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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 BinInstituteofPharmacologySchoolo
2、fMedicineShandongUniversityOrganizationofNervoussystemefferent nervous system (ENS)nautonomic nervous system (vegetative nervous system)nsomatic motor nervous system EfferentneuronsoftheautonomicnervoussystemClassification of ENS according to the released neurotransmittersvcholinergic nerve: acetylc
3、holine (Ach)vnoradrenergic nerve: noradrenaline ( NA)Classification of ENSParasympatheticnerveCentralnervoussystem Ach skeletal muscle AchNAAchAchsweat glands Ach AchAchadrenal medullasomatic motor nerve sympatheticnerveglands, smooth muscle, heart heart, vessel,smooth muscleSection 1 Neurotransmitt
4、er 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 (acetylcholine)2
5、.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+protein
6、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.ThereceptorsofENSClassification, Distribution and Effect Cho
7、linereceptors (Cholinoceptors)nM-R:muscarinenN-R:nicotineCholinoceptorsM-R:vM1-R:ganglion,CNSvM2-R:heart,presynapticsites(negativefeedback),CNSvM3-R:exocrineglands,smoothmuscle,endothelium,CNSvM4R:exocrineglands,smoothmuscle,CNSvM5-R:CNSCholinoceptorsN-R:nicotineNM-R:skeletalmuscleNN-R:ganglionandCN
8、Sadrenoceptor:NAAD-Rn1-R:postsynapticeffectorcells(especiallysmoothmuscle)n2-R:presynapticnerveterminals(negativefeedback),platelet,smoothmuscle,lipocytesadrenoceptor-Rv1-R:postsynapticeffectorcells,(especiallyheart,lipocytes,)presynapticnerveterminalsv2-R:postsynapticeffectorcells,(especiallysmooth
9、muscle)v3-R:postsynapticeffectorcells,(especiallylipocytes)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 ReceptorStructure of ligand-gated ion channel ReceptorMolecular Mechanism
10、of ligand-gated ion channel receptorn1. CholinoceptorsM-R:G-protein-coupledreceptorM1-R:Gq-protein-coupledreceptorM2-R-Gi-protein-coupledreceptorN-R:ligand-gatedionchannelreceptorn2. adrenoceptor:G-protein-coupledreceptor1R:Gq-protein-coupledreceptor2R:Gi-protein-coupledreceptor-R:Gs-protein-coupled
11、receptorMolecular Mechanism of Receptor N-RNa+,K+,Ca2+G-protein-coupledreceptorligand-gatedreceptor:(-)PKAcAMPM1-RM2-RGqGiK+,Ca2+(-)ACcAMPPLCIP3DAG1-R2-R-R(+)AC(-)ACGiGqPLC,PLA2,PLDGscAMP(-)PKA(+)PKACa2+(+)PKCterminologynadrenergic nadrenergic receptor ncholinergicncholinergic receptornpostsynaptic
12、receptornpresynaptic receptorSection2ThephysiologicalactionsofENSnCo-innervation and Dominant TheorynSympatheticactions: fightandflightresponsenParasympatheticactions: restanddigestresponseSection 3 The basic mechanisms of actions of ENS drugs n1.Direct action of receptors agonist blocker (antagonis
13、t)n2.lnfluence of neurotransmitters biosynthesis release storage conversionSection 4 The classification of the ENS drugs（三）抗胆碱酯酶药Chapter 6 parasympathomimeticsnCholinoceptor agonists (cholinomimetics)nAnticholinesterase agents (cholinesterase-inhibiting drugs)nDrugs of enhancers of ACh releaseCholin
14、oceptor AgonistsM-Ragonists:Cholineesters:acetylcholine(ACh)alkaloids:pilocarpineN-Ragonists:nicotineSection 1 M-R agonists Acetylcholine (ACh)1.unstable2.lowselectivity3.administrationroutePharmacological actions Directly activate M-R, N-Rv muscarinic actions: small dosev nicotinic actions: large d
15、ose1.muscarinic actions: small dose1.cardiovascularsystemvvessel dilate a. NO release(M3REDRF(NO)GCcGMPintracellularCa2+) b. NA releasev BP (HR)v Heart depress: negative (chronotropic, dromotropic, inotropic) effect1.muscarinic actions: small dose2.glands3.gastrointestinaltract: motility increase, s
16、ecretion stimulation4.urinarybladder: detrusor muscle (逼尿肌）contraction, trigone and sphincter relaxation: sphincter muscle of iris (虹膜） contract: miosis ciliary muscle contract: near vision2.nicotinic actions:large dosevNN-R: dominant nerve actionsvNM -R:skeletal muscle contraction alkaloidsnPilocar
17、pine（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）nArecoline（槟榔碱（槟榔碱）nOxotremorine（氧化震颤素）氧化震颤素）PilocarpinePharmacological actions: selectively activate M-R 1.Eye vmiosis :pupiliarysphinctervdecrease intraocular pressurevspasm of accommadation :ciliarymuscle2. Glands secrete increasingly (sweat gland, sa
18、livary gland)3. Smooth muscle4. Cardiovascular systemClinical uses 1.Glaucoma(青光眼）vangle-closure glaucomavopen-angle glaucoma What is Glaucoma?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.
