α, β-R agonists α-R agonists, β-R agonists Chapter 8 Adrenoceptor agonists (adrenomimetic drugs, Sympathomimetic amines) α, β-R agonists α-R agonists, β-R agonists

Section 1 Structure-activity relationship and classification

Chemistry

structure-activity relationship (1) Catecholamine (CA,儿茶酚胺) (2) -C： block MAO (3) N- ： or  selective

classifications α, β-R agonists: AD,ephedrine（麻黄碱） α-R agonists α1、α2-R agonists ：NA α1-R agonists: phenylephrine(去氧肾上腺素) α2-R agonists：oxymetazoline(羟甲唑啉）apraclonidine(阿可乐定) β-R agonists, β1、 β 2-R agonists : Isoprenaline β1-R agonists ：dobutamine(多巴酚丁胺) β2-R agonists: salbutamol（沙丁胺醇）

section 2 α、 β -R agonists Adrenaline (AD,肾上腺素) Ephedrine（麻黄碱） Dopamine (DA，多巴胺)

Adrenaline (epinephrine,AD,肾上腺素) Source and Chemistry 1. adrenal medulla: pheochromocyte( 嗜铬细胞) 2. PNMT(苯乙胺-N-甲基转移酶) TH DDC DβH PNMT Tyr→→→dopa→→→→DA→→→→NA→→→→→AD

AD

Pharmacokinetics 1. Absorption 2. Termination Uptake metabolism: MAO/COMT

3.Excretion:VMA (3甲氧4羟扁桃酸) Normal: 2-6.8mg/24h Pheochromocytoma:10-250mg /24h （嗜铬细胞瘤）

pharmacological actions: activate α, β-R 1.heart: strongly excited (β1-R) positive inotropic effect positive chronotropic effect positive dromotropic effect Coronary: dilation (1)Agonist β2-R (2)Prolong diastolic phase (3)Increase myocardial oxygen consumption adenosine↑

Advantage and disadvantage

2.vessels: (1) contraction(α-R ) Skin, mucosa: strong Kidney: strong juxtaglomerular cells(β1-R): Renin release↑ Cerebral : (2) dilation: Skeletal Muscle (β2-R) Coronary: direct effect: β2-R indirect effect: time of perfusion ↑ adenosine↑

pharmacological actions 3.BP: small dose: SBP↑, DBP ↓ large dose: SBP↑, DBP↑ Double phased response

pharmacological actions 4. smooth muscle: bronchial smooth muscle: 2, 1 Gastrointestinal tract: (negative feedback) Uterus, bladder: 2 Pupillary dilator muscle: 1

pharmacological actions 5. metabolism: ↑ 20%-30% (1)Carbohydrate: blood Glu ↑ , 2: glycogenolysis↑(糖原分解） glyconeogenesis↑(糖原异生) 2: insulin↓ : glucagon↑ (2) Lipolysis : blood fatty acid ↑ 3 : triglyceride lipase(三酰甘油酶) ↑

6. skeletal muscle 7. CNS

clinical uses 1.cardiac arrest 2.allergic shock: first choice cautions 3.bronchial asthma 4.prolongation of local anesthetic duration 5.topical hemorrhage: 0.1% 6. glaucoma

adverse reactions Arhythmia Hypertension CNS reactions contraindications

Ephedrine(麻黄碱) 陈克恢（１８９８—１９８８） 药理学家。长期致力于中药药理研究，是２０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。

Ephedrine Mechanisms: 1. direct actions：1 ,  1,2 ,  2-R 2. indirect actions Characteristics: 1. stable, orally. 2. action: slower,weaker and longer VS AD 3. central excitation 4. tachyphylaxis

