Griseofulvin
Griseofulvin
Generic Name
Griseofulvin
Mechanism
- Mitotic inhibition: Griseofulvin covalently binds to β‑tubulin, disrupting the microtubule network required for spindle formation during mitosis.
- Result: Impaired keratinocyte proliferation in the outermost layers, effectively halting fungal growth.
- Limited action: Poor penetration into skin/airways → predominantly effective in keratinized tissues; not used for systemic fungal disease.
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Pharmacokinetics
| Parameter | Detail | Notes |
| Absorption | Oral: 30–50 % bioavailability; food reduces absorption (especially high‑fat meals). | Avoid taking with high‑fat meals to maximize uptake. |
| Distribution | Widely distributed; high affinity for keratin; crosses placenta and CSF in small amounts. | Steady state in keratin ~ 6–8 days. |
| Metabolism | Predominantly hepatic via CYP2C19/3A4 → active metabolites. | Induces CYP enzymes (except CYP2C19). |
| Elimination | Renal excretion (~20 % unchanged) and biliary excretion. | Dose adjustment in advanced renal impairment not routinely required. |
| Half‑life | 14–23 h (variable). | Prolonged due to deposition in keratin. |
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Indications
- Tinea capitis (scalp) – most common use in pediatric population, especially *Microsporum* or *Trichophyton* species.
- Tinea corporis / Tinea cruris / Tinea faciei – when systemic therapy is warranted (e.g., extensive lesions, lesions refractory to topical therapy).
- Tinea unguium (onychomycosis) – as an alternative when oral antifungals such as terbinafine are contraindicated or not tolerated.
- Tinea pedis – in severe cases requiring oral therapy.
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Contraindications
- Contraindicated in patients with severe hepatic impairment, pregnancy (category D) – teratogenic potential; avoid in breastfeeding due to excretion into milk.
- Use with caution in:
- Renal dysfunction (monitor renal function, though dose adjustment is rarely needed).
- Severe malnutrition – decreased absorption → may necessitate dose adjustment.
- Grapefruit or grapefruit juice intake – CYP3A4 interaction may increase plasma levels.
- Drug interactions:
- Potentiates effects of warfarin (increased INR).
- Induces enzymes that lower plasma levels of amoxicillin-clavulanic acid, venlafaxine, carbamazepine.
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Dosing
| Population | Dose | Administration | Notes |
| Children (≤12 yr) | 30–50 mg/kg/day, divided q12 h | Oral tablets or solution | Weight‑based dosing critical for adequate exposure. |
| Adults | 1 mg/kg/day (max 200 mg) | 1–2 tablets q12 h | Use at least 6–8 weeks to allow depot saturation. |
| Tinea unguium | 100 mg/day | Daily | Extend treatment to 12–16 weeks. |
| Administration | Take with a light meal (avoid fatty foods) | Avoid alcohol | Alcohol, nutrients with fat, and grapefruit juice reduce absorption. |
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Adverse Effects
Common
• Dermatologic: flushing, erythema, pruritus.
• Gastrointestinal: nausea, vomiting, dyspepsia.
• Neurologic: headache, dizziness, fatigue.
Serious
• Hepatotoxicity – transaminase elevations; monitor liver enzymes before and during therapy.
• Hypersensitivity reactions – rash, eosinophilia.
• Bone marrow suppression – rarely; monitor CBC in prolonged therapy.
• Phototoxicity – increased sun sensitivity; advise sun protection.
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Monitoring
- Baseline: CBC, LFTs (AST, ALT, ALP, bilirubin).
- During therapy (every 2–4 weeks): Repeat LFTs; monitor for signs of hepatotoxicity.
- Therapeutic response: Clinical clearance of lesions (typically 6–8 weeks).
- Drug interactions: Check concomitant medications that influence CYP3A4/2C19.
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Clinical Pearls
- Flushing as a release indicator: Immediate flushing on drug intake is a hallmark of griseofulvin; reassure patients it is expected.
- Prolonged treatment: The drug’s efficacy relies on steady-state deposition in keratin; abrupt discontinuation often fails to eradicate infection.
- Use with *tinea capitis* pathogens: Microsporum species respond better than *Trichophyton*; consider azoles as first line if *T. tonsurans* is isolated.
- Avoid long‑term: Induction of hepatic enzymes may lead to therapeutic failure of concurrent drugs (e.g., carbamazepine).
- Pediatric dosing imperative: Weight‑based doses prevent under‑exposure, which is a common cause of relapse in children.
- Cross‑reactivity: Not markedly cross‑reactive with penicillin; can be used safely in patients with penicillin allergy.
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• *References: UpToDate, WHO Model List of Essential Medicines, Clinical Pharmacology & Therapeutics.*