Download Chapter 8 Adrenoceptor 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
OH
HO
CH
OH
CH2
H
N
CH3
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
adenosine↑
oxygen
consumption

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
α2-R agonists
1, 2 Agonists
noradrenaline(去甲肾上腺素，
norepinephrine，NA，NE)
[source and chemistry]
NA
OH
HO
CH
OH
CH2NH2
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:
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）
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