Minoxidil is an antihypertensive agent that is used largely for patients with severe and refractory hypertension not responding to conventional therapies. Minoxidil is also used topically to treat male pattern baldness. Despite its use for many years, minoxidil has not been convincingly linked to cases of clinically apparent liver injury.
Minoxidil (min ox' i dil) is one of the first antihypertensive agents developed for use in humans. Minoxidil is activated in the liver and acts to relax vascular smooth muscle by opening cell surface potassium channels causing an efflux of potassium, hyperpolarization and relaxation of smooth muscle cells. The increased vasodilation caused by minoxidil can result in a reflex increase in cardiac output and sodium retention for which reasons it is not recommended as monotherapy or as a first line agent for hypertension. Minoxidil was approved for use in the United States in 1979 and continues to be used for treatment of severe and refractory hypertension, usually in combination with beta blockers and diuretics. Minoxidil is available in tablets of 2.5 and 10 mg in generic forms and under the brand name Loniten. The usual initial dose in adults is 2.5 to 5 mg once daily, with subsequent adjustment based upon tolerance and clinical effect to a typical maintenance dose is 10 to 40 mg daily. Minoxidil has many side effects including sodium retention, edema, headache, nausea, breast tenderness, gynecomastia, hypertrichosis and rash. The effect on hair growth has led to the use of topical minoxidil to treat male pattern baldness.
Serum aminotransferase elevations during minoxidil therapy are uncommon, but have been reported even with topical administration. Despite many decades of use, oral minoxidil has not been implicated in convincing cases of clinically apparent acute liver injury. Severe rash, toxic epidermal necrolysis and Stevens Johnson syndrome have been reported after minoxidil therapy (generally arising within 2 to 6 weeks of starting), but published cases have not been marked by concurrent hepatic injury.
Mechanism of Injury
Minoxidil is metabolized by the liver, but has little effect on hepatic metabolism of other drugs. The reason for its lack of hepatotoxicity is not known.
REPRESENTATIVE TRADE NAMES
Minoxidil – Generic, Loniten®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 17 February 2014
Zimmerman HJ. Drugs used in cardiovascular disease. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 639-71. (Expert review of hepatotoxicity published in 1999; mentions that topical minoxidil has been associated with liver injury).
De Marzio DH, Navarro VJ. Antihypertensives. Hepatotoxicity of cardiovascular and
antidiabetic drugs: antihypertensives. In, Kaplowitz N, DeLeve LD, eds.
Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 522-5. (Review of hepatotoxicity of antihypertensive drugs, minoxidil is not discussed).
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745-88. (Textbook of pharmacology and therapeutics; minoxidil is metabolized in the liver to its active molecule, which relaxes vascular smooth muscle by activating the ATP-modulated potassium channel).
DiSantis DJ, Flanagan J. Minoxidil-induced Stevens-Johnson syndrome. Arch Intern Med 1981; 141: 1515. PubMed Citation (35 year old man developed rash 17 days after starting minoxidil and 12 days after starting allopurinol followed by fever and desquamation, improving on stopping and with corticosteroids; on restarting minoxidil he developed rash and fever 3 days later; no mention of liver involvement).
Colamarino R, Dubost JJ, Sauvezie B. Polymyalgia and minoxidil. Ann Intern Med 1990; 113: 256-7. PubMed Citation (4 men, ages 27-48 years, developed fatigue, muscle aches, anorexia and low grade fever 2 to 14 months after starting topical minoxidil, 3 had transient liver enzyme elevations, but none had jaundice and abnormalities resolved rapidly upon withdrawal).
Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang
H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical
features, and outcomes from a prospective study of drug-induced liver injury in
the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected from
2004 to 2008, antihypertensive agents accounted for 5% of cases and included methyldopa, irbesartan, amlodipine, lisinopril and hydralazine; none were attributed to minoxidil).
Levi N, Bastuji-Garin S, Mockenhaupt M, Roujeau JC, Flahault A, Kelly JP, Martin E, et al. Medications as risk factors of Stevens-Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics 2009; 123: e297-304. PubMed Citation (Pooled analysis of 80 cases of Stevens Johnson syndrome in children from 2 multicenter international case control studies did not confirm an association with medication use).
Callen EC, Church CO, Hernandez CL, Thompson ED. Stevens-Johnson syndrome associated with oral minoxidil: a case report. J Nephrol 2007; 20: 91-3. PubMed Citation (50 year old man developed oral blisters 1 week after starting minoxidil; liver tests were normal).
Karaoui LR, Chahine-Chakhtoura C. Fatal toxic epidermal necrolysis associated with minoxidil. Pharmacotherapy 2009; 29: 460-7. PubMed Citation (69 year old woman developed severe rash 11 days after starting minoxidil with bullae and death 2 weeks later; liver tests were normal on admission).
Drugs for hypertension. Treat Guidel Med Lett 2009; 7: 1-10. PubMed Citation (Brief overview of currently available drugs for hypertension with guidelines on their use and information on prices and toxicities; minoxidil is considered a direct vasodilator and should be given with a beta blocker or centrally acting drug to minimize reflex increase in heart rate and diuretic to avoid sodium retention; it can also cause hirsutism).
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