75. Antifungal drugs

Polyenes

The important drugs here are amphotericin (sometimes called amphotericin B), nystatin and natamycin.

Indications:

Amphotericin is the first choice for systemic fungal infections.

Nystatin and natamycin are too toxic for systemic use and instead used topically for oral and vaginal candidiasis.

Mechanism of action:

Polyenes bind to ergosterol in the fungal cell membrane, which increases the membrane permeability. This effect is fungicidal.

Pharmacokinetics:

Amphotericin is hydrophilic and therefore not orally absorbed or absorbed through the skin. It doesn’t penetrate the BBB and binds strongly to plasma proteins, mainly lipoproteins. It is excreted in urine and stool in unchanged form. It has a long half-life.

Dosing:

There exist multiple formulations of amphotericin. The first is the conventional, where it is infused IV without any special formulation.

The second is a so-called liposomal formulation, where amphotericin B is enveloped in liposomes. These liposomes are endocytosed, and so the drug is freed intracellularly. This gives fewer side effects but is more expensive.

Adverse effects:

Amphotericin is relatively toxic. The liposomal formulation has fever adverse effects.

  • Nephrotoxicity
  • QT prolongation
  • Phlebitis at the site of infusion
  • Nausea, vomiting
  • Fever, shivers, headache
    • Caused by a “cytokine storm”

Amphotericin can stimulate immune cells to release TNF-α and IL-1, which triggers the “cytokine storm” which causes fever, shivers and headache.

Azoles

Two classes of azoles exist:

  • Imidazoles
    • Ketoconazole
    • Clotrimazole
  • Triazoles
    • Fluconazole
    • Itraconazole
    • Voriconazole (2nd generation)

Indications:

Clotrimazole and ketoconazole are used to treat topical fungal infections. They’re rarely used systemically.

Fluconazole, itraconazole and voriconazole are only used systemically. They’re used to treat systemic fungal infections like cryptococcal meningitis and invasive aspergillosis.

Mechanism of action:

Azoles inhibit the synthesis of ergosterol, an important component of the fungal cell wall. It also causes a precursor of ergosterol to accumulate, and this precursor is toxic to the fungus.

Their inhibition work by inhibiting the fungal CYP450 system.

Pharmacokinetics:

All five are orally absorbed. They’re widely distributed. Fluconazole penetrates the BBB. Fluconazole and itraconazole accumulate in the keratin.

All are metabolized in the liver, except fluconazole which is mostly excreted by urine.

Interactions:

These drugs inhibit not only the fungal CYP450 system, but the human CYP450 system too, especially CYP3A4, the isoenzyme which metabolizes most drugs.

Adverse effects:

These drugs can be hepatotoxic and cause GI symptoms.

Ketoconazole has an additional side effects if used systemically: Adrenal cortex failure. This occurs because it inhibits steroid hormone synthesis in the adrenals. For this reason, it’s rarely used systemically.

Allylamines

The most important allylamine is terbinafine. It is used both systemically and topically.

Mechanism of action:

Allylamines inhibit ergosterol and cause a toxic ergosterol precursor to accumulate in the cell.

Pharmacokinetics:

Terbinafine is orally absorbed. It accumulates in keratin and is eliminated by the liver.

Echinocandins

The important echinocandins are caspofungin, micafungin and anidulafungin.

Indications:

Echinocandins are used systemically to treat invasive aspergillosis or candidiasis.

Mechanism of action:

Echinocandins inhibit the synthesis of a beta-glycan which is a component of the fungal cell wall.

Pharmacokinetics:

They’re not orally absorbed, only given IV.

Adverse effects:

They’re usually well tolerated.

  • Flushing
    • These drugs induce histamine release
  • Slight hepatotoxicity
Flucytosine

Indications:

Resistance to flucytosine develops quickly, so it’s often combined with another drug like amphotericin when used for systemic fungal infections.

Mechanism of action:

Flucytosine is converted into 5-fluorouracil inside the fungus. 5-fluorouracil is a pyrimidine analogue which is used as an antineoplastic in humans. It inhibits DNA and RNA synthesis.

Pharmacokinetics:

It is orally absorbed, widely distributed and enters the CSF. It’s eliminated by the kidney in unchanged form.

Adverse effects:

It’s well-tolerated. Side effects aren’t common.

Benzofurans

The only important benzofuran is griseofulvin.

Indications:

It’s used to treat tinea infections, like tinea pedis.

Mechanism of action:

Griseofulvin binds to microtubules, inhibiting mitosis and cytoplasmic transport.

Pharmacokinetics:

It’s orally absorbed and accumulates in keratin. It is a CYP inducer.

Adverse effects:

Fairly common

  • Hepatotoxicity
  • Teratogenic
  • Carcinogenic
Other antifungals

Amorolfine is an antifungal with a special formulation. It’s given in the form of a nail polish to treat fungal infections of the nails.

Ciclopirox is a metal chelator which inhibits metalloenzymes in the fungus. It’s only used locally.

Tolnaftate is another antifungal which is only used locally.

Topical antifungals

Both

Systemic antifungals

Nystatin

Ketoconazole

Amphotericin

Clotrimazole

Miconazole

Flucytosine

Naftifine

Terbinafine

Griseofulvin

Tolnaftate

Fluconazole

Ciclopirox

Itraconazole

Amorolfine

Voriconazole

Caspofungin

Micafungin

Anidulafungin


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