(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
The oral bioavailability of phenylephrine is 38%. Clinically significant systemic absorption may occur in ophthalmic formulations, especially at high concentrations and in cases of corneal damage. 86% of the phenylephrine dose is excreted in the urine, of which 16% is unmetabolized drug, 57% is inactive m-hydroxymendal acid, and 8% is inactive sulfate conjugate. The volume of distribution of phenylephrine is 340 liters. The mean clearance of phenylephrine is 2100 mL/min. Phenylephrine is rapidly distributed to peripheral tissues; there is evidence that the drug may be stored in certain organ compartments. The pharmacological action of phenylephrine terminates at least in part through tissue absorption. The extent to which phenylephrine enters the brain appears to be low. Phenylephrine does not appear to be extensively distributed into breast milk. After oral administration, phenylephrine is completely absorbed and undergoes extensive first-pass metabolism in the intestinal wall. The bioavailability of oral phenylephrine is approximately 38% of that of intravenous administration. Due to extensive first-pass metabolism, there is considerable inter-individual variability, and possibly even intra-individual variability, in the oral bioavailability of this drug. Peak serum concentrations occur at 0.75–2 hours after oral administration of phenylephrine (1 or 7.8 mg). Phenylephrine and its metabolites are primarily excreted in the urine. Approximately 80% and 86% of the dose, respectively, are excreted in the urine within 48 hours after oral or intravenous administration, primarily as metabolites. Approximately 2.6% of the oral dose and approximately 16% of the intravenous dose are excreted unchanged in the urine. Fifteen volunteers received either a short-term intravenous infusion of 7-3H-phenylephrine (n=4) or oral administration (10 volunteers, 1 patient undergoing portosystemic shunt). Serum levels of free 3H-phenylephrine were analyzed using ion exchange and thin-layer chromatography, and urinary radioactivity was graded. Since the 3H activity excreted in urine after intravenous and oral administration was almost identical, at 86% and 80% of the dose, respectively, it can be considered that the drug was completely absorbed into the intestine. There was a significant difference in the proportion of free phenylephrine, with 16% of the dose after intravenous administration and 2.6% after oral administration, indicating decreased bioavailability. This was confirmed by comparing the area under the serum curve, showing a bioavailability factor of 0.38. Results in patients undergoing portosystemic shunt surgery were comparable to those in healthy volunteers. Its biological half-life is 2 to 3 hours, comparable to structure-related amine drugs, with a total clearance of 2 L/h and a volume of distribution of 340 L. Metabolites/Metabolites: Phenylephrine is primarily metabolized by monoamine oxidase A, monoamine oxidase B, and SULT1A3. The major metabolite is inactive m-hydroxymandelic acid, followed by sulfate conjugates. Phenylephrine can also be metabolized to phenylephrine glucuronide. Phenylephrine is extensively metabolized in the intestinal wall (first-pass metabolism) and liver. The main metabolic pathways include sulfate conjugation (primarily in the intestinal wall) and oxidative deamination (catalyzed by monoamine oxidase (MAO)). A small amount of glucuronidation also occurs. Fifteen volunteers received short-term intravenous infusions of 7-3H-phenylephrine (n=4) or oral administration (10 volunteers, 1 patient undergoing portosystemic shunt). Serum levels of free 3H-phenylephrine were analyzed using ion exchange and thin-layer chromatography, and urinary radioactivity was graded. After oral administration, it was primarily metabolized to phenolic conjugates, while after intravenous administration, it was primarily metabolized to m-hydroxymandelic acid, again demonstrating that m-hydroxylated amines primarily undergo conjugation reactions during first-pass metabolism.
The known metabolites of phenylephrine include (2S,3S,4S,5R)-3,4,5-trihydroxy-6-[3-[(1R)-1-hydroxy-2-(methylamino)ethyl]phenoxy]oxacyclohexane-2-carboxylic acid.
Biological half-life
The effective half-life of phenylephrine after intravenous injection is 5 minutes, and the elimination half-life is 2.5 hours.
After oral or intravenous injection, the average elimination half-life of phenylephrine is 2-3 hours.

