Adrenergic
blocking drugs
Adrenergic blocking
drugs, also called sympatholytic drugs, areused to disrupt
sympathetic nervous system function. These drugs work by blocking impulse
transmission (and thus sympathetic nervous system stimulation) at adrenergic
neurons or adrenergic receptor sites. Their action at these sites can be
exerted by:
§ interrupting the action of adrenergic
(sympathomimetic) drugs
§ reducing available norepinephrine
§ preventing the action of cholinergic drugs.
Adrenergic blocking drugs are classified according
to their site of action as:
·
alpha-adrenergic blockers (or alpha
blockers)
·
beta-adrenergic blockers (or beta
blockers).
Alpha-adrenergic
blockers work by
interrupting the actions of thecatecholamines epinephrine and norepinephrine at
alpha recep-tors. This results in:
·
relaxation of the smooth muscle in blood vessels
·
increased dilation of blood vessels
·
decreased blood pressure.
Drugs in this class include:
·
alfuzosin
·
ergoloid mesylates
·
phenoxybenzamine
·
phentolamine
·
prazosin, doxazosin, and terazosin
·
tamsulosin.
Ergotamine is a mixed alpha agonist and antagonist;
at high doses, it acts as an alpha-adrenergic blocker.
The action of alpha-adrenergic blockers in the body isn’t well
un-derstood. Most of these drugs are absorbed erratically when ad-ministered
orally, and more rapidly and completely when adminis-tered sublingually.
Alpha-adrenergic blockers vary considerably in their onset of action, peak
concentration levels, and duration of action.
Alpha-adrenergic blockers work in one of two ways:
·
They interfere with or block the synthesis, storage, release, and
reuptake of norepinephrine by neurons.
·
They antagonize epinephrine, norepinephrine, or adrenergic
(sympathomimetic) drugs at alpha receptor sites.
Alpha-adrenergic blockers include drugs that block
stimulation of alpha1 receptors and
that may block alpha2 receptors.
Alpha-adrenergic blockers occupy alpha receptor
sites on the smooth muscle of blood vessels. (See How alpha-adrenergicblockers affect peripheral blood vessels.)
This prevents catecholamines from occupying and
stimulating the receptor sites. As a result, blood vessels dilate, increasing
local blood flow to the
skin and other organs. The decreased periph-eral vascular resistance
(resistance to blood flow) helps to de-crease blood pressure.
The therapeutic effect of an alpha-adrenergic
blocker depends on the sympathetic tone (the state of partial constriction of
blood vessels) in the body before the drug is administered. For instance, when
the drug is given with the patient lying down, only a small change in blood
pressure occurs. In this position, the sympathetic nerves release very little
norepinephrine.
On the other hand, when a patient stands up,
norepinephrine is re-leased to constrict the veins and shoot blood back up to
the heart. If the patient receives an alpha-adrenergic blocker, however, the
veins can’t constrict and blood pools in the legs. Because blood re-turn to the
heart is reduced, blood pressure drops. This drop in blood pressure that occurs
when a person stands up is called or-thostatic
hypotension.
Because alpha-adrenergic blockers cause smooth
muscles to relax and blood vessels to dilate, they increase local blood flow to
the skin and other organs and reduce blood pressure. As a result, they’re used
to treat:
·
benign prostatic hypertrophy
·
hypertension
·
peripheral vascular disorders (diseases of the blood vessels of the
extremities), especially those in which blood vessel spasm causes poor local
blood flow, such as Raynaud’s disease (intermit-tent pallor, cyanosis, or
redness of fingers), acrocyanosis (sym-metrical mottled cyanosis of the hands
and feet), and frostbite
·
pheochromocytoma (a catecholamine-secreting tumor that causes severe
hypertension).
Many drugs interact with alpha-adrenergic blockers,
producing a synergistic, or exaggerated, effect. The most serious interactions
are severe hypotension and vascular collapse.
These interactions can occur when these drugs are
taken with ergoloid mesylates and ergotamine:
·
Caffeine and macrolide antibiotics can increase the effects of
ergotamine.
·
Dopamine increases the pressor (rising blood pressure) effect.
·
Nitroglycerin can produce hypotension from excessive dilation of blood
vessels.
Sympathomimetics, including many over-the-counter
drugs, can increase the stimulating effects on the heart, possibly resulting in
hypotension with rebound hypertension. (See Adverse
reactionsto alpha-adrenergic blockers.)
Beta-adrenergic
blockers, the most widely
used adrenergic block-ers, prevent stimulation of the sympathetic nervous
system by in-hibiting the action of catecholamines at beta-adrenergic
receptors.
Beta-adrenergic blockers can be selective or
nonselective. Non-selective beta-adrenergic blockers affect:
·
beta1 receptor sites (located mainly in the heart)
·
beta2 receptor sites (located in the bronchi,
blood vessels, and uterus).
