1、pharmacologynGeneral introductionnDrugs acting on efferent nervous systemnDrugs acting on central nervous systemnDrugs acting on cardiovascular systemnDrugs acting on visceranChemotherapeutic agentsChapter 5 Intrduction to Pharmacologyof Efferent Nervous SystemZhang BinInstitute of PharmacologySchoo
2、l of MedicineShandong UniversityOrganization of Nervous systemefferent nervous system(ENS)nautonomic nervous system (vegetative nervous system)nsomatic motor nervous system Efferent neurons of the autonomic nervous systemClassification of ENS according to the released neurotransmittersvcholinergic n
3、erve:acetylcholine(Ach)vnoradrenergic nerve:noradrenaline(NA)Classification of ENSParasympathetic nerve Central nervous system Ach skeletal muscle Ach NA Ach Ach sweat glands Ach AchAch adrenal medullasomatic motor nerve sympathetic nerveglands,smooth muscle,heart heart,vessel,smooth muscleSection 1
4、 Neurotransmitter and Receptor of ENS nNeurotransmitter of ENSnThe receptors of ENS 一.Neurotransmitter of ENS1.Development of neurotransmitter theoryn100 years ago Chemical transmission electronic transmissionn1946 Von Euler NA(noradrenaline)n1921 loewi double frog heart experimentn1926 Dale Ach(ace
5、tylcholine)2.Biosynthesis,storage,release and termination of neurotransmittersnAch(acetylcholine)nNA(noradrenaline)inhibitor2.Biosynthesis,storage,release and termination of neurotransmitters(1)Biosynthesisncholine+acetyl coenzymeA Achntyrosine dopa DA NAcholine acetylaseTHDD DH(2)Storage +ATP+prote
6、in store in vesicles Ach NA(3)releasenexocytosisnquantal realeasen cotransmission(4)TerminationvAch:acetylcholinesterase(AchE)in synapsevNA:uptake1(neuronal uptake)75%-90%storage in vesicles MAO uptake2(non-neuronal uptake)COMTMAO 二二.The receptors of ENS Classification,Distribution and Effect Cholin
7、e receptors (Cholinoceptors)nM-R:muscarinenN-R:nicotine Cholinoceptors M-R:vM1-R:ganglion,CNSvM2-R:heart,presynaptic sites(negative feedback),CNSvM3-R:exocrine glands,smooth muscle,endothelium,CNSvM4 R:exocrine glands,smooth muscle,CNSvM5-R:CNSCholinoceptorsN-R:nicotine NM-R:skeletal muscle NN-R:gan
8、glion and CNSadrenoceptor:NA AD-Rn1-R:postsynaptic effector cells (especially smooth muscle)n2-R:presynaptic nerve terminals(negative feedback),platelet,smooth muscle,lipocytesadrenoceptor-Rv1-R:postsynaptic effector cells,(especially heart,lipocytes,)presynaptic nerve terminalsv2-R:postsynaptic eff
9、ector cells,(especially smooth muscle)v3-R:postsynaptic effector cells,(especially lipocytes)Classification of receptor according to their structurenG-protein-coupled receptor:-R,-R,M-R,DA-R,5-HT-RnLigand-gated receptors N-RStructure of G-protein-coupled ReceptorMolecular Mechanism of Gq-protein-cou
10、pled ReceptorMolecular Mechanism of Gi/s-protein-coupled ReceptorStructure of ligand-gated ion channel ReceptorMolecular Mechanism of ligand-gated ion channel receptorn1.Cholinoceptors M-R:G-protein-coupled receptor M1-R:Gq-protein-coupled receptor M2-R-Gi-protein-coupled receptor N-R:ligand-gated i
11、on channel receptorn2.adrenoceptor:G-protein-coupled receptor 1 R:Gq-protein-coupled receptor 2 R:Gi-protein-coupled receptor -R:Gs-protein-coupled receptorMolecular Mechanism of Receptor N-R Na+,K+,Ca2+G-protein-coupled receptor ligand-gated receptor:(-)PKA cAMPM1-R M2-R GqGi K+,Ca2+(-)AC cAMPPLC I
12、P3DAG1-R 2-R-R(+)AC(-)AC GiGqPLC,PLA2,PLD Gs cAMP(-)PKA(+)PKA Ca2+(+)PKCterminologynadrenergic nadrenergic receptor ncholinergicncholinergic receptornpostsynaptic receptornpresynaptic receptorSection 2The physiological actions of ENSnCo-innervation and Dominant TheorynSympathetic actions:fight and f
13、light responsenParasympathetic actions:rest and digest responseSection 3 The basic mechanisms of actions of ENS drugs n1.Direct action of receptors agonist blocker(antagonist)n2.lnfluence of neurotransmitters biosynthesis release storage conversionSection 4 The classification of the ENS drugs（三）抗胆碱酯
14、酶药Chapter 6 parasympathomimeticsnCholinoceptor agonists(cholinomimetics)nAnticholinesterase agents(cholinesterase-inhibiting drugs)nDrugs of enhancers of ACh releaseCholinoceptor AgonistsM-R agonists:Choline esters:acetylcholine(ACh)alkaloids:pilocarpineN-R agonists:nicotine Section 1 M-R agonists A
15、cetylcholine(ACh)1.unstable2.low selectivity3.administration routePharmacological actions Directly activate M-R,N-Rv muscarinic actions:small dosev nicotinic actions:large dose1.muscarinic actions:small dose1.cardiovascular systemvvessel dilate a.NO release(M3 R EDRF(NO)GC cGMP intracellular Ca2+)b.