Interactions
In patients pretreated with 2% pilocarpine hydrochloride, the use of 10% phenylephrine hydrochloride solution may cause mydriasis, but to a lesser degree than in patients who have not received miotic treatment. Pilocarpine can prevent or reduce the risk of visual impairment and increased intraocular pressure due to mydriasis in some patients and can be used to accelerate the recovery of mydriasis after ophthalmological examination. Phenylephrine can reduce ciliary injection, conjunctival injection, and accommodative myopia commonly seen with miotic treatment of glaucoma, without affecting the efficacy of glaucoma treatment. Phenylephrine may increase mydriasis when used in combination with cycloplegic anticholinergic drugs (such as atropine sulfate, cyclopentonide hydrochloride, homatropine hydrobromide, or scopolamine hydrobromide), which is clinically significant. Digitalis may increase the sensitivity of the myocardium to the effects of sympathomimetic drugs. Because monoamine oxidase (MAO) inhibitors reduce the metabolism of phenylephrine, pre-administration of MAO inhibitors can enhance the cardiac and pressor effects of phenylephrine. The synergistic effect of oral phenylephrine is stronger than that of parenteral administration because oral administration reduces intestinal metabolism, thereby increasing drug absorption. Patients taking monoamine oxidase inhibitors (MAO inhibitors) should avoid oral phenylephrine. If parenteral administration is necessary in these patients, extreme caution should be exercised, and the initial dose should be very small. Patients taking MAO inhibitors should consult their clinician before initiating rectal phenylephrine therapy. For more complete data on drug interactions of phenylephrine (12 in 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 belongs to the phenylethanolamine class of compounds, with the chemical name (1R)-2-(methylamino)-1-phenylethanol, containing a hydroxyl substituent at the 3-position of the benzene ring. It possesses various pharmacological effects, including acting as an α-adrenergic agonist, cardiotonic, mydriatic, protective agent, vasoconstrictor, sympathomimetic, and nasal decongestant. Phenylephrine belongs to the phenylethanolamine, secondary amine, and phenolic compounds. It is the conjugate base of phenylephrine (1+). Phenylephrine is an α-1-adrenergic receptor agonist used to treat hypotension, mydriasis, and to induce local vasoconstriction. The effects of phenylephrine (or neosynephrine) were first described in the literature in the 1930s. Phenylephrine was approved by the U.S. Food and Drug Administration (FDA) in 1939. Phenylephrine is an α1-adrenergic agonist. The mechanism of action of phenylephrine is as an α1-adrenergic agonist. Phenylephrine is a direct-acting sympathomimetic amine with a chemical structure related to adrenaline and ephedrine, exhibiting potent vasoconstrictive effects. Phenylephrine is a postsynaptic α-adrenergic receptor agonist that causes vasoconstriction, increases systolic/diastolic blood pressure, induces reflex bradycardia, and increases stroke volume. Phenylephrine is an α1-adrenergic agonist and can be used as a mydriatic, nasal decongestant, and cardiotonic. See also: Phenylephrine hydrochloride (salt form); lidocaine; phenylephrine (ingredients)...see more...

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Drug Indications
Phenylephrine is available in various formulations with different indications. Phenylephrine injection is indicated for the treatment of shock or hypotension caused by anesthesia. Ophthalmic preparations are indicated for mydriasis and conjunctival vasoconstriction. Intranasal preparations are used to treat nasal congestion, while topical preparations are used to treat hemorrhoids. Off-label use includes priapism and local vasoconstriction. Mechanism of Action Phenylephrine is an α1-adrenergic agonist that can cause vasoconstriction and mydriasis depending on the route and site of administration. Systemic exposure to phenylephrine can lead to α1-adrenergic receptor activation, thereby increasing systolic and diastolic blood pressure and peripheral vascular resistance. Increased blood pressure can stimulate the vagus nerve, causing reflex bradycardia. Phenylephrine primarily exerts its effects by acting directly on α-adrenergic receptors. At therapeutic doses, it does not significantly excite cardiac β-adrenergic receptors (β1-adrenergic receptors), but these receptors may be significantly activated at higher doses. Phenylephrine does not stimulate β2-adrenergic receptors in the bronchi or peripheral blood vessels. It is believed that the alpha-adrenergic effect stems from the inhibition of adenylate cyclase, thereby inhibiting the production of cyclic adenosine monophosphate (cAMP); while the beta-adrenergic effect stems from the stimulation of adenylate cyclase activity. Phenylephrine can also exert its indirect effects by releasing norepinephrine from its storage sites.

