Module 11 Flashcards
What is unusual about the administration and dosing schedule of amphotericin B?
○ Although amphotericin B has a large number of polar groups, overall it is very lipophilic and punches holes in the fungal cell membrane. It has a very large volume of distribution and very slow clearance.
○ Therefore, the efficacy is based on the total dose of the drug not the daily dose. The optimal daily dose is based on how serious the fungal infection is, and therefore, how rapid a response is required. However, although a higher daily dose is associated with higher efficacy, this must be balanced against the fact that higher daily doses are associated with a higher rate of side effects.
How is the basis for drug interactions with the imidazole and triazole antifungal agents related to their therapeutic activity?
○ Imidazole and triazole antifungal drugs work by inhibiting the conversion of lanosterol to ergosterol, a necessary component of the fungal cell membrane similar to cholesterol in mammalian cell membranes.
○ The fungal enzyme that mediates this conversion is actually a P450. Imidazole and triazole antifungal agents bind to the heme iron of the P450 and inhibit the enzyme, but they are not totally specific for fungal P450s; therefore, they also inhibit drug metabolism in humans.
What is the mechanism of action of terbinafine? How does the kinetic profile and distribution affect efficacy?
○ Terbinafine inhibits squalene epoxidase or squalene monooxygenase, the first step in the synthesis of ergosterol.
○ The epoxide product is reactive because of ring strain and this causes the linear squalene “zipping” up to form 4 rings, a rather cute reaction.
○ Terbinafine has a very large volume of distribution, due in part to noncovalent binding to keratin, and it can be detected in the nails of patients weeks after the drug has been stopped.
This distribution to keratin in nails makes it more effective than other antifungal agents for the treatment of finger and toe nail infections.
