Phenylephrine, sold under the brand namesNeosynephrine andSudafed PE among others, is amedication used as adecongestant for uncomplicatednasal congestion in the form of anasal spray or oral tablet,[5] it may be givenintravenously in cases oflow blood pressure, or used to relievehemorrhoids as asuppository.[12][14] It can also beapplied to the skin.[12][5]
Commonside effects when taken by mouth or injected includenausea,vomiting,headache, andanxiety.[12] Use on hemorrhoids is generally well tolerated.[12] Severe side effects may include aslow heart rate,intestinal ischemia,chest pain,kidney failure, andtissue death at the site of injection.[12][14] It is unclear whether its use duringpregnancy andbreastfeeding is safe.[12] Phenylephrine is aselectiveα1-adrenergic receptoragonist with minimal to noβ-adrenergic receptor agonist activity orinduction of norepinephrine release.[5][8][15] It causesconstriction of botharteries andveins.[12]
Phenylephrine was patented in 1933[16] and came into medical use in 1938.[17] It is available as ageneric medication.[14][18][19] Unlikepseudoephedrine, abuse of phenylephrine is very uncommon.[20] Its effectiveness as an oral nasal decongestant has been questioned.[12][21][22] In 2023, a U.S.Food and Drug Administration (FDA) panel concluded that the drug was ineffective as a nasal decongestant when taken orally, performing no better than placebo.[23] In November 2024, the FDA proposed to remove oral phenylephrine as an active ingredient that can be used in over-the-counter (OTC) monograph drug products for the temporary relief of nasal congestion.[24]
 | The examples and perspective in this sectiondeal primarily with US-centric section and do not represent aworldwide view of the subject. You mayimprove this section, discuss the issue on thetalk page, or create a new section, as appropriate.(January 2024) (Learn how and when to remove this message) |
 | This sectionmay beunbalanced towards certain viewpoints. Please helpimprove it by adding information on neglected viewpoints. Relevant discussion may be found on thetalk page.(July 2024) |
Phenylephrine is used as an alternative topseudoephedrine as a decongestant, the availability of which has been restricted in some countries due to a potential for use in the illicit synthesis ofmethamphetamine.[25] Its efficacy as an oral decongestant has been questioned, with several independent studies finding that it provided no more relief to sinus congestion than a placebo.[26][27][28]
A 2007 meta-analysis concluded that the evidence for its effectiveness is insufficient,[29] though another meta-analysis published shortly thereafter by researchers fromGlaxoSmithKline found the standard 10-mg dose to be more effective than a placebo; however, the fact that GSK markets many products containing phenylephrine has raised some speculation regarding selective publishing and other controversial techniques.[30] A 2007 study byWyeth Consumer Healthcare notes that 7 studies available in 1976 support the efficacy of phenylephrine at a 10 mg dosage.[31] TheFood and Drug Administration withdrew the indication "for the temporary relief of nasal congestion associated with sinusitis" in 2007.[12]
Two studies published in 2009 examined the effects of phenylephrine on symptoms ofallergic rhinitis by exposing people to pollen in a controlled, indoor environment. Neither study was able to distinguish between the effects of phenylephrine and a placebo. Pseudoephedrine andloratadine–montelukast therapy were found to be significantly more effective than both phenylephrine and placebo.[26][27]
Pseudoephedrine was previously much more commonly available in the United States. However, provisions of theCombat Methamphetamine Epidemic Act of 2005 placed restrictions on the sale in the United States of pseudoephedrine products to prevent theclandestine manufacture of methamphetamine. Since 2004, phenylephrine has been increasingly marketed as a substitute for pseudoephedrine; some manufacturers have changed the active ingredients of products to avoid restrictions on sales.[32] Phenylephrine has been off-patent for some time,[when?] and many generic brands are available.[citation needed]
In September 2023, an independent advisory committee to the U.S.Food and Drug Administration (FDA) unanimously agreed that there is insufficient evidence showing that "orally administered phenylephrine is effective as a nasal decongestant".[33] The committee also unanimously believes that this does not need further study. The FDA responded to the committee, stating it would take its advice under advisement.[23][34] In November 2024, the FDA proposed to remove oral phenylephrine as an active ingredient that can be used in over-the-counter (OTC) monograph drug products for the temporary relief of nasal congestion.[24]
