Phenylephrine

Phenylephrine is a vasoconstrictor and decongestant belonging to the alpha-1-adrenergic agonist.

Phenylephrine is approved for the treatment of Hypotension. It is also used to treat as an additive to neuraxial/peripheral nerve blockade, to treat priapism and other conditions where local vasoconstrictive effects and reduced blood flow are the desired effect.

Phenylephrine absorption is erratic and incomplete absorption, and it is readily absorbed (oral). The volume of distribution of Phenylephrine was found to be about 200-500 L (oral) with rapid distribution into peripheral tissues with minimal penetration into the brain. It is metabolized through the liver via sulfate conjugation (oral: 46%, mostly in gut wall; IV: 8%), oxidative deamination (oral: 24%; IV: 50%), and glucuronidation. Undergoes first-pass metabolism in the gut and liver by monoamine oxidase and gets excreted via urine mainly as inactive metabolites with elimination half-life of approx. 5 minutes.

The common side effects associated with Phenylephrine include Reflex bradycardia, extravasation (IV); rebound miosis (ophthalmic); Arrhythmia, ischemia, extrasystoles, palpitation, tachycardia; Dyspnoea, pulmonary oedma. Skin and subcutaneous tissue disorders: Blanching of skin, pallor, piloerection. Vascular disorders: Hypertension, hypertensive crisis.

Phenylephrine is available in the form of dosage forms such as tablets, ophthalmic solution and injection solution.

Phenylephrine is available in China, Germany, India, Japan, U.S

Phenylephrine, belonging to the alpha-1-adrenergic agonist, acts as a vasoconstrictor and decongestant. Phenylephrine works by directly stimulating alpha-1 adrenergic receptors in the arteries causing vasoconstriction (narrowing of the blood vessels)

Phenylephrine is a sympathomimetic amine that has a direct effect on α-adrenergic receptors and an indirect effect of releasing norepinephrine from its storage sites. Its main effect is systemic arterial vasoconstriction. Additionally, it produces local vasoconstriction on dilated arterioles of the conjunctiva and nasal mucosa.

The onset of action of Phenylephrine occurs within 10-15 minutes (IM/SC); 15-20 min (oral); Ophthalmic: 15 minutes (mydriasis), 20-90 minutes (maximal mydriasis), 3-8 hours (time to recovery); ≤2 minutes (intranasal). 15-30 minutes (decongestant).

The Duration of Action for Phenylephrine is approx 20 minutes (IV); 1-2 hours (IM); approx 1 hour (SC); ≤4 hours (oral); 2.5-4 hours (intranasal, dose-dependent).

The Tmax was found within 0.75-2 hours and Cmax in blood reached upto 926 pg/ml

Phenylephrine is available in the form of tablets, ophthalmic solution and injection solution.

For Tablets:

Phenylephrine tablets should be taken orally by mouth with or without water.

For Injection:

Phenylephrine Injection may be administered subcutaneously or intramuscularly in a dosage of 2 to 5 mg with further doses of 1 to 10 mg if necessary, according to response, or in a dose of 100 to 500 micrograms by slow intravenous injection as a 0.1% solution, repeated as necessary after at least 15 minutes.

For Ophthalmic Solution:

Ophthalmic phenylephrine in strengths of 2.5 and 10% is used to dilate (enlarge) the pupil. It is used before eye examinations, before and after eye surgery, and to treat certain eye conditions.

Phenylephrine is approved for the treatment of Hypotension. It is also used to treat as an additive to neuraxial/peripheral nerve blockade, to treat priapism and other conditions where local vasoconstrictive effects and reduced blood flow are the desired effect.

Phenylephrine is a direct-acting sympathomimetic amine primarily an alpha-1 adrenergic receptor agonist with minimal to no beta-adrenergic activity; therefore, it is ideal for elevating mean arterial pressure. It does so by causing venous and arterial vasoconstriction and increasing cardiac preload without having any significant direct effect on cardiac myocytes.

Phenylephrine is approved for use in the following clinical indications

Hypotension

• Alpha-1 adrenergic receptor agonist indicated for treatment of clinically important hypotension resulting primarily from vasodilation in the setting of anesthesia
• IV bolus: 40-100 mcg q1-2 min PRN, not to exceed total dose of 200 mcg
• Adjust dosage according to blood pressure goal Continuous IV infusion: If blood pressure is below the target goal, start a continuous IV infusion with an infusion rate of 10-35 mcg/min; not to exceed 200 mcg/min.

Although not approved there have been certain off label indication documented for Phenylephrine which include:

• Neuraxial/peripheral nerve blockade,
• To treat priapism and other conditions where local vasoconstrictive effects and reduced blood flow are the desired effect.

Nasal congestion:

Temporary relief of nasal congestion due to the common cold, hay fever (allergic rhinitis), or other upper respiratory allergies.