16、NA releasev BP (HR)v Heart depress:negative(chronotropic,dromotropic,inotropic)effect1.muscarinic actions:small dose2.glands 3.gastrointestinal tract:motility increase,secretion stimulation4.urinary bladder:detrusor muscle(逼尿肌）contraction,trigone and sphincter relaxation5.eye:sphincter muscle of iri
17、s(虹膜）contract:miosis ciliary muscle contract:near vision2.nicotinic actions:large dosevNN-R:dominant nerve actionsvNM-R:skeletal muscle contraction alkaloidsnPilocarpine（毛果芸香碱，匹鲁卡品）毛果芸香碱，匹鲁卡品）nMuscarine（毒蕈碱）毒蕈碱）n Arecoline（槟榔碱（槟榔碱）nOxotremorine（氧化震颤素）氧化震颤素）PilocarpinePharmacological actions:selectiv
18、ely activate M-R 1.Eye vmiosis:pupiliary sphincter vdecrease intraocular pressurevspasm of accommadation:ciliary muscle 2.Glands secrete increasingly (sweat gland,salivary gland)3.Smooth muscle4.Cardiovascular systemClinical uses 1.Glaucoma(青光眼）vangle-closure glaucomavopen-angle glaucoma What is Gla
19、ucoma?nincreased pressure within the eye.Cells inside the eye produce aqueous humor that maintains the shape of the eye and nourishes the tissues inside the eye.The balance of fluid production and drainage is responsible for maintaining normal pressure within the eye.nIn glaucoma,the drain becomes c
20、logged but the eye keeps producing fluid.Therefore,the pressure in the eye increases.The increased pressure in the eye actually can cause the eye to stretch and enlargeHow does Glaucoma affect the eye?nVision Loss.Pressure damage to the optic nerve and decreased blood flow to the retina,results in l
21、oss of vision.However,if the pressure in the eye remains uncontrolled,the retina degenerates and vision is permanently lost.Permanent blindness can occur within several hours if the pressure is very high and the glaucoma develops rapidlynPain.Humans have normal intraocular pressures between 10 and 2
22、0 mmHg.Glaucoma often results in pressures of 20-28 mmHg in humans.The pain persists in the form of a constant headache or migraine.This discomfort can result in decreased activity,less desire to play,irritability,or decreased appetite2.iritis（虹膜炎），iridocyclitis（虹膜睫状体炎）3.others:dry mouthAdverse reac
23、tions Muscarine（毒蕈碱）nAmanita muscaria （捕蝇蕈）Inocybe（丝盖伞菌属）Clitocybe（杯伞菌属）Section 2 N-R agonists nicotinenNicotine:from tobaccoAction:NM,NN,CNS and dependence (double phase)Tobacco poison:Hypertension,coronary heart disease,cerebrovascular disease,cancer,AtherosclerosisChina:Largest tobacco productive
24、 country,Largest tobacco consumption countryNo smoking！Stop smoking！Section 3 Anticholinesterase AgentsCholinesterase:true Cholinesterase(AChE)PseudocholinesteraseAnticholinesterase Agents-indirect acting cholinomimeticsClassification according to structurennon-covalent bonding agents:Edrophonium ch
25、loride(依酚氯铵):strong polarity,short tacrine(他克林):strong lipophilia,long donepezil(多奈哌齐):strong lipophilia,longnCarboxamide(氨甲酰类):Physostigmine(毒扁豆碱)Pyridostigmine(吡斯的明)Demecarium(地美溴铵)rivastigmine(利凡斯的明)norgnaophosphorus compound(有机磷化合物)亲和力亲和力亲脂性亲脂性BBB维持时间维持时间依酚氯铵依酚氯铵 一般一般弱弱短短他克林他克林较高较高强强长长多奈哌齐多奈哌齐 较
26、高较高强强长长Classification according to pharmacological propertyvReversible Anticholinesterase agentsvirreversible Anticholinesterase agents vMechanisms of actions:vPharmacological actions:1.eye 2.gastrointestinal tract（esophagus,stomach,intestine)3.motor end plate 4.glands 5.cardiovascular systemClinica
