antifungal and antiprotozoal Flashcards
what are mycoses/ mycotic infection
infection caused by fungi, chronic in nature, can be superficial and involve only skin (oral and vaginal thrush) while others may penetrate the skin causing SC or systemic infections
what are the differences in structure of a fungal cell
fungi are eukaryotic cell with rigid cell wall largely composed on chitin rather than peptidoglycan and its cell membrane contains ergosterol rather than cholesterol found in mammalian membrane
what are the classes of antifungal drugs
polyenes, antimetabolites, echinocandins, squalene epoxidase inhibitors, azoles
what are the drugs used for SC and systemic fungal infections and what classes are they
amphotericin B (polyenes), flucytosine (antimetabolite), caspofungin (echinocandins), triazole (azoles)
what are the drugs used for cutaneous fungal infections and what classes are they
nyastatin (polyenes), terbinafine (squalene epoxidase inhibitor), imidazole (azole)
what is the moa of polyenes
polyenes bind to ergosterol in plasma membranes of sensitive fungal cells and causes pore formation which results disruption of pore membrane function and causes the electrolytes esp K+ and small molecules to leak out of the cell thus resulting in cell death
what is the moa of antimetabolites
5-flucytosine enters fungal cell through cytosine specific permeases and is converted to its metabolically active form 5-FU by cytosine deaminase
a) 5-FU is converted into 5-fluorouridine triphosphate (FUTP) which is incorporated into fungal RNA in place of uridylic acid which results in inhibition of protein synthesis
b) 5-FU is metabolised into 5-fluorodeoxyuridine monophosphate (5-FdUMP) which is a potent inhibitor of thymidylate synthase, a key enzyme of DNA syntheisis
what is the moa of azoles
inhibits c14-alpha demethylase cyp450 enzyme, leading to the blocking of demethylation of lanosterol into ergosterol which is the principal sterol of fungal membranes
inhibition of ergosterol synthesis can disrupt membrane structure and function as it is important for cell wall integrity thus result in inhibition of fungal growth
what is the moa of echinocandins
strength of fungal cel wall maintained by fibrilar polysacharides like beta-1-3-glucan and chitin which covalently bond to each other and to other peptides
glucan synthase complex in plasma membrane catalyses synthesis of beta-1-3-glucan
echinocandins act by inhibiting glucan synthase complex and thus inhibits synthesis of beta-1-3-glucan which would affect cell wall synthesis and loss of structural integrity of cell wall
what is the moa of squalene epoxidase inhibitors
inhibit activity of squalene epoxidase which blocks squalene conversion into lanosterol and thus inhibit biosynthesis of ergosterol which is an essential component of fungal cell membrane
leads to toxic accumulation of squalene which causes increased membrane permeability and death of fungal cell
what are the characteristics of amphotericin B
naturally occurring polyene, lipophilic, produced by streptomyces, nodusus
what kind of activity does amphotericin B have and what are the indications for it
bactericidal and bacteriostatic effect depending on type of organism and conc of drug
effective for candida albicans, histoplasmosis, cryptococcus neoformans, aspergillus
what type of formulations can amphotericin B have
conventional and lipophilic form
what is the conventional form of amphotericin B
coformulated with sodium deoxycholate
is amphotericin B soluble or insoluble in water
insoluble
PK characteristics of amphotericin B
topical or slow IV, GI absorption negligible
extensively bound to plasma proteins, long half life, poor csf penetration but increased with inflammation and liposomal formulation have better csf penetration
low levels of drug and metabolites appear in urine over a long period of time, some eliminated via bile
what are the adverse effects of amphotericin B
fever and chills, nephrotoxicity, electrolyte imbalances, htn, bone marrow suppression, anemia, thrombophlebitis
what pregnancy category is amphotericin B
category B
is 5-flucytosine soluble or insoluble in water
soluble
what is the concern with 5-flucytosine
resistance
what is the type of activity for 5-flucytosine and what are its indications
fungistatic
narrow spectrum as some fungi lack cytosine deaminase
used for systemic yeast infections or with amphotericin B for cryptococcus (meningitis and pulmonary infection) and candidiasis
what are the mechanisms of resistance for 5-flucytosine
- mutations in the enzymes resulting in decreased level of the enzymes
- increased synthesis of cytosine during therapy
PK characteristics of 5-flucytosine
PO
good csf penetration
80% excreted unchanged in urine, renal dose adjustments requied
what are the adverse effects of 5-flucytosine
GI, severe bone marrow suppression due to 5-FU metabolite, hepatotoxicity
