Phenylephrine

Absorption

Phenylephrine is 38% orally bioavailable. Clinically significant systemic absorption of ophthalmic formulations is possible, especially at higher strengths and when the cornea is damaged.

Toxicity

Patients experiencing and overdose may present with headache, hypertension, reflex bradycardia, tingling limbs, cardiac arrhythmias, and a feeling of fullness in the head. Overdose may be treated by supportive care and discontinuing phenylephrine, chronotropic medications, and vasodilators. Subcutaneous phentolamine may be used to treat tissue extravasation.

Description

This synthetic drug has both chemical and pharmacological similarities to norepinephrine. A characteristic quality of phenylephrine is the distinctly expressed selectivity to α- adrenoreceptors, especially α1-adrenoreceptors. Although phenylephrine increases the contractibility of blood vessels, in practical terms it is not considered a cardiostimulant.

Chemical properties

White or almost white, crystalline powder.

The Uses of Phenylephrine

L-Phenylephrine is an adrenergic α1A receptor agonist (Ki = 1.4 μM) that demonstrates selectivity against the α1B and α1C receptor subtypes (Kis = 23.9 and 47.8 μM, respectively). By stimulating adrenergic α1 receptors, L-phenylephrine can induce aortic smooth muscle contractions, although reported relative affinity and potency values in rabbit are 5-fold weaker compared to that of L-norepinephrine. This compound is frequently used to precontract smooth muscle in preparations designed to study the properties of various vasodilator agents. Because L-phenylephrine acts on adrenergic α1 receptors in the arterioles of the nasal mucosa to produce constriction, it has been examined clinically as an oral decongestant.

The Uses of Phenylephrine

Phenylephrine is used in hypotension, paroxysmal supraventricular tachycardia, and shock. It is also used locally, particularly in the form of nasal spray, for relieving edema.

Background

Phenylephrine is an alpha-1 adrenergic receptor agonist used to treat hypotension, dilate the pupil, and induce local vasoconstriction. The action of phenylephrine, or neo-synephrine, was first described in literature in the 1930s.
Phenylephrine was granted FDA approval in 1939.

Indications

Phenylephrine is available in various drug formulations, which have different indications. Phenylephrine injections are indicated to treat hypotension caused by shock or anesthesia. The ophthalmic formulation is indicated to induce mydriasis and conjunctival vasoconstriction. The intranasal formulation is used to treat congestion, and a topical formulation is used to treat hemorrhoids. Off-label uses include priapism and induction of local vasoconstriction.

What are the applications of Application

L-phenylephrine is an α1 adrenergic receptor agonist

Definition

ChEBI: A member of the class of the class of phenylethanolamines that is (1R)-2-(methylamino)-1-phenylethan-1-ol carrying an additional hydroxy substituent at position 3 on the phenyl ring.

brand name

Afrin 4 Hour Nasal Spray (Schering-Plough Health Care); Biomydrin (Parke-Davis); Mydfrin (Alcon); Neo-Synephrine (Sterling Health U.S.A.); Nostril (Boehringer Ingelheim);Fenox;Forte;Isopto;Minims;Visadron.

General Description

(Neo-Synephrine, a prototypical selectivedirect-acting 1-agonist) differs from E only inlacking a p-OH group. It is orally active, and its DOA isabout twice that of E because it lacks the catechol moietyand thus is not metabolized by COMT. However, its oralbioavailability is less than 10% because of its hydrophilicproperties (log P＝0.3), intestinal 3 -O-glucuronidation/sulfation and metabolism by MAO. Lacking the p-OHgroup, it is less potent than E and NE but it is a selectiveα1-agonist and thus a potent vasoconstrictor. It is usedsimilarly to metaraminol and methoxamine for hypotension.Another use is in the treatment of severe hypotensionresulting from either shock or drug administration. It alsohas widespread use as a nonprescription nasal decongestantin both oral and topical preparations. When applied tomucous membranes, it reduces congestion and swelling byconstricting the blood vessels of the membranes. In theeye, it is used to dilate the pupil and to treat open-angleglaucoma. In addition, it is used in spinal anesthesia toprolong the anesthesia and to prevent a drop in blood pressureduring the procedure. It is relatively nontoxic and produceslittle CNS stimulation. Metaraminol is just anotherexample.

Pharmacokinetics

Phenylephrine is an alpha-1 adrenergic agonist that raises blood pressure, dilates the pupils, and causes local vasoconstriction. Ophthalmic formulations of phenylephrine act for 3-8 hours while intravenous solutions have an effective half life of 5 minutes and an elimination half life of 2.5 hours. Patients taking ophthalmic formulations of phenylephrine should be counselled about the risk of arrhythmia, hypertension, and rebound miosis. Patients taking an intravenous formulation should be counselled regarding the risk of bradycardia, allergic reactions, extravasation causing necrosis or tissue sloughing, and the concomitant use of oxytocic drugs.

