(R)-(-)-Phenylephrine has pKi values of 5.86, 4.87, and 4.70 for α1D, α1B, and α1A receptors, respectively, making it a selective α1-adrenergic receptor agonist [1][2]. This myocardium may be the target of treatment for myocardial fibrosis because phenylephrine stimulates cardiac fibroblasts, indicating that Ca (2+)/CaN/NFAT does not drive phenylephrine-induced cardiac fibroblast proliferation [3].

Both p38-MAPK isoforms were rapidly activated by 12 times (maximum at 10 min) upon perfusion of the heart with 100 μM phenylephrine. α1-Syntropin is responsive to anesthetics that enhance the heart's contractility, including phenylephrine. Newborn ventricular myocytes' SAPKs and JNKs are activated by phenylephrine[4]. Phenylephrine has the ability to speed up the absorption of pulmonary edema and raise the alveolar fluid clearance rate of air volume ventilation transport [5].

Absorption, Distribution and Excretion
Phenylephrine is 38% orally bioavailable. Clinically significant systemic absorption of ophthalmic formulations is possible, especially at higher strengths and when the cornea is damaged.
86% of a dose of phenylephrine is recovered in the urine with 16% as the unmetabolized drug, 57% as the inactive meta-hydroxymendelic acid, and 8% as inactive sulfate conjugates.
The volume of distribution of phenylephrine is 340L.
Phenylephrine has an average clearance of 2100mL/min.
Phenylephrine undergoes rapid distribution into peripheral tissues; there is some evidence that the drug may be stored in certain organ compartments. The pharmacologic effects of phenylephrine are terminated at least partially by uptake of the drug into tissues. Penetration of phenylephrine into the brain appears to be minimal. Phenylephrine does not appear to be distributed to any great extent into breast milk.
Phenylephrine is completely absorbed following oral administration and undergoes extensive first-pass metabolism in the intestinal wall. The bioavailability of phenylephrine following oral administration is approximately 38% relative to IV administration. Because of extensive first-pass metabolism, there is considerable interindividual and possibly intraindividual variation in oral bioavailability of the drug. Following oral administration of phenylephrine (1 or 7.8 mg), peak serum concentrations occur at 0.75-2 hours.
Phenylephrine and its metabolites are excreted mainly in urine. Following oral or IV administration, approximately 80 or 86% of the dose, respectively, is excreted in urine within 48 hours, principally as metabolites; approximately 2.6% of an oral dose or 16% of an IV dose is excreted in urine as unchanged drug.
7-3H-phenylephrine was given to 15 volunteers by a short-infusion n = 4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free 3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. As almost the same 3H-activity was excreted in urine after i.v. and p.o. administration, 86% and 80% of the dose respectively, complete enteral absorption can be assumed. A considerable difference was seen in the fraction of free phenylephrine, i.v. 16% of the dose versus p.o. 2.6%, which suggested reduced bioavailability. This was confirmed by comparison of the areas under the serum curve, which showed a bioavailability factor of 0.38. The result for the patient with porto-caval anastomosis was comparable to that in the normal volunteers. The biological half-life of 2 to 3hr was comparable to that of structurally related amines, as were the total clearance of 2 L/hr, and the volume of distribution of 340 L.

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Metabolism / Metabolites
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.
Phenylephrine undergoes extensive metabolism in the intestinal wall (first-pass) and in the liver. The principal routes of metabolism involve sulfate conjugation (primarily in the intestinal wall) and oxidative deamination (by monoamine oxidase (MAO)); glucuronidation also occurs to a lesser extent.
7-3H-phenylephrine was given to 15 volunteers by a short-infusion n = 4) or p.o. (10 volunteers, 1 patient with porto-caval anastomosis). Analysis of serum for free 3H-phenylephrine and fractionation of urinary radioactivity was performed by ion-exchange and thin-layer chromatography. ... Metabolism to phenolic conjugates mainly after oral ingestion, and to m-hydroxymandelic acid after i.v. injection, again demonstrated that m-hydroxylated amines are predominantly conjugated during the "first-pass" metabolism.
Phenylephrine has known human metabolites that include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenoxy]oxane-2-carboxylic acid.

