Editing Phenylephrine

{{Short description|Decongestant medication}}
{{Use dmy dates|date=May 2022}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Watchedfields = changed
| verifiedrevid = 464201108
| image = Phenylephrine Structural Formula V1.svg
| image_class = skin-invert-image
| alt = Skeletal formula of phenylephrine
| image2 = (R)-Phenylephrine molecule ball.png
| alt2 = Ball-and-stick model of the phenylephrine molecule

<!-- Clinical data -->| pronounce = {{IPAc-en|ˌ|f|ɛ|n|əl|ˈ|ɛ|f|r|iː|n|,_|f|iː|-|,_|-|ɪ|n|audio=LL-Q1860 (eng)-Naomi Persephone Amethyst (NaomiAmethyst)-phenylephrine.wav}}
| tradename = Neosynephrine, Sudafed PE, others<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="DrugBank" /><ref name="Drugs.com-International" />
| Drugs.com = {{drugs.com|monograph|phenylephrine}}
| MedlinePlus = 
| licence_EU = yes
| DailyMedID = Phenylephrine
| licence_US = 
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment = 
| pregnancy_category = 
| routes_of_administration = [[By mouth]], [[intranasal]], [[Ophthalmic drug administration|ophthalmic]], [[intravenous therapy|intravenous]], [[intramuscular injection|intramuscular]], [[rectal administration|rectal]]<ref name="RichardsLopezMaani2023" /><ref name="Drugs@FDA" /><ref name="DailyMed" />
| class = [[Alpha-adrenergic agonist#α1 agonist|α<sub>1</sub>-adrenergic receptor agonist]]; [[vasopressor]]
| ATCvet = 
| ATC_prefix = C01 <!-- scheduled to be C05AX06 in 2024 -->
| ATC_suffix = CA06
| ATC_supplemental = {{ATC|R01|AA04}}, {{ATC|R01|AB01}} (combinations), {{ATC|R01|BA03}}, {{ATC|S01|FB01}}, {{ATC|S01|GA05}}, {{ATC|C05|AX06}}

<!-- Legal status -->| legal_AU = S2
| legal_AU_comment = 
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment = 
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = GSL
| legal_UK_comment = 
| legal_US = OTC
| legal_US_comment = /{{nbsp}}Rx-only
| legal_EU = 
| legal_EU_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment = 
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->| bioavailability = [[Oral administration|Oral]]: conflicting—38%<ref name="Eccles2007" /><ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" /><ref name="Medsafe2004" /> or 0.003%<ref name="AtkinsonPottsAnderson2015" />
| protein_bound = 95%{{Citation needed|date=August 2024}}
| metabolism = [[Liver]] and [[intestine]]s (via [[oxidative deamination]] by [[MAO-A]] and [[MAO-B]]; [[sulfation]]; [[glucuronidation]])<ref name="RichardsLopezMaani2023" /><ref name="Eccles2007" /><ref name="DrugBank" /><ref name="AtkinsonPottsAnderson2015" /><ref name="ChuaBenrimojTriggs1989" />
| metabolites = • [https://pubchem.ncbi.nlm.nih.gov/compound/3-Hydroxymandelic-acid ''meta''-Hydroxymandelic acid]<ref name="ChuaBenrimojTriggs1989" /><ref name="DrugBank" /><br />• [[Sulfate]] [[conjugation (biochemistry)|conjugate]]s<ref name="ChuaBenrimojTriggs1989" /><ref name="DrugBank" /><br />• [[Glucuronide]] [[conjugation (biochemistry)|conjugates]]<ref name="ChuaBenrimojTriggs1989" />
| onset = IV: Very rapid<ref name=AHFS2022/><br />Oral: 15–20{{nbsp}}min<ref name=AHFS2022/><ref name="ChuaBenrimojTriggs1989" /><br />Intranasal: <2{{nbsp}}min<ref name="ChuaBenrimojTriggs1989" /><br />Eye drop: <30{{nbsp}}min<ref name="ChuaBenrimojTriggs1989" />
| elimination_half-life = 2–3{{nbsp}}hours<ref name="Eccles2007" /><ref name="RichardsLopezMaani2023" /><ref name="DrugBank" /><ref name="KanferDowseVuma1993" />
| duration_of_action = IV: 20 min–5 h<ref name=AHFS2022/><ref name="ChuaBenrimojTriggs1989" /><br />Oral: 2–4{{nbsp}}h<ref name=AHFS2022/><ref name="ChuaBenrimojTriggs1989" /><br />Intranasal: 0.5–4{{nbsp}}h<ref name="ChuaBenrimojTriggs1989" /><br />Eye drop: 3–7{{nbsp}}h<ref name="ChuaBenrimojTriggs1989" />
| excretion = [[Urine]]: 86% (3–16% unchanged)<ref name="RichardsLopezMaani2023" /><ref name="Eccles2007" /><ref name="DrugBank" />

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 59-42-7
| CAS_number2 = 61-76-7
| CAS_supplemental = 
| PubChem = 6041
| IUPHAR_ligand = 485
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00388
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5818
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1WS297W6MV
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08365
| KEGG2 = D00511
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8093
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1215
| NIAID_ChemDB = 
| PDB_ligand = 
| synonyms = Phenephrine; Fenefrine; <small>L</small>-''m''-Synephrine; Metaoxedrine; Neo-Oxedrine; Mesatonum; Neosynephrine; Adrianol; (''R'')-β,3-Dihydroxy-''N''-methylphenethylamine<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com-International" />

<!-- Chemical data -->| IUPAC_name = 3-[(1''R'')-1-Hydroxy-2-(methylamino)ethyl]phenol
| C = 9
| H = 13
| N = 1
| O = 2
| SMILES = O[C@H](c1cc(O)ccc1)CNC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H13NO2/c1-10-6-9(12)7-3-2-4-8(11)5-7/h2-5,9-12H,6H2,1H3/t9-/m0/s1
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = SONNWYBIRXJNDC-VIFPVBQESA-N
}}
<!-- Definition and medical uses -->

'''Phenylephrine''', sold under the brand names '''Neosynephrine''' and '''Sudafed PE''' among others, is a [[medication]] used as a [[decongestant]] for uncomplicated [[nasal congestion]] in the form of a [[nasal spray]] or oral tablet,<ref name="RichardsLopezMaani2023">{{cite book | vauthors = Richards E, Lopez MJ, Maani CV |chapter = Phenylephrine |date=2023 | chapter-url = http://www.ncbi.nlm.nih.gov/books/NBK534801/ | title = StatPearls |access-date=2023-04-27 |place=Treasure Island, Florida |publisher=StatPearls Publishing |pmid=30521222 }}</ref> to [[mydriasis|dilate the pupil]], to increase [[blood pressure]] given [[intravenous therapy|intravenously]] in cases of [[hypotension|low blood pressure]], and to relieve [[hemorrhoids]] as a [[suppository]].<ref name="AHFS2022">{{cite web |date=2 March 2022 |title=Phenylephrine Monograph for Professionals |url=https://www.drugs.com/monograph/phenylephrine.html |access-date=9 May 2022 |website=Drugs.com |publisher=AHFS |quote=However, efficacy of oral phenylephrine for this use [as a decongestant] has been questioned.}}</ref><ref name="BNF76" /> It can also be [[transdermal administration|applied to the skin]].<ref name="AHFS2022" /><ref name="RichardsLopezMaani2023" />

