18.04.2 Antifungal Drugs

The fungal cell membrane is made up of ergosterol, which differs from the phospholipid plasma membrane of mammalian cells. Thus, drugs that interfere with ergosterol will affect the fungal cell membrane, but not have effects in humans e.g. adverse effects. Amphotericin is a mixture of anti-fungal substances derived from the bacteria, Streptomyces. Amphotericin binds to ergosterol to create pores in the fungi cell membrane (Figure 18.4), and this leads to the death of the fungus i.e. is fungicidal.

Amphotericin is poorly absorbed after oral administration, and is not used orally. Amphotericin is used either topically or intravenously. One common adverse effect with amphotericin is renal toxicity, which occurs in 80% of people who are treated with it. Amphotericin also causes hypokalemia in a quarter of the people treated with it, and this hypokalemia may require treatment with potassium supplements. Because of its serious adverse effects, amphotericin is not used in minor fungal infections. Rather amphotericin is used in serious fungal infections e.g. treatment of fungal meningitis, pulmonary aspergillosis. Amphotericin lozenges have been developed to treat oral thrush. As there is little systemic absorption from these, there is little risk of adverse effects.

Another anti-fungal drug that is mainly used for serious fungal infections is caspofungin. Caspofungin inhibits the synthesis of 1,3-β-glycan, a glucose polymer required for synthesis of fungal cell membrane. It is used intravenously. There are many common adverse effects with caspofungin (fever, nausea, vomiting, diarrhea), which limits its use to serious fungal infections such as invasive thrush and aspergillosis. In aspergillosis, the first choice drug is an azole, and caspofungin is second choice.

The azoles, such as fluconazole inhibit the enzyme lanosine demethylase (Figure 18.4), which is important in the conversion of lanosterol to ergosterol, the final step in the synthesis of ergosterol.

Figure 18.4 Site of action of some antifungal drugs (Copyright QUT, Sheila Doggrell)

Fluconazole is active after oral administration or after intravenous administration. High concentrations of fluconazole get into the cerebral spinal fluid, and therefore reach the brain. For this reason, it is the drug of choice for the treatment of fungal meningitis. Fluconazole is fungistatic, which means it stops the growth of the fungi, but does not kill them (i.e. it is not fungicidal). The unwanted effects of fluconazole are mild. The main problem when using fluconazole is that it inhibits the enzyme CYP3A4 (which is the CYP metabolising enzyme for many drugs). Inhibition of CYP3A4 with fluconazole leads to increased levels of lignocaine, neviparine etc. Fluconazole is used in the treatment of thrush and tinea.

Terbinafine is the anti-fungal drug that is commonly used for the treatment of fungal infections of the nails, which is a common fungal infection. Terbinafine inhibits the enzyme squalene epoxidase, which is involved in the conversion of squalene to lanosterol, in the early part of synthesis of fungal cell membranes (Figure 18.4). Terbinafine is active after oral or topical administration. Terbinafine is highly lipophilic, and is rapidly absorbed and taken up by nails and adipose tissue. Terbinafine is very effective for fungal infections of nails.

Griseofulvin interferes with fungal microtubules. It is fungistatic. It is reserved for when oral, long-term use is needed. For instance, griseofulvin is used in tinea of head, skin, nails, groin, and feet, which is unresponsive to agents that are topically administered.