Clinical Use

Phenylephrine is a potent direct-acting α1-agonist with clinical effects similar to those of noradrenaline. It causes widespread vasoconstriction with an increase in arterial pressure, reflex bradycardia and decrease in cardiac output. It may be administered by i.v. bolus (50–100μg boluses) and i.v. infusion (50–150μgmin –1) to maintain arterial pressure during general anaesthesia or other causes of low SVR. It may also be used topically as a nasal decongestant or mydriatic. There is some evidence suggesting a paradoxical reduction in cerebral oxygen delivery.

Safety Profile

Poison by ingestion, subcutaneous, intravenous, intraperitoneal, and intraduodenal routes. Human systemic effects by ocular route: blood pressure increase. An experimental teratogen. Other experimental reproductive effects. A nasal decongestant. When heated to decomposition it emits toxic fumes of NOx.

Synthesis

Phenylephrine, 1-(3-hydroxyphenyl)-2-methylaminoethanol (11.1.16), which differs from epinephrine, in that it does not have a hydroxyl group at C4 of the aromatic ring, is synthesized by an analogous scheme of making epinephrine; however, instead of using ω-chloro-3,4-dihydroxyacetophenone, ω-chloro-3-dihydroxyacetophenone is used [11,22,23].

Veterinary Drugs and Treatments

Phenylephrine has been used to treat hypotension and shock (after adequate volume replacement), but many clinicians prefer to use an agent that also has cardiostimulatory properties. Phenylephrine is recommended for use to treat hypotension secondary to drug overdoses or idiosyncratic hypotensive reactions to drugs such as phenothiazines, adrenergic blocking agents, and ganglionic blockers. Its use to treat hypotension resulting from barbiturate or other CNS depressant agents is controversial. Phenylephrine has been used to increase blood pressure to terminate attacks of paroxysmal supraventricular tachycardia, particularly when the patient is also hypotensive. Phenylephrine has been used to both treat hypotension and prolong the effects of spinal anesthesia.
Ophthalmic uses of phenylephrine include use for some diagnostic eye examinations, reducing posterior synechiae formation, and relieving pain associated with complicated uveitis. It has been applied intranasally in an attempt to reduce nasal congestion.

in vitro

in neonatal rat cardiomyocytes, 50 μm l-phenylephrine treatment could protect cells from apoptosis induced by hypoxia (95% n2 and 5% co2) and serum deprivation through α-adrenergic receptor stimulation [2]. besides, in neural progenitor cells (npcs), 10 μm l-phenylephrine could increase npcs proliferation by approximately 160% [3]. furthermore, in cultured rat neonatal cms (ncms), l-phenylephrine could increase cross-sectional area, and significantly increase il-6 mrna levels, while decreasing pgc1α mrna levels [4].

in vivo

studies in sprague-dawley male rats found that, local infiltration of l-phenylephrine could induce cutaneous anesthesia in a dose dependent manner, which could be significantly inhibited by α1-adrenergic receptor antagonists [5].

Metabolism

Phenylephrine is mainly metabolized by monoamine oxidase A, monoamine oxidase B, and SULT1A3. The major metabolite is the inactive meta-hydroxymandelic acid, followed by sulfate conjugates. Phenylephrine can also be metabolized to phenylephrine glucuronide.

References

[1] lomasney j w, cotecchia s, lorenz w, et al. molecular cloning and expression of the cdna for the alpha 1a-adrenergic receptor. the gene for which is located on human chromosome 5.[j]. journal of biological chemistry, 1991, 266(10): 6365-6369.
[2] zhu h, mcelweewitmer s, perrone m, et al. phenylephrine protects neonatal rat cardiomyocytes from hypoxia and serum deprivation-induced apoptosis.[j]. cell death & differentiation, 2000, 7(9): 773-784.
[3] hiramoto t, ihara y, watanabe y, et al. α-1 adrenergic receptors stimulation induces the proliferation of neural progenitor cells in vitro[j]. neuroscience letters, 2006, 408(1): 25-28.
[4] planavila a, redondo i, hondares e, et al. fibroblast growth factor 21 protects against cardiac hypertrophy in mice[j]. nature communications, 2013.
[5] shieh j, chu c, wang j, et al. epinephrine, phenylephrine, and methoxamine induce infiltrative anesthesia via α1-adrenoceptors in rats[j]. acta pharmacologica sinica, 2009, 30(9): 1227-1236.
[6] hatton r c, winterstein a g, mckelvey r p, et al. efficacy and safety of oral phenylephrine: systematic review and meta-analysis[j]. annals of pharmacotherapy, 2007, 41(3): 381-390.