Hemorrhoids are caused by swollenveins in therectal area.[35] Phenylephrine can be used topically to prevent symptoms of hemorrhoids. Phenylephrine causes the constriction of vascular smooth muscle and is often used in the treatment of hemorrhoids to narrow the swollen veins and relieve the attendant pain. However, veins contain less vascular smooth muscle in their walls than arteries. Products for treatment may also include substances that will form a protective barrier over the inflamed area, resulting in less pain whenfeces are passed.[36]
Phenylephrine hydrochloride at 0.25% is used as avasoconstrictor insuppository formulations for hemorrhoid treatment.[37]
Phenylephrine is used as an eye drop to dilate the pupil to facilitate visualization of the retina. It is often used in combination withtropicamide as a synergist when tropicamide alone is not sufficient. Narrow-angleglaucoma is acontraindication to phenylephrine use. As amydriatic, it is available in 2.5% and 10%eye drops. Phenylephrine eye drops are applied to the eye after a topical anesthetic is applied.[38]
Phenylephrine has been used as anintracameral injection into the anterior chamber of the eye to arrestintraocular bleeding occurring duringcataract andglaucomasurgery.[39]
Phenylephrine is commonly used as avasopressor to increase the blood pressure in unstable patients withhypotension (low blood pressure), especially resulting fromseptic shock.[40][41] Such use is common insurgery andanesthesia or critical-care practices;[40][41] it is especially useful in counteracting the hypotensive effect ofepidural andspinal anesthesia, as well as the vasodilating effect of bacterial toxins and the inflammatory response insepsis andsystemic inflammatory response syndrome.
Because of itsvasoconstrictive effect, phenylephrine can cause severenecrosis if it infiltrates the surrounding tissues. Because of this, it should be given through a central line if at all possible. Damage may be prevented or mitigated by infiltrating the tissue with the alpha-blockerphentolamine by subcutaneous injection.[42]
In clinical studies, phenylephrine, administeredintravenously, increases blood pressure, decreasescardiac output, increases cerebral blood flow, and decreases cerebral tissue oxygen saturation.[40][41] The decreases in cardiac output, increases in cerebral blood flow, and decreases in cerebral tissue oxygen saturation with phenylephrine are all related to the degree of blood pressure increase.[40] The decrease in cardiac output is primarily due to a decrease inheart rate and a modest decrease instroke volume.[40] The decrease in heart rate is due to activation of thearterial baroreflex, which regulates heart rate in response to changes in blood pressure.[40][41] Because of the decrease in cardiac output, phenylephrine is anegative inotropic agent.[40] Its effects on cardiac output and cerebral oxygenation are unfavorable, and on account of this, the use of phenylephrine in the treatment of intraoperative hypotension is now being recommended against and moved away from in favor of other agents without these adverse effects likeephedrine anddopamine.[40][41]
When taken orally, phenylephrine has a threshold dose of about 50 mg to affect the cardiovascular system, a dose at which the drug decreases heart rate and slightly increases arterial blood pressure.[8] Additionally, anover-the-counter dose of 60 mg produces a slight increase in heart rate with no detectable changes in blood pressure.[8] However, other literature reports that doses over 15 mg affect the cardiovascular system, including increases in blood pressure and decreases in heart rate.[11] Higher doses, like 150 mg, more robustly affect the cardiovascular system.[9]
Phenylephrine has been used in the treatment ofpostural orthostatic tachycardia syndrome (POTS).[43] It has been found to improvevascular resistance, enhance circulatory support, and improve symptoms oforthostatic intolerance in people with the condition.[43] It has been described as particularly effective in people withneuropathic POTS.[43] However, phenylephrine has not been specifically approved for the treatment of POTS, and data on this use are limited.[43] This is also the case with other medications used in the treatment of POTS.[43]
Phenylephrine has been used in the treatment ofpriapism.[44][45]
Phenylephrine is available in the form oforaltablets andsyrups for use as anasal decongestant, as anintravenoussolution to treathypotension, as anophthalmic solution, spray, oreye drop to causepupil dilation, and as acocoa buttersuppository, among other forms.[6][7] It was also previously available as a meteredaerosol forinhalation, but this formulation was discontinued.[6]
Phenylephrine is available both alone and incombination with other drugs.[6][7] These other drugs includeantihistamines likechlorpheniramine,doxylamine,promethazine, andmepyramine (pyrilamine);analgesics likeparacetamol (acetaminophen),ibuprofen,ketorolac, andcodeine;cough suppressants likedextromethorphan;expectorants likeguiafenesin;anticholinergics likecyclopentolate andtropicamide; andβ-adrenergic receptor agonists likeisoprenaline (isoproterenol).[6][7] It is used in combination with antihistamines and analgesics in cough and cold preparations, with anticholinergics in ophthalmic formulations, and with β-adrenergic receptor agonists in inhalational forms.[6][7] Intravenous phenylephrine is always formulated by itself.[6]