<!-- Side effects and mechanism -->
Common [[side effect]]s when taken by mouth or injected include [[nausea]], [[vomiting]], [[headache]], and [[anxiety]].<ref name=AHFS2022/> Use on hemorrhoids is generally well tolerated.<ref name=AHFS2022/> Severe side effects may include a [[bradycardia|slow heart rate]], [[intestinal ischemia]], [[angina|chest pain]], [[kidney failure]], and [[tissue death]] at the site of injection.<ref name=AHFS2022/><ref name=BNF76/> It is unclear whether its use during [[pregnancy]] and [[breastfeeding]] is safe.<ref name=AHFS2022/> Phenylephrine is a [[binding selectivity|selective]] [[alpha-1 adrenergic receptor|α<sub>1</sub>-adrenergic receptor]] [[agonist]] with minimal to no [[beta-adrenergic receptor|β-adrenergic receptor]] agonist activity or [[norepinephrine releasing agent|induction of norepinephrine release]].<ref name="RichardsLopezMaani2023" /><ref name="Eccles2007" /><ref name="ODonnell1995" /> It causes [[vasoconstriction|constriction]] of both [[arteries]] and [[veins]].<ref name=AHFS2022/>

<!-- History, society, and culture -->
Phenylephrine was patented in 1933<ref>{{US Patent|1932347}}, application 1928, expired 1950</ref> and came into medical use in 1938.<ref name=Fis2006>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=541|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA541}}</ref> It is available as a [[generic medication]].<ref name="BNF76">{{Cite book |url=https://books.google.com/books?id=EPFomgEACAAJ |title=BNF 76 : September 2018 - March 2019 | publisher = British Medical Association, Royal Pharmaceutical Society of Great Britain | author = Joint Formulary Committee |year=2018 |isbn=9780857113382 |location=London |pages=188–189 |oclc=1021215075}}</ref><ref>{{cite web | title=Competitive Generic Therapy Approvals | website=U.S. [[Food and Drug Administration]] (FDA) | date=29 June 2023 | url=https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | access-date=29 June 2023 | archive-date=29 June 2023 | archive-url=https://web.archive.org/web/20230629233651/https://www.fda.gov/drugs/generic-drugs/competitive-generic-therapy-approvals | url-status=dead }}</ref><ref>{{cite web | title=First Generic Drug Approvals 2023 | website=U.S. [[Food and Drug Administration]] (FDA) | date=30 May 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003621/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref> Unlike [[pseudoephedrine]], abuse of phenylephrine is very uncommon.<ref>{{cite web |title=Max Strength Decongestant Tablets |url=http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con014437.pdf |url-status=dead |archive-url=https://web.archive.org/web/20190819052429/http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con014437.pdf |archive-date=19 August 2019 |access-date=10 January 2019 |website=www.mhra.gov.uk |page=10}}</ref> Its effectiveness as an oral nasal decongestant has been questioned.<ref name="AHFS2022" /><ref name="Hatton2022">{{cite journal |vauthors=Hatton RC, Hendeles L |date=March 2022 |title=Why Is Oral Phenylephrine on the Market After Compelling Evidence of Its Ineffectiveness as a Decongestant? |journal=Ann Pharmacother |volume=56 |issue=11 |pages=1275–1278 |doi=10.1177/10600280221081526 |pmid=35337187 |s2cid=247712448}}</ref><ref name="Lowe2022">{{cite journal |vauthors=Lowe D |date=March 2022 |title=The Uselessness of Phenylephrine |url=https://www.science.org/content/blog-post/uselessness-phenylephrine |journal=Science |type=blog}}</ref> 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.<ref name="christensen23" /> 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.<ref name="FDA PR 20241107">{{cite press release | title=FDA Proposes Ending Use of Oral Phenylephrine as OTC Monograph Nasal Decongestant Active Ingredient After Extensive Review | website=U.S. [[Food and Drug Administration]] (FDA) | date=7 November 2024 | url=https://www.fda.gov/news-events/press-announcements/fda-proposes-ending-use-oral-phenylephrine-otc-monograph-nasal-decongestant-active-ingredient-after | archive-url=https://web.archive.org/web/20241107144040/https://www.fda.gov/news-events/press-announcements/fda-proposes-ending-use-oral-phenylephrine-otc-monograph-nasal-decongestant-active-ingredient-after | url-status=dead | archive-date=7 November 2024 | access-date=10 November 2024}}</ref>

== Medical uses ==

=== Decongestant ===
{{Globalize|section|US-centric section|date=January 2024}}
{{Unbalanced|section|reason=|date=July 2024}}

Phenylephrine is used as an alternative to [[pseudoephedrine]] as a decongestant, whose availability has been restricted in some countries due to a potential for use in the illicit synthesis of [[methamphetamine]].<ref name="Presley_2018">{{cite journal | vauthors = Presley B, Bianchi B, Coleman J, Diamond F, McNally G | title = Efficiency of extraction and conversion of pseudoephedrine to methamphetamine from tamper-resistant and non-tamper-resistant formulations | journal = Journal of Pharmaceutical and Biomedical Analysis | volume = 156 | pages = 16–22 | date = July 2018 | pmid = 29684907 | doi = 10.1016/j.jpba.2018.04.016 | s2cid = 13660478 | doi-access = free }}</ref> 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.<ref name="danzig09">{{cite journal | vauthors = Horak F, Zieglmayer P, Zieglmayer R, Lemell P, Yao R, Staudinger H, Danzig M | title = A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber | journal = Annals of Allergy, Asthma & Immunology | volume = 102 | issue = 2 | pages = 116–20 | date = February 2009 | pmid = 19230461 | doi = 10.1016/S1081-1206(10)60240-2 | publication-date = February 2009 |quote = Phenylephrine was not significantly different from placebo in the primary end point.}}</ref><ref name="yao09">{{cite journal | vauthors = Day JH, Briscoe MP, Ratz JD, Danzig M, Yao R | title = Efficacy of loratadine-montelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit | journal = Annals of Allergy, Asthma & Immunology | volume = 102 | issue = 4 | pages = 328–38 | date = April 2009 | pmid = 19441605 | doi = 10.1016/S1081-1206(10)60339-0 |quote = There were no statistically significant differences between phenylephrine and placebo for any measures.}}</ref><ref name="Hendeles2006">{{cite journal | vauthors = Hendeles L, Hatton RC | title = Oral phenylephrine: an ineffective replacement for pseudoephedrine? | journal = The Journal of Allergy and Clinical Immunology | volume = 118 | issue = 1 | pages = 279–80 | date = July 2006 | pmid = 16815167 | doi = 10.1016/j.jaci.2006.03.002 | doi-access = free }}</ref>