27、l Uses 1.Myasthenia gravis (重症肌无力):NeostigminePyridostigmine(吡斯的明)Ambenonium chloride (安贝氯胺)Clinical Uses2.Postoperative abdominal distension;Urinary retention:Neostigmine3.glaucoma:Physostigmine(毒扁豆碱)Demecarium(地美溴铵)4.intoxication of d-tubocurarine:Neostigmine，Edrophonium chloride(依酚氯铵):5.Alzheimer
28、s disease:tacrine,donepezil,rivastigmine,galanthamin 6.Supraventricular tachyarrhythmias Common used agentsReversible Anticholinesterase agents Neostigmine(新斯的明）vactions：1.Inhibit AChE2.Activate NM-R on motor endplate3.Strong effect on skeletal muscle4.Not into CNSvUses:1.Myasthenia gravis:Skeletal
29、muscle contraction po,sc,im iv2.Postoperative abdominal distension;Urinary retention 3.intoxication of d-tubocurarine and atropine 4.Supraventricular tachyarrhythmias5.GlaucomaAdverse reactions:nCholinergic overexcitation (cholinergic crisis)Treatment:atropine d-tubocurarine Pyridostigmine(吡斯的明)nWea
30、ker than Neostigminenslower than NeostigminenLonger than NeostigminenNot into CNSnUsed to treat Myasthenia gravisnContraindication:mechanical ileus，urinary obstruction Physostigminencharacteristics 1.Stronger than neostigmine 2.Can enter CNS 3.Have no direct action on Rnactions：1.eye 2.systemic acti
31、onnUses:1.Glaucoma 2.Intoxication of anticholine agents:Atropine Tricyclic antidepressant Dibenzothiazine antipsychotics nComparison to pilocarpine 1.More rapid 2.Stronger 3.longernDonepezilnRivastigminenTacrine Alzheimers diseaseReversible anticholinesterase agentsvneostigminePyridostigmineAmbenoni
32、umGalanthamine:Myasthenia gravisvPhysostigmineDemecarium:Glaucoma vEdrophonium chloride:diagnostic test for myasthenia gravisvDonepezilrivastigmineTacrine:Alzheimers diseaseIrreversible Anticholinesterase Agents-Organophosphates vMechanisms of intoxicationvPathway of intoxication vsigns of acute int
33、oxication 1.M manifestation(muscarinic excess)2.N manifestation(nicotinic effects)3.CNS effectsvChronic intoxication Prevention and treatment of organophosphates intoxication vPrevention vTreatment of acute intoxication 1.maintenance of vital signs 2.Decontamination to prevent further absorption 3.S
34、ymptomatic treatment 1)atropine 2)cholinesterase reactivatorCholinesterase ReactivatorsPralidoxime iodide(PAM):碘解磷定Mechanisms of actiontherapeutic effect 1.inhibit Nm manifestationstrong 2.inhibit M manifestationweak 3.CNS 碘解磷定磷酰化AChE复合物复合物磷酰化碘解磷定磷酰化碘解磷定AChEPralidoxime chloride(PAM-Cl):氯解磷定 better w
35、ater-solubility im and iv little adverse reactionChapter 7 cholinoceptor-blocking drugsnM-R blockersnN-R blockers:NN-R blockers NM-R blockersMuscarinic cholinoceptor-blocking drugs nAtropine and atropine-like alkaloidsnSynthetic atropine substitutesatropine-like alkaloids and their resources植物植物 主要生
36、物碱主要生物碱 颠茄颠茄(atropa belladonna)莨菪碱莨菪碱(hyoscyamine)曼陀罗曼陀罗(datura stramonium)莨菪碱莨菪碱洋金花洋金花(datrua sp)东莨菪碱东莨菪碱 (scopolamine)莨菪莨菪(hyoscyamus niger)莨菪碱莨菪碱 唐古特莨菪唐古特莨菪(scopolia tangutica)山莨菪碱山莨菪碱 (anisodamine)n 樟柳碱樟柳碱(anisodine颠茄颠茄莨菪莨菪曼陀罗曼陀罗洋金花洋金花Atropinenpharmacological actions:block M-R block NN-R in larg