Phenylephrine iscontraindicated in people withhypertension,hyperthyroidism, andheart disease due to itsvasoconstrictor effects.[8] Relative contraindications include people withRaynaud's syndrome due to vasoconstriction, those takingmonoamine oxidase inhibitors (MAOIs) due to inhibition of the metabolism of phenylephrine, and people withprostate problems due to potential exacerbation ofurinary retention.[8][46]
Phenylephrine taken orally at indicated doses is usuallywell-tolerated.[11] It may causeside effects such asheadache,reflex bradycardia,excitability,restlessness, andcardiac arrhythmias.[12] At higher than indicated doses, phenylephrine can increaseblood pressure and decreaseheart rate.[11] A 45 mg dose of phenylephrine can increase systolic blood pressure by 20 mmHg.[11] Possibleside effects ofintravenous phenylephrine aredose-dependent and may includebradycardia andreactive hypertension.[11]
The primary side effect of phenylephrine ishigh blood pressure. People with high blood pressure are typically advised to avoid products containing it. Because this medication is asympathomimetic amine withoutβ-adrenergic receptoragonist activity, it does not increase contractility force and output of the cardiac muscle. It may increase blood pressure, resulting in aslow heart rate through stimulation of vascular (likely carotid) baroreceptors. A common side effect during IV administration is reflex bradycardia.[47] The low concentration eye drops do not cause blood pressure changes and the changes with the higher dose drops do not last long.[48]
The cardiovascular effects of phenylephrine may be potentiated in people withhypertension.[11]Hypertensive crisis with phenylephrineeye drops has been reported in people with hypertension.[11] In people with underlyingcardiovascular disease, phenylephrine has been found to increase blood pressure and cause associated impairment in myocardial perfusion.[11] Other reported side effects of phenylephrine have included increased blood pressure,vasoconstriction resulting inworsened orthostatic tolerance,atrial fibrillation followingcoronary artery bypass surgery,decreased cerebral oxygenation, bradycardia in people withspinal cord injury,cardiac arrhythmias,pulmonary edema,myocardial infarction, andmicrovascular occlusion syndrome.[11] Rarely,stroke has been reported with phenylephrine, including in the oral, topical, and intravenous forms.[11]
Due to the increased risk of side effects in people with hypertension, phenylephrine is not suggested for use in this population.[49][8]
Prostatic hyperplasia can also be worsened by use, and chronic use can lead to reboundhyperemia.[50] People with a history of anxiety or panic disorders, or on anticonvulsant medication for epilepsy, should not take this substance. The drug interaction might produce seizures. Some patients have been shown to have an upset stomach, severe abdominal cramping, and vomiting issues connected to taking this drug.[51]
Phenylephrine is pregnancy category C. Due to the lack of studies done in animals and humans, it is unknown whether there is harm to the fetus. Phenylephrine should only be given to pregnant women who have a clear need.[51]
Extended use may causerhinitis medicamentosa, a condition ofreboundnasal congestion.[52]
Phenylephrine is susceptible tometabolism bymonoamine oxidase.[8][11] Because of this,monoamine oxidase inhibitors (MAOIs) can inhibit the metabolism of phenylephrine and increase exposure to the medication.[8][11] Whereas a 45 mg oral dose of phenylephrine alone increasessystolic blood pressure by 20 mmHg, use of this dose in people on MAOIs increases systolic blood pressure by more than 60 mmHg.[11]
Phenylephrine can interact with otheradrenergic drugs, such asbeta blockers likepropranolol,α1-adrenergic receptor antagonists likechlorpromazine,α2-adrenergic receptor agonists likeclonidine,norepinephrine reuptake inhibitors likeatomoxetine andamitriptyline, and MAOIs (which increase norepinephrine levels).[5] It can also interact withcorticosteroids likeprednisone, which sensitize the vasculature to sympathomimetics and augment their vasoconstrictive effects, and withergot alkaloids, which also havevasoconstrictor effects and can have additive or synergistic effects with phenylephrine.[5] In addition, combination of phenylephrine with othersympathomimetic drugs can increasepressor effects and the risk of hemorrhagic stroke.[5] Other drugs that may decrease the effects of phenylephrine may includecalcium channel blockers,ACE inhibitors andbenzodiazepines.[53] Patients taking these medications may need a higher dose of phenylephrine to achieve a comparable increase in blood pressure.[53] Concomitant use of phenylephrine with the preceding agents may necessitate dose adjustments.
