Description: Phenylephrine is a synthetic sympathomimetic amine with selectivity for the alpha-1-adrenergic receptor. Phenylephrine lacks significant inotropic and chronotropic effects. Pharmacologically, it most closely resembles the older drug methoxamine. Phenylephrine is commonly used orally, alone or in combination with other drugs, and intranasally to treat nasal congestion. When administered topically to the eye, it induces mydriasis and, thus, phenylephrine is often used as a diagnostic aid in ophthalmology. Phenylephrine may reduce heart rate and cardiac output as a reflex response to its potent vasopressor effects, which is the rationale for its use to treat paroxysmal supraventricular tachycardia. Since it is a potent vasoconstrictor, phenylephrine injection can be used as a vasopressor. However the predominance of alpha-effects and lack of beta-1 inotropic effects limits the use of phenylephrine for the treatment of shock states. Phenylephrine substantially reduces splanchnic blood flow in septic shock patients.[9182] Alternative vasopressors which have additional inotropic effects such as dopamine or norepinephrine are preferred for the treatment of septic shock.[9182] Phenylephrine may have an advantage in treating shock states associated with tachycardia due to its lack of chronotropic effects. Phenylephrine was originally approved by the FDA in 1938.

Mechanism of Action: Phenylephrine is a potent vasoconstrictor. It possesses both direct and indirect sympathomimetic effects. Phenylephrine is used parenterally to achieve cardiovascular effects. The dominant effect is agonism at alpha-adrenergic receptors (direct effect). In therapeutic doses, the drug has no substantial stimulant effect on the beta-adrenergic receptors of the heart (beta1-adrenergic receptors), although activation of these receptors can occur when very large doses are given. Phenylephrine does not stimulate beta-adrenergic receptors of the bronchi or peripheral blood vessels (beta2-adrenergic receptors). It is believed that alpha-adrenergic effects result from inhibition of cyclic adenosine-3',5'-monophosphate (cAMP) production through inhibition of the enzyme adenyl cyclase, whereas beta-adrenergic effects result from stimulation of adenyl cyclase activity. Phenylephrine also releases norepinephrine from its nerve terminal storage sites (indirect effect). Although the manufacturer reports that there is no decrease in effectiveness with repeated injections of phenylephrine, some investigators have reported that tachyphylaxis can develop. Phenylephrine lacks direct inotropic and chronotropic effects on the heart.[9321] The main effect of systemic doses is vasoconstriction, resulting in constriction of most vascular beds including renal, splanchnic, and pulmonary blood vessels. Pulmonary vascular resistance may increase and a slight reduction in cardiac output may occur. Reflex bradycardia may occur, which can be reversed by atropine.

Phenylephrine may be used to treat paroxysmal supraventricular tachycardia based on its effects to reduce heart rate as a reflex mechanism in response to its alpha-1-agonist vasoconstrictive effects.

A dose-ranging study in septic shock patients, escalating doses ranging from 0.5 to 8 mcg/kg/min IV at 30 minute intervals, has reported linear dose-related increases in mean arterial pressure (MAP) and systemic vascular resistance index (SVRI).[9336] Although phenylephrine has been reported to increase cardiac output in septic patients based on limited data [9336], cardiac output may be reduced in some patients, presumably due to increased systemic vascular resistance and potential for reflex bradycardia.[9182] [9321] Phenylephrine substantially reduces splanchnic blood flow in septic shock patients.

Phenylephrine is used orally and intranasally to stimulate alpha-adrenergic receptors on the nasal mucosa (direct effect) causing vasoconstriction of local vessels. The vasoconstrictive action decreases mucosal edema, thereby leading to a decongestant effect.

Within the eye, phenylephrine also stimulates alpha-adrenergic receptors (direct effect). Stimulation of these receptors on the dilator muscle and arterioles of the conjunctiva leads to profound mydriasis and vasoconstriction, respectively.

Pharmacokinetics: Phenylephrine is administered orally, intranasally, ophthalmically, and parenterally. When administered orally, phenylephrine is irregularly absorbed from and readily metabolized in the GI tract. After IV administration, a pressor effect occurs almost immediately and persists for 15—20 minutes. After IM administration, a pressor effect occurs within 10—15 minutes and persists for 30 minutes to 1—2 hours. After subcutaneous administration, a pressor effect occurs within 10—15 minutes and persists for 50 minutes to 1 hour. After oral inhalation of phenylephrine in combination with isoproterenol, pulmonary effects occur within a few minutes and persist for about 3 hours. Occasionally, enough phenylephrine can be absorbed after oral inhalation to produce systemic effects. The duration of action after intranasal administration ranges 30 minutes to 4 hours. The duration of the mydriatic effect is roughly 3 hours after administration of the 2.5% solution but may be as long as 7 hours after the 10% solution.

The pharmacologic effects of phenylephrine are terminated at least partially by uptake of the drug into tissues. Phenylephrine is metabolized in the liver and intestine by the enzyme monoamine oxidase (MAO). The metabolites and their route and rate of excretion have not been identified.

References
9182. Beale RJ, Hollenberg SM, Vincent JL, et al. Vasopressor and inotropic support in septic shock: an evidence-based review. Crit Care Med 2004;32:S455—65.

9321. Phenylephrine hydrochloride injection package insert. Deerfield, IL: Baxter Healthcare Corporation; 2003 Feb.

9336. Flancbaum L, Dick M, Dasta J, et al. A dose-response study of phenylephrine in critically ill, septic surgical patients. Eur J Clin Pharmacol 1997;51:461—5.


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