Chapter 9 adrenoceptor blocking drugs

(Adrenoceptor antagonists)

α-R antagonists

β-R antagonists

α 、 β-R antagonists

Section 1 α-R antagonists

α1, α2-R antagonists

α1-R antagonists

α2-R antagonists

Basic actions of α-R antagonists

1.CVS effects (1)α1-R antagonistic effects:

Endogenous CA blockage: BP↓

(Postural hypotension)

Exogenous CA blockage: “adrenaline reversal”

(2) α2-R antagonistic effects:

presynaptic 2 antagonism –NE release ↑

CNS 2 antagonism -sympathetic activity ↑

Basic actions of α-R antagonists

2.other effects(1) Prostate and bladder sphincter α1-R

antagonism: dilation

(2) insular α2-R antagonism: insulin ↑

Classification

Ⅰ. α1, α2-R antagonists 1.short-term acting: phentolamine ( 酚妥拉明 ),

tolazoline ( 妥拉唑啉 ) 2. long-term acting: phenoxybenzamine( 酚苄明 )

Ⅱ. α1-R antagonists: prazosin( 哌唑嗪 )

Ⅲ. α2-R antagonists: yohimbine( 育亨宾 )

α1, α2-R antagonistsphentolamine ( 酚妥拉明 , regitine, 立其丁 )

competitive α-R antagonists

pharmacological actions 1.vessels : dilation; BP ↓ Mechanism:

(1) direct action

(2) 1-R blockade: “adrenaline reversal”

pharmacological actions

2.heart: excitation, CO ↑ HR ↑Mechanism:

(1) BP ↓excite heart

(2) 2-R blockade

3.other effects: cholinergic action

histamine-like action

clinical uses

1. peripheral vasospasmatic disorders: eg. Raynaud’s syndrome, 雷诺氏综合征 2. local vasoconstrictor excess (eg, NA)

3. shock :

a. dilate vessel peripheral resistance↓ ( 肺血管 )

b. excite heart Co↑

c. pulse pressure↑ improve viscera hemoperfusion, relief microcirculation disturbance

Phentolamine+ NE

4. CHF and AMI Pathophysiology: Cardia insufficiency arteriovenous reflex

contraction

Phentolamine: dilate vesselcardiac load↓ Co↑5. diagnosis and treatment of pheochromocytoma6. others: male sexual dysfuction 甲磺酸酚妥拉明分散片（伟哥）

adverse reactions

1.cardiovascular reaction: Postural hypotension, tachycardia,

angina, arrhythmia

2.gastrointestinal reaction: stomachache, diarrhea, vomiting, ulceration

Tolazoline( 妥拉唑啉 )

Characteristics (compared with phentolamine ) weaker in antagonism, stronger in cholinergic and histamine-like

effects.

Used to treat peripheral vasospasmatic disorders and pheochromocytoma

phenoxybenzamine( 酚苄明 )

Noncompetitive antagonism

Pharmacokinetics:

Slow onset(1h), long duration(3-4d)

pharmacological actions

1.α1-R antagonistic effects :

slow, strong and long.

(Postural hypotension)

2. HA-R antagonistic effects

clinical uses

1. peripheral vasospasmatic disorders

2. pheochromocytoma

3. Shock

4. Urinary obstruction caused by benign prostatic hyperplasia

adverse reactions

Postural hypotension,

tachycardia (palpitation),

nasal congestion

CNS inhibition

α1-R antagonists

Prazosin( 哌唑嗪 ) Terazosin （特拉唑嗪） Doxazosin （多沙唑嗪）Actions: decrease BP, but weak influence on HR

Clinical uses:

1. HBP

2. CHF

3. Urinary obstruction caused by benign prostatic hyperplasia

Tamsulosin ( 坦洛新 ) Block α1A-R (prostate) > α1B-R (blood vessel)

High effect on prostatic hyperplasia

(compare with phenoxybenzamine and prazosin)

