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
what labs should be monitored when using 5-flucytosine in view of its adverse effects
severe bone marrow suppression monitor leukocytes and PLT weekly
hepatotocity monitor ALT and AST weekly
what are examples of echinocandins
caspofungin, micafungin, anidulafungin
what is the spectrum of activity of echinocandins
second line for invasive aspergillus (behind amphotericin B and azoles), first line for invasive candidiasis incl azole resistant
PK properties of echinocandins
poor oral F
extensive protein binding 97%, low csf penetration
metabolised slowly by hydrolysis and N-acetylation, not metabolised by cyp
eliminated in urine and feces, not renally cleared so do not need renal dose adjustments
what are the adverse effects of echinocandins
minimal, DDIs for caspofungin and micafungin
what pregnancy category is echinocandins
category C
what are examples of triazoles
fluconazole, posaconazole, itraconazole, voriconazole
what are the mechanisms of resistance to triazoles
- mutation of the c14alpha-demethylase gene
- efflux pumps
what type of activity does triazoles have
fungistatic
what are the indications for fluconazole
candida, meningitis, histoplasmosis
what are the indications for posaconazole
candida, aspergillus, fusarium, zygomycetes
what are the indications for itraconazole
wider spectrum than fluconazole
histoplasmosis, blastomycosis, aspergillosis if intolerant to amphotericin B
onychomycosis if immunocompromised
esophageal and oropharyngeal candidiasis
what are the indications for voriconazole
broad spectrum, first line for invasive aspergillosis
candida
PK characteristics of fluconazole
PO (almost completely absorbed from GI tract), IV
long half life, well distributed into body fluids and breast milk, csf conc can reach 50-90%
renally cleared, excreted unchanged in urine, renal dose adjustments required
what are the adverse side effects of fluconazole
GI (N,V, headache, skin rash)
hepatotoxicity
QT prolongation
hair loss
what is the pregnancy category of fluconazole
category C
PK characteristics of posaconazole
PO (capsules, syrup), IV
F increased with high fat meal, F of syrup lower and further decreased with PPI
long half life, poor csf penetration
mainly eliminated by feces no need for renal dose adjustment if PO
what is contained in IV posaconazole and what is its effect
IV posaconazole contains cyclodextrin which is nephrotoxic
what are the adverse effects of posaconazole
GI (N,V, rash, headache)
hepatotoxicity
QT prolongation
what pregnancy category is posaconazole
category C
PK characteristics of itraconazole
PO (capsules, solution)
absorption decreased in presence of antacid and PPI, lower pH better absorption
well distributed into most tissues incl bone and adipose, poor csf penetration
metabolised in liver
drug and its inactive metabolites excreted in feces and urine, no renal adjustments if PO
what are the adverse effects of itraconazole
GI (N,V, headache, skin rash)
hepatotoxicity
QT prolongation
cardiotoxicity
what is periostitis
inflamm of bone tissue
what drug can cause periostitis
voriconazole
PK characteristics of voriconazole
PO (tablets, syrups)
best taken on empty stomach, high oral F
penetrate well into tissues, good csf penetration
metabolised by cyp (do not take with PPI)
inactive metabolites excreted via urine no renal dose adjustments
what are the adverse effects of voriconazole
GI (N, V, headache, skin rash)
hepatotoxicity
QT prolongation
nephrotoxicity
periostitis
what pregnancy category is voriconazole
category D
what are the drug interactions for triazoles
all triazoles inhibit 3a4 and interfere with 2c9 and 2c19 cyp450 isoenzymes
can triazoles be used in pregnancy
no, it is teratogenic
what are examples of imidazoles
clotrimazole, miconazole
what is the route of administration of imidazoles
topical
what are the indications for imidazoles
tinea cruris, tinea pedis, tinea corporis, oropharyngeal candidiasis, vulvovaginal candidiasis
what does capitis refer to
scalp
what does faciei refer to
face
what does corporis refer to
arms, legs, trunk
what does barbae refer to
facial hair
what does manuum refer to
hands, palm
what does cruris refer to
groin
what does pedis refer to
feet
what does unguium refer to
fingernails, toenails
what is the spectrum of activity of imidazoles
epidermophyton, microsporum, trichophyton, candida, malassezia
what are the indications specifically for clotrimazole
dermatophyte infections
vulvovaginal/ pharyngeal/ cutaenous candidiasis
what are the indications specifically for miconazole
tinea cruris, pedis, versicolor
vulvovaginal candidiasis
PK characteristics of clotrimazole
powder, cream, lotion, pessary, troce (lozenge)
<0.5% absorbed after application, 3-10% if vagina
absorbed and metabolised in liver, excreted in bile
what are the adverse effects of clotrimazole
contact dermatitis
vulvar irritation
edema
GI disturbances if PO
elevated liver enzymes if PO
PK characteristics of miconazole
cream, lotion, powder, pessary, oral gel
readily penetrates stratum corneum of skin and persists for more than 4 days after application
less than 1% absorbed into blood, no more than 1.3% from vagina
what are the adverse effects of miconazole
contact dermatitis, vulvar irritation, edema, GI disturbances if PO
what route is nyastatin
topical, PO
why is nyastatin not given parenterally
systemic toxicity
what is the indications for nyastatin
oropharyngeal, vulvovaginal, cutaenous candidiasis
PK characteristics of nyastatin
oral (suspensions, tablets), pessary, cream
not absorbed from GI tract, skin or vagina
what are the adverse effects of nyastatin
rare after PO, skin irritation if topical
what does trichophyton, microsporum and epidermophyton cause
tinea
what are the indications for terbinafine and what route
onychomycoses (PO)
tinea capitis (PO)
tinea cruris (topical)
tinea corporis (topical)
tinea pedis (topical)
PK characteristics of terbinafine
oral, IV
40% F due to first pass metabolism
highly protein bound and accumulates in keratin
extensively metabolised by several cyp450
excreted mainly in urine
what special populations is terbinafine c/i for
moderate to severe renal impairment or hepatic dysfunction
nursing mothers as secreted into breast milk
what are the adverse effects of terbinafine
GI disturbances, headache, rash, elevation of liver enzymes (AST, ALT)
what pregnancy category is terbinafine
PO - category B
vaginal - category A
what are the drug interactions of terbinafine
terbinafine is an inhibitor of cyp450
