Continuing Education Activity

Ketoconazole is a drug used in the management and treatment of fungal infections. It is in the imidazole antifungal class of medications. This activity describes the indications, actions, and contraindications of ketoconazole as a valuable agent in treating fungal infections. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to members of the interprofessional team in the treatment of patients with fungal infection.

Objectives:

• Identify the mechanism of action of ketoconazole.
• Describe the adverse effects of ketoconazole.
• Review the appropriate monitoring of ketoconazole.
• Summarize some interprofessional team strategies for improving care coordination and communication to advance ketoconazole and improve outcomes.

Indications

Ketoconazole has approval for use in the treatment of fungal infections of the skin and systemic fungal infections.[1] These include blastomycosis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, and chromomycosis. The most common use of ketoconazole for skin infections is that of tinea versicolor.[2] Due to the advent of more effective fungal infection treatment options, ketoconazole is typically not the first-line medication anymore. It should only be an option when other first-line treatments are not available or not tolerated by the patient.[3] 

The use of this drug requires a careful risk-benefit analysis when selecting ketoconazole as the treatment of fungal infections. Clinicians should avoid using ketoconazole in the treatment of onychomycosis, cutaneous dermatophyte, and candida infections.[3] Ketoconazole is not indicated in the treatment of fungal meningitis because it does not penetrate the cerebrospinal fluid. Some of the off-label uses of ketoconazole include Cushing syndrome and prostate cancer.[4]

Mechanism of Action

Ketoconazole works as an antifungal agent by inhibiting the cytochrome P450 14α-demethylase enzyme. This enzyme is responsible for inhibiting the biosynthesis of triglycerides and phospholipids by fungi.[5] More specifically, ketoconazole inhibits the synthesis of lanosterol, a necessary precursor for ergosterol biosynthesis. Ergosterol is needed to maintain the integrity of the membrane of fungi.[6] Without ergosterol, the fluidity of the membrane increase, which in turn prevents fungal growth. Ketoconazole, in high doses, can competitively bind to androgen receptors, such as that of testosterone and dihydrotestosterone, which can decrease the activity of testosterone and dihydrotestosterone in prostate cancer. Ketoconazole can also inhibit the enzymes 17-alpha-hydroxylase and 17,20-lyase, which are necessary for the synthesis of steroids in the adrenal cortex, including testosterone.[7] 

Ketoconazole inhibits the activity of the enzyme 21-hydroxylase. This enzyme is essential for synthesizing mineralocorticoids and glucocorticoids, such as cortisol, in the adrenal cortex.[8] By inhibiting enzymes involved in cortisol synthesis, ketoconazole can be a treatment option for Cushing syndrome.[9]

Administration

Ketoconazole is available in tablet form and as a topical agent in creams, foams, and shampoos.[10] It is also available in mixture products. The oral form of ketoconazole is used for systemic administration and must be taken at least two hours before any antacids.[11] The high pH of the gastric contents would decrease absorption, so appropriate timing of administration is paramount to its absorption and subsequent efficacy. Adult and pediatric patients with achlorhydria should be given ketoconazole tablets with an acidic beverage to decrease pH and allow for optimal absorption.

Topical ketoconazole is only for external use. It should not be ingested or used intravaginally. The eyes and mucous membranes should also be avoided. Patients should apply the cream and gel only to the affected area and the areas immediately surrounding it. The foam should be applied directly to the infected area to avoid melting in the hands. Handwashing is necessary after the application of the cream and gel to prevent any adverse reactions from the medication. The shampoo application should be slathered onto the scalp and rinsed thoroughly.

