Pharmacology of Amphotericin B

Amphotericin B Pharmacology

• Amphotericin B elimination is unchanged in anephric patients.
• Hepatic or biliary disease has no known effect on the metabolism of the drug in humans.
• The primary route of excretion is through the bile.
• No dose adjustment is required in patients with compromised renal or hepatic function.
• The terminal phase of elimination has a half-life of approximately 15 days due to extensive binding to tissues.

Amphotericin B Untoward Effects

• All patients receiving amphotericin B therapy should be hospitalized, at least during the initiation of therapy.
• A test dose of 1 mg i.v. should be administered to gauge the severity of the reaction and guide the initial dosing regimen and premedication strategy.
• Infusion-related toxicity includes fever, chills, electrolyte imbalance, GI disturbances, and hypotension.
• Slower toxicity includes nephrotoxicity, liver test abnormalities, and anemia due to reduced production of erythropoietin by damaged renal tubular cells.
• Renal damage is the most significant of the slower toxicity, and renal impairment is seen in all patients treated with therapeutic doses of amphotericin B.

Mechanism of Action

• Amphotericin B is a polyene antibiotic that binds to ergosterol, reducing the level of ergosterol in the fungal cell membrane.
• It has the broadest spectrum of activity among all antifungal drugs.
• It is used as a "magic bullet" for systemic fungal infections, but is also the most toxic.

Administration and Precautions

• Intrathecal infusion is used for fungal meningitis.
• Low lipid solubility prevents it from crossing the blood-brain barrier.
• It is not recommended for oral administration due to its ineffectiveness.
• It should be administered IV, but not metabolized by the liver, to avoid toxicity.
• A low amount can cross the placenta, but it is still toxic and should be avoided during pregnancy.
• Hospitalization is necessary to monitor and reverse any toxic effects that may appear.
• Premedication with antihistamines and antipyretics can help alleviate adverse effects.

Interactions and Side Effects

• Rifampin and tetracyclin can enhance the activity of amphotericin B.
• Nephrotoxicity can be reduced by pre-hydration, monitoring plasma levels, and combination therapy with flotazin.
• Liposomal amphotericin B is associated with fewer toxic effects.
• The most common side effect is GI distress, and other possible side effects include allergic rash, eosinophilia, transient abnormalities of hepatic function, and thrombocytopenia.
• It can increase plasma concentrations of phenytoin, sulfonylureas, warfarin, and cyclosporine.