Phenylephrine

Phenylephrine
Skeletal formula of phenylephrine
Ball-and-stick model of the phenylephrine molecule
Systematic (IUPAC) name
(R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol
Clinical data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, intranasal, ophthalmic, intravenous, intramuscular
Legal status
Legal status
Pharmacokinetic data
Bioavailability 38% through GI tract
Protein binding 95%
Metabolism Hepatic (monoamine oxidase)
Biological half-life 2.1–3.4 h
Identifiers
CAS Number 59-42-7 YesY
61-76-7 (hydrochloride)
ATC code C01CA06 (WHO) R01AA04 (WHO), R01AB01 (WHO) (combinations), R01BA03 (WHO), S01FB01 (WHO), S01GA05 (WHO)
PubChem CID 6041
IUPHAR/BPS 485
DrugBank DB00388 YesY
ChemSpider 5818 YesY
UNII 1WS297W6MV YesY
KEGG D08365 YesY
ChEBI CHEBI:8093 YesY
ChEMBL CHEMBL1215 YesY
Chemical data
Formula C9H13NO2
Molar mass 167.205 g/mol
  (verify)

Phenylephrine is a selective α1-adrenergic receptor agonist of the phenethylamine class used primarily as a decongestant, as an agent to dilate the pupil, and to increase blood pressure. Phenylephrine is marketed as an alternative for the decongestant pseudoephedrine, though clinical studies show phenylephrine, taken orally at the recommended dose, to be no more effective than placebo.[1][2] Phenylephrine can also cause a decrease in heart rate through reflex bradycardia.[3]

Medical uses

Decongestant

Phenylephrine is used as a decongestant sold as an oral medicine or as a nasal spray. It is a common ingredient in over-the-counter decongestants. Other decongestants include oxymetazoline and pseudoephedrine.

Phenylephrine is used as an alternative for pseudoephedrine in decongestant medicines due to pseudoephedrine's use in the illicit manufacture of methamphetamine. Its efficacy as an oral decongestant has been questioned, with multiple studies not being able to come to an agreement.[1][2]

Pharmacists Leslie Hendeles and Randy Hatton of the University of Florida suggested in 2006 that oral phenylephrine is ineffective as a decongestant at the 10-mg dose used, arguing that the studies used for the regulatory approval of the drug in the United States in 1976 were inadequate to prove effectiveness at the 10-mg dose, and safety at higher doses.[4]

A 2007 meta-analysis by Hatton et al. concluded that the evidence for its effectiveness is insufficient,[5] though another meta-analysis published shortly thereafter by researchers from GlaxoSmithKline found the standard 10-mg dose to be significantly 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.[6] A 2007 study by Wyeth Consumer Healthcare notes that 7 studies available in 1976 support the efficacy of phenylephrine at a 10 mg dosage.[7]

Two studies published in 2009 examined the effects of phenylephrine on symptoms of allergic rhinitis by exposing sufferers 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.[1][2]

The Food and Drug Administration has stood by its 1976 approval of phenylephrine for nasal congestion as the debate continues.[8]

Hemorrhoids

Hemorrhoids are caused by swollen veins in the rectal area.[9] 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 presumably to narrow the swollen veins and relieve the attendant pain. However, veins--unlike arteries--do not contain vascular smooth muscle in their walls so the mechanism by which pain relief is achieved is likely related to something other than vascular change alone. Products for treatment may also include substances that will form a protective barrier over the inflamed area, resulting in less pain when faeces are passed.[10]

Pupil dilatation

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 mydriatic, it is available in 2.5% and 10% minims. Phenylephrine eye drops are applied to the eye after a topical anestheic is applied.[11]

Vasopressor

Phenylephrine is commonly used as a vasopressor to increase the blood pressure in unstable patients with hypotension, especially resulting from septic shock. Such use is common in anesthesia or critical-care practices; it is especially useful in counteracting the hypotensive effect of epidural and subarachnoid anesthetics, as well as the vasodilating effect of bacterial toxins and the inflammatory response in sepsis and systemic inflammatory response syndrome. The elimination half life of phenylephrine is about 2.5 to 3.0 hours.[12] The clinical effects of a single intravenous bolus dose of phenylephrine are short lived and needs to be repeated every 10–15 minutes. Commonly the drug is given as a carefully titrated intravenous infusion with a syringe pump or volumetric pump.

