Amphotericin B

Mechanism of action (Pharmacodynamics)

Unlike azoles or allylamines, which disrupt sterol synthesis, amphotericin B targets the preformed molecule. Its affinity for fungal membrane ergosterol is 500 times higher than for human cell cholesterol.

By binding to ergosterol, the drug exerts a dual damaging effect:

1. Pore formation (main pathway) — membrane integrity is compromised, leading to leakage of intracellular contents.
2. Free radical generation (additional pathway) — toxic radicals destabilize the membrane.

Depending on the drug concentration and the susceptibility of a particular pathogen, the effect can be either fungistatic or fungicidal.

Pharmacokinetics and Dosage Forms

For systemic action, the drug is administered intravenously. The duration of action after infusion is 4–6 hours. Excretion is carried out by the kidneys. The initial half-life ($t_{1/2}$) is 24–48 hours; however, with regular use, the drug accumulates in tissues, and $t_{1/2}$ increases up to 15 days. For infections caused by Coccidioides, intrathecal administration is relevant.

Formulations:

• Powder in vials of 50,000 IU for IV administration (solvent supplied).
• Inhalation powder.
• Ointment 15 g and 30 g (1 g contains 30,000 IU).

Indications and combination therapy

The drug is used for severe systemic mycoses. To increase efficacy and reduce toxicity, it is often combined with the antimetabolite flucytosine.

Mechanism of synergy: amphotericin B damages the fungal plasma membrane, which facilitates the uptake of flucytosine into the cell. This provides several clinical advantages:

• Reduction of the amphotericin B dose (decrease in side effects).
• Shortening of the total course duration.
• Prevention of resistance (it develops rapidly with monotherapy of flucytosine).

Main indications for the combination: cryptococcal meningoencephalitis and endocarditis, aspergillosis, CNS and urinary tract candidiasis.

Polyene antibiotics are also used for etiotropic therapy of dysbiosis (active proliferation of fungi of the genus Candida) caused by the intake of broad-spectrum antibiotics.

Side effects (with IV administration)

The toxicity of standard amphotericin B (deoxycholate) is high. Reactions are divided into immediate and delayed (organ-specific).

• Acute reactions ("Cytokine storm"): release of TNF-$\alpha$ and IL-1 by immune cells. Manifests as chills, fever, and hypotension during the first hours of infusion. Management: reduction of the infusion rate, premedication with NSAIDs (paracetamol) or glucocorticoids (hydrocortisone).
• Nephrotoxicity (key effect): constriction of renal afferent arterioles leads to ischemia and proximal tubule injury. Clinical presentation: hypokalemia, hypomagnesemia, acidosis, cylindruria. Requires potassium and magnesium replacement therapy.
• Hematotoxicity: thrombocytopenia and anemia. Anemia is associated with decreased erythropoietin synthesis by damaged kidneys (treated with recombinant erythropoietin).
• Neurotoxicity: headache, tremor, seizures, polyneuropathy,paresis, visual disturbances (diplopia).
• Other: dyspepsia, local reactions (thrombophlebitis), allergies.

Lipid formulations: toxicity reduction strategy

To protect normal tissues (especially proximal renal tubules), the active substance is encapsulated in lipid carriers — liposomes. Drug release occurs only upon direct contact with the fungal cell.

Representatives: liposomal amphotericin B (Ambisome), lipid complex (Abelcet), colloidal dispersion (Amphocil).

Their clinical efficacy is identical to the standard drug, but toxicity is significantly lower. The main disadvantage is high cost. Indications: severe systemic mycoses in patients with renal failure.

Prescription Examples

Depending on the localization of the process, the drug is prescribed systemically, by inhalation, or topically.

Intravenous infusion: Rp.: Amphotericini B 50 000 ED D.t.d. N. 10 S. Intravenously by drip infusion at a dose of 250 IU/kg of body weight (administered every other day), after preliminary dissolution in the supplied solvent.

Inhalation: Rp.: Pulv. Amphotericini B pro inhalationibus 50 000 ED D.t.d. N. 10 S. Dissolve the contents of the vial in 10 ml of water for injections. Administer by inhalation 5–10 ml of the solution (containing 5,000 IU in 1 ml).

Topical (ointment): Rp.: Ung. Amphotericini B 30.0 D.S. Apply a thin layer to the affected skin areas.

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Mechanism of action of flucytosine: intracellular activation to 5-fluorouracil and blockade of thymidylate synthase.
• Azoles (fluconazole, voriconazole): inhibition of 14-demethylase and dependence on cytochrome P-450.
• Allylamines (terbinafine): blockade of squalene epoxidase at early stages of sterol synthesis.
• Pathogenesis of dysbiosis during antibiotic therapy and principles of its correction.
• Comparative characteristics of polyene antibiotics (amphotericin B, nystatin, natamycin).

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