7 Adrenoceptor antagonist drugs

-receptor
antagonist

-receptor antagonist

1 Basic pharmacology of -receptor antagonist drugs

2 Clinical pharmacology of alpha blocker
3 Basic pharmacology of -receptor antagonist drugs
4 Clinical pharmacology of beta blocker

Adrenoceptor
catecholamine
receptor antagonist

selective
receptor
1. Relative selectivity of antagonists for adrenoceptors. [Fig. 10-1 Katzung]

1 Basic pharmacology of -receptor antagonist drugs

Mechanism of action
-receptor antagonist
antagonist
receptor
reversible
reversible
phentolamine, tolazoline, prazocin, labetalol
irreversible phenoxybenzamine
reactive ethyleneimmonium compound
receptor
irreversible

receptor
irreversible
phenoxybenzamine
nitrogen mustard
form
covalent bond
block receptor

1. Dose-response curves to NE in the presence of two different -adrenoceptor blocking drugs. The tension produced in
isolated strips of cat spleen, a tissue rich in receptors, was measured in response to graded doses of norepinephrine. Left:
Tolazoline, a reversible blocker, shifted the curve to the right without decreasing the maximum response when present at
concentrations of 10 and 20 mol/L. Right: Dibenamine, an analog of phenoxybenzamine and irreversible in its action, reduced
the maximum responses attainable at both concentrations tested. [Fig. 10-2 Katzung]

Pharmacological effects
1. Cardiovascular effects
Arteriolar tone
venous tone
-receptor vascular smooth muscle
receptor
peripheral vascular resistance
-Blocker
postural hypotension reflex tachycardia
tachycardia
2-presynaptic receptor
NE
-receptor
-blocker
volume
2. Other effects
-blocker bladder base prostate
resistance urine flow
Specific agents

blood

a. Phentolamine
imidazoline derivative
potent competitive antagonist 1Phentolamine
serotonin
phentolamine
agonist muscarinic receptor histamine receptor
H1- H2-receptor

myocardial infarction
phentolamine
b. Tolazoline
phentolamine
c. Ergot derivatives
Dihydroergotamine, ergotamine

Cardiac stimulation
diarrhea
pheochromocytoma

2- receptor
phentolamine

severe tachycardia, arrhythmia,

gastric acid secretion

reversible -block
serotonin (5-HT) receptor

d. Phenoxybenzamine
48
-receptor
e. Prazosin

receptor
irreversible
covalent bond
1-receptor
selective
prazosin
postural hypotension tachycardia

piperazinyl quinazoline
1-receptor
low affinity 2-receptor
tachycardia
f. Terazosin
Reversible 1-selective antagonist
g. Doxazosin
h. Tamsulosin
Competitive 1-antagonist
BPH
smooth muscle contraction
i. Alfuzosin

selectivity 1A-receptor
1A receptor
subtype

non-selective antagonist

1B-receptor
prostatic

2 Clinical pharmacology of -blockers

1. Pheochromocytoma
2. Hypertensive emergencies
3. Chronic hypertension

1-selective blocker
Prazosin family
systemic hypertension
postural hypotension
non-selective -blocker
4. Peripheral vascular disease
5. Local vasoconstrictor excess
6. Urinary obstruction
7. Male sexual dysfunction

mild to moderate

3 Basic pharmacology of -blockers

-blocker
-receptor
competitive -blocker
pure
antagonist
-receptor
-receptor
-blocker
partial agonist
-receptor
maximal response
partial agonist receptor
endogenous ligand receptor
partial agonist
-blocker intrinsic sympathomimetic activity (ISA) -blocker
affinity 12-receptor
isoproterenol
potent -receptor agonist
Pharmacodynamics of -blockers
2. Properties of several beta-receptor blocking drugs [Table 10-2 Katzung]

-receptor

partial agonist

local anesthetic action

1. Effects on cardiovascular systems

-blockers
renin angiotensin aldosterone system (RAA system)

