Chapter: Modern Pharmacology with Clinical Applications: Antifungal Drugs

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Amphotericin B

Amphotericin B (Fungizone), a polyene antifungal drug produced by the actinomycete Streptomyces nodosus, consists of a large ring structure with both hydrophilic and lipophilic regions.

AMPHOTERICIN B

 

Chemistry and Mechanism of Action

 

Amphotericin B (Fungizone), a polyene antifungal drug produced by the actinomycete Streptomyces nodosus, consists of a large ring structure with both hydrophilic and lipophilic regions. Polyene antifungal drugs bind to the fungal cell membrane component ergosterol, lead-ing to increased fungal cell membrane permeability and the loss of intracellular constituents. Amphotericin has a lesser affinity for the mammalian cell membrane com-ponent cholesterol, but this interaction does account for most adverse toxic effects associated with this drug.

 

Antifungal Spectrum

 

Amphotericin B is used to treat systemic disseminated fungal infections caused by Candida spp., Cryptococcus neoformans, and the invasive dimorphic fungi (Asper-gillus spp., Histoplasma capsulatum, Coccidioides immi-tis, Blastomyces dermatitidis, and Sporothrix schenckii). Intravenous amphotericin B remains the treatment of choice for serious invasive fungal infections unrespon-sive to other agents.

 

The development of resistance during amphotericin B therapy is rarely clinically significant but has been re-ported; relative resistance expressed through alter-ations in membrane ergosterols has resulted in fungal isolates with reduced growth rates and reduced viru-lence. Infections with organisms intrinsically resistant to amphotericin B, such as Candidia lusitaniae and Pseudallescheria boydii, are uncommon but may be in-creasing in frequency.

 

 

Absorption, Distribution, Metabolism, and Excretion

 

Amphotericin B is primarily an intravenous drug; ab-sorption from the intestinal tract is minimal. After infu-sion the drug is rapidly taken up by the liver and other organs and is then slowly released back into the circula-tion, where 90% of the drug is bound to protein. Its ini-tial half-life is about 24 hours; the second elimination phase has a half-life of 15 days. The initial phase com-prises elimination from both a central intravascular and a rapidly equilibrating extravascular compartment; the second, longer phase represents elimination from stor-age sites in a slowly equilibrating extravascular com-partment.

 

Drug concentrations in pleural fluid, peritoneal fluid, synovial fluid, aqueous humor, and vitreous hu-mor approach two-thirds of the serum concentration when local inflammation is present. Meningeal and am-niotic fluid penetration, with or without local inflamma-tion, is uniformly poor. Measurement of serum, urine, or cerebrospinal fluid drug levels has not been used clini-cally.

 

The major route of elimination of amphotericin B is by metabolism, with little intact drug detected in urine or bile. About 5% of amphotericin B is excreted in the urine as active drug, with drug still detectable in the urine 7 or more weeks after the last dose. Serum levels are not elevated in renal or hepatic failure, and the drug is not removed by hemodialysis.

 

Clinical Uses

 

Amphotericin B is most commonly used to treat serious disseminated yeast and dimorphic fungal infections in immunocompromised hospitalized patients. As addi-tional experience has been gained in the treatment of fungal infections with the newer azoles, the use of am-photericin B has diminished; if azole drugs have equiv-alent efficacy, they are preferred to amphotericin B be-cause of their reduced toxicity profile and ease of administration. For the unstable neutropenic patient with Candida albicans fungemia, amphotericin B is the drug of choice. For the stable nonneutropenic patient with C. albicans fungemia, fluconazole appears to be an acceptable alternative. For the AIDS patient with mod-erate to severe cryptococcal meningitis, amphotericin B appears to be superior to fluconazole for initial treat-ment; once infection is controlled, fluconazole in a daily oral dose is superior to and more convenient than weekly intravenous amphotericin B in the prevention of clinical relapses. For the AIDS patient with dissemi-nated histoplasmosis, the treatment is similar; ampho-tericin B is preferred for the initiation of treatment, but once infection is controlled, daily oral itraconazole is preferred to intermittently dosed amphotericin B for suppression of chronic infection. Most forms of blasto-mycosis and sporotrichosis in normal hosts no longer require amphotericin B treatment.

 

Amphotericin B remains the drug of choice in the treatment of invasive aspergillosis, locally invasive mu-cormycosis, and many disseminated fungal infections occurring in immunocompromised hosts (the patient population most at risk for serious fungal infections). For example, the febrile neutropenic oncology patient with persistent fever despite empirical antibacterial therapy is best treated with amphotericin B for possible Candida spp. sepsis.

 

Adverse Effects

 

Fever, chills, and tachypnea commonly occur shortly af-ter the initial intravenous doses of amphotericin B; this is not generally an allergic hypersensitivity to the drug, which is extremely rare. Continued administration of amphotericin B is accomplished by premedication with acetaminophen, aspirin, and/or diphenhydramine or the addition of hydrocortisone to the infusion bag.

 

Nephrotoxicity is the most common and the most se-rious long-term toxicity of amphotericin B administra-tion. This drug reduces glomerular and renal tubular blood flow through a vasoconstrictive effect on afferent renal arterioles, which can lead to destruction of renal tubular cells and disruption of the tubular basement membrane. Wasting of potassium and magnesium in the urine secondary to renal tubular acidosis usually results in hypokalemia and hypomagnesemia and necessitates oral or intravenous replacement of the minerals. Nephrotoxicity can be lessened by avoiding the con-comitant administration of other nephrotoxic agents, such as aminoglycosides. Keeping patients well hy-drated probably reduces nephrotoxicity; saline infu-sions prior to amphotericin B dosing have been advo-cated, and concomitant diuretic therapy should be avoided. Prolonging the infusion rate has been studied as a potential means of decreasing amphotericin B tox-icity. Infusing the daily dose over 1 or 4 hours seems to make little difference, but recent data suggest that a continuous infusion of amphotericin B (giving the daily dose over 24 hours) decreases infusion-related adverse effects such as fever and also reduces nephrotoxicity. Increasing the dosing interval for amphotericin B to every other day may lessen nephrotoxicity only if the total dose of the drug delivered is reduced.

 

Normochromic normocytic anemia is the most com-mon hematological side effect of amphotericin B ad-ministration; thrombocytopenia and leukopenia are much less common. Infusion of the drug into a periph-eral vein usually causes phlebitis or thrombophlebitis. Nausea, vomiting, and anorexia are a persistent prob-lem for some patients.

 

Lipid Formulations of Amphotericin B

 

Three lipid formulations of amphotericin B (ampho-tericin B colloidal dispersion: Amphocil, Amphotec; amphotericin B lipid complex: Ablecet; and liposomal amphotericin B: Ambisome) have been developed in an attempt to reduce the toxicity profile of this drug and to increase efficacy. Formulating amphotericin with lipids alters drug distribution, with lower levels of drug in the kidneys, reducing the incidence of nephrotoxicity. The lipid formulations appear to be equivalent to conven-tional amphotericin B both in the treatment of docu-mented fungal infections and in the empirical treatment of the febrile neutropenic patient. While less toxic, the lipid formulations are significantly more expensive than conventional amphotericin B.

 

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