1、Chapter 8 Adrenoceptor agonists(adrenomimetic drugs,Sympathomimetic amines),-R agonists-R agonists,-R agonists Section 1 Structure-activity relationship and classification Chemistry structure-activity relationship(1)Catecholamine(CA,(CA,儿茶酚胺儿茶酚胺)(2)-C：block MAO(3)N-：or selective classifications,-R a
2、gonists:AD,ephedrine（麻黄碱）麻黄碱）-R agonistsv 1、2-R agonists：NAv 1-R agonists:phenylephrine(去氧肾上腺素去氧肾上腺素)v 2-R agonists：oxymetazoline(羟甲唑啉）羟甲唑啉）apraclonidine(阿可乐定阿可乐定)-R agonists,v 1、2-R agonists:Isoprenalinev 1-R agonists：dobutamine(多巴酚丁胺多巴酚丁胺)v 2-R agonists:salbutamol（沙丁胺醇）沙丁胺醇）section 2 、-R agonistsA
3、drenaline(AD,肾上腺素肾上腺素)Ephedrine（麻黄碱）麻黄碱）Dopamine(DA，多巴胺多巴胺)Adrenaline(epinephrine,AD,肾上腺素肾上腺素)Source and Chemistry1.adrenal medulla:pheochromocyte(嗜铬细胞嗜铬细胞)2.PNMT(苯乙胺苯乙胺-N-甲基转移酶甲基转移酶)n TH DDC DH PNMTnTyrdopaDANAAD ADCHOHOHOHCH2NHCH3Pharmacokinetics1.Absorption2.Termination n Uptaken metabolism:MAO/C
4、OMT3.Excretion:VMA(3甲氧甲氧4羟扁桃酸羟扁桃酸)n Normal:2-6.8mg/24hn Pheochromocytoma:10-250mg/24h （嗜铬细胞瘤）嗜铬细胞瘤）pharmacological actions:activate,-R1.heart:strongly excited(1-R)positive inotropic effect positive chronotropic effect positive dromotropic effect Coronary:dilation(1)Agonist 2-R(2)Prolong diastolic ph
5、ase(3)Increase myocardial oxygen consumption adenosinenAdvantage and disadvantage2.vessels:(1)contraction(-R)Skin,mucosa:strong Kidney:strong juxtaglomerular cells(1-R):Renin release Cerebral:(2)dilation:Skeletal Muscle(2-R)Coronary:direct effect:2-R indirect effect:time of perfusion adenosine pharm
6、acological actions3.BP:small dose:SBP,DBP large dose:SBP,DBP Double phased response pharmacological actions4.smooth muscle:bronchial smooth muscle:2,1Gastrointestinal tract:(negative feedback)Uterus,bladder:2Pupillary dilator muscle:1 pharmacological actions5.metabolism:20%-30%(1)Carbohydrate:blood
7、Glu ,2:glycogenolysis(糖原分解）糖原分解）glyconeogenesis(糖原异生糖原异生)2:insulin :glucagon(2)Lipolysis:blood fatty acid 3:triglyceride lipase(三酰甘油酶三酰甘油酶)n6.skeletal musclen7.CNSclinical uses 1.cardiac arrest2.allergic shock:first choice cautions3.bronchial asthma4.prolongation of local anesthetic duration5.topica
8、l hemorrhage:0.1%6.glaucoma adverse reactionsArhythmiaHypertensionCNS reactionscontraindicationsEphedrine(麻黄碱麻黄碱)n陈克恢陈克恢（）药理学家。长期致力于中药药理研究，是世纪国际药理学的一代宗师，也是现代中药药理学研究的创始人。他的突出贡献是，首先发现麻黄素的药理作用，为推动交感胺类化合物的化学合成奠定了基础，并为从天然产物中寻找开发新药起了典范作用。他还发现解救急性氰化合物中毒的方法，并被沿用至今。EphedrinenMechanisms:1.direct actions：1,1,2
9、,2-R 2.indirect actions nCharacteristics:1.stable,orally.2.action:slower,weaker and longer VS AD 3.central excitation 4.tachyphylaxisnActions:1.CNS effects 2.CVS 3.Smooth muscle 4.Increase skeletal muscle tension ephedrinenclinical uses1.bronchial asthma2.nasal congestion3.hypotensive states4.Allerg