A 2007 meta-analysis concluded that the evidence for its effectiveness is insufficient,<ref name="Annals">{{cite journal | vauthors = Hatton RC, Winterstein AG, McKelvey RP, Shuster J, Hendeles L | title = Efficacy and safety of oral phenylephrine: systematic review and meta-analysis | journal = The Annals of Pharmacotherapy | volume = 41 | issue = 3 | pages = 381–90 | date = March 2007 | pmid = 17264159 | doi = 10.1345/aph.1H679 | s2cid = 25627664 | url = http://www.theannals.com/cgi/content/abstract/aph.1H679v1 | format = abstract | archive-url = https://web.archive.org/web/20070227143703/http://www.theannals.com/cgi/content/abstract/aph.1H679v1 | url-status = dead | archive-date = 27 February 2007 | url-access = subscription }}(published online Jan 2007)</ref> though another meta-analysis published shortly thereafter by researchers from [[GlaxoSmithKline]] 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.<ref name="GSK">{{cite journal | vauthors = Kollar C, Schneider H, Waksman J, Krusinska E | title = Meta-analysis of the efficacy of a single dose of phenylephrine 10 mg compared with placebo in adults with acute nasal congestion due to the common cold | journal = Clinical Therapeutics | volume = 29 | issue = 6 | pages = 1057–70 | date = June 2007 | pmid = 17692721 | doi = 10.1016/j.clinthera.2007.05.021 }}</ref> A 2007 study by [[Wyeth Consumer Healthcare]] notes that 7 studies available in 1976 support the efficacy of phenylephrine at a 10&nbsp;mg dosage.<ref name="Desjardins2007">{{cite journal | vauthors = Desjardins PJ, Berlin RG | title = Efficacy of phenylephrine | journal = British Journal of Clinical Pharmacology | volume = 64 | issue = 4 | pages = 555–6; author reply 557 | date = October 2007 | pmid = 17610531 | pmc = 2048561 | doi = 10.1111/j.1365-2125.2007.02935.x }}</ref> The [[Food and Drug Administration]] withdrew the indication "for the temporary relief of nasal congestion associated with sinusitis" in 2007.<ref name=AHFS2022/>

Two studies published in 2009, examined the effects of phenylephrine on symptoms of [[allergic rhinitis]] by exposing people to pollen in a controlled, indoor environment. Neither study was able to distinguish between the effects of phenylephrine or a placebo. Pseudoephedrine and [[loratadine]]–[[montelukast]] therapy were found to be significantly more effective than both phenylephrine and placebo.<ref name="danzig09"/><ref name="yao09"/>

Pseudoephedrine was previously much more commonly available in the United States.  However, provisions of the [[Combat Methamphetamine Epidemic Act of 2005]] placed restrictions on the sale in the United States of pseudoephedrine products to prevent the [[clandestine chemistry|clandestine 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.<ref name="HeraldTribune">{{cite news|date=30 January 2007|title=All stuffed up: Reformulated cold medicines might not be able to do the job|newspaper=[[Sarasota Herald-Tribune]]|url=http://www.heraldtribune.com/apps/pbcs.dll/article?AID=/FP/20070130/HEALTHMATTERS/70129001/1025/NEWS06|url-status=dead|access-date=25 April 2023|archive-url=https://web.archive.org/web/20070301095838/http://www.heraldtribune.com/apps/pbcs.dll/article?AID=%2FFP%2F20070130%2FHEALTHMATTERS%2F70129001%2F1025%2FNEWS06|archive-date=1 March 2007|vauthors= Hillenmeyer K}}</ref> Phenylephrine has been off-patent for some time,{{when|date=April 2024}} and many generic brands are available.{{Citation needed|date=June 2020}}

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".<ref>{{cite web | title=FDA clarifies results of recent AC meeting on oral phenylephrine | website=U.S. [[Food and Drug Administration]] (FDA) | date=14 September 2023 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-results-recent-advisory-committee-meeting-oral-phenylephrine | archive-url=https://web.archive.org/web/20230914174151/https://www.fda.gov/drugs/drug-safety-and-availability/fda-clarifies-results-recent-advisory-committee-meeting-oral-phenylephrine | url-status=dead | archive-date=14 September 2023 | access-date=14 September 2023}}</ref> 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.<ref name="christensen23">{{cite news | vauthors = Christensen J |date=12 September 2023 |title=Popular OTC medicines for colds and allergies don't work, FDA panel says |work=CNN |url=https://www.cnn.com/2023/09/12/health/phenylephrine-tablets-ineffective-fda-panel-says/index.html |access-date=12 September 2023}}</ref><ref>{{Cite web | vauthors = Constantino AK |date=2023-09-12 |title=Decongestant found in many cold, allergy medicines doesn't actually work, FDA advisors say |url=https://www.cnbc.com/2023/09/12/decongestant-phenylephrine-ineffective.html |access-date=2023-09-12 |website=CNBC }}</ref> 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.<ref name="FDA PR 20241107" />

=== Hemorrhoids ===
[[Hemorrhoids]] are caused by swollen [[veins]] in the [[rectal]] area.<ref>{{cite web | url = http://www.mayoclinic.org/diseases-conditions/hemorrhoids/basics/definition/con-20029852 | title = Hemorrhoids | publisher = Mayo Clinic }}</ref> 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 when [[feces]] are passed.<ref>{{cite web | url = https://www.webmd.com/drugs/2/drug-76444/phenylephrine-rectal/details |title = Phenylephrine HCl Suppository | work = WebMD | access-date = 4 April 2015 }}</ref>

Phenylephrine hydrochloride at 0.25% is used as a [[vasoconstriction|vasoconstrictor]] in [[suppository]] formulations for hemorrhoid treatment.<ref name="Suppository-Label">{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a23ded81-78ba-c199-a8f0-aaf360b216ff | work = DailyMed | title = Preparation H – cocoa butter and phenylephrine hydrochloride suppository | publisher = U.S. National Institutes of Health |access-date=4 April 2015}}</ref>

=== Pupil dilation ===
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Phenylephrine is used as an eye drop to dilate the pupil to facilitate visualization of the retina. It is often used in combination with [[tropicamide]] as a synergist when tropicamide alone is not sufficient. Narrow-angle [[glaucoma]] is a [[contraindication]] to phenylephrine use. As a [[mydriasis|mydriatic]], it is available in 2.5% and 10% [[eye drop]]s. Phenylephrine eye drops are applied to the eye after a topical anesthetic is applied.<ref>{{cite web | title = Phenylephrine Hydrochloride Ophthalmic Solution, USP 2.5% — Sterile | url = http://akorn.com/documents/catalog/sell_sheets/17478-205-10.pdf | archive-url = https://web.archive.org/web/20160303234455/http://akorn.com/documents/catalog/sell_sheets/17478-205-10.pdf | archive-date = 3 March 2016 | url-status = dead | publisher = Akorn }}</ref>

=== Intraocular bleeding ===
Phenylephrine has been used as an [[intracameral injection]] into the anterior chamber of the eye to arrest [[intraocular hemorrhage|intraocular bleeding]] occurring during [[cataract]] and [[glaucoma]] [[eye surgery|surgery]].<ref>{{cite journal | vauthors = Bizrah M, Corbett MC | title = Intracameral Phenylephrine to Arrest Intraoperative Intraocular Bleeding: A New Technique | journal = Ophthalmology and Therapy | volume = 8 | issue = 1 | pages = 137–141 | date = March 2019 | pmid = 30771215 | pmc = 6393249 | doi = 10.1007/s40123-019-0165-y }}</ref>

=== Low blood pressure ===
Phenylephrine is commonly used as a [[vasopressor]] to increase the blood pressure in unstable patients with [[hypotension]] (low blood pressure), especially resulting from [[septic shock]].<ref name="MengSunZhao2024" /><ref name="LarsonAndersonThomson2021">{{cite journal | vauthors = Larson S, Anderson L, Thomson S | title = Effect of phenylephrine on cerebral oxygen saturation and cardiac output in adults when used to treat intraoperative hypotension: a systematic review | journal = JBI Evid Synth | volume = 19 | issue = 1 | pages = 34–58 | date = January 2021 | pmid = 32941358 | doi = 10.11124/JBISRIR-D-19-00352 | url = }}</ref> Such use is common in [[surgery]] and [[anesthesia]] or critical-care practices;<ref name="MengSunZhao2024" /><ref name="LarsonAndersonThomson2021" /> it is especially useful in counteracting the hypotensive effect of [[epidural]] and [[spinal anesthesia]], as well as the vasodilating effect of bacterial toxins and the inflammatory response in [[sepsis]] and [[systemic inflammatory response syndrome]].

