CLINICAL PHARMACOLOGY
Isoproterenol acts directly on beta-adrenergic receptors of tissues supplied by sympathetic nerves. The beta-adrenergic effects stem from the release of cyclic AMP following the activation of the enzyme adenyl cyclase. Therapeutic doses of isoproterenol result in relaxation of the smooth muscle of the bronchial tree and decrease in peripheral vascular resistance; increased cardiac output and stroke volume may occur due to its positive inotropic and chronotropic action. The coronary arteries may be dilated, increasing the blood flow. Isoproterenol also inhibits uterine motility and causes decreased tone and motility of intestinal musculature even when epinephrine causes contraction.
In patients with bronchial constriction, isoproterenol relieves bronchospasm, increases pulmonary function, decreases residual air, and facilitates lung clearance by increasing ciliary motility and mucous transport. Bronchodilatation occurs quickly after oral inhalation and lasts up to one hour. It is one of the most potent bronchodilators known and can be used in patients who do not respond to the bronchodilating action of epinephrine. The drug will prevent or overcome histamine-induced asthma in both experimental animals and man, and is effective when used prophylactically.
Isoproterenol has a cardio-accelerating effect, but its vasoconstricting action is less pronounced than that of epinephrine. Therapeutic doses may produce a slight increase in systolic blood pressure but a slight decrease in diastolic. Larger doses may cause peripheral vasodilation in the renal, mesenteric, and femoral beds; some patients respond with a decrease in diastolic but no change in systolic pressure. Such effects are usually of very short duration.
Pharmacokinetics:
The average plasma half-life for isoproterenol given intravenously in seven healthy volunteers was four minutes while the average half-life of the drug administered by aerosol to five patients was five minutes. In children, the decline in plasma concentration was biphasic, with a half-life during the first phase of two to five minutes and of three to seven hours during the second phase. A plasma concentration of 0.03 ng/ml was found within minutes, following an aerosol inhalation dose of 500 mcg.
Excretion following inhalation administration is primarily renal and the major metabolite is the sulfate conjugate of isoproterenol. When the drug is administered directly into the bronchial tree, it is inactivated by the enzyme catechol- o -methyl transferase, and the predominant metabolite is 3- o -methylisoproterenol sulfate. The explanation for this difference is supported by the observation that most (90%) of an aerosol dose is deposited in the mouth and pharynx and is swallowed. The swallowed isoproterenol is converted to its sulfate conjugate in the gut wall, and to a lesser extent in the liver. The remaining isoproterenol is excreted as follows: 1% to 2% unchanged, 1% to 2% free methylated metabolite, and small amounts of metabolites in the bile.
Recent studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta agonists and methylxanthines were concomitantly administered. The significance of these findings when applied to human usage is currently unknown.
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