Because of its 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.[13]

Phenylephrine hydrochloride at 0.25% is used as a vasoconstrictor in some suppository formulations.[14]

Priapism

Phenylephrine is used by urologists to abort priapism. It is diluted with normal saline and injected directly into the corpora cavernosa. The mechanism of action is to cause constriction of the blood vessels entering into the penis, thus causing decreased blood flow and relieving the priapism. An injection is given every 3–5 minutes. If priapism is not resolved in 1 hour, another form of therapy is considered.[15]

Side effects

Heart

The primary side effect of phenylephrine is high blood pressure. People with high blood pressure are typically advised to avoid products containing it. Because this medication is a sympathomimetic amine without beta-adrenergic activity, it does not increase contractility force and output of the cardiac muscle. It may increase blood pressure resulting in a slow heart rate through stimulation of vascular (likely carotid) baroreceptors. A common side effect during IV administration is reflex bradycardia.[16] The low concentration eye drops do not cause blood pressure changes and the changes with the higher dose drops do not last long.[17]

Other

Prostatic hyperplasia can also be worsened by use, and chronic use can lead to rebound hyperemia.[18] 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.[19]

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.[19]

Extended use may cause rhinitis medicamentosa, a condition of rebound nasal congestion.[20]

Interactions

The increase in blood pressure effect of phenylephrine may be increased by drugs such as monoamine oxidase inhibitors, tricyclic antidepressants, and hydrocortisone. Patients taking these medications may need a lower dose of phenylephrine to achieve a similar increase in blood pressure.

Drugs that may decrease the effects of phenylephrine may include calcium channel blockers, ACE inhibitors and benzodiazepines. Patients taking these medications may need a higher dose of phenylephrine to achieve a comparable increase in blood pressure.[21]

Mechanism of action

Oral phenylephrine is extensively metabolized by monoamine oxidase,[22] an enzyme that is present on the outside of cells, throughout the body.[23] Compared to intravenous pseudoephedrine, phenylephrine has a reduced and variable bioavailability; only up to 38%.[22][24] Phenylephrine is a sympathomimetic drug, which means that it mimics the actions of epinephrine (commonly known as adrenaline) or norepinephrine. Phenylephrine selectively binds to alpha receptors which cause blood vessels to constrict. Phenylephrine may cause side effects such as headache, reflex bradycardia, excitability, restlessness and cardiac arrhythmias. Phenylephrine is not suggested for use in patients with hypertension.[25]

Whereas pseudoephedrine causes both vasoconstriction and increase of mucociliary clearance through its nonspecific adrenergic activity, phenylephrine's selective α-adrenergic agonism causes vasoconstriction alone, creating a difference in their methods of action.

Substitute for pseudoephedrine

Pseudoephedrine and phenylephrine are both used as decongestants; and, until recently, pseudoephedrine was much more commonly available in the United States. This has changed because provisions of the Combat Methamphetamine Epidemic Act of 2005 placed restrictions on the sale of pseudoephedrine products to prevent the 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 the restrictions on sales.[8] Phenylephrine has been off patent for some time, and many generic brands are available.

