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Chapter 11
Adrenoceptor Antagonist Drugs
Cao Yongxiao 曹永孝
Department of Pharmacology
[email protected];029-82655140
http://pharmacology.xjtu.edu.cn
1
Drugs blocking adrenoceptors vary dramatically
according to the drug’s selectivity for αand
βreceptors.
Their major effect is to occupy eitherα, or β
receptors and
prevent their
activation by
catecholamines and
related agonists.
2
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Nonselectiveαantagonists can
treat pheochromocytoma
(secrete catecholamines).
α1-selective antagonists are used
in hypertension and
benign prostatic
hyperplasia (BPH).
3
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Beta-receptor antagonist drugs are firmly established
in the treatment of
hypertension, ischemic heart disease, arrhythmias,
endocrinologic and neurologic disorders, and other
conditions.
4
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I BASIC PHARMACOLOGY OF THE ALPHARECEPTOR ANTAGONIST DRUGS
Mechanism of Action
Alpha-receptor antagonists may be
reversible or irreversible.
Reversible antagonists can
dissociate from receptors.
Phentolamine, tolazoline, prazosin
and labetalol are reversible.
Phenoxybenzamine is irreversible.
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5
Cardiovascular Effects
α- antagonist drugs block α receptors, dilate vascular
smooth muscle, lower peripheral resistance and BP;
can prevent the pressor effects of αagonists.
In the case of epinephrine with
both αand β2 effects, αreceptor
antagonism may convert a
pressor to a depressor response
which is called epinephrine
reversal.
6
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Alpha-receptor antagonists may cause postural
hypotension and reflex tachycardia.
Postural hypotension
is due to antagonism
of sympathetic
nervous system
stimulation of α1
receptors in venous
smooth muscle.
7
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Minor effects in other tissues
miosis and nasal stuffiness.
The radial muscle is
innervated by alpha
receptor. Its blockade
by antagonists results
in miosis.
The smooth muscles of the iris
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stuffiness
Alpha 1-receptor blockade
of base of the bladder and
the prostate is associated
with decreased resistance
to the flow of urine.
Benign Prostatic Hyperplasia
(BPH).
9
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SPECIFIC AGENTS
Phentolamine is a potent competitive antagonist at bothα1
and α2 receptors.
It reduces peripheral resistance through blockade of α.
It can stimulate the heart due to baroreflex mechanisms
resulting in sympathetic stimulation.
It blocks α2 receptors, enhance
release of NE from sympathetic
nerves, contributing to cardiac
stimulation via β receptors.
10
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Phentolamine also inhibits responses to serotonin
(5-HT) and activate M and histamine (H)
receptors, has multiple potential actions,
The principal adverse effects are cardiac
stimulation, such as tachycardia, arrhythmias,
myocardial ischemia and nasal congestion as well
as headache.
Phentolamine has been used in pheochromocytoma.
11
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Tolazoline is similar to phentolamine.
It has limited clinical application in the treatment
of pulmonary hypertension in newborn infants
with respiratory distress syndrome.
Ergot derivatives, eg，
Ergotamine, dihydroergotamine
cause reversible α-receptor blockade.
12
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Phenoxybenzamine binds covalently to αreceptors,
causing irreversible blockade of long duration (2 d).
It is somewhat selective for α1 receptors.
It reduces BP when sympathetic tone is high and little fall in
BP in normal supine individuals.
It inhibits reuptake of NE by
blocking α2 on presynaptic
terminals and increase cardiac output.
It also blocks histamine (H1), ACh, and serotonin receptors as
well as αreceptors.
13
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The adverse effects of phenoxybenzamine derive
from its α-receptor –blocking action.
The most important are postural hypotension,
tachycardia and nasal stuffiness.
Since phenoxybenzamine enters the CNS,
it may cause less specific effects, including
fatigue, sedation, and nausea.
14
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Prazosin is highly selective for α1 receptors, leads to
vasodilation.
It is effective in the management of hypertension.
It has relatively low affinity for α2 receptors (1/ 1000).
This may explain the relative absence of tachycardia.
Terazosin is another reversible α1-selective antagonist
that is effective in hypertension.
Terazosin has high bioavailability but is extensively
metabolized in the liver. Its half-life is 9-12 h.
15
II. Clinical Pharmacology of the Alpha-ReceptorBlocking Drugs
Pheochromocytoma
Phenoxybenzamine and phentolamine
are most useful in the pre-operative
management of pheochromocytoma.
