Monograph of Griseofulvin

Importance in Pharmacology and Medicine

Griseofulvin occupies an important niche in the therapeutic armamentarium against fungal infections. Its unique mode of action—binding to fungal microtubules and disrupting mitotic spindle formation—provides a mechanistic alternative to other antifungals that target ergosterol synthesis or cell membrane integrity. Consequently, it offers a valuable option for patients intolerant to or refractory to azole therapy. Additionally, its pharmacokinetic characteristics, particularly extensive distribution into keratinous tissues, render it especially effective for dermatophyte infections that involve hair shafts and nail beds.

Learning Objectives

Describe the pharmacodynamic and pharmacokinetic profile of griseofulvin.
• Explain the mechanism of action and its implications for therapeutic efficacy and resistance.
• Identify clinical indications, dosing regimens, and monitoring parameters.
• Recognize potential drug interactions and adverse effect profiles.
• Apply knowledge of griseofulvin to clinical case scenarios involving dermatophytic infections.

Fundamental Principles

Core Concepts and Definitions

Griseofulvin is classified as a fungicidal macrolide, distinguished from fungistatic agents by its capacity to kill fungal cells rather than merely inhibit growth. The drug is chemically a lactone macrocycle with a carboxylic acid moiety, which confers lipophilic characteristics conducive to penetration of keratinized tissues. It is considered a first‑generation antifungal, preceding the advent of triazoles and echinocandins.

Theoretical Foundations

The therapeutic activity of griseofulvin hinges upon its interaction with fungal microtubules. By binding to the β‑tubulin subunit, it induces a conformational change that prevents polymerization of tubulin dimers into microtubules. This disruption impairs spindle formation during mitosis, leading to cell cycle arrest and eventual cell death. The specificity this interaction for fungal tubulin, as opposed to tubulin, underlies its relative safety profile, though cross-reactivity can occur under high systemic exposure.

Key Terminology

• Dermatophyte: A fungal species that infects keratinized tissues, including Trichophyton, Microsporum, and Epidermophyton.
• Mitotic spindle: A microtubule‑based structure responsible for chromosome segregation during cell division.
• K_max: The maximum plasma concentration achieved after drug administration.t_1/2: The elimination half‑life, indicating the time required for plasma concentration to reduce by 50 %.
• Bioavailability: The fraction of an administered dose that reaches systemic circulation unchanged.

Detailed Explanation

Mechanism of Action

Griseofulvin exerts its antifungal effect by targeting the fungal cytoskeleton. The binding to β‑tubulin stabilizes the microtubule network in a nonfunctional state, thereby preventing the dynamic required for mitotic spindle assembly. This inhibition leads to arrest in metaphase, subsequent apoptosis, and depletion of viable fungal cells. The drug’s activity is concentration‑dependent; higher plasma concentrations enhance the probability of complete fungal eradication, yet also increase the risk of systemic side effects.

Pharmacodynamics

In vitro susceptibility indicates a minimal inhibitory concentration (MIC) range of 0.5–2 µg/mL for common dermatophytes. The time‑kill curves demonstrate a linear relationship between concentration and fungicidal activity, with a lag phase observed at sub‑MIC levels. The post‑antifungal effect (PAFE) is modest, implying that continuous exposure is necessary to maintain therapeutic efficacy.

Pharmacokinetics

Griseofulvin is administered orally and exhibits moderate absorption across the gastrointestinal tract, with a bioavailability of approximately 30 % to 40 %. Peak plasma concentrations (C_max) are typically reached within 2– hours post‑dose. The elimination half‑life (t_1/2) ranges from 12 to 16 hours, allowing for once‑daily dosing in most therapeutic regimens. Renal excretion accounts for roughly 20 % of the dose, while hepatic metabolism via glucuronidation and sulfation mediates the majority of clearance. The drug demonstrates extensive distribution into keratinized tissues, achieving concentrations up to 30‑fold higher than plasma levels in hair and nails.

Mathematical Relationships

The plasma over time can be modeled using a first‑order elimination equation:
C(t) = C₀ × e^-k·t, where k = ln(2)/t_1/2.
The under the concentration–time curve (AUC) is calculated as:
AUC = Dose ÷ Clearance.
The steady‑state concentration (C_ss) achieved with a dosing interval τ (in hours) is given by:
C_ss = (F × Dose) ÷ (Cl × τ),
where F represents bioavailability and Cl denotes clearance.

Factors Affecting Pharmacokinetics

• Food Intake: High‑fat meals may reduce absorption by up to 20 %.
• Gastrointestinal Motility: Accelerated transit can diminish bioavailability.
• Hepatic Function: Impaired glucuronidation can prolong t_1/2.
• Drug Interactions: Concomitant use of enzyme inducers (e.g., carbamazepine) may accelerate metabolism, whereas inhibitors (e.g., ketoconazole) can increase systemic exposure.

