Griseofulvin Monograph

Introduction

Griseofulvin is a systemic antifungal agent originally isolated from the mold Penicillium griseofulvum. It is classified as a fungistatic medication that interferes with fungal cell division by binding to microtubules. The drug has been employed primarily for dermatophyte infections of the skin, hair, and nails. Its historical significance stems from its role as one of the first orally administered antifungals, establishing a foundation for subsequent antifungal development. In contemporary practice, griseofulvin remains a valuable therapeutic option, particularly in settings where newer agents are contraindicated, unavailable, or cost-prohibitive. The monograph aims to elucidate the pharmacological properties, clinical applications, and practical considerations associated with griseofulvin, thereby enhancing the prescribing competence of medical and pharmacy students.

Learning Objectives

• Describe the pharmacodynamic mechanism of action of griseofulvin.
• Explain the pharmacokinetic profile, including absorption, distribution, metabolism, and excretion.
• Identify major factors influencing therapeutic response and drug interactions.
• Apply evidence-based principles to design appropriate dosing regimens for common dermatophyte infections.
• Analyse clinical case scenarios to demonstrate problem‑solving strategies involving griseofulvin.

Fundamental Principles

Core Concepts and Definitions

Griseofulvin is defined as a semi‑synthetic fungistatic agent that exerts its activity by disrupting the mitotic spindle apparatus in fungal cells. The term “fungistatic” indicates inhibition of fungal proliferation rather than outright killing. The drug is structurally related to the natural product griseofulvin, and its pharmacological activity is attributed to its affinity for β‑tubulin subunits.

Theoretical Foundations

Theoretical understanding of griseofulvin’s action centers on the microtubule dynamics within eukaryotic cells. By binding to β‑tubulin, griseofulvin stabilises microtubules, preventing the depolymerisation required for mitotic spindle assembly. Consequently, fungal cells are arrested in the metaphase of the cell cycle, leading to suppression of growth. This mechanistic insight is pivotal for predicting activity against rapidly dividing dermatophytes while sparing mammalian cells, which exhibit lower drug affinity for their microtubules.

Key Terminology

• Dermatophytes: Fungi that infect keratinized tissues, including skin, hair, and nails.
• Mitotic spindle: Microtubule structure that segregates chromosomes during cell division.
• β‑tubulin: Protein subunit of microtubules targeted by griseofulvin.
• Fungistatic: Agent that halts fungal growth without causing cell death.
• Pharmacokinetics (PK): Study of drug absorption, distribution, metabolism, and excretion.
• Pharmacodynamics (PD): Study of drug effects on the body and mechanisms of action.

Detailed Explanation

Pharmacodynamics of Griseofulvin

Griseofulvin’s antifungal activity is mediated through irreversible binding to β‑tubulin heterodimers, thereby stabilising microtubules and inhibiting their dynamic reorganisation. The drug’s action is most pronounced during active mitosis, which explains its preferential effect on rapidly dividing dermatophytes. The fungistatic nature of griseofulvin results in a concentration‑dependent response, with higher plasma concentrations correlating with greater inhibition of growth. The therapeutic window is relatively narrow; therefore, therapeutic drug monitoring (TDM) may be considered in certain populations to ensure adequate exposure while minimizing toxicity.

Pharmacokinetics: Absorption, Distribution, Metabolism, Excretion

Absorption

Oral absorption of griseofulvin is variable, with a bioavailability of approximately 30–50 %. Food intake markedly enhances absorption; therefore, patients are advised to take the medication with a meal or a fat‑rich snack. The time to reach peak plasma concentration (T_max) generally occurs 4–8 h post‑dose. Rapid absorption is followed by a biphasic decline, indicating an initial distribution phase and a subsequent elimination phase.

Distribution

After absorption, griseofulvin distributes extensively into keratinous tissues, achieving concentrations several times higher than plasma levels. This tissue accumulation underpins the drug’s clinical efficacy against dermatophyte infections of skin, hair, and nails. The volume of distribution (V_d) is estimated at 1.2–1.5 L/kg, reflecting moderate tissue penetration. Griseofulvin is highly protein‑bound (~90 %) mainly to albumin, which can influence free drug availability and interaction potential with other highly bound medications.

Metabolism

Metabolism occurs predominantly in the liver through conjugation with glucuronic acid, forming glucuronide metabolites that are pharmacologically inactive. Minor oxidation pathways are also implicated, but the extent is comparatively limited. The metabolic process is subject to inter‑individual variability, partially due to genetic polymorphisms in glucuronidation enzymes. Consequently, hepatic impairment may lead to reduced clearance and elevated plasma concentrations.

Excretion

Approximately 70–80 % of the administered dose is excreted unchanged in the bile and feces, while the remaining portion is eliminated via the kidneys. Renal clearance is minimal; hence, dose adjustment in patients with renal dysfunction is generally unnecessary. However, the biliary excretion pathway suggests that cholestatic liver disease may impair drug elimination, potentially necessitating therapeutic monitoring.