Because of its [[vasoconstriction|vasoconstrictive]] effect, phenylephrine can cause severe [[necrosis]] 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-blocker [[phentolamine]] by subcutaneous injection.<ref name="Cooper2008">{{cite journal | vauthors = Cooper BE | title = Review and update on inotropes and vasopressors | journal = AACN Advanced Critical Care | volume = 19 | issue = 1 | pages = 5–13; quiz 14–15 | date = 2008 | pmid = 18418098 | doi = 10.1097/01.AACN.0000310743.32298.1d | s2cid = 39192378 }}</ref>

In clinical studies, phenylephrine, administered [[intravenous administration|intravenously]], increases blood pressure, decreases [[cardiac output]], increases cerebral blood flow, and decreases cerebral tissue oxygen saturation.<ref name="MengSunZhao2024">{{cite journal | vauthors = Meng L, Sun Y, Zhao X, Meng DM, Liu Z, Adams DC, McDonagh DL, Rasmussen M | title = Effects of phenylephrine on systemic and cerebral circulations in humans: a systematic review with mechanistic explanations | journal = Anaesthesia | volume = 79 | issue = 1 | pages = 71–85 | date = January 2024 | pmid = 37948131 | doi = 10.1111/anae.16172 | url = | doi-access = free }}</ref><ref name="LarsonAndersonThomson2021" /> 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.<ref name="MengSunZhao2024" /> The decrease in cardiac output is primarily due to a decrease in [[heart rate]] and a modest decrease in [[stroke volume]].<ref name="MengSunZhao2024" /> The decrease in heart rate is due to activation of the [[baroreflex|arterial baroreflex]], which regulates heart rate in response to changes in blood pressure.<ref name="MengSunZhao2024" /><ref name="LarsonAndersonThomson2021" /> Because of the decrease in cardiac output, phenylephrine is a [[Inotrope#Negative inotropic agents|negative inotropic agent]].<ref name="MengSunZhao2024" /> 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 like [[ephedrine]] and [[dopamine]].<ref name="MengSunZhao2024" /><ref name="LarsonAndersonThomson2021" />

When taken orally, phenylephrine has a threshold dose of about 50{{nbsp}}mg to affect the cardiovascular system, a dose at which the drug decreases heart rate and slightly increases arterial blood pressure.<ref name="Eccles2007" /> Additionally, an [[over-the-counter drug|over-the-counter]] dose of 60{{nbsp}}mg produces a slight increase in heart rate with no detectable changes in blood pressure.<ref name="Eccles2007" /> However, other literature reports that doses over 15{{nbsp}}mg affect the cardiovascular system, including increases in blood pressure and decreases in heart rate.<ref name="AtkinsonPottsAnderson2015" /> Higher doses, like 150{{nbsp}}mg, more robustly affect the cardiovascular system.<ref name="ChuaBenrimojTriggs1989" />

===Other uses===
Phenylephrine has been used in the treatment of [[postural orthostatic tachycardia syndrome]] (POTS).<ref name="LyongaNogongeNyange2024">{{cite journal | vauthors = Lyonga Ngonge A, Nyange C, Ghali JK | title = Novel pharmacotherapeutic options for the treatment of postural orthostatic tachycardia syndrome | journal = Expert Opin Pharmacother | volume = 25 | issue = 2 | pages = 181–188 | date = February 2024 | pmid = 38465412 | doi = 10.1080/14656566.2024.2319224 | url = }}</ref> It has been found to improve [[vascular resistance]], enhance circulatory support, and improve symptoms of [[orthostatic intolerance]] in people with the condition.<ref name="LyongaNogongeNyange2024" /> It has been described as particularly effective in people with [[neuropathy|neuropathic]] POTS.<ref name="LyongaNogongeNyange2024" /> However, phenylephrine has not been specifically approved for the treatment of POTS and data on this use are limited.<ref name="LyongaNogongeNyange2024" /> This is also the case with other medications used in the treatment of POTS.<ref name="LyongaNogongeNyange2024" />

Phenylephrine has been used in the treatment of [[priapism]].<ref name="JiangChristakosFam2014">{{cite journal | vauthors = Jiang P, Christakos A, Fam M, Sadeghi-Nejad H | title = Prophylactic phenylephrine for iatrogenic priapism: a pilot study with Peyronie's patients | journal = Korean J Urol | volume = 55 | issue = 10 | pages = 665–669 | date = October 2014 | pmid = 25324950 | pmc = 4198766 | doi = 10.4111/kju.2014.55.10.665 | url = }}</ref><ref name="MartinCocchio2016">{{cite journal | vauthors = Martin C, Cocchio C | title = Effect of phenylephrine and terbutaline on ischemic priapism: a retrospective review | journal = Am J Emerg Med | volume = 34 | issue = 2 | pages = 222–224 | date = February 2016 | pmid = 26597497 | doi = 10.1016/j.ajem.2015.10.029 | url = }}</ref>

===Available forms===
Phenylephrine is available in the form of [[oral administration|oral]] [[tablet (pharmacy)|tablet]]s and [[syrup]]s for use as a [[nasal decongestant]], as an [[intravenous]] [[solution (chemistry)|solution]] to treat [[hypotension]], as an [[ophthalmology|ophthalmic]] solution, spray, or [[eye drop]] to cause [[pupil dilation]], and as a [[cocoa butter]] [[suppository]], among other forms.<ref name="Drugs@FDA">{{cite web | title=Drugs@FDA: FDA-Approved Drugs | website=accessdata.fda.gov | publisher = Food and Drug Administration | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | archive-url=https://web.archive.org/web/20161104020633/http://www.accessdata.fda.gov/scripts/cder/daf/index.cfm | url-status=dead | archive-date=4 November 2016 | access-date=21 July 2024}}</ref><ref name="DailyMed">{{cite web | title=Search Results for phenylephrine | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=phenylephrine&pagesize=200&page=1 | access-date=21 July 2024}}</ref> It was also previously available as a metered [[aerosol]] for [[inhalational administration|inhalation]], but this formulation was discontinued.<ref name="Drugs@FDA" />

