Release ACh Effects Postsynaptic Presynaptic ACh Metabolism Acetylcholinesterase(AChE) ACh Choline + Acetate AChE,Cholinergic Terminal,Regulation - by auto-receptors ACh acting on presynaptic M2-cholinergic receptors - by hetero-receptors NE acting on presynaptic a2-adren

10、ergic receptors - by metabolism (extra-neuronal),Acetylcholine Release by exocytosis,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 butyrylcholineste

11、rase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

12、Ligand-gated Ion Channels NMJ 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

13、 for near vision) CNS: activation，yet ACh can hardly pass BBB,M receptors : end organs and effect of activation,NN receptors（ N1 receptors ） Sympathetic and parasympathetic ganglia Adrenal medulla NM receptors （N2 receptors ） The Neuromuscular Junction (NMJ) (Contraction of skeletal muscles),N recep

14、tors : subtypes and location,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 as and 3 bs,The Neuromuscular Junction (NMJ),Myasthenia G

15、ravis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 cholinerg

16、ic signaling and to remove the antibodies (blood dialysis),M- and N- Receptors,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,ACh,Cholinesterase inhibitors (Anticholinesterases) Reversible

17、: neostigmine 新斯的明 Irreversible: organophosphates,Indirect actions,Cholinergic antagonists,Drug classification,Cholinomimetics:Direct-acting drugs,AChEResistant,AChDerivatives,Bond cleaved by AChE,乙酰胆碱,乙酰甲胆碱,卡巴胆碱,氯贝胆碱,Bethanechol is most commonly used, particularly post-operation for the treatment o

18、f paralytic ileus（麻痹性肠梗阻） and urinary retention（尿储留）,Cholinomimetics:Direct-acting drugs,Natural Muscarinic Agonists,(Most to least nicotinic),匹鲁卡品 毛果云香硷,槟榔碱,毒蕈碱,amanita muscaria (mushroom),pilocarpus (S. Amer. shrub),areca or betal nuts (India,E. Indies),Atropa belladonna = atropine,Amanita muscari

19、a = muscarine,“Food” Poisoning,Deadly Nightshade, 癫茄,Pilocarpus= Pilocarpine,Areca nuts= Arecoline,Poisoning causes muscarinic overstimulation or blocking (for belladonna only) - salivation, lacrimation(流泪), visual disturbances; - abdominal colic and diarrhea - bronchospasm and bradycardia - hypoten

20、sion; shock Treatment is with atropine,“Food” Poisoning,Muscarinic Agonists: Parasympathetic Effects 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 Inh

21、ibitors: 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),quaternary amines effective in periphery only tertiary amines effective in periphery and CNS （fat-soluble）,

22、二甲氨基甲酰化AChE,氨甲酰类,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, gl

23、ands, 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

24、室上速） Antidote for tubocurarine （筒箭毒碱） and related drug poisoning,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 poison

25、ing of depolarizing skeletal muscle relaxants (e.g. succinylcholine琥珀胆碱),Acetylcholinesterase Inhibitors: Carbamates,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 C

26、an 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 Dihydrogala

27、nthamine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,These agents are used as pesticides or for glaucoma or for biothreat,Acetylcholinesterase Inhibitors: Irreversible,Bond is hydrolyzed in binding to the enzyme,For ophthalmic use,Acetyl

28、cholinesterase Inhibitors: Organophosphates,Effects of Organophosphates are irreversible (covalent bond formation),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,异氟磷,解磷定,单烷

29、氧基磷酰化AChE,老化,(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 i

30、ntoxication usually occupational poisoning plasma AChE activity ,神经衰弱症候群 weakness, restlessness, anxiety, tremor, miosis, ,Acetylcholinesterase Inhibitors: Organophosphates,(2) Detoxication Elimination of poison; Supportive therapy Antidotes Atropineantagonizing muscarinic effects; early, larger dose, and repeated use Cholinesterase reactivatorsreactivation of phosphated AChE; moderate-severe p