10、y(urticaria,angioneuroedema)adverse reactionsnCardiac and CNS excitation dopamine(DA,多巴胺多巴胺)qPharmacokinetics:ivd,short t1/2,not across BBBq pharmacological actions activate,1,DA-R,NA releasepharmacological actions1.Cardiovascular system:vessel:dilation(D1A-R),contraction(-R)Small dose:DBP(D1A-R)SBP
11、 Midddle dose:SBP(1-R)DBPLarge dose:DBP(-R)SBP2.renal vessels:small dose dilation(D1A-R)large dose contraction(-R)clinical uses1.shock2.chronic heart failure(CHF)3.acute renal failure(ARF)Mephentermine(美芬丁胺,wyamine,恢压敏)nSimilar to ephedrine(direct,indirect)ncentral excitationnUsed to prevent hypoten
12、sion statenUsed to treat nasal congestionsection 3 -R agonistsv-R agonistsv 1、2-R agonistsv 1-R agonistsv 2-R agonists 1,2 Agonists noradrenaline(去甲肾上腺素，去甲肾上腺素，norepinephrine，NA，NE)source and chemistry CHOHOHOHCH2NH2NApharmacokineticspharmacological actionsstrongly activate 1,2-Rslightly activate 1-
13、R.pharmacological actions1.vessels:contraction(-R)q coronary vessels:dilation(similar to AD)q presynaptic adrenergic terminals(2-R):NE negative feedback2.heart:excitation(1-R)3.BP:small dose:SBP DBP large dose:SBP DBP4.others:weaker than ADclinical uses n1.shock：early n2.hypotension caused by drugs
14、intoxication n3.upper digestive tract hemorrhageadverse reactionsn1.local ischemia and necrosisn2.acute renal failure metaraminol(间羟胺间羟胺,aramine,阿拉明阿拉明)Mechanisms1.direct actions 2.indirect actionsCharacteristics1.weaker and longer than NA2.little adverse reactions:renal failure,arrhythmias3.tachyph
15、ylaxisUses substitute for NA in treatment of shock 1-R AgonistsnPhenylephrine(去氧肾上腺素去氧肾上腺素)nMethoxamine(甲氧明甲氧明)Phenylephrine and methoxamine 1.selective 1-R agonists:shock,hypotension2.renal vasoconstriction:significant 3.paroxysmal supraventricular tachycardia4.phenylephrinemydriasis(rapid,weak,sho
16、rt)2-R AgonistsnPeripheral 2-R Agonists:oxymetazoline(羟甲唑啉羟甲唑啉)：nasal congestion apraclonidine(阿可乐定阿可乐定):GlaucomanCentral 2-R Agonists：HBP clonidine(可乐定可乐定)，methyldopa（甲基多巴（甲基多巴）Section4-R agonists1、2-R agonist1-R agonists 2-R agonists1、2-R agonistIsoprenaline(Isop,异丙肾上腺素异丙肾上腺素)npharmacological acti
17、ons:strongly activate 1、2-Rpharmacological actions1.heart:excitation(1-R)positive inotropic effect positive chronotropic effect positive dromotropic effect pharmacological actions2.vessels:Skeletal Muscle blood vessel(2-R)Coronary:direct effect:2-R indirect effect:3.BP:SBP DBPpharmacological actions
18、v4.smooth muscle:relaxation especially bronchial smooth muscleclinical uses n1.cardiac arrestn2.atrial ventricular block(AVB)n3.bronchial asthma1-R agonists:dobutamine(多巴酚丁胺多巴酚丁胺)Characteristicsv1.selective 1-R agonistv2.inotropic effectchronotropic effect （in therapeutic dose）v3.Used in CHF caused by AMIv4.tachyphylaxis2-R agonistsnSalbutamal(沙丁胺醇，舒喘灵沙丁胺醇，舒喘灵)nTerbutaline(特布他林，间羟舒喘灵特布他林，间羟舒喘灵)nClinical use:bronchial asthma