Phenylephrine is available both alone and in [[combination drug|combination]] with other drugs.<ref name="Drugs@FDA" /><ref name="DailyMed" /> These other drugs include [[antihistamine]]s like [[chlorpheniramine]], [[doxylamine]], [[promethazine]], and [[mepyramine]] (pyrilamine); [[analgesic]]s like [[paracetamol]] (acetaminophen), [[ibuprofen]], [[ketorolac]], and [[codeine]]; [[cough suppressant]]s like [[dextromethorphan]]; [[expectorant]]s like [[guiafenesin]]; [[anticholinergic]]s like [[cyclopentolate]] and [[tropicamide]]; and [[beta agonist|β-adrenergic receptor agonist]]s like [[isoprenaline]] (isoproterenol).<ref name="Drugs@FDA" /><ref name="DailyMed" /> 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.<ref name="Drugs@FDA" /><ref name="DailyMed" /> Intravenous phenylephrine is always formulated by itself.<ref name="Drugs@FDA" />

==Contraindications==
Phenylephrine is [[contraindication|contraindicated]] in people with [[hypertension]], [[hyperthyroidism]], and [[heart disease]] due to its [[vasoconstriction|vasoconstrictor]] effects.<ref name="Eccles2007" /> Relative contraindications include people with [[Raynaud's syndrome]] due to vasoconstriction, those taking [[monoamine oxidase inhibitor]]s (MAOIs) due to inhibition of the metabolism of phenylephrine, and people with [[prostate]] problems due to potential exacerbation of [[urinary retention]].<ref name="Eccles2007" /><ref name="JohnsonHricik1993" />

== Side effects ==
Phenylephrine taken orally at indicated doses is usually [[tolerability|well-tolerated]].<ref name="AtkinsonPottsAnderson2015" /> It may cause [[side effect]]s such as [[headache]], [[reflex bradycardia]], [[stimulation|excitability]], [[psychomotor agitation|restlessness]], and [[cardiac arrhythmia]]s.<ref name=AHFS2022/> At higher than indicated doses, phenylephrine can increase [[blood pressure]] and decrease [[heart rate]].<ref name="AtkinsonPottsAnderson2015" /> A 45{{nbsp}}mg dose of phenylephrine can increase systolic blood pressure by 20{{nbsp}}mmHg.<ref name="AtkinsonPottsAnderson2015" /> Possible [[side effect]]s of [[intravenous administration|intravenous]] phenylephrine are [[dose dependency|dose-dependent]] and may include [[bradycardia]] and [[hypertension|reactive hypertension]].<ref name="AtkinsonPottsAnderson2015" />

=== Heart ===
The primary side effect of phenylephrine is [[hypertension|high blood pressure]]. People with high blood pressure are typically advised to avoid products containing it. Because this medication is a [[sympathomimetic]] amine without [[β-adrenergic receptor]] [[agonist]] activity, it does not increase contractility force and output of the cardiac muscle. It may increase blood pressure resulting in a [[reflex bradycardia|slow heart rate]] through stimulation of vascular (likely carotid) baroreceptors. A common side effect during IV administration is reflex bradycardia.<ref>{{cite web | url = http://reference.medscape.com/drug/vazculep-phenylephrine-342444 | title = Phenylephrine (Rx) | work = Medscape | access-date = 4 April 2015}}</ref> The low concentration eye drops do not cause blood pressure changes and the changes with the higher dose drops do not last long.<ref name="StavertMcGuinessHarper2015">{{cite journal | vauthors = Stavert B, McGuinness MB, Harper CA, Guymer RH, Finger RP | title = Cardiovascular Adverse Effects of Phenylephrine Eyedrops: A Systematic Review and Meta-analysis | journal = JAMA Ophthalmology | volume = 133 | issue = 6 | pages = 647–652 | date = June 2015 | pmid = 25789577 | doi = 10.1001/jamaophthalmol.2015.0325 | doi-access = free }}</ref>

The cardiovascular effects of phenylephrine may be potentiated in people with [[hypertension]].<ref name="AtkinsonPottsAnderson2015" /> [[Hypertensive crisis]] with phenylephrine [[eye drop]]s has been reported in people with hypertension.<ref name="AtkinsonPottsAnderson2015" /> In people with underlying [[cardiovascular disease]], phenylephrine has been found to increase blood pressure and cause associated impairment in myocardial perfusion.<ref name="AtkinsonPottsAnderson2015" /> Other reported side effects of phenylephrine have included increased blood pressure, [[vasoconstriction]] resulting in [[orthostatic hypotension|worsened orthostatic tolerance]], [[atrial fibrillation]] following [[coronary artery bypass surgery]], [[cerebral hypoxia|decreased cerebral oxygenation]], bradycardia in people with [[spinal cord injury]], [[cardiac arrhythmia]]s, [[pulmonary edema]], [[myocardial infarction]], and [[microvascular occlusion|microvascular occlusion syndrome]].<ref name="AtkinsonPottsAnderson2015" /> Rarely, [[stroke]] has been reported with phenylephrine, including in the oral, topical, and intravenous forms.<ref name="AtkinsonPottsAnderson2015" />

Due to the increased risk of side effects in people with hypertension, phenylephrine is not suggested for use in this population.<ref name="IV-Label-1" /><ref name="Eccles2007" />

===Others===
[[Prostatic hyperplasia]] can also be worsened by use, and chronic use can lead to rebound [[hyperemia]].<ref name=pharmnemonics>{{Cite book | vauthors = Shen H |title=Illustrated Pharmacology Memory Cards: PharMnemonics|year=2008|publisher=Minireview|isbn=978-1-59541-101-3|page=3}}</ref> 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.<ref name="IV-Label-2">{{cite web | title = Phenylephrine Hydrochloride injection, for intravenous use | url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203826s000lbl.pdf | archive-url = https://web.archive.org/web/20141103082217/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203826s000lbl.pdf | url-status = dead | archive-date = 3 November 2014 | publisher = U.S. Food and Drug Administration }}</ref>

Phenylephrine is pregnancy category C. Due to the lack of studies done in animals and in humans, it is not known whether there is harm to the fetus. Phenylephrine should only be given to pregnant women who have a clear need.<ref name="IV-Label-2"/>

Extended use may cause [[rhinitis medicamentosa]], a condition of [[rebound effect|rebound]] [[nasal congestion]].<ref name="nasal">{{cite web|url=https://www.drugs.com/mmx/neo-synephrine-nasal-spray.html|title=Neo-Synephrine Nasal Spray Drug Information, Professional|work=drugs.com|access-date=4 April 2015|archive-date=11 May 2015|archive-url=https://web.archive.org/web/20150511221150/http://www.drugs.com/mmx/neo-synephrine-nasal-spray.html|url-status=dead}}</ref>

== Interactions ==
Phenylephrine is susceptible to [[drug metabolism|metabolism]] by [[monoamine oxidase]].<ref name="Eccles2007" /><ref name="AtkinsonPottsAnderson2015">{{cite journal | vauthors = Atkinson HC, Potts AL, Anderson BJ | title = Potential cardiovascular adverse events when phenylephrine is combined with paracetamol: simulation and narrative review | journal = Eur J Clin Pharmacol | volume = 71 | issue = 8 | pages = 931–938 | date = August 2015 | pmid = 26022219 | pmc = 4500855 | doi = 10.1007/s00228-015-1876-1 | url = }}</ref> Because of this, [[monoamine oxidase inhibitor]]s (MAOIs) can inhibit the metabolism of phenylephrine and increase exposure to the medication.<ref name="Eccles2007" /><ref name="AtkinsonPottsAnderson2015" /> Whereas a 45{{nbsp}}mg oral dose of phenylephrine alone increases [[systolic blood pressure]] by 20{{nbsp}}mmHg, use of this dose in people on MAOIs increases systolic blood pressure by more than 60{{nbsp}}mmHg.<ref name="AtkinsonPottsAnderson2015" />