The dosage and the duration of treatment should be as per the clinical judgment of the treating physician

• Phenylephrine is available in various dosage strength 0.1 mg/ml, 10 mg/ml, 0.12%, 2.5%, 10%, 5 mg, 10 mg

Phenylephrine is available in the form of an injection solution, tablets, and ophthalmic solutions.

Dose Adjustment in Kidney patient:

No dose adjustment is required

Dose Adjustment in Hepatic Impairment Patient:

No dosage adjustment is required.

Dose Adjustment in the pediatric patient:

Severe Hypotension/Shock

• <2 years: Safety and efficacy not established
• ≥2 years : 5-20 mcg/kg IV once; THEN 0.1-0.5 mcg/kg/min IV; not to exceed 3-5 mcg/kg/min IV

Sinus Congestion

• <12 years: Safety and efficacy not established
• ≥12 years: 10 mg PO q4hr PRN; not to exceed 60 mg/24 hr

Ointment: Topical or rectal:

For external and/or intrarectal use only. Prior to application, cleanse the affected area by patting or blotting with an appropriate cleansing wipe. Apply ointment to clean and dry the rectal area at night, in the morning, and/or after each bowel movement (up to 4 times daily). When using the applicator for intrarectal use, remove the protective cover from the applicator and attach it to the tube. Lubricate the applicator well, then gently insert it into the rectum. Thoroughly cleanse the applicator after each use and replace the protective cover.

Nasal congestion:

Infants and Children <2 years:

Limited data available: 0.5% solution: Intranasal: Instill 0.1 mL in each nostril as a single dose . In a double-blind, placebo-controlled trial in 20 infants (mean age: 4 months) with bronchiolitis results showed, improved respiratory scores and oxygen saturation; however, statistical significance was not reached. In another randomized, double-blind, placebo-controlled trial, 23 pediatric patients (age range: 6 to 18 months) with the common cold showed improvement in nasal obstruction which was not considered significant; no effect on middle ear pressures was observed.

Children ≥2 years:

2 to <6 years: 0.125% solution: Intranasal: Instill 1 drop in each nostril every 2-4 hours as needed. Note: Consult product specific information for further details.

Little Noses Decongestant: Instill 2 to 3 drops in each nostril every 4 hours as needed

6 to 12 years: 0.25% solution: Intranasal: Instill 1 to 3 sprays in each nostril every 4 hours as needed

Adolescents: 0.25% to 1% solutions: Intranasal: Instill 1 to 3 drops or sprays every 4 hours as needed

Dosage adjustment for concomitant therapy:

Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult the drug interactions database for more information

Nasal congestion: Oral:

Children 4 to 5 years: 2.5 mg every 4 hours; maximum daily dose: 15 mg in 24 hours.

Children 6 to 11 years: 5 mg every 4 hours; maximum daily dose: 30 mg in 24 hours.

Children ≥12 years and Adolescents: 10 mg every 4 hours; maximum daily dose: 60 mg in 24 hours.

Suppository:

For rectal use only. Cleanse the affected area by patting or blotting with an appropriate cleansing wipe; gently dry by patting with a tissue or soft cloth prior to insertion. Remove the foil wrapper. Insert into the rectum at night, in the morning, and/or after each bowel movement (up to 4 times daily)

Mydriasis: Ophthalmic:

2.5% Solution: Infants, Children, and Adolescents: Instill 1 drop 15 to 30 minutes prior to the procedure; administer every 3 to 5 minutes; maximum total dose: 3 drops per eye.

10% Solution: Children and Adolescents: Instill 1 drop 15 to 30 minutes prior to the procedure; administer every 3 to 5 minutes as needed; maximum total dose: 3 drops per eye

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult the drug interactions database for more information.

Phenylephrine should be used for the treatment of essential or primary Hypotension.

Hypotension: Eat more fruits, vegetables, and low-fat dairy foods. Cut back on foods that are high in saturated fat, cholesterol, and trans fats. Eat more whole-grain foods, fish, poultry, and nuts.

The dietary restriction should be individualized as per the patient's requirements.

Phenylephrine may be contraindicated in the following

• Severe hypertension, ventricular tachycardia, severe hyperthyroidism.
• Ophthalmic (10% solution): Close-angle glaucoma. Children and elderly.
• Cold preparations should not be used in children <2 years.
• Concomitant or within 14 days of MAOI use (oral).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows.

• Exacerbation of Angina, Heart Failure, or Pulmonary Arterial Hypertension

Because of its pressor effects, phenylephrine hydrochloride can precipitate angina in patients with severe arteriosclerosis or history of angina, exacerbate underlying heart failure, and increase pulmonary arterial pressure.

• Bradycardia

Phenylephrine hydrochloride can cause severe bradycardia and decreased cardiac output.

• Risk in Patients with Autonomic Dysfunction

The pressor response to adrenergic drugs, including phenylephrine, can be increased in patients with autonomic dysfunction, as may occur with spinal cord injuries.

• Skin and Subcutaneous Necrosis

Extravasation of phenylephrine can cause necrosis or sloughing of tissue.

