Usage
Ketoconazole is prescribed for the treatment of serious systemic fungal infections like blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. It’s specifically indicated for patients who haven’t responded to or cannot tolerate other antifungal therapies. It’s also used off-label for Cushing’s syndrome and recurrent tinea versicolor. Ketoconazole is classified as an azole antifungal. It works by inhibiting the synthesis of ergosterol, a crucial component of fungal cell membranes. This disruption leads to increased fungal cell membrane permeability and ultimately fungal cell death.
Alternate Names
Ketoconazole is also known by the brand name Nizoral. There are no widely recognized international or regional variations of the generic name.
How It Works
Pharmacodynamics: Ketoconazole primarily exerts its antifungal effect by inhibiting the fungal cytochrome P450 enzyme lanosterol 14α-demethylase. This enzyme is essential for the conversion of lanosterol to ergosterol, a vital component of fungal cell membranes. The resulting ergosterol depletion alters membrane fluidity and function, ultimately leading to fungal cell death.
Pharmacokinetics:
- Absorption: Ketoconazole is best absorbed in an acidic environment. Conditions that reduce stomach acidity, such as achlorhydria or the use of acid-reducing medications, can significantly impair absorption.
- Metabolism: Ketoconazole is extensively metabolized in the liver, primarily by the CYP3A4 enzyme system.
- Elimination: Ketoconazole is mainly excreted in the feces, with a small portion excreted in urine.
Mode of Action: Ketoconazole binds to the heme iron of lanosterol 14α-demethylase, preventing the demethylation of lanosterol and blocking ergosterol synthesis.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: The primary mechanism involves the inhibition of the fungal cytochrome P450 enzyme lanosterol 14α-demethylase.
Elimination Pathways: Predominantly hepatic metabolism and biliary excretion with minimal renal excretion.
Dosage
Standard Dosage
Adults:
- Initial dose: 200 mg orally once daily.
- Dose increase: If the clinical response is inadequate, the dose may be increased to 400 mg orally once daily. For severe infections, doses up to 1200 mg/day in divided doses have been used.
- Maximum daily dose: The maximum recommended dose is generally 400 mg daily for fungal infections.
Children:
- Children 2 years and older: 3.3 to 6.6 mg/kg of body weight orally once daily.
- Children younger than 2 years: Use and dose must be determined by a doctor.
Special Cases:
- Elderly Patients: No specific dose adjustment is generally recommended, but caution is advised due to potential for decreased hepatic function. Close monitoring is necessary.
- Patients with Renal Impairment: No specific dose adjustment is typically required.
- Patients with Hepatic Dysfunction: Oral ketoconazole is contraindicated in patients with acute or chronic liver disease.
- Patients with Comorbid Conditions: Caution is necessary in patients with adrenal insufficiency or those under prolonged physiological stress. Careful monitoring of adrenal function is required.
Clinical Use Cases
Ketoconazole’s primary clinical use is for the oral treatment of systemic fungal infections. Its use in settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations isn’t standard practice and lacks supportive evidence.
Dosage Adjustments
Dosage adjustments are primarily guided by the patient’s clinical response and tolerability. In cases of insufficient response to initial doses, gradual dose escalation may be considered. For patients with hepatic dysfunction, oral ketoconazole is contraindicated.
Side Effects
Common Side Effects:
- Nausea
- Vomiting
- Abdominal pain
- Headache
- Dizziness
- Pruritus
Rare but Serious Side Effects:
- Hepatotoxicity (liver damage)
- Adrenal insufficiency
- QT prolongation
- Torsades de pointes
Long-Term Effects:
Chronic complications from prolonged ketoconazole use can include liver damage and adrenal insufficiency.
Adverse Drug Reactions (ADR):
Clinically significant ADRs include hepatotoxicity, QT prolongation, torsades de pointes, and adrenal insufficiency. These require immediate medical intervention.
Contraindications
- Acute or chronic liver disease
- Known hypersensitivity to ketoconazole
- Concomitant use with medications known to prolong the QT interval (e.g., dofetilide, quinidine, pimozide) and other contraindicated drugs (e.g., cisapride, midazolam, triazolam, ergot alkaloids)
Drug Interactions
Ketoconazole is a potent inhibitor of the CYP3A4 enzyme system and can interact with numerous medications. Clinically significant interactions can occur with:
- Medications metabolized by CYP3A4 (e.g., warfarin, cyclosporine, tacrolimus)
- QT-prolonging drugs (e.g., dofetilide, quinidine, pimozide)
- Antacids and H2 blockers (reduce ketoconazole absorption)
Pregnancy and Breastfeeding
Ketoconazole is classified as Pregnancy Category C. It’s not recommended during pregnancy unless the potential benefits outweigh the risks. Ketoconazole is excreted in breast milk. It’s generally advised to avoid breastfeeding while taking this medication.
Drug Profile Summary
- Mechanism of Action: Inhibits fungal ergosterol synthesis.
- Side Effects: Nausea, headache, abdominal pain, hepatotoxicity, QT prolongation.
- Contraindications: Liver disease, hypersensitivity, concomitant use of QT-prolonging drugs.
- Drug Interactions: CYP3A4 inhibitors and substrates, QT-prolonging drugs.
- Pregnancy & Breastfeeding: Not recommended unless benefits outweigh risks.
- Dosage: Adults: 200–400 mg/day; Children: 3.3–6.6 mg/kg/day.
- Monitoring Parameters: Liver function tests, adrenal function tests (if applicable), ECG (for QT prolongation).
Popular Combinations
Ketoconazole isn’t typically used in combination with other antifungals for the treatment of systemic mycoses.
Precautions
- Monitor liver function tests regularly.
- Monitor for signs and symptoms of adrenal insufficiency in at-risk patients.
- Avoid alcohol consumption as it may increase the risk of hepatotoxicity.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Ketoconazole?
A: Adults: 200-400 mg orally once daily. Children (2 years and older): 3.3-6.6 mg/kg orally once daily.
Q2: What are the most common side effects of Ketoconazole?
A: Nausea, vomiting, abdominal pain, headache, dizziness, and itching.
Q3: What are the serious side effects of Ketoconazole?
A: Liver damage (hepatotoxicity), QT interval prolongation, adrenal insufficiency.
Q4: What are the contraindications for using Ketoconazole?
A: Liver disease, known hypersensitivity to ketoconazole, concomitant use with certain medications like cisapride, pimozide, and dofetilide.
Q5: Does Ketoconazole interact with other medications?
A: Yes, it can interact with many medications, including warfarin, cyclosporine, some statins, and antacids.
Q6: Can Ketoconazole be used during pregnancy?
A: It should only be used if the potential benefit justifies the potential risk to the fetus.
Q7: Is Ketoconazole safe to use while breastfeeding?
A: Generally, it’s recommended to avoid breastfeeding while taking ketoconazole.
Q8: What should be monitored while a patient is on Ketoconazole?
A: Liver function tests and, in certain cases, adrenal function and ECG.
Q9: How long does treatment with Ketoconazole typically last?
A: The duration of therapy varies depending on the infection but can range from several weeks to six months or longer.
A: Oral ketoconazole is not recommended for superficial fungal infections due to the risk of systemic side effects. Topical formulations are available for these conditions.
