Page created on October 11, 2019. Last updated on April 8, 2022 at 12:37

Polyenes

Compounds

• Amphotericin B
• Nystatin
• Natamycin

Indications

Amphotericin is the first choice for severe 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 disrubt fungal cell wall synthesis by binding to ergosterol in the fungal cell membrane, which leads to formation of pores in the membrane, causing leakage of cellular components. 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 (severe)
• 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”.

Azoles

Compounds

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 fungal CYP450 system, thereby inhibiting the synthesis of ergosterol, an important component of the fungal cell wall.

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 not used systemically.

Allylamines

Compounds

• Terbinafine

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

Indications

Terbinafine is used to treat onychomycosis (Tinea unguium), pityriasis versicolor, cutaneous candidiasis.

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

Compounds

• Caspofungin
• Micafungin
• Anidulafungin

Indications

Echinocandins are used systemically to treat invasive aspergillosis or candidiasis.

Dosing

They’re not orally absorbed, only given IV.

Mechanism of action

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

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.

Adverse effects

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

Benzofurans

Compounds

• Griseofulvin

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	Terbinafine	Flucytosine
Natamycin		Griseofulvin
Tolnaftate		Fluconazole
Ciclopirox		Itraconazole
Amorolfine		Voriconazole
Naftifine		Caspofungin
		Micafungin
		Anidulafungin