They can control hypertension and
reverse chronic changes
resulting
Phenoxybenzamine
is useful
in the chronic treatment of
inoperable
or metastatic
pheochromocytoma.
from catecholamine
secretion
such as
Beta-receptor antagonists may be required to reverse the
plasma volume contraction.
cardiac effects of excessive catecholamines.
16
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HYPERTENSIVE EMERGENCIES
Labetalol has been used in
hypertensive emergency.
The α-adrenoceptor antagonists are
most useful when increased BP
reflects excess of αagonists.
In this circumstance, which may result from
overdosage of sympathomimetic drugs,
pheochromocytoma, phentolamine can be used
to control high BP.
17
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Chronic Hypertension
Prazosin family of α1-selective antagonists are
efficacious in the treatment of hypertension.
However, their efficacy in preventing heart failure
for hypertension has been questioned.
The adverse effect is postural hypotension, which
may be severe after the first dose.
Nonselective α antagonists are not used in
primary hypertension.
18
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Peripheral Vascular Disease
Theα-receptor-blocking drugs have
been tired in the treatment of peripheral
vascular occlusive disease.
Local Vasoconstrictor Excess
Phentolamine has been used to
reverse the vasoconstriction caused
by infiltration of αagonists (NE)
into subcutis during intravenous administration.
The αantagonist is administered by local
infiltration into the ischemic tissue.
19
Urinary Obstruction
Alpha-receptor blockade
can improve urine flow in BPH.
The mechanism involves
reversal of smooth muscle
contraction in the enlarged
prostate and in the bladder base.
Phenoxybenzamine,
prazosin, doxazocin, and
terazosin are efficacious,
particularly in patients with
hypertension.
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20
III. Basic Pharmacology of the Beta-ReceptorAntagonist Drugs
Beta-blocking drugs occupy βreceptors and reduce
receptor occupy by catecholamines and other βagonists.
Most β-blocking drugs are pure antagonists; ie, after being
occupied, βreceptor causes no activation.
Some are partial agonists; ie, they cause partial activation
of the receptor, less than that caused by the full agonist.
Partial agonists inhibit the activation of receptors in the
presence of high catecholamine concentrations but
moderately activate the receptors in the absence of
endogenous agonists.
21
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The partial agonist in this example has high affinity for the receptor, so it remains bound for a
long time once it reaches the binding site. As a result, when the partial agonist is present at high
concentration, most of the receptors are occupied most of the time. However, because it has lower
"efficacy" than the full agonist, only a fraction of the bound receptors can activate effector
molecule. Therefore, the maximum response produced by the partial agonist is less than 100% of
the maximum response of the system.
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Partial agonist
Affinity
Low intrinsic activity
Low efficacy
对激动剂：
小剂量激动
大剂量拮抗
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Another major difference among the βreceptor-blocking drugs concerns their relative
affinities forβ1 and β2 receptors.
Some of these antagonists have a higher
affinity for β1 than forβ2 receptors
The selectivity is dose-related, ie, it tends to
diminish at higher concentrations.
Other major differences among β antagonists
relate to their pharmacokinetics.
24
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Pharmacodynamics of theβ-ReceptorAntagonist Drugs
Most of the effects of these
drugs are due to occupancy
and blockade of βreceptors.
However, some actions may be due to partial
agonist activity at βreceptors and local anesthetic
action, which differ among the β-blockers.
25
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Effects on the Cardiovascular System
Beta-adrenoceptor-blocking drugs are of major clinical
importance in the treatment of hypertension.
The mechanisms include
.
effects on the heart and
blood vessels, the renninangiotensin system, and
the CNS
Conventional doses do not cause hypotension in healthy
individuals with normal BP.
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Heart
Beta-receptor antagonists
have prominent effects on
the heart.
The negative inotropic and chronotropic effects.
Slowed atrioventricular conduction with an increased PR
interval is a related result of adrenoceptor blockade in the
atrioventricular node.
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Vascular System
Theβ-antagonists
blockade β2-receptors, contracting vessel,
antagonize the release of rennin, dilating vessel.
In any event, while the acute effects of these drugs may
include a rise in peripheral resistance.
Chronic drug administration leads to a fall in peripheral
resistance in patients with hypertension.
Effects on the Respiratory Tract
Blockade of the β2 receptors in
bronchus increases airway
resistance, particularly in asthma.
Beta 1 antagonists have advantage over nonselective
βantagonists when blockade of β1 in the heart is desired
and β2 blockade is undesirable .
