Pharmacology
Summary
Amphotericin, flucytosine, and nystatin are all used as antifungal agents. Amphotericin is notorious for its toxicity, despite its efficacy against various serious fungal infections such as candida, cryptococcus, and aspergillus. The drug binds to ergosterol in fungal cell membranes, forming pores and leading to cell death. Resistance to Amphotericin arises when a fungal pathogen decreases the ergosterol in its membrane, preventing the drug from inserting pores. Amphotericin has various adverse effects, including infusion-related immediate reactions, and more prolonged, cumulative toxicity that manifests as renal impairment, leading to type 1 renal tubular acidosis, and anemia.
Nystatin shares its mechanism with amphotericin, binding to ergosterol in fungal cell membranes to cause cell lysis. It is used topically to treat mucocutaneous candidiasis and is also used as an oral rinse to treat oropharyngeal candidiasis. Flucytosine is a fluorinated cytosine that is converted into 5-fluorouracil (5-FU) by fungal cytosine deaminase (absent in human cells). 5-FU is further converted and ultimately inhibits fungal DNA and RNA synthesis. Flucytosine is frequently used in combination with amphotericin to treat cryptococcal meningitis.
Lesson Outline
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FAQs
Amphotericin is an antifungal drug that works by binding to ergosterol, a component of the fungal cell membrane. This binding forms pores within the membrane, resulting in leakage of cellular components and eventual cell death. This action is specific to fungal cells due to their ergosterol composition, differing from the cholesterol-based membranes of human cells. Additionally, with derivatives like liposomal formulations of amphotericin, there is a decrease in the drug's non-selective binding to mammalian cholesterol membranes, which ostensibly lowers its toxicity.
Immediate infusion-related toxicities of amphotericin mainly consist of hypotension, headache, fevers, chills, and thrombophlebitis. These occur immediately after or during the administration of the drug, especially when administered intravenously.
Intrathecal administration of amphotericin for the treatment of fungal infections of the central nervous system (CNS) can have severe side effects such as seizures, along with other CNS adversities. The drug is directly administered into the spinal canal to control infections, which can cause these reactions.
Flucytosine acts differently on fungal cells compared to amphotericin. Cytosine deaminase in fungal cells converts flucytosine, a fluorinated cytosine, into 5-fluorouracil. This conversion ends up halting the synthesis of fungal DNA and RNA, stopping the proliferation of fungal cells. Because they act differently, combining flucytosine and amphotericin is often an effective treatment for infections such as cryptococcal meningitis.
Both amphotericin and nystatin have similar mechanisms of action, as they both bind to ergosterol present in the fungal cell membrane to form pores, leading to cell death. However, they are typically employed in different clinical situations. Amphotericin is normally used to treat severe systemic fungal infections, while nystatin is commonly used for treating Candida infections, ranging from mucocutaneous to oropharyngeal candidiasis.
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