19、The balance of fluid production and drainage is responsible for maintaining normal pressure within the eye. nIn glaucoma, the drain becomes clogged 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
20、 and enlargeHow does Glaucoma affect the eye?nVision Loss. Pressure damage to the optic nerve and decreased blood flow to the retina, results in loss of vision. However, if the pressure in the eye remains uncontrolled, the retina degenerates and vision is permanently lost. Permanent blindness can oc
21、cur within several hours if the pressure is very high and the glaucoma develops rapidlynPain. Humans have normal intraocular pressures between 10 and 20 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 discomfor
22、t 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 :drymouthAdverse reactions Muscarine（毒蕈碱）nAmanita muscaria （捕蝇蕈）Inocybe（丝盖伞菌属）Clitocybe（杯伞菌属）Section2N-RagonistsnicotinenNicotine: from tobaccoAction: NM, NN, CNS
23、and dependence (double phase) Tobacco poison: Hypertension, coronary heart disease, cerebrovascular disease, cancer , AtherosclerosisChina:Largesttobaccoproductivecountry,LargesttobaccoconsumptioncountryNo smoking！ Stop smoking！Section 3 Anticholinesterase AgentsCholinesterase: true Cholinesterase (
24、AChE) PseudocholinesteraseAnticholinesterase Agents-indirect acting cholinomimeticsClassification according to structurennon-covalent bonding agents: Edrophonium chloride (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
25、): 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)亲和亲和力力亲脂亲脂性性BBB维持维持时间时间依酚依酚氯铵氯铵一般一般弱弱短短他克他克林林较高较高强强长长多奈多奈哌齐哌齐较高较高强强长长Classification according to pharmacological propertyvReversible Anticholinesterase agentsvirreversible Anticholineste
26、rase agents vMechanisms of actions:vPharmacological actions: 1. eye 2. gastrointestinal tract（esophagus, stomach, intestine) 3. motor end plate 4. glands 5. cardiovascular systemClinical Uses 1. Myasthenia gravis (重症肌无力): NeostigminePyridostigmine(吡斯的明)Ambenonium chloride (安贝氯胺) Clinical Uses2. Post
27、operative 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. Alzheimers disease: tacrine, donepezil, rivastigmine, galanthamin 6. Supraventricular tachyarrhythmias Common
28、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 muscle contraction po, sc, im iv2. Postoperative abdominal distension; Urinary retention
29、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)nWeaker than Neostigminenslower than NeostigminenLonger than NeostigminenNot into
30、 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 actionnUses: 1. Glaucoma 2. Intoxication of anticholine agents: Atropine T
31、ricyclic antidepressant Dibenzothiazine antipsychotics nComparison to pilocarpine 1. More rapid 2. Stronger 3. longernDonepezilnRivastigminenTacrine Alzheimers diseaseReversible anticholinesterase agentsvneostigminePyridostigmineAmbenoniumGalanthamine: Myasthenia gravisvPhysostigmineDemecarium : Gla
32、ucoma vEdrophonium chloride: diagnostic test for myasthenia gravisvDonepezilrivastigmineTacrine:Alzheimers diseaseIrreversible Anticholinesterase Agents-Organophosphates vMechanisms of intoxicationvPathway of intoxication vsigns of acute intoxication 1.M manifestation (muscarinic excess ) 2.N manife
33、station(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.Symptomatic treatment 1) atropine 2) cholinesterase reac
34、tivatorCholinesterase 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 water-solubility im and iv little adverse reactio
