Introduction
Ketoconazole is a synthetic broad-spectrum antifungal agent belonging to the imidazole class. First approved by the FDA in 1981, it was among the first oral antifungal medications effective against systemic fungal infections. While its systemic use has declined due to safety concerns and the availability of newer antifungals, ketoconazole remains an important therapeutic option in dermatology as a topical formulation and has unique applications in endocrinology.
Mechanism of Action
Ketoconazole exerts its antifungal effects primarily through inhibition of ergosterol synthesis. It blocks cytochrome P450-dependent 14α-demethylation of lanosterol, which is essential for converting lanosterol to ergosterol, a critical component of fungal cell membranes. This disruption leads to increased membrane permeability and leakage of cellular contents.
Additionally, ketoconazole demonstrates significant inhibition of human cytochrome P450 enzymes, particularly CYP3A4, which accounts for its drug interaction profile and its off-label use in Cushing's syndrome through suppression of cortisol synthesis.
Indications
FDA-Approved Indications:- Topical formulations: Treatment of tinea corporis, tinea cruris, tinea pedis, tinea versicolor, cutaneous candidiasis, and seborrheic dermatitis
- Shampoo: Treatment of dandruff and seborrheic dermatitis of the scalp
- Systemic fungal infections (currently limited due to hepatotoxicity risk)
- Off-label: Cushing's syndrome (adrenal steroidogenesis inhibition)
Dosage and Administration
Topical formulations:- Cream, ointment: Apply to affected area once or twice daily
- Shampoo: Use twice weekly for 4 weeks, allowing 3-5 minutes before rinsing
- Adults: 200-400 mg once daily
- Children >2 years: 3.3-6.6 mg/kg once daily
- Hepatic impairment: Contraindicated in oral form
- Renal impairment: No dosage adjustment required
- Elderly: Use with caution due to increased risk of hepatotoxicity
Pharmacokinetics
Absorption: Oral administration requires gastric acidity for adequate absorption (bioavailability ~75%). Food improves absorption. Distribution: Widely distributed to body tissues and fluids, including synovial fluid, saliva, and skin. Protein binding ~99%. Metabolism: Extensive hepatic metabolism via CYP3A4 and other enzymes. Elimination: Primarily fecal excretion (57%) with renal elimination of metabolites (13%). Half-life: Biphasic - initial 2 hours, terminal 8 hours.Contraindications
- Hypersensitivity to ketoconazole or other azole antifungals
- Acute or chronic liver disease
- Concurrent use with drugs that prolong QT interval
- Concomitant administration with cisapride, disopyramide, dofetilide, dronedarone, methadone, quinidine, or ranolazine
- Pregnancy
Warnings and Precautions
Black Box Warning: Oral ketoconazole carries risk of hepatotoxicity, adrenal insufficiency, and drug interactions- Hepatotoxicity: May be severe and sometimes fatal; monitor liver function tests
- Adrenal insufficiency: Monitor for signs and symptoms
- QT prolongation: May occur with oral administration
- Avoid concurrent use with CYP3A4 substrates
- Topical use: May cause local irritation, pruritus, and burning sensation
Drug Interactions
Major Interactions:- CYP3A4 substrates: Increased levels of drugs such as alfentanil, alprazolam, atorvastatin, benzodiazepines, calcium channel blockers, carbamazepine, cyclosporine, digoxin, lovastatin, midazolam, quinidine, simvastatin, tacrolimus, warfarin
- Drugs that prolong QT interval: Additive risk of torsades de pointes
- Antacids, H2-receptor antagonists, proton pump inhibitors: Reduced ketoconazole absorption
- Rifampin, isoniazid: Decreased ketoconazole levels
Adverse Effects
Common:- Topical: Burning, itching, irritation at application site
- Oral: Nausea, vomiting, abdominal pain, pruritus, headache
- Hepatotoxicity (elevated LFTs, hepatitis, hepatic failure)
- Adrenal insufficiency
- QT prolongation and torsades de pointes
- Anaphylaxis
- Thrombocytopenia
Monitoring Parameters
For oral therapy:- Liver function tests at baseline, frequently during therapy, and as clinically indicated
- Serum cortisol and ACTH levels if used for Cushing's syndrome
- ECG monitoring for QT prolongation
- Signs and symptoms of adrenal insufficiency
- Therapeutic response and fungal culture results
- Clinical response
- Local skin reactions
Patient Education
- Complete full course of therapy even if symptoms improve
- For oral form: Report any signs of liver problems (yellowing skin/eyes, dark urine, fatigue)
- Avoid alcohol during therapy
- Topical forms: For external use only; avoid eyes and mucous membranes
- Shampoo: Leave on scalp for 3-5 minutes before rinsing
- Inform all healthcare providers about ketoconazole use
- Use effective contraception during oral therapy
- Oral form requires gastric acidity; avoid concomitant antacids
References
1. FDA Drug Safety Communication: FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. FDA, 2013. 2. Gupta AK, Lyons DCA. The rise and fall of oral ketoconazole. J Cutan Med Surg. 2015;19(4):352-357. 3. Katzung BG, Trevor AJ. Basic & Clinical Pharmacology. 14th ed. McGraw-Hill Education, 2017. 4. Lexicomp Online. Ketoconazole: Drug Information. Wolters Kluwer Clinical Drug Information, 2023. 5. Roberts DT, Taylor WD, Boyle J. Guidelines for treatment of onychomycosis. Br J Dermatol. 2003;148(3):402-410. 6. Sonino N, Boscaro M. Medical therapy for Cushing's disease. Endocrinol Metab Clin North Am. 1999;28(1):211-222.