Phenylephrine can interact with other [[adrenergic]] drugs, such as [[beta blocker]]s like [[propranolol]], [[alpha-1 blocker|α<sub>1</sub>-adrenergic receptor antagonist]]s like [[chlorpromazine]], [[alpha-2 agonist|α<sub>2</sub>-adrenergic receptor agonist]]s like [[clonidine]], [[norepinephrine reuptake inhibitor]]s like [[atomoxetine]] and [[amitriptyline]], and MAOIs (which increase norepinephrine levels).<ref name="RichardsLopezMaani2023" /> It can also interact with [[corticosteroid]]s like [[prednisone]], which sensitize the vasculature to sympathomimetics and augment their vasoconstrictive effects, and with [[ergot alkaloid]]s, which also have [[vasoconstriction|vasoconstrictor]] effects and can have additive or synergistic effects with phenylephrine.<ref name="RichardsLopezMaani2023" /> In addition, combination of phenylephrine with other [[sympathomimetic]] drugs can increase [[pressor]] effects and the risk of hemorrhagic stroke.<ref name="RichardsLopezMaani2023" /> Other drugs that may decrease the effects of phenylephrine may include [[calcium channel blockers]], [[ACE inhibitors]] and [[benzodiazepine]]s.<ref name="IV-Label-3" /> Patients taking these medications may need a higher dose of phenylephrine to achieve a comparable increase in blood pressure.<ref name="IV-Label-3">{{cite web | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204300lbl.pdf |title=Vazculep Package Insert | publisher = U.S. Food and Drug Administration }}</ref> Concomitant use of phenylephrine with the preceding agents may necessitate dose adjustments.

[[Acetaminophen]] (paracetamol) has been found to increase exposure to oral phenylephrine.<ref name="AtkinsonPottsAnderson2015" /> It more than doubles phenylephrine's [[bioavailability]], reduces its [[absorption (pharmacokinetics)|absorption]] half-time by 50%, increases phenylephrine levels by approximately 2-fold, and increases peak phenylephrine levels by 4-fold, with substantial [[interindividual variability]].<ref name="AtkinsonPottsAnderson2015" /> Phenylephrine is widely formulated with acetaminophen in combination products.<ref name="AtkinsonPottsAnderson2015" /> The combination may increase the cardiovascular effects of phenylephrine.<ref name="AtkinsonPottsAnderson2015" /> The mechanism of the interaction between phenylephrine and acetaminophen is unknown, but it has been suggested that it may be due to saturation of [[sulfation]] [[metabolic pathway|pathways]] by acetaminophen that also participate in phenylephrine metabolism.<ref name="AtkinsonPottsAnderson2015" />

== Pharmacology ==

=== Pharmacodynamics ===
Phenylephrine is a [[binding selectivity|selective]] [[agonist]] of the [[α1-adrenergic receptor|α<sub>1</sub>-adrenergic receptor]], one of the [[biological target]]s of the [[catecholamine]] [[hormone]]s and [[neurotransmitter]]s [[epinephrine]] (adrenaline) and [[norepinephrine]] (noradrenaline).<ref name="Eccles2007" /><ref name="RichardsLopezMaani2023" /><ref name="ODonnell1995" /> It is a [[full agonist]] of the α<sub>1</sub>-adrenergic receptor in most assessed [[tissue (biology)|tissue]]s.<ref name="Chess-WilliamsWilliamsonBroadley1990">{{cite journal | vauthors = Chess-Williams RG, Williamson KL, Broadley KJ | title = Whether phenylephrine exerts inotropic effects through alpha- or beta-adrenoceptors depends upon the relative receptor populations | journal = Fundam Clin Pharmacol | volume = 4 | issue = 1 | pages = 25–37 | date = 1990 | pmid = 2160415 | doi = 10.1111/j.1472-8206.1990.tb01014.x | url = }}</ref> The drug has weak, minimal, or no agonist activity at the [[α2-adrenergic receptor|α<sub>2</sub>-adrenergic receptor]] or the [[β-adrenergic receptor]]s.<ref name="Eccles2007" /><ref name="RichardsLopezMaani2023" /><ref name="ODonnell1995" /> At the β-adrenergic receptors, it is a [[partial agonist]].<ref name="Chess-WilliamsWilliamsonBroadley1990" />

Phenylephrine also has relatively little or no activity as a [[norepinephrine releasing agent]].<ref name="Eccles2007" /><ref name="ODonnell1995" /> As such, it has little activity as an indirectly acting [[sympathomimetic]] and non-selective activator of [[adrenergic receptor]]s.<ref name="Eccles2007" /><ref name="ODonnell1995" /> This is in contrast to related sympathomimetics like [[pseudoephedrine]].<ref name="Eccles2007" /> However, more recent research suggests that phenylephrine may actually be more [[potency (pharmacology)|potent]] as a norepinephrine releasing agent than has previously been thought.<ref name="Al-KhrasaniKaradiGalambos2022">{{cite journal | vauthors = Al-Khrasani M, Karadi DA, Galambos AR, Sperlagh B, Vizi ES | title = The Pharmacological Effects of Phenylephrine are Indirect, Mediated by Noradrenaline Release from the Cytoplasm | journal = Neurochem Res | volume = 47 | issue = 11 | pages = 3272–3284 | date = November 2022 | pmid = 35945308 | pmc = 9546997 | doi = 10.1007/s11064-022-03681-2 | url = }}</ref> This might help to explain certain unexpected [[pharmacodynamics|pharmacodynamic]] effects of the drug.<ref name="Al-KhrasaniKaradiGalambos2022" />

Because of its α<sub>1</sub>-adrenergic receptor agonism, phenylephrine is a directly acting sympathomimetic [[vasoconstrictor]]<ref name="Eccles2007" /><ref name="ODonnell1995">{{cite journal | vauthors = O'Donnell SR | title = Sympathomimetic vasoconstrictors as nasal decongestants | journal = Med J Aust | volume = 162 | issue = 5 | pages = 264–267 | date = March 1995 | pmid = 7534374 | doi = 10.5694/j.1326-5377.1995.tb139882.x | url = }}</ref> and produces both [[vein|venous]] and [[artery|arterial]] [[vasoconstriction]].<ref name="IV-Label-1">{{cite web | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=72348406-e74f-46c5-b93d-34d07cffe1fd | title = Phenylephrine hydrochloride injection |work=DailyMed | publisher = U.S. National Institutes of Health |access-date=4 April 2015}}</ref><ref name="RichardsLopezMaani2023" /> The term ''sympathomimetic'' means that it mimics the actions of epinephrine or norepinephrine.<ref name="CostaGrandoMilandri2022" />

Phenylephrine works as a [[nasal decongestant]] by causing local vasoconstriction in the nose.<ref name="ODonnell1995" /> Whereas the related sympathomimetic decongestant [[pseudoephedrine]] causes both vasoconstriction and increase of [[mucociliary clearance]] through its non-specific adrenergic activity, phenylephrine's selective α<sub>1</sub>-adrenergic receptor agonism causes vasoconstriction alone, resulting in a difference in their methods of action.{{Citation needed|date=June 2020}}