Adverse Effects

Systemic ketoconazole administration most commonly causes gastrointestinal side effects.[12] These include nausea, vomiting, constipation, abdominal pain, dry mouth, flatulence, and tongue discoloration. It can also cause adrenal insufficiency due to its role in the inhibition of enzymes in the steroid synthesis pathway. Decreases in cortisol synthesis can lead to orthostatic hypotension.[13] In high doses, it can also cause gynecomastia in males.[14] Ketoconazole can cause severe liver injury and jaundice.[15] 

Hypersensitivity reactions have also been reported, such as anaphylaxis and urticaria. High-dose ketoconazole has been shown to cause an increase in long bone fragility and lead to fracture. Other side effects include alcohol intolerance, decreased platelet count, epistaxis, fatigue, hot flash, hyperlipidemia, insomnia, myalgia, nervousness, paresthesia, and peripheral edema. Topical ketoconazole can cause dermatological reactions, including pruritis, stinging, and dryness at the application site. There are also reports of dry hair, dry scalp, and oily hair when using ketoconazole-containing shampoo. Less common adverse effects include abnormal hair texture, alopecia, angioedema, contact dermatitis, eye irritation, headache, hypersensitivity reaction, impetigo, and pyogenic granuloma.[16]

Contraindications

Ketoconazole is contraindicated in patients with acute or chronic liver disease due to its association with hepatotoxicity, which can be fatal. It is contraindicated in adrenal insufficiency because high doses of ketoconazole inhibit adrenocortical function.[17] Ketoconazole should not be given to patients with a known hypersensitivity reaction to ketoconazole.[15] Ketoconazole should never be co-administered with HMG-CoA reductase inhibitors because it can increase the risk of myopathy.[18] 

Ketoconazole is contraindicated in patients taking benzodiazepines because it can increase plasma concentrations and lead to sedation. Ketoconazole should never be administered to patients on antiarrhythmic drugs, cisapride, pimozide, quinidine, and ranolazine because it can cause QT prolongation and torsade de pointes.[19] In patients with increased bone fragility, such as post-menopausal women and the elderly, ketoconazole should be used with caution to avoid the risk of fracture. The CYP3A4 liver enzyme metabolizes ketoconazole, and use requires caution in patients taking drugs that inhibit CYP3A4 or are metabolized by CYP3A4.[19] Ketoconazole can also be present in breast milk, so breastfeeding is not recommended when using the drug.[20]

Monitoring

Due to its hepatoxic effects, patients taking oral ketoconazole should have their hepatic function monitored, which is through hepatic function tests such as aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, albumin, and prothrombin time (PT).

Hepatic function tests should take place at baseline, frequently during ketoconazole therapy, and after therapy has ceased. Period calcium and phosphorous levels are recommended for patients on long-term therapy with ketoconazole. The adrenal function also requires monitoring during treatment with ketoconazole. This monitoring is possible by measuring blood levels of sodium, potassium, cortisol, and adrenocorticotropic hormone (ACTH).[21]

Toxicity

The Food and Drug Administration warns that oral dosing of ketoconazole can lead to hepatotoxicity and adrenal insufficiency and that ketoconazole-associated hepatotoxicity is common. There are many off-label uses for ketoconazole. Therefore, careful selection of ketoconazole as a treatment is necessary due to serious hepatoxic side effects.[21]

Enhancing Healthcare Team Outcomes

Managing the administration and usage of ketoconazole requires an interprofessional team of healthcare professionals, including nurses, laboratory technologists, pharmacists, and several physicians in different specialties. Since the usage of ketoconazole can result in adverse effects such as hepatotoxicity and adrenal insufficiency, it is important to monitor liver and adrenal function in patients considered for ketoconazole treatment. This monitoring requires that each member of the healthcare team monitor patient for signs of acute liver failure not only with laboratory evidence but also clinically by recognizing the signs of liver dysfunction. In addition, since there are off-label and over-the-counter uses of ketoconazole, it is important to educate patients about the adverse effects of this drug and the proper use of the medication. Therefore, the interprofessional model for patient care when using ketoconazole therapy is crucial to driving optimal patient outcomes while reducing the potential for adverse effects. [Level 5]

Review Questions

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• Comment on this article.