37、e dosepharmacological actions1.glands:secretionsalivary,sweat lacrimal,respiratory gastric acid,pancreatic,intestinal juice2.eyes (1)mydriasis (2)increase intraocular pressure (3)paralysis of accommodation3.splanchnic smooth muscle:relaxation(spasmodic)GI tract,detrusor muscle of bladder:significant
38、 Bile tract,bronchial,uterine(子宫):weak4.heart:(1)HR Therapeutic dose:decrease (presynaptic M1blockade)Large dose:increase(block vagal effect on M2 R)(2)A-V conduction:5.vessels:dilation(in large dose)(1)Direct effect (2)Compensative reaction by temperature rise6.CNS:excitationOrgan sensitivity:Gland
39、 eye splanchnic smooth muscle cardiovascular system CNS.Clinical Uses1.Anti-smooth muscle spasm2.Pre-anaesthesia medication agent3.Ophthalmological use (1)iridocyclitis (2)optometry (3)examination of retina4.Bradyarrhythmias5.Shock(septic shock):Cautions6.Intoxication of organophosphateadverse react
40、ions 1.Common Side Effects2.Acute Poisoningminimal lethal dose:adults 80130mg children-10mgPrevention1.Decontamination:to prevent further absorption2.Antidotes:Parasympathomimetics3.Maintenance of vital signscontraindictionsv Glaucomav prostatic hypertrophy anisodamine(654-2)山莨菪碱nCharacteristic of a
41、ctions 1.high selectivity(smooth muscle and vessels)2.little side effect(not pass through BBB)nUses 1.septic shock 2.visceral colics.Scopolamine(东莨菪碱东莨菪碱)Characteristics 1.CNS actions:depression(strong)2.peripheral actions:glands:strong others:weakvUses:1.preanaesthesia medication 2.prevention motio
42、n sickness 3.Parkinson disease 4.traditional medicine anaesthesia中药麻醉n华佗（公元141203年）n“麻沸散”n曼陀罗(洋金花)n徐州医学院附属医院:中药麻醉汤(针剂)n东莨菪碱 Section 2 Synthetic atropine substitutesnSynthetic MydriaticsnSynthetic AntispasmaticsnSelective M1 AntagonistsSynthetic MydriaticsnHomatropine(后马托品后马托品)nTropicamide(托吡卡胺托吡卡胺)n
43、Cyclopentolate(环喷托酯环喷托酯)nEucatropine(尤卡托品尤卡托品)Comparison of some mydriaticsdrugsconcentration(%)mydriasisparalysis of accommodationpeak(m)duration(d)peak(h)duration(d)atropine1.0304071013712homatropine1.02.04060120.5113tropicamide0.51.020400.250.50.50.25cyclopentolate 0.530305050 110.251eucatropine2
44、.05.0301/121/4nUses:iridocyclitis optometry examination of retinaSynthetic AntispasmaticsQuaternary amines(季胺类季胺类)：Propantheline bromide(溴丙胺太林，普鲁本辛溴丙胺太林，普鲁本辛)1.selective blockade of GI tract:2.ulceration,GI spasm,bladder stimulation3.neuromuscular block action:toxic dose4.low BBB permeability Quater
45、nary amines(季胺类季胺类)：Ipratropium bromide(异丙托溴胺异丙托溴胺)1.Relieve bronchospasm by inhalation2.Uses:chronic obstructive pulmonary disease,bronchial asthma3.ganglionic block action stronger than atropine 4.low BBB permeabilityTertiary amines(叔胺类叔胺类)：Mydriatics Anticholinergic in CNS Antispasmatic agents Be
46、nactyzine(贝那替嗪，胃复康）贝那替嗪，胃复康）1.Relieve smooth muscle spasm2.Antianxiety effect Selective M1 AntagonistsnPirenzepine(哌仑西平哌仑西平)nTelenzepine(替仑西平替仑西平)nInhibit secretion of gastric acidnClinical use:peptic ulcernNot into CNS受体亚型分布效应N1受体N2受体M1受体M2受体M3受体神经节肾上腺髓质骨骼肌神经节窦房节房室节心肌平滑肌外分泌腺神经节除极儿茶酚胺释放骨骼肌收缩介导迟发性兴奋突触后电位延缓自发除极，减慢心率减慢传导速度降低收缩力收缩分泌增多受体亚型分布效应1受体2受体1受体2受体3受体血管平滑肌生殖道泌尿道平滑肌肝脏小肠平滑肌心脏胰岛细胞血管平滑肌血小板神经末梢心脏肾小球旁器细胞平滑肌肝脏脂肪组织收缩收缩肝糖原分解松弛增强收缩力减少胰岛素分泌收缩聚集减少去甲肾上腺素释放兴奋增加肾素分泌松弛肝糖原分解脂肪分解
