Fluconazole

Usage

Fluconazole is prescribed for the treatment of a variety of fungal infections. It belongs to the triazole class of antifungals. It works by inhibiting the synthesis of ergosterol, a crucial component of the fungal cell membrane. This disruption leads to increased cell membrane permeability and ultimately fungal cell death.

Alternate Names

Fluconazole is also known by its popular brand name, Diflucan.

How It Works

Pharmacodynamics: Fluconazole exerts its antifungal effect by inhibiting the fungal cytochrome P450 enzyme 14α-demethylase, which is essential for ergosterol synthesis. This leads to altered cell membrane structure and function, resulting in fungal cell death.

Pharmacokinetics: Fluconazole is well-absorbed orally, with bioavailability exceeding 90%. It exhibits excellent penetration into various body fluids and tissues, including cerebrospinal fluid. It is primarily excreted unchanged in the urine via renal pathways. Fluconazole is metabolized to a minor extent by CYP enzymes, mainly CYP2C9 and CYP3A4.

Mode of Action: Fluconazole specifically targets fungal 14α-demethylase, a key enzyme in the ergosterol biosynthesis pathway. This selective inhibition disrupts fungal cell membrane integrity.

Elimination Pathways: Primarily renal excretion, with minimal hepatic metabolism by CYP2C9 and CYP3A4.

Dosage

Standard Dosage

Adults:

• Vaginal Candidiasis: 150 mg single oral dose.
• Oropharyngeal Candidiasis: 200 mg on the first day, followed by 100 mg once daily for 7-14 days (or longer if needed).
• Esophageal Candidiasis: 200 mg on the first day, followed by 100 mg once daily for at least 3 weeks.
• Systemic Candidiasis: 400 mg on the first day, followed by 200 mg once daily. Dose may be increased to 400 mg daily depending on clinical response.
• Cryptococcal Meningitis: 400 mg on the first day, followed by 200 mg once daily for 10-12 weeks (or longer, depending on clinical response).
• Prophylaxis of Candidiasis in Immunocompromised Patients: 50-400 mg once daily, starting several days before anticipated neutropenia and continuing for 7 days after neutrophil count recovers.

Children:

• Dosing is based on weight (mg/kg) and the specific infection being treated. Generally, the daily dose ranges from 3 mg/kg to 12 mg/kg.
• Mucosal Candidiasis: 3 mg/kg once daily (a loading dose of 6 mg/kg may be used on the first day).
• Systemic Candidiasis/Cryptococcal infections: 6-12 mg/kg once daily, depending on the severity of the infection.
• Children 0-4 weeks: Same mg/kg dosing as older children, but administered every 72 hours in the first 2 weeks of life, and every 48 hours in weeks 3-4.

Special Cases:

• Elderly Patients: Dosage adjustments based on creatinine clearance may be needed.
• Patients with Renal Impairment: Dosage adjustments are required based on creatinine clearance (see below).
• Patients with Hepatic Dysfunction: Caution is advised, but specific dosage adjustments are not routinely recommended.
• Patients with Comorbid Conditions: Careful monitoring is essential, and dosage adjustments may be necessary.

Clinical Use Cases

Dosing for clinical scenarios such as intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations should follow the guidelines for the specific infection being treated and be adjusted based on the patient’s renal function and other clinical factors.

Dosage Adjustments

• Renal Impairment:

  • CrCl > 50 mL/min: 100% of dose.
  • CrCl ≤ 50 mL/min: 50% of dose.
  • Hemodialysis: 100% of dose after each dialysis session.

Side Effects

Common Side Effects:

• Headache
• Diarrhea
• Nausea
• Abdominal pain
• Rash

Rare but Serious Side Effects:

• Hepatotoxicity (liver damage)
• Stevens-Johnson Syndrome
• Toxic Epidermal Necrolysis
• QT prolongation
• Seizures

Long-Term Effects:

With prolonged use, potential chronic complications can include liver dysfunction and electrolyte imbalances.

Adverse Drug Reactions (ADR):

Serious ADRs requiring immediate intervention include severe skin reactions (SJS/TEN), hepatotoxicity, and cardiac arrhythmias.

Contraindications

• Hypersensitivity to fluconazole or other azole antifungals.
• Co-administration with cisapride or terfenadine.

Drug Interactions

Fluconazole interacts with numerous medications. Clinically significant interactions include:

• CYP450 Interactions: Fluconazole inhibits CYP2C9, CYP2C19, and CYP3A4, potentially increasing the concentrations of drugs metabolized by these enzymes (e.g., warfarin, phenytoin, sulfonylureas, some statins).
• QT Prolonging Drugs: Concurrent use with other QT prolonging drugs should be avoided.
• Immunosuppressants: Fluconazole can increase levels of tacrolimus and cyclosporine.

Pregnancy and Breastfeeding

• Pregnancy: Fluconazole is generally avoided during pregnancy, especially high doses during the first trimester, due to the risk of congenital anomalies. Low doses for vaginal candidiasis are generally considered safe.
• Breastfeeding: Fluconazole is present in breast milk at concentrations lower than maternal plasma levels. It is generally considered safe to use while breastfeeding.

Drug Profile Summary

• Mechanism of Action: Inhibits fungal ergosterol synthesis.
• Side Effects: Headache, diarrhea, nausea, rash, hepatotoxicity (rare).
• Contraindications: Hypersensitivity, co-administration with cisapride or terfenadine.
• Drug Interactions: Numerous, including CYP450 interactions and QT prolonging drugs.
• Pregnancy & Breastfeeding: Avoid high doses during pregnancy; generally safe during breastfeeding.
• Dosage: Variable depending on infection and patient factors.
• Monitoring Parameters: Liver function tests, renal function, electrolyte levels, ECG (in patients at risk for QT prolongation).

Popular Combinations

Fluconazole is often used in combination with topical antifungals for the treatment of certain infections like vaginal candidiasis or onychomycosis.

Precautions

• Monitor liver and renal function.
• Assess for QTc prolongation.
• Pre-screening for drug allergies and potential drug interactions.
• Caution in patients with hepatic or renal impairment.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Fluconazole?

A: Dosage varies depending on the infection and patient factors. See detailed dosage guidelines above.

Q2: What are the most common side effects?

A: Headache, diarrhea, nausea, and rash.

Q3: Is Fluconazole safe during pregnancy?

A: High doses during the first trimester are associated with congenital anomalies and should be avoided. Low doses for vaginal candidiasis are generally considered safe.

Q4: Can Fluconazole be used while breastfeeding?

A: Yes, it is generally considered safe to use while breastfeeding.

Q5: What are the major drug interactions with Fluconazole?

A: Fluconazole interacts with many drugs metabolized by CYP450 enzymes, QT prolonging agents, and immunosuppressants.

Q6: What is the mechanism of action of Fluconazole?

A: It inhibits fungal ergosterol synthesis by targeting the enzyme 14α-demethylase.

Q7: How is Fluconazole eliminated from the body?

A: Primarily through renal excretion.

Q8: What precautions should be taken when prescribing Fluconazole?

A: Monitor liver and renal function, assess for QTc prolongation, and screen for drug allergies and potential drug interactions.

Q9: What should be done in case of a suspected Fluconazole overdose?

A: Supportive care and symptomatic treatment should be provided. Hemodialysis may be helpful in removing the drug from the body.

Q10: Are there any contraindications to using Fluconazole?

A: Yes, hypersensitivity to fluconazole or other azole antifungals, and co-administration with cisapride or terfenadine are contraindicated.