Nonselective beta-adrenergic blockers include
carteolol, carvedilol, labetalol, levobunolol, metipranolol, penbutolol,
pin-dolol, sotalol, nadolol, propranolol, and timolol. (Carvedilol and
labetalol also block alpha1 receptors.)
Selective beta-adrenergic blockers primarily affect
beta1-adrenergic sites. They include acebutolol,
atenolol, betaxolol, bisoprolol, esmolol, and metoprolol.
Some beta-adrenergic blockers, such as pindolol and
acebutolol, have intrinsic sympathetic activity. This means that instead of
at-taching to beta receptors and blocking them, these beta-adrenergic blockers
attach to beta receptors and stimulate them. These drugs are sometimes
classified as partial agonists.
Beta-adrenergic blockers are usually absorbed
rapidly and well from the GI tract and are somewhat protein-bound. Food doesn’t
inhibit—and may even enhance—their absorption. Some beta-adrenergic blockers
are absorbed more completely than others.
The onset of action of beta-adrenergic blockers is
primarily dose-and drug-dependent. The time it takes to reach peak
concentra-tion levels depends on the administration route. Beta-adrenergic
blockers given I.V. reach peak levels much more rapidly than those taken by
mouth.
Beta-adrenergic blockers are distributed widely in
body tissues, with the highest concentrations found in the:
·
heart
·
liver
·
lungs
·
saliva.
Except for nadolol and atenolol, beta-adrenergic
blockers are me-tabolized in the liver. They’re excreted primarily in urine,
either unchanged or as metabolites, but can also be excreted in feces, bile
and, to some degree, breast milk.
Beta-adrenergic blockers have widespread effects in
the body be-cause they produce their blocking action not only at adrenergic
nerve endings but also in the adrenal medulla.
Effects on the heart include increased peripheral
vascular resis-tance, decreased blood pressure, decreased force of the heart’s
contractions, decreased oxygen consumption by the heart, slowed impulse
conduction between the atria and ventricles, and de-creased cardiac output (the
amount of blood the heart pumps each minute). (See How beta-adrenergic blockers work.)
Some beta-adrenergic blocker effects depend on
whether the drug is classified as selective or nonselective.
Selective beta-adrenergic blockers, which prefer to
block beta1-receptor sites, reduce stimulation of the
heart. They’re often referred to as cardioselective
beta-adrenergic blockers.
Nonselective beta-adrenergic blockers, which block
both beta1- and beta2-receptor sites, not only reduce stimulation of the heart but also cause
the bronchioles of the lungs to constrict. For instance, nonselective
beta-adrenergic blockers can cause bron-chospasm in patients with chronic obstructive
lung disease. This adverse effect isn’t seen when cardioselective drugs are
given at lower doses.
Beta-adrenergic blockers are used to treat many
conditions and are under investigation for use in many more. As mentioned
previ-ously, their clinical usefulness is based largely (but not exclusive-ly)
on how they affect the heart. (See Are
beta-adrenergic block-ers underused in elderly patients?)
Beta-adrenergic blockers can be prescribed after a
heart attack to prevent another heart attack or to treat:
·
angina
·
heart failure
·
hypertension
·
cardiomyopathy (a disease of the heart muscle)
·
supraventricular arrhythmias (irregular heartbeats that origi-nate in
the atria, SA node, or atrioventricular node).
Beta-adrenergic blockers are also used to treat:
·
anxiety
·
cardiovascular symptoms associated with thyrotoxicosis (over-production
of thyroid hormones)
·
essential tremor
·
migraine headaches
·
open-angle glaucoma
·
pheochromocytoma (tumor of the adrenal gland).
Many drugs can interact with beta-adrenergic
blockers to cause potentially dangerous effects. Some of the most serious
effects in-clude cardiac or respiratory depression, arrhythmias, severe
bronchospasm, and severe hypotension that can lead to vascular collapse. Other
interactions can also occur:
·
Increased effects or
toxicity can occur when cimetidine, digox-in, or calcium channel blockers
(primarily verapamil) are taken with beta-adrenergic blockers.
·
Decreased effects can
occur when rifampin, antacids, calcium salts, barbiturates, or
anti-inflammatories, such as indomethacin and salicylates, are taken with
beta-adrenergic blockers.
·
Lidocaine toxicity may
occur when lidocaine is taken with beta-adrenergic blockers.
·
The requirements for
insulin and oral antidiabetic drugs can be altered when these drugs are taken
with beta-adrenergic blockers.
·
The ability of
theophylline to produce bronchodilation is im-paired by nonselective
beta-adrenergic blockers.
·
Clonidine taken with a
nonselective beta-adrenergic blocker can cause life-threatening hypertension
during clonidine withdrawal.
·
Sympathomimetics taken
with nonselective beta-adrenergic blockers can cause hypertension and reflex
bradycardia. (See Ad-verse reactions to
beta-adrenergic blockers.)
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