Actions: 1. CNS effects 2. CVS 3. Smooth muscle 4. Increase skeletal muscle tension

ephedrine clinical uses 1.bronchial asthma 2.nasal congestion 3.hypotensive states 4. Allergy (urticaria, angioneuroedema)

adverse reactions Cardiac and CNS excitation

dopamine (DA,多巴胺) Pharmacokinetics: ivd, short t1/2, not across BBB pharmacological actions activateα, β1 , DA -R, ↑NA release

pharmacological actions 1.Cardiovascular system: vessel: dilation (D1A-R), contraction (α-R) Small dose: DBP↓ (D1A-R) SBP→ Midddle dose: SBP↑ (β1 -R) DBP↑→ Large dose: DBP↑ (α-R) SBP↑ 2. renal vessels : small dose dilation (D1A-R) large dose contraction (α-R)

clinical uses 1.shock 2.chronic heart failure(CHF) 3.acute renal failure (ARF)

Mephentermine (美芬丁胺,wyamine,恢压敏) Similar to ephedrine (direct, indirect) central excitation Used to prevent hypotension state Used to treat nasal congestion

section 3 α-R agonists α-R agonists α1、α2-R agonists α1-R agonists

1, 2 Agonists noradrenaline(去甲肾上腺素，norepinephrine，NA，NE) [source and chemistry]

NA

pharmacokinetics

pharmacological actions strongly activate α1, α2 -R slightly activate β1-R.

pharmacological actions 1.vessels: contraction(α-R) coronary vessels :dilation (similar to AD) presynaptic adrenergic terminals (α2-R):NE ↓ negative feedback 2.heart: excitation(β1-R) 3.BP: small dose: SBP↑ DBP→ large dose: SBP↑ DBP↑ 4.others: weaker than AD

clinical uses 1.shock：early 2.hypotension caused by drugs’ intoxication 3.upper digestive tract hemorrhage

adverse reactions 1.local ischemia and necrosis 2.acute renal failure

metaraminol (间羟胺, aramine, 阿拉明) [Mechanisms]1.direct actions 2.indirect actions [Characteristics] 1. weaker and longer than NA 2.little adverse reactions: renal failure, arrhythmias 3.tachyphylaxis [Uses] substitute for NA in treatment of shock

1-R Agonists Phenylephrine(去氧肾上腺素) Methoxamine(甲氧明)

Phenylephrine and methoxamine 1.selective α1-R agonists: shock, hypotension 2. renal vasoconstriction: significant 3. paroxysmal supraventricular tachycardia 4.phenylephrine→mydriasis(rapid, weak, short)

2-R Agonists Peripheral 2-R Agonists: apraclonidine(阿可乐定): Glaucoma oxymetazoline(羟甲唑啉)： nasal congestion apraclonidine(阿可乐定): Glaucoma Central 2-R Agonists：HBP clonidine(可乐定)， methyldopa （甲基多巴）

β1、 β2-R agonist β1-R agonists β2-R agonists Section4 β-R agonists β1、 β2-R agonist β1-R agonists β2-R agonists

β1、 β2-R agonist Isoprenaline (Isop,异丙肾上腺素) pharmacological actions: strongly activate β1、 β2-R

pharmacological actions 1.heart: excitation (β1-R) positive inotropic effect positive chronotropic effect positive dromotropic effect

pharmacological actions 2.vessels: Skeletal Muscle blood vessel (β2-R) Coronary: direct effect: β2-R indirect effect: 3.BP: SBP↑ DBP↓

pharmacological actions 4. smooth muscle: relaxation especially bronchial smooth muscle

clinical uses 1. cardiac arrest 2. atrial ventricular block(AVB) 3. bronchial asthma

β1-R agonists: dobutamine (多巴酚丁胺) [Characteristics] 1. selective β1-R agonist 2. inotropic effect>chronotropic effect （ in therapeutic dose） 3. Used in CHF caused by AMI 4. tachyphylaxis

β2-R agonists Salbutamal(沙丁胺醇，舒喘灵) Terbutaline(特布他林，间羟舒喘灵) Clinical use: bronchial asthma