-blocker
negative inotropic
PR interval
2-mediated vasodilation

negative chronotropic effect

slow arterioventricular conduction
adrenoceptor atrioventricular node
-blocker
peripheral vascular resistance
-receptor
-blocker
renin
sympathetic nervous system
acute effect
-blocker
peripheral vascular resistance
peripheral vascular
resistance
renin
angiotensin II
vascoconstriction
2. Effects on respiratory tract
2-recptor
-blocker
1-receptor
acebutolol,
atenolol, betaxolol, bisoprolol, celiprolol, esmolol metoprolol
3. Effects on eyes
-blocker
intraocular pressure

aqueous humor

glaucoma
4. Metabolic and endocrine effects
-Blocker
lipolysis
sympathetic nervous system
carbohydrate
metabolism
-blocker
glycogenolysis
-blocker
hypoglycemia
1-selective blocker
glycogen reserve
hypoglycemia recovery
non-selective -blocker
5. Effects not related to -blockade
Intrinsic sympathomimetic activity partial agonist
-receptor
partial agonist
intrinsic sympathomimetic activity
acebutolol, carteolol, celiprolol, labetalol, penbutolol, pindolol
-blocker
bradycardia bronchoconstriction
pure -antagonist
-blocker
local anesthetic action
Na+ channel nerve
Specific agents
a. Propranolol
b. Metoprolol, Atenolol, Acebutolol, Betaxolol, Bisoprolol, Celiprolol, Esmolol
1-selective antagonists
propranolol
bronchoconstriction

c. Nadolol
Non-selective -blocker
d. Timolol
non-selective -blocker
e. Partial -receptor agonist
acebutolol, carteolol, celiprolol, labetalol, penbutolol, pindolol

topical

(angina)
pure antagonist

-blockers bradycardia abnormal plasma lipid

f. Labetalol
racemic mixture
asymmetrical center 2
(S,S)
(R,S) isomer inactive
S,R-isomer
potent -blocker R,R-isomer potent -blocker
g. Carvedilol, medroxalol, bucindolol
-receptor
Non-selective -blocker
carvedilol
-receptor
catecholamine -receptor
O2 free radical initiated lipid
peroxidation
vascular smooth muscle mitogenesis
Adrenoceptor
CHF
4 Clinical pharmacology of -blockers
1. Hypertension
2. Ischemic heart disease
3. Cardiac arrhythmia
4. Other CVS disorder
5. Glaucoma
6. Hyperthyroidism
7. Neurologic disease
8. Miscellaneous
Choice of -blockers
Propranolol
standard therapy
blocker
-blocker
hyperthyroidism

-blocker

-receptor
pure antagonist

Clinical toxicity of -blockers

propranolol
sedation, sleep disturbance, depression

rash, fever, drug allergy,

psychotic reaction

-blocker

low lipid solubility

nadolol, atenolol
-blockers
2-receptor

-blockers

-receptor
1-selective

compensated CHF
sympathetic drive
cardiac output
++
Ca channel blocker verapamil

(long term)

-blockers
,
,
-blocker
(ischemic heart disease)
up-regulation -receptor
half-life
propranolol, metoprolol
-blocker
Hypoglycemia
blocker
1 (insulin-dependent DM)
hypoglycemia
1-selective blockers
-blocker
hypoglycemia hyperthyroidism

Katzung BG, ed. Basic and clinical pharmacology, 8th ed. New York: Lange medical books/McGraw-Hill;
2001.
Rang HP, Dale MM, Ritter JM, Pharmacology. 4th ed. Edinburgh: Churchill Livingstone; 2000.
.
1; 2539.

1.

Phentolamine
tachycardia
.

2. Phenoxybenzamine
half-life
.

3. Phenoxybenzamine
maximum response

dose-response curve
.

-blocker

Pheochromocytoma
.

5.

irreversible -blocker

Phentolamine
plasma

4.

6. -blocker
7. Propranolol

BPH
Partial agonist
.

8. Labetalol
.

Carvedilol

10. -blocker
.

-adrenoceptor

-blocker

-adrenoceptor

Selective 1-blocker
.

bradycardia

.
.

-blocker

Prazosin

(hyperlipidemia)

9.

non-selective -blocker

hypertension
Selective -blocker

acebutolol

asthma

Propranolol

CHF
.