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Biological Half-Life
Intravenous phenylephrine has an effective half life of 5 minutes and an elimination half life of 2.5 hours.
The elimination half-life of phenylephrine averages 2-3 hours following oral or IV administration

Interactions
Administration of a 10% solution of phenylephrine hydrochloride to patients pretreated with 2% pilocarpine hydrochloride produces mydriasis but to a lesser degree than occurs in patients who are not receiving the miotic. Pilocarpine may prevent or reduce visual disturbances and the risk of increased intraocular pressure associated with mydriasis in some patients and may be used to hasten recovery from mydriasis after ophthalmologic examination. Phenylephrine may reduce ciliary and conjunctival congestion and accommodative myopia often encountered when miotics are used alone in the treatment of glaucoma, without compromising the effectiveness of glaucoma therapy.
Concomitant administration of phenylephrine with cycloplegic antimuscarinic drugs such as atropine sulfate, cyclopentolate hydrochloride, homatropine hydrobromide, or scopolamine hydrobromide produces increased dilation of the pupil which is of clinical value.
The possibility that digitalis can sensitize the myocardium to the effects of sympathomimetic drugs should be considered.
The cardiac and pressor effects of phenylephrine are potentiated by prior administration of monoamine oxidase (MAO) inhibitors because the metabolism of phenylephrine is reduced. The potentiation is greater following oral administration of phenylephrine than after parenteral administration of the drug because reduction of the metabolism of phenylephrine in the intestine results in increased absorption of the drug. Oral administration of phenylephrine to patients receiving a MAO inhibitor should be avoided. Parenteral administration of phenylephrine to these patients, if unavoidable, should be undertaken with extreme caution and initial doses should be small. Patients should consult a clinician before initiating anorectal phenylephrine therapy if they are receiving an MAO inhibitor.
For more Interactions (Complete) data for PHENYLEPHRINE (12 total), please visit the HSDB record page.

[1]. Pharmacological pleiotropism of the human recombinant alpha1A-adrenoceptor: implications foralpha1-adrenoceptor classification. Br J Pharmacol. 1997 Jul;121(6):1127-35.

[2]. Selectivity of agonists for cloned alpha 1-adrenergic receptor subtypes. Mol Pharmacol. 1994 Nov;46(5):929-36.

[3]. Phenylephrine promotes cardiac fibroblast proliferation through calcineurin-NFAT pathway. Front Biosci (Landmark Ed). 2016 Jan 1;21:502-13.

[4]. Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart. Biochem J. 1998 Jun 1;332 ( Pt 2):459-65.

[5]. Effect of phenylephrine on alveolar fluid clearance in ventilator-induced lung injury. Chin Med Sci J. 2013 Mar;28(1):1-6.

Phenylephrine is 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. It has a role as an alpha-adrenergic agonist, a cardiotonic drug, a mydriatic agent, a protective agent, a vasoconstrictor agent, a sympathomimetic agent and a nasal decongestant. It is a member of phenylethanolamines, a secondary amino compound and a member of phenols. It is a conjugate base of a phenylephrine(1+).
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.
Phenylephrine is an alpha-1 Adrenergic Agonist. The mechanism of action of phenylephrine is as an Adrenergic alpha1-Agonist.
Phenylephrine is a direct-acting sympathomimetic amine chemically related to adrenaline and ephedrine with potent vasoconstrictor property. Phenylephrine is a post-synaptic alpha-adrenergic receptor agonist that causes vasoconstriction, increases systolic/diastolic pressures, reflex bradycardia, and stroke output.
An alpha-1 adrenergic agonist used as a mydriatic, nasal decongestant, and cardiotonic agent.
See also: Phenylephrine Hydrochloride (has salt form); Lidocaine; phenylephrine (component of) ... View More ...

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Drug Indication
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.

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Mechanism of Action
Phenylephrine is an alpha-1 adrenergic agonist that mediates vasoconstriction and mydriasis depending on the route and location of administration. Systemic exposure to phenylephrine also leads to agonism of alpha-1 adrenergic receptors, raising systolic and diastolic pressure as well as peripheral vascular resistance. Increased blood pressure stimulates the vagus nerve, causing reflex bradycardia.
Phenylephrine acts predominantly by a direct effect on alpha-adrenergic receptors. In therapeutic doses, the drug has no substantial stimulant effect on the beta-adrenergic receptors of the heart (beta1-adrenergic receptors) but substantial activation of these receptors may occur when larger 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 the inhibition of the production of cyclic adenosine-3',5'-monophosphate (cAMP) by inhibition of the enzyme adenyl cyclase, whereas beta-adrenergic effects result from stimulation of adenyl cyclase activity. Phenylephrine also has an indirect effect by releasing norepinephrine from its storage sites.

