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Chapter: Modern Pharmacology with Clinical Applications: Adrenomimetic Drugs

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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.

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.

Directly Acting Adrenomimetic Drugs

Phenylephrine, Metaraminol, and Methoxamine

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

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

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.

Indirectly Acting Adrenomimetic Drugs

Ephedrine

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.

Pharmacological Actions

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.

Clinical Uses

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.

Adverse Effects

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

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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