Flucytosine

BRAND NAMES

Ancobon (most widely known international brand)

MECHANISM OF ACTION

Flucytosine is an antifungal antimetabolite that is taken up by susceptible fungal cells and converted into 5-fluorouracil (5-FU) by fungal cytosine deaminase. The active metabolite then interferes with fungal RNA and DNA synthesis by inhibiting thymidylate synthase and disrupting protein synthesis. This leads to inhibition of fungal cell growth and replication. It is typically fungistatic and is often used in combination therapy to prevent resistance.

PHARMACOKINETICS

Absorption

Flucytosine is rapidly and well absorbed after oral administration, with bioavailability close to 90–100%. Peak plasma concentrations are usually reached within 1–2 hours.

Distribution

It is widely distributed throughout body fluids, including cerebrospinal fluid (CSF), making it useful for treating central nervous system fungal infections. Plasma protein binding is low (~2–4%).

Metabolism

A portion of flucytosine is converted by intestinal and microbial flora into 5-fluorouracil (5-FU), which contributes to both antifungal activity and toxicity.

Elimination

Flucytosine is primarily eliminated unchanged by the kidneys through glomerular filtration. The elimination half-life is approximately 3–6 hours in normal renal function but is prolonged in renal impairment.

PHARMACODYNAMICS

Flucytosine inhibits fungal growth by interfering with nucleic acid and protein synthesis after intracellular conversion to 5-FU. It is active against Cryptococcus neoformans and Candida species. Due to rapid resistance development, it is rarely used alone and is combined with amphotericin B or azole antifungals for synergistic effect.

ADMINISTRATION

Flucytosine is administered orally in capsule form and sometimes intravenously (where available). It is used in combination therapy for severe systemic fungal infections, especially cryptococcal meningitis.

DOSAGE AND STRENGTH

Dosage is weight-based and adjusted according to renal function. Therapeutic drug monitoring is often required to avoid toxicity, as narrow therapeutic index is a concern.

DRUG INTERACTIONS

Flucytosine has increased toxicity when combined with other bone marrow–suppressing drugs. It may also have additive effects with amphotericin B, requiring careful monitoring of renal and hematologic parameters.

FOOD INTERACTIONS

No significant food interactions are known. It can be taken with or without food, though gastrointestinal tolerance may improve when taken with meals.

CONTRAINDICATIONS

Flucytosine is contraindicated in patients with hypersensitivity to the drug. Caution is required in patients with severe bone marrow suppression or significant renal impairment.

SIDE EFFECTS

• Bone marrow suppression (leukopenia, thrombocytopenia)

• Nausea and vomiting

• Diarrhea

• Liver enzyme elevation

• Rash (rare)

OVER DOSAGE

Overdose of flucytosine is clinically important because it has a narrow therapeutic index, and toxicity is strongly related to elevated blood levels, especially in patients with renal impairment. The most serious effects are bone marrow suppression, which can lead to leukopenia, thrombocytopenia, and anemia.

TOXICITY

Overdose of Flucytosine can cause severe bone marrow suppression, leading to leukopenia, thrombocytopenia, and anemia. Gastrointestinal toxicity and hepatotoxicity may also occur. Neurotoxicity is possible in severe cases due to accumulation. Management includes stopping the drug, supportive care, and hemodialysis in cases of significant renal impairment or high serum levels.