Acetaminophen (paracetamol) has been found to increase exposure to oral phenylephrine.[11] It more than doubles phenylephrine'sbioavailability, reduces itsabsorption half-time by 50%, increases phenylephrine levels by approximately 2-fold, and increases peak phenylephrine levels by 4-fold, with substantialinterindividual variability.[11] Phenylephrine is widely formulated with acetaminophen in combination products.[11] The combination may increase the cardiovascular effects of phenylephrine.[11] The mechanism of the interaction between phenylephrine and acetaminophen is unknown, but it has been suggested that it may be due to saturation ofsulfationpathways by acetaminophen that also participates in phenylephrine metabolism.[11]
Phenylephrine is aselectiveagonist of theα1-adrenergic receptor, one of thebiological targets of thecatecholaminehormones andneurotransmittersepinephrine (adrenaline) andnorepinephrine (noradrenaline).[8][5][15] It is afull agonist of the α1-adrenergic receptor in most assessedtissues.[54] The drug has weak, minimal, or no agonist activity at theα2-adrenergic receptor or theβ-adrenergic receptors.[8][5][15] At the β-adrenergic receptors, it is apartial agonist.[54]
Phenylephrine also has relatively little or no activity as anorepinephrine releasing agent.[8][15] As such, it has little activity as an indirectly actingsympathomimetic and non-selective activator ofadrenergic receptors.[8][15] This is in contrast to related sympathomimetics likepseudoephedrine.[8] However, more recent research suggests that phenylephrine may actually be morepotent as a norepinephrine releasing agent than has previously been thought.[55] This might help to explain certain unexpectedpharmacodynamic effects of the drug.[55]
Because of its α1-adrenergic receptor agonism, phenylephrine is a directly acting sympathomimeticvasoconstrictor[8][15] and produces bothvenous andarterialvasoconstriction.[49][5] The termsympathomimetic means that it mimics the actions of epinephrine or norepinephrine.[56]
Phenylephrine works as anasal decongestant by causing local vasoconstriction in the nose.[15] Whereas the related sympathomimetic decongestantpseudoephedrine causes both vasoconstriction and increase ofmucociliary clearance through its non-specific adrenergic activity, phenylephrine's selective α1-adrenergic receptor agonism causes vasoconstriction alone, resulting in a difference in their methods of action.[citation needed]
Phenylephrine is rapidlyabsorbed from thegastrointestinal tract when takenorally.[8] However, its absorption is incomplete and erratic.[9] Because of extensivefirst-pass metabolism, phenylephrine has an oralbioavailability of only about 38% relative tointravenous administration.[8][3][9][10] However, another source has stated that the bioavailability of phenylephrine is poorly documented and may actually be as low as 0.003%.[11] Thetime to peak concentrations is 1.0 to 1.3 hours.[8]
Thesteady-statevolume of distribution of phenylephrine is 340 L.[5]
Phenylephrine does not cross theblood–brain barrier and hence is aperipherally selective drug with nocentral nervous system activity.[40][41][8][15] Its lack of blood-brain barrier permeability is related to itshydroxyl groups and highhydrophilicity.[8][46] The lack of central permeation with phenylephrine is in contrast to certain other related decongestant and sympathomimetic agents likepseudoephedrine,ephedrine, andphenylpropanolamine.[46][8][15]
Phenylephrine ismetabolized in theintestines andliver prior to reaching the systemic circulation when taken orally.[8] It is extensively metabolized during first-pass metabolism due to susceptibility tomonoamine oxidases, similarly toepinephrine.[8][5][3][9] Phenylephrine is metabolized viaoxidativedeamination by bothMAO-A andMAO-B.[5][3][9] In contrast to epinephrine andnorepinephrine, phenylephrine is not acatecholamine, and is not metabolized bycatechol O-methyltransferase (COMT).[15] Besides monoamine oxidase, phenylephrine is also metabolized bysulfation andglucuronidationconjugation.[5][3] Non-oral routes of phenylephrine, likeintranasal,ophthalmic, andparenteral, do not undergo first-pass metabolism in the gastrointestinal tract.[9]
The majormetabolite of phenylephrine ismeta-hydroxymandelic acid, which is inactive.[3][9] Lesser metabolites of phenylephrine includesulfate andglucuronide conjugates, which are also inactive.[3][9]
