Antifungal drugs

Key examples

• Nystatin
• Clotrimazole
• Fluconazole

 

Common indications

1. Treatment of local fungal infections, including of the oropharynx, vagina or skin. They may be applied topically (nystatin, clotrimazole) or taken orally (fluconazole).
2. Systemic treatment of invasive or disseminated fungal infections. Specialist treatment is required for these infections, which will not be discussed further in this book.

 

Mechanisms of action

• Fungal cell membranes contain ergosterol. As ergosterol is not seen in animal or human cells it is a target for antifungal drugs. 
• Polyene antifungals (e.g. nystatin) bind to ergosterol in fungal cell membranes, creating a polar pore which allows intracellular ions to leak out of the cell. This can kill or slow growth of the fungi.
• Imidazole (e.g. clotrimazole) and triazole antifungals (e.g. fluconazole) inhibit ergosterol synthesis, impairing cell membrane synthesis, cell growth and replication. 
• Resistance to antifungals is unusual but can occur during long-term treatment in immunosuppressed patients. 
• Mechanisms include alteration of membrane synthesis to exclude ergosterol, changes in target enzymes or increased drug efflux.

 

Important adverse effects

• Topical nystatin and clotrimazole have few adverse effects apart from occasional local irritation where applied. 
• The most common adverse effects of fluconazole are gastrointestinal upset (including nausea, vomiting, diarrhoea and abdominal pain), headache, hepatitis and hypersensitivity causing skin rash. 
• Rare but potentially life-threatening reactions include: severe hepatic toxicity; prolonged QT interval predisposing to arrhythmias; and severe hypersensitivity, including cutaneous reactions and anaphylaxis.

 

Warnings

• Nystatin and clotrimazole have no major contraindications.
• Fluconazole should be prescribed with caution in patients with liver disease because of the risk of hepatic toxicity. 
• A dose reduction is required in moderate renal impairment. 
• It should be avoided in pregnancy due to the risk of fetal malformation.

 

Important interactions

• There are no significant drug interactions with nystatin or clotrimazole.
• Fluconazole inhibits cytochrome P450 enzymes, causing an increase in plasma concentrations and risk of adverse effects when prescribed with drugs that are metabolised by P450 enzymes, including phenytoin, carbamazepine, warfarin, diazepam, simvastatin and sulphonylureas. It may reduce the antiplatelet actions of clopidogrel, a pro-drug which requires activation by liver metabolism. 
• It also increases the risk of serious arrhythmias if prescribed with drugs that prolong the QT interval, such as amiodarone, antipsychotics, quinine, quinolone and macrolide antibiotics and SSRIs