antifungal and antiprotozoal Flashcards
what can anti fungal drugs be split into? what kind of drugs are there
- For subcutaneous and systemic mycotic infections
a. Amphotericin B
b. Antimetabolites antifungals like flucytosine
c. Echinocandins
i. Caspofungin
d. Azole antifungals
i. triazoles- For cutaneous mycotic infections
a. Nystatin
b. Squalene epoxidase inhibitors
i. Terbinafine
c. Azole antifungals
Imidazoles
- For cutaneous mycotic infections
What is amphotericin B
○ A naturally occurring polyene antifungal
Produced by streptomyces nodosus
what does amphotericin do
○ Binds to ergosterol in plasma membranes of sensitive fungal cells to form pores
○ Pores disrupts membrane function
§ Allows electrolytes and small molecules to leak from the cell and resulting in cell death
what is amphotericin active against
candida albicans
cryptococcus neoformans
many strains of aspergillus
How as amphotericin B administered
topical or slow IV
why must amphotericin B coformulated with sodium deoxycholate
because they are insoluble in water, can coformulate to form liposomes
How is the CSF penetration of amphotericin B
poor CSF penetration, increases with inflammation
how is amphotericin B excreted
low level of drugs and metabolite appear in urine over a long period of time, some eliminated in bile.
What are the adverse reactions of amphotericin B
fever and chills
nephrotoxicity (most important)
- can cause renal vasoconstriction, can reduce glomerular filtration rate by more than half. Need hydrate patients adequately
hypotension, shock like fall in blood pressure
What is 5- flucytosine
○ Is a water soluble fluorinated pyrimidine analogue
What does 5-FC do
interferes with fungi DNA synthesis and protein synthesis
is 5-FC fungistatic or fungicidal
fungistatic
What is 5-FC usually paired with
amphotericin B, which allows 5-Fc to penetrate the cell
what is the pk of 5-FC
○ Well absorbed orally
○ Penetrates into CSF
○ 80% of given dose excreted unchanged in urine
Dose must be adjusted in patients with compromised renal function
What are the adverse effects of 5-FC
GI effects
Bone marrow suppression which is the most serious
hepatotoxicity
Cat C in pregnancy
What is the mechanism for echinocandins
○ Inhibits the activity of glucan synthase complex, resulting in loss of structural integrity of cell wall
what is the distribution of echinocandin
○ Undergo extensive protein binding unable to penetrate into CSF
what antifungal activity does caspofungin have
§ Good first line option for patients with invasive candidiasis including candidemia
§ Second line option for invasive aspergillosis in patients with who cannot take or failed amphotericin B
what are some adverse effets
GIT related symptoms like fever, chills, rashes, skin flushing, thrombocytopenia
What is the mechanism of triazole
○ Inhibit C-14 a-demethylase ( a CYP450 enzyme). Blocks the demethylation of lanosterol to ergosterol
○ Inhibition of ergosterol biosynthesis disrupts membrane structure and function
§ Inhibits fungal cell growth
What are the adverse effects of itraconazole and voriconazole
itraconazole associated with cardiotoxicity
voriconazole associated with neurotoxicity
What kind of resistance could happen to triazoles
○ Mutations in the C-14 a-demethylase gene that lead to decreased azole binding
○ Some strains of fungi have developed efflux pumps that pump the azole out of the cell
What are some adverse effects of triazoles
nausea, vomiting, headache, skin rashes, hepatotoxicity, Interferes with CYP450 enzymes resulting in drug drug interactions
What are the contraindications for triazoles
azoles are considered teratogenic, should be avoided in pregnancy unless benefits outweigh risk
What is the pregnancy cat for fluconazole itraconazole and voriconazole
cat C for the first 2, cat D for the last
What is imidazole indicated for
○ Have a wide range of activity including candida
-Topical imidazoles have a variety of uses
-Tinea corporis( affect arms, legs and trunk)
- Tinea cruris ( jock itch, affect groin area
-Tinea pedis
- Vulvovaginal and oropharyngeal candidiasis
What are some adverse effect of miconazole
§ Contact dermatitis, vulvular irritation, edema
§ Gi disturbance when taken orally
Oral use of clotrimazole is associated with elevated liver enzymes
What is nyastatin
a polyene antifungal with its structure, mechanism of action, resistance profile similar to amphotericin B
What is nyastatin used to treat
○ Treat oropharyngeal candidiasis, intravaginally for vulvovaginal candidiasis, or topically for cutaneous candidiasis
what is the mechanism of action for terbinafine
○ Inhibits squalene epoxidase, block the biosynthesis of ergosterol
what is terbinafine active against
trichophyton, a genus of fungy that causes tinea infections
What is terbinafine used for
○ Oral terbinafine treat dermatophyte onychomycoses ( fungal infection of nails) and tinea capitis( scalp infection)
§ Because need to accumulate in keratin for it to be effective
○ Topical terbinafine
§ Used to treat tinea pedis, tinea corporis, and tinea cruris
What is the pharmacokinetics of terbinafine
○ Bioavailability 40% only due to first pass metabolism
§ Highly protein bound and deposited in skin, nails and adipose tissues
○ Oral terbinafine extensively metabolised by several cyp450 isoenzymes
Mainly excreted via urine
who should avoid using terbinafine
patients with moderate to severe renal impairment or hepatic dysfunction
What are some adverse effects of terbinafine
Gi disturbance, headache, rash
what are some contraindications of terbinafine
should not be given to nursing mothers as it accumulates in breast milk
is an inhibitor of yp450 isoenzyme, concomitant use with substrates of that isoenzyme may result in an increase of adverse effects against those agents
What are the types of antiprotozoal agent
metronidazole
What activity does metronidazole have
have activity against luminal and systemic infections
What is the mechanism of action of metronidazole
§ Nitro group of metronidazole serve as electron acceptor, forming reduced cytotoxic free radicals that result in protein and DNA damage
□ Results in the death of the E. histolytica trophozoites
What is metronidazole indicated against
anaerobes
§ Used in localised and aggressive periodontitis in combination with amoxicillin or ciprofloxacin, and in anaerobic infections § May be used in conditions involving obligate anaerobes such as fusobacterium prevotella, porphyromonas species such as dentoalveolar abscess and pericoronitis § Amebic infections caused by protozoa like e. histolytica, trichomonas vaginalis, giardia lambila § Anaerobes like bacteroides specifies and CDAD
- H pylori
how is metronidazole absorbed
completely and rapidly absorbed after oral administration
how is metronidazole distributed
§ Distributes well throughout body and tissues and fluids
□ Therapeutic levels can be found in vaginal and seminal fluids, saliva, breast milk, CSF
How is metronidazole metabolised
Hepatic oxidation of metronidazole side chain by mixed function oxidase, followed by glucuronidation to form at least 2 major active metabolites, which are reduced to inactive metabolites by gut flora
what can affect the rate of metabolism of metronidazole
concomittant treatment with inhibitors of CYP450
What are the adverse effects of metronidazole
GI, nausea, vomiting, epigastric disease
unpleasant metallic taste
optical and peripheral neuropathy
oral moniliasis
may potentiate effect of warfarin, avoid taking with alcohol