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Therapeutic Uses
Adrenergic alpha-Agonists; Cardiotonic Agents; Mydriatics; Nasal Decongestants; Sympathomimetics; Vasoconstrictor Agents
Nasal phenylephrine is indicated for the symptomatic relief of nasal congestion due to the common cold or hay fever, sinusitis, or other upper respiratory allergies. /Included in US product labeling/
Nasal phenylephrine may be useful in the adjunctive therapy of middle ear infections by decreasing congestion around the eustachian ostia. /Included in US product labeling/
Nasal phenylephrine is used for relief of sinus congestion. /NOT included in US product labeling/
For more Therapeutic Uses (Complete) data for PHENYLEPHRINE (18 total), please visit the HSDB record page.

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Drug Warnings
Because it is not known whether phenylephrine is distributed into milk, the drug should be used with caution in nursing women.
Administration of phenylephrine to patients in late pregnancy or labor may cause fetal anoxia and bradycardia by increasing contractility of the uterus and decreasing uterine blood flow. ... It is also not known whether the drug can cause fetal harm when administered to pregnant women. Phenylephrine should be used during pregnancy only when clearly needed.
Ophthalmic use of phenylephrine occasionally causes systemic sympathomimetic effects such as palpitation, tachycardia, premature ventricular contractions, occipital headache, pallor or blanching, trembling or tremors, increased perspiration, and hypertension. In one patient, hypertension severe enough to cause subarachnoid hemorrhage followed insertion of a cotton wick saturated with 10% phenylephrine hydrochloride in the lower conjunctival cul-de-sac. ... Systemic effects occur only rarely after topical application of solutions containing 2.5% or less of phenylephrine hydrochloride to the conjunctiva but are more likely to occur if the drug is instilled after the corneal epithelium has been damaged (e.g., by trauma or instrumentation) or permeability is increased by tonometry, inflammation, surgery of the eye or adnexa, or topical application of a local anesthetic; when the eye or adnexa are diseased; or when lacrimation is suppressed such as during anesthesia. The risk of severe hypertension is greatest in infants receiving instillations of 10% phenylephrine hydrochloride solutions.
In patients with shock, pressor therapy is not a substitute for replacement of blood, plasma, fluids, and/or electrolytes. Blood volume depletion should be corrected as fully as possible before phenylephrine is administered. In an emergency, the drug may be used as an adjunct to fluid volume replacement or as a temporary supportive measure to maintain coronary and cerebral artery perfusion until volume replacement therapy can be completed, but phenylephrine must not be used as sole therapy in hypovolemic patients. Additional volume replacement also may be required during or after therapy with the drug, especially if hypotension recurs. Monitoring of central venous pressure or left ventricular filling pressure may be helpful in detecting and treating hypovolemia; in addition, monitoring of central venous or pulmonary arterial diastolic pressure is necessary to avoid overloading the cardiovascular system and precipitating congestive heart failure. Hypoxia and acidosis, which also may reduce the effectiveness of phenylephrine, must be identified and corrected prior to or concurrently with administration of the drug.
For more Drug Warnings (Complete) data for PHENYLEPHRINE (24 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C9H13NO2

167.2

167.095

59-42-7

Phenylephrine hydrochloride;61-76-7

6041

White to light yellow solid powder

1.159 g/cm3

341.1ºC at 760 mmHg

171°C

163.4ºC

-55.5 ° (C=5, 1mol/L HCl)

1.035

3

3

3

12

130

1

CNC[C@@H](C1=CC(=CC=C1)O)O

SONNWYBIRXJNDC-VIFPVBQESA-N

InChI=1S/C9H13NO2/c1-10-6-9(12)7-3-2-4-8(11)5-7/h2-5,9-12H,6H2,1H3/t9-/m0/s1

3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenol

Metasynephrine; Metaoxedrin; Phenylephrine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~299.03 mM)
H2O : ~5 mg/mL (~29.90 mM)

Solubility in Formulation 1: 10 mg/mL (59.81 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with heating and sonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)