Antifungal Drugs Flashcards
General Information on Fungal Infections
Fungus: Yeast(candida) or Mold(aspergillus)
Eukaryotes therefore difficult to selectively target
Considered opportunistic infections
Either superficial or systemic
Common superficial fungal infections
Dermatomycoses: caused by dermatophytes
Candidiasis: caused by candida albicans
Dimorphic Fungi: not opportunistic, in tropical climate
Susceptible Population for Fungal Infection
Recent surgery IV canula Prosthesis Broad spectrum ABs Immunocompromised
Targets for Antimycotics
DNA synthesis
Mitotic spindle
Ergosterol synthesis/ general Cell Wall synthesis/function
Membrane function
Amphotericin B
Chemistry
Pharmacokinetics
Preparations
SYSTEMIC
Chemistry
Polyene Macrolide; amphoteric
Water insoluble
-> Preps: complexed with sodium
encapsulated with liposomes: less nephrotoxic
IV
Strong PPB
Long T1/2
Broad spectrum, even some protozoa es leishmaniasis
Crosses BBB poorly–> intrathecal admin possible
Slow renal and biliary excretion
Amphotericin B
Mechanism of Action
Side Effects
Selectively toxic: high affinity to ergosterol
Interrupts membrane stability: forms pore in membrane
Able to integrate via hydrophobic part
Resistance due to low ergosterol content
SE Renal toxicity: mainly reversible Hypokalemia Anaemia (decreased EPO) Cytokine Storm Hepatotoxicity
Synergistic with flucytosine in cryptococcoses
Flucytosine
General
Pharmacokinetics
SYSTEMIC
Combined to decrease resistance (mutation)
For candidiasis and crytococcoses
IV or orally administered
Widely distributed in body, incl CSF
90% excreted unchanged via urine
Flucytosine
MoA
SE
Selective toxicity: selective: flucytosine–> antimetabolites
Uptake req protein not present in humans (not same #)
Converted to antimetabolite: 5 flurouracil only in fungi
enyme: cytosine deaminase
5 FU is a pyrimidine analogue–> false brick
Also: inhibition of thymidilate synthase
SE
GIT disturbance (bacterial activation in GIT)
Anaemia
Azoles
General incl MoA
Imidazole: 2Ns; mostly topical use as interfere with
human steroid hormone synthesis
Triazoles: 3Ns
Synthetic; broad spectrum
Need acidic condition for absorption
MoA
Selective inhibition of fungal CYP450 (14a demethylase)
CYP450 responsible for ergosterol synthesis
May affect some humans–> drug interactions
Fluconazole
SYSTEMIC
Oral or IV
ONLY ONE TO REACH HIGH CONC IN CSF (less PPB)
–> 1st choice in fungal meningitis/ invasive candidiasis
SE
GIT disturbance
Steven Johnson Syndrome
Itraconazole
SYSTEMIC
Oral; food increases absorption
Extensive hepatic metabolism
Doesn’t penetrate CSF (strong PPB)
SE
GIT disturbance
Steven Johnson Syndrome
Voriconazole
SYSTEMIC
also used for aspergillosis
Clotrimazole and Econazole
TOPICALLY
toxic for systemic use
Candidiasis and dermatophytosis
Ketoconizole
TOPICALLY ex mucocutaneous candidiasis
well absorbed from GIT (req low pH)
Antacids decrease absorption
widely distributed in body except CSF
SE
Hepatotoxic (rare but fatal) may progress post stop th
GIT disturbance
REM: interfere with steroid synthesis
symp: gynecomastia, decreased libido, menstrual irreg.
Miconazole
TOPICAL (or oral for oral thrush; vaginal thrush)
athletes foot…
Terbinafine
Can be used systemically and locally
only effective against dermatophytes
nail fungal infection, athletes foot
Inhibits squalene oxidase–> inhibits ergosterol synth
SE GIT disturbance rash headache increased liver function test
