OTHER
ADRENOMIMETIC AGENTS
A number of adrenomimetic
amines are not cate-cholamines. Some of these are directly acting amines that
must interact with adrenoceptors to produce a re-sponse in effector tissues.
Some directly acting com-pounds, such as phenylephrine and methoxamine,
acti-vate α-adrenoceptors almost exclusively, whereas others, like albuterol
and terbutaline, are nearly pure β - adrenoceptor agonists. Drugs that exert
their pharma-cological actions by releasing norepinephrine from its neuronal
stores (indirectly acting) produce effects that are similar to those of
norepinephrine. They tend to ex-ert strong α-adrenoceptor activity, but β 1-adrenoceptor activity
typical of norepinephrine, such as myocardial stimulation, also occurs.
Some of the indirectly acting
adrenomimetic amines are used primarily for their vasoconstrictive properties.
They are applied locally to the nasal mucosa or to the eye. Other amines are
used as bronchodilators, while still others are used exclusively for their
ability to stim-ulate the CNS. Many noncatecholamine adrenomimetic amines
resist enzymatic destruction, have prolonged ac-tions, and are orally
effective. The indirectly acting drugs are effective only when given in large
doses, and they often produce tachyphylaxis.
These drugs are directly
acting adrenomimetic amines that exert their effects primarily through an
action on α-adrenoceptors. Consequently, these agents have little or no direct
action on the heart. All three drugs increase both systolic and diastolic blood
pressures through their vasoconstrictor action. The pressor response is
accom-panied by reflex bradycardia, no change in the contrac-tile force of the
heart, and little change in cardiac out-put. They do not precipitate cardiac
arrhythmias and do not stimulate the CNS.
Phenylephrine is not a
substrate for COMT, while metaraminol and methoxamine are not metabolized by
either COMT or MAO. Consequently, their duration of action is considerably
longer than that of norepineph-rine. Following intravenous injection, pressor
responses to phenylephrine may persist for 20 minutes, while pres-sor responses
to metaraminol and methoxamine may last for more than 60 minutes.
The clinical uses of these
drugs are associated with their potent vasoconstrictor action. They are used to
re-store or maintain blood pressure during spinal anesthe-sia and certain other
hypotensive states. The reflex bradycardia induced by their rapid intravenous
injec-tion has been used to terminate attacks of paroxysmal atrial tachycardia.
Phenylephrine is commonly used as a nasal decongestant, although occasional
nasal mucosal damage has occurred from injudicious use of the nasal spray. It
is also employed in ophthalmology as a mydri-atic agent. Phenylephrine,
however, should not be given to patients with closed-angle glaucoma before
iridec-tomy, since further increases in intraocular pressure may result. In
dentistry, phenylephrine is used to pro-long the effectiveness of a local
anesthetic.
Dobutamine (Dobutrex), in contrast to dopamine, does
not produce a significant proportion of its cardiac effects through the release
of norepinephrine from adrenergic nerves; dobutamine acts directly on β 1-adrenoceptors in the heart.
Dobutamine exerts a greater effect on the contractile force of the heart
relative to its effect on the heart rate than does dopamine. Dobutamine
increases the oxygen demands on the heart to a lesser extent than does
dopamine. Like dopamine, although at higher doses, it produces vasodilation of
renal and mesenteric blood vessels. Dobutamine may be more useful than dopamine
in the treatment of cardiogenic shock.
Terbutaline and albuterol are
relatively selective β2-adrenoceptor agonists. Both have a longer duration of action than
isoproterenol because they are not metabo-lized by COMT. Like isoproterenol,
they are not me-tabolized by MAO and are not transported into adren-ergic
neurons. Terbutaline and albuterol are effectively administered either orally
or subcutaneously. Because of their selectivity for β2-adrenoceptors, they produce
less cardiac stimulation than does isoproterenol but are not completely without
effects on the heart.
Therapeutically, terbutaline
and albuterol are used to treat bronchial asthma and bronchospasm associated
with bronchitis and emphysema .
Side effects include
nervousness, tremor, tachycar-dia, palpitations, headache, nausea, vomiting,
and sweat-ing. The frequency of appearance of these adverse ef-fects is
minimized, however, when the drugs are given by inhalation.
Ephedrine is a naturally
occurring alkaloid that can cross the blood-brain barrier and thus exert a
strong CNS-stim-ulating effect in addition to its peripheral actions. The
lat-ter effects are primarily due to its indirect actions and de-pend largely
on the release of norepinephrine. However, ephedrine may cause some direct
receptor stimulation, particularly in its bronchodilating effects. Because it
re-sists metabolism by both COMT and MAO, its duration of action is longer than
that of norepinephrine. As is the case with all indirectly acting adrenomimetic
amines, ephedrine is much less potent than norepinephrine; in addition,
tachyphylaxis develops to its peripheral actions. Unlike epinephrine or
norepinephrine, however, ephe-drine is effective when administered orally.
Ephedrine increases systolic
and diastolic blood pressure; heart rate is generally not increased.
Contractile force of the heart and cardiac output are both increased. Ephedrine
produces bronchial smooth muscle relaxation of prolonged duration when
adminis-tered orally. Aside from pupillary dilation, ephedrine has little
effect on the eye.
Ephedrine is useful in
relieving bronchoconstriction and mucosal congestion associated with bronchial
asthma, asthmatic bronchitis, chronic bronchitis, and bronchial spasms. It is
often used prophylactically to prevent asthmatic attacks and is used as a nasal
decon-gestant, as a mydriatic, and in certain allergic disorders. Although its
bronchodilator action is weaker than that of isoproterenol, its oral
effectiveness and prolonged duration of action make it valuable in the
treatment of these conditions. Because of
their oral effectiveness and greater
bronchiolar selectivity, terbutaline and albuterol are replacing ephedrine for
bronchodilation.
Symptoms of overdose are
related primarily to car-diac and CNS effects. Tachycardia, premature systoles,
insomnia, nervousness, nausea, vomiting, and emotional disturbances may
develop. Ephedrine should not be used in patients with cardiac disease,
hypertension, or hyperthyroidism
Amphetamine is an indirectly
acting adrenomimetic amine that depends for its action on the release of
nor-epinephrine from noradrenergic nerves. Its pharmaco-logical effects are
similar to those of ephedrine; how-ever, its CNS stimulant activity is somewhat
greater. Both systolic and diastolic blood pressures are increased by oral
dosing with amphetamine. The heart rate is fre-quently slowed reflexively.
Cardiac output may remain unchanged in the low- and moderate-dose range.
The therapeutic uses of
amphetamine are based on its ability to stimulate the CNS. The D-isomer (dex-troamphetamine)
is three to four times as potent as the L-isomer in producing CNS effects. It has been
used in the treatment of obesity because of its anorexic effect, although
tolerance to this effect develops rapidly. It prevents or overcomes fatigue and
has been used as a CNS stimulant. Amphetamine
is no longer recom-mended for these uses because of its potential for abuse. Amphetamine
is useful in certain cases of narcolepsy or minimal brain dysfunction.
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