Ketoconazole | Pharmacology Mentor

Generic Name

Ketoconazole

Inhibition of lanosterol 14α‑demethylase (CYP51) – blocks ergosterol synthesis, compromising fungal cell membrane integrity.
Azole structure binds to the heme iron of the enzyme, preventing sterol production.
Result: fungicidal activity against dermatophytes, yeasts, and some molds; fungistatic against others.

Absorption: Oral bioavailability ~50 % in healthy subjects; reduced in steatotic liver disease or with food.
Distribution: Highly protein‑bound (>95 %); lipophilic; penetrates skin and mucous membranes well.
Metabolism: First‑pass hepatic oxidation primarily via CYP3A4 and CYP2C19; extensive metabolism leads to several active metabolites.
Excretion: ~60 % renal, the rest biliary/fecal.
Half‑life: ~8 h (oral); longer (up to 12–18 h) for systemic therapy.

Contraindications:
Known hypersensitivity to ketoconazole or other azoles
Active liver disease (ALT/AST >3 × ULN)
Significant hepatic impairment or cholestasis
Warnings:
Hepatotoxicity: Monitor liver enzymes weekly for first 4 weeks of systemic therapy.
Drug interactions:
Potentiates CYP3A4 inhibitors (e.g., clarithromycin, azithromycin) → ↑ ketoconazole levels
Reduces efficacy of drugs metabolized by CYP3A4 (e.g., oral contraceptives, warfarin, statins)
Cardiac: QTc prolongation (rare)
Dermatologic: Photosensitivity reactions with topical use.

Topical:
2 % solution: apply to affected area twice daily; wash off after 5–10 min.
2 % cream (10 % solution): same dosing.
10 % solution for onychomycosis: 5 min exposure, repeat 2–3 days weekly.
2–3 % shampoo for tinea capitis: 5–10 min, three times weekly.
Oral (not routinely recommended):
200 mg twice daily for 14 days (with 1 mg/kg loading dose) for systemic mycoses.
200 mg daily for hormone disorders.
Adjust for renal/hepatic impairment; avoid in severe hepatic disease.

Baseline: ALT, AST, total bilirubin, alkaline phosphatase, potassium, BNP (if heart failure), QTc.
During therapy:
Weekly LFTs (first month); every 4 weeks thereafter.
Potassium each month when > 6 months on systemic therapy.
Clinical signs: jaundice, dark urine, abdominal pain.
Drug interaction checks: Review concomitant meds metabolized by CYP3A4.

“Ketoconazole still matters for hormone disorders.” Even though newer azoles are preferred, ketoconazole remains the drug of choice for oral suppression of adrenal androgen production in hirsutism and acne due to inexpensive cost and effective potency.
“Wash‑off matters.” Because the topical formulation is rinsed off after 5–10 min, patient education is critical—over‑exposure leads to skin irritation and photosensitivity.
“When kidneys fail, use it cautiously.” Renal excretion accounts for a large portion of clearance; dose adjustment is warranted in severe renal impairment and the drug should be avoided if creatinine clearance <30 mL/min when systemic therapy is considered.
“Check for CYP3A4 synergy.” Patients on clarithromycin or azithromycin may require a dose reduction or discontinuation due to synergistic CYP3A4 inhibition, which dramatically elevates ketoconazole plasma levels and risk of hepatotoxicity.
“Adrenal suppression risk.” Ketoconazole can inhibit 11β‑hydroxylase and 17,20‑lyase enzymes, occasionally provoking adrenal insufficiency—beware especially in patients with pre‑existing adrenal dysfunction or on steroids.