Drug Interactions

Griseofulvin is a known inducer of cytochrome P450 3A4 (CYP3A4), potentially reducing the efficacy of other medications metabolized by this. Conversely, potent CYP3A4 inhibitors may raise plasma concentrations of griseofulvin, increasing the risk of toxicity. Additionally, the drug’s interaction with oral contraceptives has been reported, leading to reduced contraceptive efficacy owing to enhanced metabolism of estrogen components.

Adverse Effect Profile

Common adverse events include gastrointestinal disturbances (nausea, vomiting, abdominal discomfort), dermatological reactions (rash, pruritus), and neurological symptoms (headache, dizziness). Rare but serious events comprise hepatotoxicity, visual disturbances (particularly optic neuritis), and bone marrow suppression risk of these effects escalates with higher doses and prolonged therapy.

Clinical Significance

Relevance to Drug Therapy

Griseofulvin’s ability to penetrate keratinized tissues renders it particularly effective for infections localized to hair, skin, and nails. Its fungicidal nature ensures a higher likelihood of eradication compared to fungistatic agents, especially in cases of extensive dermatophytosis. Moreover, its distinct mechanism of action offers a therapeutic advantage in patients who exhibit intolerance or resistance to azole-based antifungals.

Practical Applications

Therapeutic regimens typically involve oral administration of 100 mg to 200 mg per day, adjusted by weight and severity of infection. For tinea capitis, a common dosing strategy is 5 mg/kg/day divided into two doses. Treatment duration often ranges from 4 to 12 weeks, contingent clinical response and laboratory confirmation of fungal eradication. Periodic monitoring of liver function tests and complete blood counts is advisable to detect early signs of hepatotoxicity or myelosuppression.

Clinical Examples

Consider a patient presenting with extensive tinea corporis on the lower extremities. Initiation of griseofulvin at 200 mg daily is reasonable, with a scheduled follow‑up after 4 weeks to assess resolution. If residual lesions persist, extending therapy to 8 weeks may be justified. In, a child with tinea capitis may require a higher dose of 5 mg/kg/day for 6 to 8 weeks, given the need to achieve sufficient drug concentrations within hair follicles.

Clinical Applications/Examples

Case Scenario 1: Tinea Capitis in Children

Age: 8 years; Diagnosis: Trichophyton tonsurans infection confirmed by KOH preparation. Dosing: 5 mg/kg/day orally, divided into two doses. Duration: 6 weeks. Monitoring: Liver enzymes and complete blood count at baseline, 3 weeks, and 6 weeks. Expected outcome elements as evidenced by negative KOH after 6 weeks.Case Scenario 2: Onychomycosis in an Elderly Patient

Age: 68 years; Diagnosis: Trichophyton rubrum infection of the toenails. Dosing: 200 mg orally once daily for 12 weeks. Monitoring: Baseline and bi‑weekly liver function tests. Potential interactions: Patient is on carbamazine for seizure control; thus, careful consideration of CYP3A4 induction is warranted, potentially necessitating dose adjustment or therapeutic monitoring.

Case Scenario 3: Systemic Antifungal Consideration in Immunocompromised Host

>Patient: 45‑year‑old with HIV/AIDS; presents with extensive tinea corporis Griseofulvin is generally contraindicated in severe immunosuppression due to limited efficacy against non‑dermatophyte molds. Alternative options include terbinafine or fluconazole, depending on susceptibility testing. If griseofulvin is chosen, a lower dose (e.g., 100 mg/day) with close for adverse effects and drug interactions is mandatory.

Summary/Key Points

• Griseofulvin is a systemic antifungal that disrupts fungal microtubule polymerization, leading to fungicidal activity.
• Its pharmacokinetic profile features moderate oral absorption, a half‑life of 12–16 hours, and extensive penetration into keratinized tissues.
• Typical dosing regimens range from 100 mg to 200 mg daily, with weight‑based adjustments for pediatric tinea capitis.
• Clinical monitoring should include periodic liver function tests and complete blood counts to detect hepatotoxicity or bone marrow suppression.
• Drug interactions with CYP3A4 inducers and inhibitors must be considered, particularly regarding oral contraceptives and other antiepileptics.
• Adverse effects may encompass gastrointestinal upset, dermatologic reactions, and, rarely, visual disturbances or hepatotoxicity.
• Griseofulvin remains a valuable therapeutic option for dermatophytic infections, especially when alternative agents are contraindicated or ineffective.

In closing, the comprehensive understanding of griseofulvin’s pharmacology, clinical applications, and safety considerations is essential for optimal patient management in dermatology and infectious disease practice.

References

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8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.