===Pharmacokinetics===

====Absorption====
Phenylephrine is rapidly [[absorption (pharmacokinetics)|absorbed]] from the [[gastrointestinal tract]] when taken [[oral administration|orally]].<ref name="Eccles2007" /> However, its absorption is incomplete and erratic.<ref name="ChuaBenrimojTriggs1989">{{cite journal | vauthors = Chua SS, Benrimoj SI, Triggs EJ | title = Pharmacokinetics of non-prescription sympathomimetic agents | journal = Biopharm Drug Dispos | volume = 10 | issue = 1 | pages = 1–14 | date = 1989 | pmid = 2647163 | doi = 10.1002/bdd.2510100102 | url = }}</ref> Because of extensive [[first-pass metabolism]], phenylephrine has an oral [[bioavailability]] of only about 38% relative to [[intravenous administration]].<ref name="Eccles2007" /><ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" /><ref name="Medsafe2004">{{cite web|orig-date=25 November 2004|date=23 May 2013|title=Recommendation on phenylephrine|url=https://www.medsafe.govt.nz/profs/class/Minutes/2001-2005/mccMin25Nov2004.htm|publisher=[[Medsafe]]|access-date=25 April 2023}}</ref> However, another source has stated that the bioavailability of phenylephrine is poorly documented and may actually be as low as 0.003%.<ref name="AtkinsonPottsAnderson2015" /> The [[Tmax (pharmacology)|time to peak]] concentrations is 1.0 to 1.3{{nbsp}}hours.<ref name="Eccles2007" />

====Distribution====
The [[steady-state (pharmacokinetics)|steady-state]] [[volume of distribution]] of phenylephrine is 340{{nbsp}}L.<ref name="RichardsLopezMaani2023" />

Phenylephrine does not cross the [[blood–brain barrier]] and hence is a [[peripherally selective drug]] with no [[central nervous system]] activity.<ref name="MengSunZhao2024" /><ref name="LarsonAndersonThomson2021" /><ref name="Eccles2007" /><ref name="ODonnell1995" /> Its lack of blood-brain barrier permeability is related to its [[hydroxyl group]]s and high [[hydrophilicity]].<ref name="Eccles2007" /><ref name="JohnsonHricik1993" /> The lack of central permeation with phenylephrine is in contrast to certain other related decongestant and sympathomimetic agents like [[pseudoephedrine]], [[ephedrine]], and [[phenylpropanolamine]].<ref name="JohnsonHricik1993" /><ref name="Eccles2007" /><ref name="ODonnell1995" />

====Metabolism====
Phenylephrine is [[metabolism|metabolized]] in the [[intestine]]s and [[liver]] prior to reaching the systemic circulation when taken orally.<ref name="Eccles2007" /> It is extensively metabolized during first-pass metabolism due to susceptibility to [[monoamine oxidase]]s, similarly to [[epinephrine]].<ref name="Eccles2007" /><ref name="RichardsLopezMaani2023" /><ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" /> Phenylephrine is metabolized via [[oxidation|oxidative]] [[deamination]] by both [[MAO-A]] and [[MAO-B]].<ref name="RichardsLopezMaani2023" /><ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" /> In contrast to epinephrine and [[norepinephrine]], phenylephrine is not a [[catecholamine]], and is not metabolized by [[catechol O-methyltransferase]] (COMT).<ref name="ODonnell1995" /> Besides monoamine oxidase, phenylephrine is also metabolized by [[sulfation]] and [[glucuronidation]] [[conjugation (biochemistry)|conjugation]].<ref name="RichardsLopezMaani2023" /><ref name="DrugBank" /> Non-oral routes of phenylephrine, like [[intranasal administration|intranasal]], [[ophthalmic drug administration|ophthalmic]], and [[parenteral administration|parenteral]], do not undergo first-pass metabolism in the gastrointestinal tract.<ref name="ChuaBenrimojTriggs1989" />

The major [[metabolite]] of phenylephrine is [https://pubchem.ncbi.nlm.nih.gov/compound/3-Hydroxymandelic-acid ''meta''-hydroxymandelic acid], which is inactive.<ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" /> Lesser metabolites of phenylephrine include [[sulfate]] and [[glucuronide]] conjugates, which are also inactive.<ref name="DrugBank" /><ref name="ChuaBenrimojTriggs1989" />

Unlike phenylephrine, related sympathomimetics with a [[methyl group]] at the α carbon (i.e., [[substituted amphetamine|amphetamine]]s), like [[ephedrine]], [[pseudoephedrine]], [[phenylpropanolamine]], [[methoxamine]], and [[methoxyphenamine]], are resistant to degradation by monoamine oxidase.<ref name="ChuaBenrimojTriggs1989" />

====Elimination====
Phenylephrine is primarily [[excretion|excreted]] in [[urine]].<ref name="RichardsLopezMaani2023" /><ref name="DrugBank" /> It is recovered 86% in urine.<ref name="DrugBank" /> The drug is excreted in urine 3 to 16% unchanged, 57% as [https://pubchem.ncbi.nlm.nih.gov/compound/3-Hydroxymandelic-acid ''meta''-hydroxymandelic acid], and 8% as [[sulfate]] [[conjugation (biochemistry)|conjugates]].<ref name="Eccles2007" /><ref name="DrugBank" /> [[Glucuronide]] conjugates constitute a smaller portion of phenylephrine.<ref name="ChuaBenrimojTriggs1989" />

Phenylephrine has a relatively short [[elimination half-life]] of 2.0 to 3.0{{nbsp}}hours regardless of [[route of administration]].<ref name="Eccles2007" /><ref name="RichardsLopezMaani2023" /><ref name="DrugBank" /><ref name="KanferDowseVuma1993">{{cite journal | vauthors = Kanfer I, Dowse R, Vuma V | title = Pharmacokinetics of oral decongestants | journal = Pharmacotherapy | volume = 13 | issue = 6 Pt 2 | pages = 116S–128S; discussion 143S–146S | year = 1993 | pmid = 7507589 | doi = 10.1002/j.1875-9114.1993.tb02780.x | s2cid = 23528004 }}</ref><ref name="ChuaBenrimojTriggs1989" /> Its lack of metabolism by COMT is said to be responsible for its much longer [[duration of action]] than related agents like [[norepinephrine]].<ref name="ODonnell1995" />

==Chemistry==
Phenylephrine is a [[substituted phenethylamine]] and can also be referred to [[chemical structure|structurally]] as (''R'')-β,3-dihydroxy-''N''-methylphenethylamine.<ref name="Elks2014" /><ref name="PubChem" /><ref name="DrugBank" /> It is closely [[structural analog|structurally related]] to [[epinephrine]] (adrenaline; 3,4,β-trihydroxy-''N''-methylphenethylamine), differing from it only in the absence of one [[hydroxyl group]] on the [[phenyl ring]].<ref name="Eccles2007">{{cite journal | vauthors = Eccles R | title = Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse | journal = Br J Clin Pharmacol | volume = 63 | issue = 1 | pages = 10–14 | date = January 2007 | pmid = 17116124 | pmc = 2000711 | doi = 10.1111/j.1365-2125.2006.02833.x | url = | quote = 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].}}</ref> It is a [[chirality|chiral]] compound and is used as the [[enantiopure drug|enantiopure]] (''R'')-[[stereoisomer]].<ref name="KanferDowseVuma1993" /><ref name="Elks2014" /> The [[racemic mixture|racemic]] form has not been formally named or used.<ref name="Elks2014" />