References

  1. 1 2 3 Horak, F.; Zieglmayer, P.; Zieglmayer, R.; Lemell, P.; Yao, R.; Staudinger, H.; Danzig, M. (11 November 2008). "A placebo-controlled study of the nasal decongestant effect of phenylephrine and pseudoephedrine in the Vienna Challenge Chamber". Annals of Allergy, Asthma & Immunology (February 2009) 102 (2): 116–20. doi:10.1016/S1081-1206(10)60240-2. PMID 19230461.
  2. 1 2 3 Day, J. H.; Briscoe, M. P.; Ratz, J. D.; Danzig, M.; Yao, R. (2009). "Efficacy of loratadine-montelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit". Annals of Allergy, Asthma & Immunology 102 (4): 328–338. doi:10.1016/S1081-1206(10)60339-0. PMID 19441605.
  3. ↑ "UCSF drug learning module: Phenylephrine". UCSF. UCSF. Retrieved 5 February 2015.
  4. ↑ Heldeles, L. and Hatton, R. (2006). "Oral phenylephrine: An ineffective replacement for pseudoephedrine?". Journal of Allergy and Clinical Immunology 118 (1): 279–280. doi:10.1016/j.jaci.2006.03.002. PMID 16815167.
  5. ↑ Hatton, R.C.; et al. (2007). "Efficacy and Safety of Oral Phenylephrine: A Systematic Review and Meta-Analysis" (abstract). Annals of Pharmacotherapy 41 (3): 381–390. doi:10.1345/aph.1H679. PMID 17264159.(published online Jan 2007)
  6. ↑ Kollar, C.; Schneider, H.; Waksman, J.; Krusinska, E. (2007). "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". Clinical Therapeutics 29 (6): 1057–1070. doi:10.1016/j.clinthera.2007.05.021. PMID 17692721.
  7. ↑ Desjardins, P.J. & Berlin, R.G. (2007). "Efficacy of phenylephrine". British Journal of Clinical Pharmacology 64 (4): 555–556. doi:10.1111/j.1365-2125.2007.02935.x.
  8. 1 2 Hilenmeyer, K. (30 January 2007). "All stuffed up". Southwest Florida Herald-Tribune.
  9. ↑ http://www.mayoclinic.org/diseases-conditions/hemorrhoids/basics/definition/con-20029852
  10. ↑ "phenylephrine rectal". webmd.com. Retrieved 4 April 2015.
  11. ↑ http://akorn.com/documents/catalog/sell_sheets/17478-205-10.pdf
  12. ↑ Kanfer, I; Dowse, R; Vuma, V (1993). "Pharmacokinetics of oral decongestants". Pharmacotherapy 13 (6): 116S–128S; discussion 143S–146S. PMID 7507589.
  13. ↑ Cooper, B. E. (2008). Review and Update on Inotropes and Vasopressors. AACN Advanced Critical Care, 19, 5–15.
  14. ↑ "DailyMed - PREPARATION H- cocoa butter and phenylephrine hydrochloride suppository". nih.gov. Retrieved 4 April 2015.
  15. ↑ "Priapism : American Urological Association". auanet.org. Retrieved 4 April 2015.
  16. ↑ "Medscape: Medscape Access". medscape.com. Retrieved 4 April 2015.
  17. ↑ Stavert B, McGuinness MB, Harper CA, Guymer RH, Finger RP (2015). "Cardiovascular Adverse Effects of Phenylephrine Eyedrops: A Systematic Review and Meta-analysis". JAMA Ophthalmol 133 (6): 647–52. doi:10.1001/jamaophthalmol.2015.0325. PMID 25789577.
  18. ↑ Shen, Howard (2008). Illustrated Pharmacology Memory Cards: PharMnemonics. Minireview. p. 3. ISBN 1-59541-101-1.
  19. 1 2 http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203826s000lbl.pdf
  20. ↑ "Neo-Synephrine Nasal Spray Drug Information, Professional". drugs.com. Retrieved 4 April 2015.
  21. ↑ "Vazculep_FINAL_PI.pdf" (PDF). google.com. Retrieved 4 April 2015.
  22. 1 2 "DrugBank: Phenylephrine (DB00388)". drugbank.ca. Retrieved 4 April 2015.
  23. ↑ Shih JC, Chen K; Chen (August 2004). "Regulation of MAO-A and MAO-B gene expression". Curr. Med. Chem. 11 (15): 1995–2005. doi:10.2174/0929867043364757. PMID 15279563.
  24. ↑ NZ Medicines and Medical Devices Safety Authority recommendation on phenylephrine (November 2004)
  25. ↑ "DailyMed - PHENYLEPHRINE HYDROCHLORIDE- phenylephrine hydrochloride injection". nih.gov. Retrieved 4 April 2015.

External links

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