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Therapeutic Uses
Adrenergic alpha agonist; cardiotonic; mydriatic; nasal decongestant; sympathomimetic; vasoconstrictor
Nasal phenylephrine is indicated for relieving nasal congestion caused by the common cold, hay fever, sinusitis, or other upper respiratory tract allergies. /Included in US product label/
Nasal phenylephrine can be used as an adjunct treatment for otitis media by reducing congestion around the opening of the Eustachian tube. /Included in US product label/
Nasal phenylephrine is used to relieve sinus congestion. /Not included in US product label/
For more complete data on the therapeutic uses of phenylephrine (18 types), please visit the HSDB record page.

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Drug Warnings
Because it is unknown whether phenylephrine is excreted in breast milk, breastfeeding women should use this medication with caution.
Administration of phenylephrine to patients during late pregnancy or labor may cause fetal hypoxia and bradycardia by increasing uterine contractions and reducing uterine blood flow. …It is currently unknown whether this medication may cause harm to the fetus when used in pregnant women. Phenylephrine should only be used during pregnancy when clearly necessary.
Ophthalmic phenylephrine may occasionally cause systemic sympathomimetic effects, such as palpitations, tachycardia, premature ventricular contractions, occipital headache, pallor or paleness, tremor or shaking, excessive sweating, and hypertension. There has been one case where a patient developed severe hypertension sufficient to cause subarachnoid hemorrhage after a swab soaked in 10% phenylephrine hydrochloride solution was inserted into the lower palpebral conjunctival sac. Systemic adverse reactions are extremely rare when phenylephrine hydrochloride solution at concentrations of 2.5% or lower is applied topically to the conjunctiva; however, they are more likely to occur when the medication is instilled after corneal epithelial damage (e.g., trauma or instrumentation), or when corneal permeability is increased due to intraocular pressure measurement, inflammation, ocular or adnexal surgery, or the application of local anesthetics, or when there is pre-existing ocular or adnexal disease, or when tear secretion is suppressed (e.g., during anesthesia). Infants are at the highest risk of developing severe hypertension when using 10% phenylephrine hydrochloride solution as eye drops. For patients in shock, vasopressors should not replace the replenishment of blood, plasma, body fluids, and/or electrolytes. Hypovolemia should be corrected as much as possible before administering phenylephrine. In emergency situations, this drug can be used as an adjunct to fluid resuscitation or as a temporary support measure to maintain coronary and cerebral artery perfusion until fluid resuscitation is completed. However, phenylephrine should never be used as the sole treatment for patients with hypovolemia. Additional fluid resuscitation may be required during or after treatment with this drug, especially in cases of recurrent hypotension. Monitoring central venous pressure or left ventricular filling pressure helps detect and treat hypovolemia; furthermore, monitoring central venous pressure or pulmonary artery diastolic pressure is crucial to avoid cardiovascular overload and induction of congestive heart failure. Hypoxemia and acidosis can also reduce the efficacy of phenylephrine, and therefore these conditions must be identified and corrected before or during administration. For more complete data on drug warnings for phenylephrine (24 in total), please visit the HSDB record page. Pharmacodynamics: Phenylephrine is an α1-adrenergic agonist that raises blood pressure, dilates the pupil, and causes local vasoconstriction. The duration of action of ophthalmic phenylephrine preparations is 3–8 hours, while the effective half-life of intravenous injection is 5 minutes, and the elimination half-life is 2.5 hours. Patients using ophthalmic phenylephrine preparations should be informed of the risks of arrhythmias, hypertension, and rebound mydriasis. Patients receiving intravenous formulations should be informed of the risks of bradycardia, allergic reactions, extravasation leading to necrosis or tissue sloughing, and the risks associated with concurrent use of oxytocin-like 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.)