Phenoxybenzamine: ↓BP, palpitation

Prazosin: ↓BP

Tamsulosin: have no effect on BP and HR

α2-R antagonists

Yohimbine ( 育亨宾 )

uses1. tool agent for research

2. impotence ( 阳痿 ) ：痿必治

Section 2 β-R antagonists

β 1,β2-R antagonist

β 1-R antagonist

α、 β -R antagonist

classification 1.β 1,β2-R antagonist

1A ： Propranolol( 普萘洛尔 ), Timolol （噻吗 ~ ） 1B ： pindolol （吲哚 ~ ） 2.β 1-R antagonist

2A ： atenolol （阿替 ~ ） , metoprolol （美托 ~ ） 2B ： Acebutolol( 醋丁 ~)

3. α, , β -R antagonist

Labetalol （拉贝 ~ ） , carvedilol( 卡维地洛 )

Intrisic sympathomimetic activity (ISA)partial agonistic activity (PAA)

Characteristics of Pharmacokinetics: affected by liposolubility

1.absorption: first pass elimination (propranolol is obvious, atenolol is not )

2.distribution:BBB (propranolol, atenolol)

3.elimination: hepatic metabolism andKidney excretion (propranolol, atenolol)

4. individual variation

basic actions of β-R antagonist

1. β-R blocking action:

1) cardiovascular effects: heart : depression (β1) vessels: contraction

a. blockβ2-R

b. Co↓vasoconstriction BP↓

basic actions of β-R antagonist

2) bronchial smooth muscle :β23) metabolism:β2a. Delay recovery of blood glucose

after insuline(insulinehypoglycemia

increase CA releaseactivateα,β

glycogenolysisblood glucose↑)b. Inhibit lipoclasis

4) Renin release:β1(propranolol)

5) ↓intraocular pressure (timolol)

basic actions of β-R antagonist 2.intrinsic sympathominetic activity(ISA)

partial agonistic activity (PAA)

Characteristic of drugs with ISA

basic actions of β-R antagonist

3.membrane stabilizing action:

in large dose (local anesthetic action)

clinical uses

1.arrhythmias (tachyarrhythmia) 2. hypertension 3. angina pectoris, myocardial infarction 4.CHF 5.others: hyperthyroidism,

glaucoma

adverse actions

1. bronchial asthma 2. cardiovascular reaction 3. induce Raynaud’s syndrome 4. rebound phenomenon: 5. others: hypoglycemia,

depression

Some β-R antagonists

1A Propranolol( 普萘洛尔 ), Timolol （噻吗洛尔） 1B Pindolol （吲哚洛尔）2A Atenolol （阿替洛尔） Metoprolol （美托洛尔）2B Acebutolol( 醋丁洛尔 ) 3 Labetalol （拉贝洛尔）

1A ： nonselective, no ISA Propranolol( 普萘洛尔 ),

1.pharmacokinetics: high liposolubility

2.uses: HBP, arrhythmia, CHF, myocardial ischemia, hyperthyroidism Timolol （噻吗洛尔）1.actions: strongest

2.uses: glaucoma (block β-R of ciliary body aqueous humor↓)

1B:nonselective, ISA

Pindolol （吲哚洛尔）Actions: stronger than propranolol

Uses: HBP

2A: selective, no ISA

Atenolol （阿替洛尔 , 氨酰心安） : long t1/2 Metoprolol （美托洛尔 , 美多心安）

3: α 、 β-R antagonists Labetalol （拉贝洛尔 , 柳胺苄心定）1.β-R blockage>α-R blockage

2. β-R blockage<propranlol

3.α-R blockage<phentolamine

4. ISA (β2-R)

5. used in HBP, angina pectoris

3: α 、 β-R antagonists carvedilol ( 卡维地洛 ) 1.β-R blockage>α-R blockage 2. used in HBP, CHF