Phenylephrine is the ''N''-[[methyl group|methyl]]ated [[chemical derivative|derivative]] of [[norfenefrine]] (3,β-dihydroxyphenethylamine).<ref name="Elks2014" /> The [[racemic mixture|racemic]] ''N''-[[ethyl group|ethyl]] [[structural analog|analogue]] is [[etilefrine]] (ethylphenephrine).<ref name="Elks2014" /> [[Synephrine]] (''p''-synephrine, oxedrine; 4,β-dihydroxyphenethylamine) is a [[positional isomer]] of phenylephrine.<ref name="CostaGrandoMilandri2022">{{cite journal | vauthors = Costa VM, Grando LG, Milandri E, Nardi J, Teixeira P, Mladěnka P, Remião F | title = Natural Sympathomimetic Drugs: From Pharmacology to Toxicology | journal = Biomolecules | volume = 12 | issue = 12 | date = November 2022 | page = 1793 | pmid = 36551221 | pmc = 9775352 | doi = 10.3390/biom12121793 | doi-access = free | url = }}</ref> In contrast to epinephrine and [[norepinephrine]] (noradrenaline; 3,4,β-trihydroxyphenethylamine), phenylephrine is not a [[catecholamine]] since it does not have two hydroxyl groups on its phenyl ring.<ref name="ODonnell1995" /> Besides the catecholamines, the chemical structure of phenylephrine somewhat resembles that of [[amphetamine]] (α-methylphenethylamine).<ref name="JohnsonHricik1993">{{cite journal | vauthors = Johnson DA, Hricik JG | title = The pharmacology of α-adrenergic decongestants | journal = Pharmacotherapy | volume = 13 | issue = 6 Pt 2 | pages = 110S–115S; discussion 143S–146S | date = 1993 | pmid = 7507588 | doi = 10.1002/j.1875-9114.1993.tb02779.x| url = }}</ref> However, phenylephrine does not have a [[methyl group]] at the α [[carbon]] and hence is not an amphetamine itself.<ref name="JohnsonHricik1993" />

Phenylephrine is a [[small molecule|small-molecule]] compound with the [[molecular formula]] C<sub>9</sub>H<sub>13</sub>NO<sub>2</sub> and a [[molecular weight]] of 167.205{{nbsp}}g/mol.<ref name="PubChem" /><ref name="DrugBank" /> It is a highly [[hydrophilic]] compound, with an experimental [[partition coefficient|log P]] of -0.3.<ref name="Xiao2020">{{cite book | vauthors = Xiao K | title=Analytical Scientists in Pharmaceutical Product Development: Task Management and Practical Knowledge | publisher=Wiley | year=2020 | isbn=978-1-119-54782-2 | url=https://books.google.com/books?id=-xH6DwAAQBAJ&pg=PA122 | access-date=21 July 2024 | page=122 | quote = 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.}}</ref><ref name="PubChem">{{cite web | title=Phenylephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/6041 | access-date=21 July 2024}}</ref><ref name="DrugBank">{{cite web | title=Phenylephrine: Uses, Interactions, Mechanism of Action | website=DrugBank Online | date=25 November 2022 | url=https://go.drugbank.com/drugs/DB00388 | access-date=21 July 2024}}</ref> Phenylephrine is used medically almost always as the [[hydrochloride]] [[salt (chemistry)|salt]].<ref name="IndexNominum2000" /><ref name="Elks2014" /> However, the [[free base]] form and the [[tannate]] salt have also been used pharmaceutically to a much lesser extent.<ref name="IndexNominum2000" />

[[Pivenfrine]] is the 3-[[pivalate]] [[ester]] of phenylephrine and has much greater [[lipophilicity]] in comparison.<ref name="Elks2014" /><ref name="PubChem-Pivenfrine">{{cite web | title=Pivenfrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/130545 | access-date=1 September 2024}}</ref>

==History==
Phenylephrine was first patented in 1927 and was first introduced for medical use in 1938.<ref name="DeolAlvarezElrabi2023">{{cite journal | vauthors = Deol N, Alvarez G, Elrabi O, Chen G, Ferraro N | title = A comparative review of epinephrine and phenylephrine as vasoconstrictors in dental anesthesia: exploring the factors behind epinephrine's prevalence in the US | journal = J Dent Anesth Pain Med | volume = 23 | issue = 6 | pages = 293–302 | date = December 2023 | pmid = 38076507 | pmc = 10703557 | doi = 10.17245/jdapm.2023.23.6.293 | url = | quote = Phenylephrine, a synthetic selective alpha-1 adrenergic agonist, first received its patent in 1927 and was introduced for medical use in 1938 [8].}}</ref>

==Society and culture==

===Names===
Phenylephrine is the [[generic term|generic name]] of the drug and its {{Abbrlink|INN|International Nonproprietary Name}}, {{Abbrlink|BAN|British Approved Name}}, and {{Abbrlink|DCF|Dénomination Commune Française}}, while its {{Abbrlink|USAN|United States Adopted Name}} and {{Abbrlink|BANM|British Approved Name}} in the case of the [[hydrochloride]] [[salt (chemistry)|salt]] are phenylephrine hydrochloride.<ref name="Elks2014">{{cite book | vauthors = Elks J | title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies | publisher=Springer US | year=2014 | isbn=978-1-4757-2085-3 | url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA61 | access-date=22 July 2024 | pages=61,1001}}</ref><ref name="IndexNominum2000">{{cite book | author=Schweizerischer Apotheker-Verein | title=Index Nominum 2000: International Drug Directory | publisher=Medpharm Scientific Publishers | year=2000 | isbn=978-3-88763-075-1 | url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA826 | access-date=22 July 2024 | page=826}}</ref><ref name="MortonHall2012">{{cite book | vauthors = Morton IK, Hall JM | title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms | publisher=Springer Netherlands | year=2012 | isbn=978-94-011-4439-1 | url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA219 | access-date=22 July 2024 | page=219}}</ref><ref name="Drugs.com-International" /> Synonyms of phenylephrine include phenephrine, fenefrine, <small>L</small>-m-synephrine, metaoxedrine, neo-oxedrine, mesatonum, neosynephrine, and m-sympatol.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="Drugs.com-International" /> Brand names of phenylephrine include Neosynephrine or Neo-Synephrine and Sudafed PE, among numerous others.<ref name="Elks2014" /><ref name="IndexNominum2000" /><ref name="DrugBank" /><ref name="Drugs.com-International" />

===Availability===
Phenylephrine is available worldwide as a [[prescription drug]] in many different [[pharmaceutical form|formulations]].<ref name="Drugs.com-International">{{cite web | title=Phenylephrine (International database) | website=Drugs.com | date=7 July 2024 | url=https://www.drugs.com/international/phenylephrine.html | access-date=22 July 2024}}</ref>

==References==
{{Reflist}}

{{Cardiac stimulants excluding cardiac glycosides}}
{{Nasal preparations}}
{{Mydriatics and cycloplegics}}
{{Adrenergic receptor modulators}}
{{Monoamine releasing agents}}
{{Phenethylamines}}
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