35、nChapter 7 cholinoceptor-blocking drugsnM-R blockersnN-R blockers: NN-R blockers NM-R blockersMuscariniccholinoceptor-blockingdrugs nAtropineandatropine-likealkaloidsnSyntheticatropinesubstitutesatropine-likealkaloidsandtheirresources植物植物 主要生物碱主要生物碱 颠茄颠茄( (atropabelladonna) ) 莨菪碱莨菪碱( (hyoscyamine)曼陀
36、罗曼陀罗( (daturastramonium) ) 莨菪碱莨菪碱洋金花洋金花( (datruasp) ) 东莨菪碱东莨菪碱 (scopolamine)莨菪莨菪( (hyoscyamusniger) ) 莨菪碱莨菪碱 唐古特莨菪唐古特莨菪( (scopoliatangutica) ) 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Atropinenpharmacologicalactions:blockM-RblockNN-Rinlargedosepharmacologicalactions1.glands:secret
37、ionsalivary,sweatlacrimal,respiratorygastricacid,pancreatic,intestinaljuice2.eyes(1)mydriasis(2)increaseintraocularpressure(3)paralysisofaccommodation3.splanchnicsmoothmuscle:relaxation(spasmodic)GItract,detrusormuscleofbladder:significantBiletract,bronchial,uterine(子宫):weak4.heart:(1)HRTherapeuticd
38、ose:decrease (presynapticM1blockade)Largedose:increase(blockvagaleffectonM2R)(2)A-Vconduction:5.vessels:dilation(inlargedose)(1)Directeffect(2)Compensativereactionbytemperaturerise6.CNS:excitationOrgan sensitivity: Gland eye splanchnic smooth muscle cardiovascular system CNS.ClinicalUses1.Anti-smoot
39、hmusclespasm2.Pre-anaesthesiamedicationagent3.Ophthalmologicaluse(1)iridocyclitis(2)optometry(3)examinationofretina4.Bradyarrhythmias5.Shock(septic shock):Cautions6.Intoxicationoforganophosphateadversereactions1.Common Side Effects2.AcutePoisoningminimallethaldose:adults80130mgchildren-10mgPreventio
40、n1.Decontamination:topreventfurtherabsorption2.Antidotes:Parasympathomimetics3.Maintenanceofvitalsignscontraindictionsv Glaucomav prostatic hypertrophy anisodamine(654-2)山莨菪碱nCharacteristicofactions 1.high selectivity(smooth muscle and vessels) 2.little side effect (not pass through BBB)nUses 1.sept
41、ic shock 2.visceral colics. Scopolamine(东莨菪碱东莨菪碱)Characteristics1.CNSactions:depression(strong)2.peripheralactions:glands:strongothers:weakvUses:1.preanaesthesiamedication2.preventionmotionsickness3.Parkinsondisease4.traditionalmedicineanaesthesia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(
42、针剂) n东莨菪碱 Section2SyntheticatropinesubstitutesnSyntheticMydriaticsnSyntheticAntispasmaticsnSelectiveM1AntagonistsSyntheticMydriaticsnHomatropine(后马托品后马托品)nTropicamide(托吡卡胺托吡卡胺)nCyclopentolate(环喷托酯环喷托酯)nEucatropine(尤卡托品尤卡托品)Comparisonofsomemydriaticsdrugsconcentration(%)mydriasisparalysisofaccommodat
43、ionpeak(m)duration(d)peak(h)duration(d)atropine1.03040 71013712homatropine1.02.04060 120.5113tropicamide0.51.02040 0.250.50.50.25cyclopentolate0.530305050 110.251eucatropine2.05.0301/121/4nUses:iridocyclitisoptometryexaminationofretinaSyntheticAntispasmaticsQuaternaryamines(季胺类季胺类)：Propanthelinebrom
44、ide(溴丙胺太林，普鲁本辛溴丙胺太林，普鲁本辛)1.selectiveblockadeofGItract:2.ulceration,GIspasm,bladderstimulation3.neuromuscularblockaction:toxicdose4.lowBBBpermeabilityQuaternaryamines(季胺类季胺类)：Ipratropiumbromide(异丙托溴胺异丙托溴胺)1.Relievebronchospasmbyinhalation2.Uses:chronicobstructivepulmonarydisease,bronchialasthma3.gang
45、lionicblockactionstrongerthanatropine4.lowBBBpermeabilityTertiaryamines(叔胺类叔胺类)：MydriaticsAnticholinergicinCNSAntispasmaticagentsBenactyzine(贝那替嗪，胃复康）贝那替嗪，胃复康）1.Relievesmoothmusclespasm2.AntianxietyeffectSelectiveM1AntagonistsnPirenzepine( (哌仑西平哌仑西平) )nTelenzepine( (替仑西平替仑西平) )nInhibitsecretionofgastricacidnClinicaluse:pepticulcernNotintoCNS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
