Clinical Pharmacology
Isoproterenol acts directly on beta-adrenergic receptors and phenylephrine acts directly on alpha-adrenergic receptors. The beta-adrenergic effects stem from the release of cyclic AMP following activation of the enzyme adenyl cyclase. Alpha-adrenergic effects probably result from inhibition of adenyl cyclase. Isoproterenol produces bronchodilatation, systemic vasodilation, mild hypotension, and tachycardia. Phenylephrine produces mild bronchodilatation, systemic vasoconstriction, mild hypertension, and bradycardia. These two drugs appear to act synergistically to allow the expression of each product's ability to relax bronchial smooth muscle. The vasoconstrictor effect of phenylephrine reduces bronchiolar blood flow thereby producing a decongestant effect, promotes retention of the drug in the bronchial mucosa, and blocks the tachycardia of isoproterenol. After oral inhalation of the combination, the pulmonary effects occur within a few minutes and persist up to three hours.
Studies demonstrate that the ventilatory effects of isoproterenolphenylephrine are superior to those obtained with the administration of isoproterenol alone. Because isoproterenol is a potent vasodilator that lowers blood pressure and acts upon the heart to increase cardiac output and pulse rate, its combination with phenylephrine results in a product with fewer cardiovascular effects. Studies have shown the absence of tachycardia and hypotension.
Isoproterenol alone often lowers arterial blood oxygen (PO2). Several studies have shown that the combination of isoproterenol and phenylephrine rarely produces a significant drop in arterial oxygen tension while usually producing an increase in PaO2 in asthmatic patients.
Pharmacokinetics: The average half-life for isoproterenol administered by aerosol was five minutes. A plasma concentration of 0.03 ng/ml was found within minutes following an inhalation dose of 500 mcg isoproterenol.
Isoproterenol excretion following oral or inhalation administration is primarily renal. When given by inhalation, the major metabolite is the sulfate conjugate of the drug. 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, swallowed, and 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.
Plasma levels following inhalation of phenylephrine have not been reported. Following oral and intravenous administrations, the average half-life was about 2.5 hours. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase. About 80% of a dose is recovered in the urine, primarily as phenolic conjugates and m -hydroxymandelic acid. About 16% of a dose is excreted as unchanged drug following intravenous administration and, due to first pass metabolism, less than 3% is excreted unchanged following oral dosing.
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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