• Pressor Effect with Concomitant Oxytocic Drugs

Oxytocic drugs potentiate the pressor effect of sympathomimetic pressor amines including phenylephrine hydrochloride, with the potential for hemorrhagic stroke.

• Allergic Reactions

This product contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

· Peripheral and Visceral Ischemia

Phenylephrine hydrochloride can cause excessive peripheral and visceral vasoconstriction and ischemia to vital organs, particularly in patients with extensive peripheral vascular disease.

· Renal Toxicity

Phenylephrine hydrochloride can increase the need for renal replacement therapy in patients with septic shock.

Monitor renal function.

Consumption of alcohol is not recommended while receiving this medicine as it may increase the risk of adverse effects and lowers the blood pressure.

Phenylephrine use in breastfeeding patients is not recommended.

Pregnancy Category (FDA): There is no FDA guidance on the usage of Phenylephrine (oral) in women who are pregnant.

Limit caffeine intake (examples: coffee, teas, colas, chocolate and some herbal supplements) while taking Phenylephrine. Also avoid medicines containing additional Caffeine whenever possible.

• Common Adverse effects:

Hemodynamic compromise, Dizziness, peripheral ischemia, dry mouth, asthenia, and somnolence.

• Less Common adverse effects:

• Rare adverse effects:

Bradycardia, decompensated heart failure, cardiac arrest, and heart block.

The clinically relevant drug interactions of Phenylephrine is briefly summarized here.

• Taking MAO inhibitors with this medication may cause a serious (possibly fatal) drug interaction.
• Avoid taking MAO inhibitors (isocarboxazid, linezolid, metaxalone, methylene blue, moclobemide, phenelzine, procarbazine, rasagiline, safinamide, selegiline, tranylcypromine) during treatment with this medication.
• Concomitant use with adrenergic blocking agents (e.g., phentolamine), phenothiazine drugs (e.g., chlorpromazine) and amiodarone may cause antagonistic effects.
• May potentiate pressor effects of oxytocic drugs and CV depressant effects of inhalational anaesthetics (e.g., cyclopropane, halothane).
• May increase risk of arrhythmias with cardiac glycosides and quinidine. May enhance the effects of anticholinergic drugs (e.g., TCAs).

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Symptoms:

Headache, nausea, vomiting, paranoid psychosis, hallucinations, seizures, cerebral hemorrhage, palpitation, paresthesia, reflex bradycardia, cardiac arrhythmia (e.g., ventricular tachycardia and extrasystoles), sensation of fullness in the head and tingling of extremities.

Management:

Symptomatic and supportive treatment. α-adrenergic blockers (e.g., phentolamine) may be used to treat severe hypertension.

Pharmacodynamics:

• Phenylephrine is a direct-acting sympathomimetic amine that functions as an alpha-1 adrenergic agonist. Its chemical structure is related to epinephrine and ephedrine and possesses potent vasoconstriction properties when given intravenously or applied directly to mucosal membranes.
• The overall effect of intravenous phenylephrine on cardiac output and end perfusion is likely more complex and variable based on bolus versus infusion dosing, volume status, baseline heart rate, autonomic tone, and cardiac pathology.
• These variations are attributable to the degree of vasoconstriction which can temporarily increase preload, arterial constriction which will increase systemic vascular resistance and afterload, and the presence of reflex bradycardia leading to an overall mixed effect on cardiac output depending on the patient population.
• Regarding ophthalmic administration, phenylephrine binds alpha-1 receptors that innervate the iris dilator muscle yielding smooth muscle contraction and subsequent dilation of the pupil, which can assist in fundoscopic exams, exposure in certain surgeries, and treatment of various conditions.

Pharmacokinetics:

• Absorption:

Erratic and incomplete absorption. Readily absorbed (oral). Bioavailability: Approx 40% (oral). Time to peak plasma concentration: 0.75-2 hours; 20 minutes (ophthalmic).

• Distribution:

Rapid distribution into peripheral tissues with minimal penetration into the brain. Volume of distribution: 200-500 L (oral).

• Metabolism:

Metabolized in the liver via sulfate conjugation (oral: 46%, mostly in gut wall; IV: 8%), oxidative deamination (oral: 24%; IV: 50%), and glucuronidation. Undergoes first-pass metabolism in the gut and liver by monoamine oxidase.

• Excretion:

Via urine (mainly as inactive metabolites). Elimination half-life: Approx 5 minutes (α-phase); 2-3 hours (terminal phase).

1. https://www.webmd.com/drugs/2/drug-21821/phenylephrine-oral/details
2. https://www.drugs.com/mtm/phenylephrine.html
3. https://go.drugbank.com/drugs/DB00388
4. https://www.ncbi.nlm.nih.gov/books/NBK534801/
5. https://my.clevelandclinic.org/health/drugs/20850-phenylephrine-oral-tablet
6. Start B, McGuinness MB, et,al. Cardiovascular adverse effects of phenylephrine eyedrops: a systematic review and meta-analysis. JAMA ophthalmology. 2015 Jun 1;133(6):647-52.