Unlike phenylephrine, related sympathomimetics with amethyl group at the α carbon (i.e.,amphetamines), likeephedrine,pseudoephedrine,phenylpropanolamine,methoxamine, andmethoxyphenamine, are resistant to degradation by monoamine oxidase.[9]
Phenylephrine is primarilyexcreted inurine.[5][3] It is recovered 86% in urine.[3] The drug is excreted in urine 3 to 16% unchanged, 57% asmeta-hydroxymandelic acid, and 8% assulfateconjugates.[8][3]Glucuronide conjugates constitute a smaller portion of phenylephrine.[9]
Phenylephrine has a relatively shortelimination half-life of 2.0 to 3.0 hours regardless ofroute of administration.[8][5][3][13][9] Its lack of metabolism by COMT is said to be responsible for its much longerduration of action than related agents likenorepinephrine.[15]
Phenylephrine is asubstituted phenethylamine and can also be referred tostructurally as (R)-β,3-dihydroxy-N-methylphenethylamine.[1][57][3] It is closelystructurally related toepinephrine (adrenaline; 3,4,β-trihydroxy-N-methylphenethylamine), differing from it only in the absence of onehydroxyl group on thephenyl ring.[8] It is achiral compound and is used as theenantiopure (R)-stereoisomer.[13][1] Theracemic form has not been formally named or used.[1]
Phenylephrine is theN-methylatedderivative ofnorfenefrine (3,β-dihydroxyphenethylamine).[1] TheracemicN-ethylanalogue isetilefrine (ethylphenephrine).[1]Synephrine (p-synephrine, oxedrine; 4,β-dihydroxyphenethylamine) is apositional isomer of phenylephrine.[56] In contrast to epinephrine andnorepinephrine (noradrenaline; 3,4,β-trihydroxyphenethylamine), phenylephrine is not acatecholamine since it does not have two hydroxyl groups on its phenyl ring.[15] Besides the catecholamines, the chemical structure of phenylephrine somewhat resembles that ofamphetamine (α-methylphenethylamine).[46] However, phenylephrine does not have amethyl group at the αcarbon and hence is not an amphetamine itself.[46]
Phenylephrine is asmall-molecule compound with themolecular formula C9H13NO2 and amolecular weight of 167.205 g/mol.[57][3] It is a highlyhydrophilic compound, with an experimentallog P of -0.3.[58][57][3] Phenylephrine is used medically almost always as thehydrochloridesalt.[2][1] However, thefree base form and thetannate salt have also been used pharmaceutically to a much lesser extent.[2]
Pivenfrine is the 3-pivalateester of phenylephrine and has much greaterlipophilicity in comparison.[1][59]
Phenylephrine was first patented in 1927 and was first introduced for medical use in 1938.[60]
Phenylephrine is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française, while itsUSANTooltip United States Adopted Name andBANMTooltip British Approved Name in the case of thehydrochloridesalt are phenylephrine hydrochloride.[1][2][61][4] Synonyms of phenylephrine include phenephrine, fenefrine,L-m-synephrine, metaoxedrine, neo-oxedrine, mesatonum, neosynephrine, and m-sympatol.[1][2][4] Brand names of phenylephrine include Neosynephrine or Neo-Synephrine and Sudafed PE, among numerous others.[1][2][3][4]
Phenylephrine is available worldwide as aprescription drug in many differentformulations.[4]
PE and PDE are sympathomimetic vasoconstrictors that are closely related to adrenaline in structure, as illustrated in Figure 1. PE differs chemically from adrenaline only in the absence of one hydroxyl group from the benzene ring. [...] PE is a relatively selective α1 agonist. It has weak α2 adrenoceptor agonist activity and low β-agonist activity. Most of the α1 agonist activity is due to a direct action on α receptors with relatively little indirect effect via noradrenaline release [11].
However, efficacy of oral phenylephrine for this use [as a decongestant] has been questioned.
Phenylephrine was not significantly different from placebo in the primary end point.
There were no statistically significant differences between phenylephrine and placebo for any measures.
Second, having multiple polar groups on its molecular structure makes phenylephrine like to interact with water molecules as well. Indeed, the log P (Octanol/Water Partition Coefficient) value of phenylephrine is —0.3, which shows the strong hydrophilicity of this molecule.
Phenylephrine, a synthetic selective alpha-1 adrenergic agonist, first received its patent in 1927 and was introduced for medical use in 1938 [8].
-Phenylephrine_molecule_ball.png)