Pharmacokinetic Parameters

The following relationships describe key PK parameters:

• C_max = Dose ÷ V_d
• t_1/2 = 0.693 ÷ k_el
• AUC = Dose ÷ Clearance

In practice, the elimination rate constant (k_el) can be derived from plasma concentration data using the equation C(t) = C₀ × e^-k_elt. The area under the concentration‑time curve (AUC) provides an integrated measure of drug exposure, which is critical for dose optimisation.

Mathematical Models and Relationships

Griseofulvin follows a two‑compartment model with first‑order absorption and elimination. The concentration‑time profile can be expressed as:

C(t) = (F × Dose × k_a)/(V_d × (k_a – k_el)) × (e^-k_elt – e^-k_at)

where F is the fraction absorbed, k_a is the absorption rate constant, and k_el is the elimination rate constant. This model assists in predicting steady‑state concentrations and informs dosing interval decisions.

Factors Affecting the Process

• Food Intake: Enhances absorption; fasting reduces bioavailability.
• Age: Elderly patients may exhibit reduced hepatic clearance.
• Genetic Polymorphisms: Variations in UDP‑glucuronosyltransferase genes can alter metabolic rates.
• Drug Interactions: Concomitant administration of potent inducers (e.g., rifampicin) may increase clearance; inhibitors (e.g., cimetidine) may reduce it.
• Underlying Disease: Cholestasis may impair biliary excretion, leading to accumulation.

Clinical Significance

Relevance to Drug Therapy

Griseofulvin remains a cornerstone for treating tinea capitis, tinea corporis, tinea pedis, and onychomycosis caused by dermatophytes. Its systemic administration allows for comprehensive coverage of both superficial and deep fungal tissues. While newer azole agents possess superior potency and tolerability profiles, griseofulvin’s cost‑effectiveness and established safety margin render it a viable first‑line option in resource‑limited settings.

Practical Applications

Dosing regimens are typically weight‑based: 15–20 mg kg^-1 orally once daily for children; 200–300 mg orally once daily for adults. The duration of therapy ranges from 6–12 weeks depending on the site of infection and patient age. Adjunctive measures, such as topical antifungal agents and meticulous hygiene practices, are recommended to enhance therapeutic outcomes and reduce recurrence.

Clinical Examples

Case 1: A 12‑year‑old male presents with asymptomatic scaling of the scalp. Microscopic examination confirms tinea capitis. A regimen of 20 mg kg^-1 daily for 12 weeks is initiated and continued beyond clinical resolution to eradicate subclinical infection. Monitoring for hepatotoxicity is advised, given the patient’s age and potential for variable metabolism.

Case 2: A 45‑year‑old female reports persistent nail discoloration. Onychomycosis is confirmed via KOH preparation. Griseofulvin 200 mg daily is prescribed for 12 weeks, with periodic assessment of liver enzymes to detect early signs of cholestasis.

Clinical Applications/Examples

Case Scenarios

Scenario A: A 35‑year‑old patient with HIV infection presents with extensive tinea corporis. The patient is on antiretroviral therapy that includes efavirenz, a known CYP3A4 inducer. Griseofulvin’s metabolism may be accelerated, potentially reducing efficacy. Adjusting the dose upward or switching to a different antifungal with a more robust therapeutic index could be considered.

Scenario B: An elderly patient (≥70 years) with chronic liver disease is diagnosed with tinea pedis. The risk of impaired biliary excretion necessitates careful dosing. Starting at 200 mg daily, with dose escalation only if therapeutic drug monitoring indicates subtherapeutic levels, is advisable.

Problem‑Solving Approaches

• Evaluate the patient’s renal and hepatic function prior to initiating therapy.
• Assess concomitant medications for potential interactions that may alter griseofulvin clearance.
• Employ weight‑based dosing in pediatric populations to achieve optimal therapeutic levels.
• Implement therapeutic drug monitoring in patients with significant pharmacokinetic variability.
• Advise patients on the importance of adherence to a complete course to prevent relapse.

Summary/Key Points

• Griseofulvin is a fungistatic agent that disrupts microtubule dynamics in dermatophytes.
• Its pharmacokinetic profile is characterized by variable oral absorption, extensive keratinous tissue distribution, hepatic glucuronidation, and biliary excretion.
• Weight‑based dosing (15–20 mg kg^-1 daily) is standard for children, while adults receive 200–300 mg daily.
• Therapeutic drug monitoring may be useful in patients with hepatic impairment or significant drug–drug interactions.
• Clinical efficacy is well established for tinea capitis, tinea corporis, tinea pedis, and onychomycosis, with a favorable safety profile when appropriately monitored.
• Key practical pearls include administering the medication with food, monitoring liver function tests, and ensuring complete treatment duration to prevent recurrence.

References

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