References

1.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): May 18, 2017. Antifungal Agents. [PMC free article: PMC547852] [PubMed: 31643715]

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Patel V, Liaw B, Oh W. The role of ketoconazole in current prostate cancer care. Nat Rev Urol. 2018 Oct;15(10):643-651. [PubMed: 30154429]

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Hu Z, He B, Ma L, Sun Y, Niu Y, Zeng B. Recent Advances in Ergosterol Biosynthesis and Regulation Mechanisms in Saccharomyces cerevisiae. Indian J Microbiol. 2017 Sep;57(3):270-277. [PMC free article: PMC5574775] [PubMed: 28904410]

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Bhasin S, Sikka S, Fielder T, Sod-Moriah U, Levine HB, Swerdloff RS, Rajfer J. Hormonal effects of ketoconazole in vivo in the male rat: mechanism of action. Endocrinology. 1986 Mar;118(3):1229-32. [PubMed: 3081326]

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Engelhardt D, Weber MM, Miksch T, Abedinpour F, Jaspers C. The influence of ketoconazole on human adrenal steroidogenesis: incubation studies with tissue slices. Clin Endocrinol (Oxf). 1991 Aug;35(2):163-8. [PubMed: 1934533]

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Loli P, Berselli ME, Tagliaferri M. Use of ketoconazole in the treatment of Cushing's syndrome. J Clin Endocrinol Metab. 1986 Dec;63(6):1365-71. [PubMed: 3023421]

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Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE. Ketoconazole shampoo: effect of long-term use in androgenic alopecia. Dermatology. 1998;196(4):474-7. [PubMed: 9669136]

11.

Khozeimeh F, Shahtalebi MA, Noori M, Savabi O. Comparative evaluation of ketoconazole tablet and topical ketoconazole 2% in orabase in treatment of Candida-infected denture stomatitis. J Contemp Dent Pract. 2010 Mar 01;11(2):017-24. [PubMed: 20228983]

12.

Sohn CA. Evaluation of ketoconazole. Clin Pharm. 1982 May-Jun;1(3):217-24. [PubMed: 6309466]

13.

Gupta AK, Daigle D, Foley KA. Drug safety assessment of oral formulations of ketoconazole. Expert Opin Drug Saf. 2015 Feb;14(2):325-34. [PubMed: 25409549]

14.

DeFelice R, Johnson DG, Galgiani JN. Gynecomastia with ketoconazole. Antimicrob Agents Chemother. 1981 Jun;19(6):1073-4. [PMC free article: PMC181611] [PubMed: 6267997]

15.

Gupta AK, Lyons DC. The Rise and Fall of Oral Ketoconazole. J Cutan Med Surg. 2015 Jul-Aug;19(4):352-7. [PubMed: 25775613]

16.

Choi FD, Juhasz MLW, Atanaskova Mesinkovska N. Topical ketoconazole: a systematic review of current dermatological applications and future developments. J Dermatolog Treat. 2019 Dec;30(8):760-771. [PubMed: 30668185]

17.

Daneshmend TK, Warnock DW. Clinical pharmacokinetics of ketoconazole. Clin Pharmacokinet. 1988 Jan;14(1):13-34. [PubMed: 3280211]

18.

Kempen HJ, van Son K, Cohen LH, Griffioen M, Verboom H, Havekes L. Effect of ketoconazole on cholesterol synthesis and on HMG-CoA reductase and LDL-receptor activities in Hep G2 cells. Biochem Pharmacol. 1987 Apr 15;36(8):1245-9. [PubMed: 3036162]

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Lee HC, Tl Huang K, Shen WK. Use of antiarrhythmic drugs in elderly patients. J Geriatr Cardiol. 2011 Sep;8(3):184-94. [PMC free article: PMC3390066] [PubMed: 22783304]

20.

McGregor JA, Pont A. Contraindication of ketoconazole in pregnancy. Am J Obstet Gynecol. 1984 Nov 15;150(6):793-4. [PubMed: 6093540]

21.

Yan JY, Nie XL, Tao QM, Zhan SY, Zhang YD. Ketoconazole associated hepatotoxicity: a systematic review and meta- analysis. Biomed Environ Sci. 2013 Jul;26(7):605-10. [PubMed: 23895707]

Disclosure: Hadeer Sinawe declares no relevant financial relationships with ineligible companies.

Disclosure: Damian Casadesus declares no relevant financial relationships with ineligible companies.