However, no available β1-selective antagonist is
sufficiently specific to completely avoid interactions
with β2 adrenoceptors.
They should be avoided in patients with asthma.
C. Effects on the Eye
Several β-blocking agents reduce intraocular
pressure, especially in glaucomatous eyes.
The mechanism
usually is
decreased
aqueous humor
production
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D. Metabolic and Endocrine Effects
Beta-receptor antagonists such as propranolol
inhibit lipolysis.
The effects on carbohydrate metabolism are less
clear, but they should be used with caution in
insulin-dependent diabetic patients.
The chronic use of β-adrenoceptor antagonists has
been associated with increased plasma VLDL and
decreased concentrations of HDL cholesterol.
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E. Effects not Related to Beta-Blockade
Local anesthetic action, also known as
“membrane-stabilizing” action, is a prominent
effect of several β-blockers.
This action is the result of local anesthetic
blockade of sodium channels.
However, this effect is not important, since the
concentration in plasma usually achieved by
these routes is too low for the anesthesia.
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Clinical Application
Hypertension
The β-adrenoceptor-blocking
drugs are effective and well
tolerated in hypertension.
While many hypertensive patients will respond to a βblocker used alone, the drugs is often used with either a
diuretic or a vasodilator.
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Ischemic Heart Disease
Beta-adrenoceptor blockers reduce
the frequency of anginal episodes
and improve exercise tolerance in
patients with angina.
These actions relate to the blockade of cardiac
βreceptors, resulting in decreased cardiac work and
reduction in oxygen demand. Slowing of the heart rate
may contribute to clinical benefits.
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Cardiac Arrhythmias
Beta antagonists are effective in both
supraventricular and ventricular
arrhythmias. By increasing the
atrioventricular nodal refractory period,
β antagonists slow ventricular rates in
atrial flutter and fibrillation.
They can also reduce ventricular ectopic beats, particularly
precipitated by catecholamines.
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Other Cardiovascular Disorders
Beta-receptor antagonists can increase
stroke volume in some patients with
obstructive cardiomyopathy.
This is due to the slowing of ventricular
ejection and decreased outflow resistance.
Beta-antagonists are useful in dissecting
aortic aneurysm to decrease the rate of
development of systolic pressure.
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Glaucoma
β-blocking drugs can reduce production
of aqueous humor and decrease
intraocular pressure in glaucoma.
Timolol and related βantagonists are suitable for local
use in the eye because they lack local anesthetic
properties.
Betaxolol, carteolol, levobunolol, and metipranolol are
newer β-receptor antagonists for the glaucoma.
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Hyperthyroidism
Excessive catecholamine action is an
important aspect of hyperthyroidism.
The β antagonists have salutary effects
in this condition.
These beneficial effects relate to blockade of
adrenoceptors and to the inhibition of peripheral
conversion of thyroxine to triiodothyronine.
Propranolol has been used extensively in patients with
thyroid storm.
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Neurologic Diseases
Propranolol reduce the frequency and
intensity of migraine headache.
Other β-receptor antagonists with preventive
efficacy include metoprolol and probably also
atenolol, timolol, and nadolol.
The mechanism is not known.
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CHOIC OF A BETA-ADRENOCEPTOR
ANTAGONIST DRUG
Propranolol is the standard against.
It is a safe and effective drug for many indications
布莱克(1924～) 英国药理学家
1964年研制出治疗冠心病的代
表药—心得安。
1988年获Nobel Prize 。
Sir James W. Black
The Nobel Prize in Physiology
or Medicine 1988
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CLINICAL TOXICITY OF THE BETARECEPTOR ANTAGONIST DRUGS
A variety of minor toxic effects have been reported.
Beta 2-receptor blockade by nonselective agents
commonly causes worsening of preexisting asthma and
airway obstruction in normal individuals.
Beta-receptor blockade depresses myocardial
contractility and excitability.
Caution must be exercised in using β-receptor
antagonists in compensated heart failure.
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Beta-blockers may interact with the calcium
antagonist; hypotension, bradycardia, heart failure,
conduction abnormalities have all been described.
These adverse effects may even arise in
susceptible patients taking a topical (ophthalmic)
β-blocker and oral verapamil.
Patients with ischemic heart disease may be at
increased risk if β-blockade is suddenly interrupted,
which might involve up-regulation of the βreceptors.
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I am glad to share my knowledge with you,
and I want you to become a master
of the subject, pharmacology
Thanks a million
for your co-operation
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