I3 Anti-fungals Flashcards
Amphotericin B (polyene) (Resistance)
Fungi reduce the amount of ergosterol in their cell membrane so the level of the drug’s target has been decreased.
Fungi chemically modify ergosterol thereby decreasing binding to the drug.
Some fungi strains are just resistant
Nystatin (polyene)
Similar to Amphotericin B in mechanism of action.
Too toxic for parenteral administration and is only used topically/locally to skin and mucous membranes
Most effective in treating local Candida sp.
Caspofungin (Echinocandins)
newest class of antifungal agents spectrum of antifungal action of these drugs is limiited to Aspergillus and Candida species
Terbinafine
Mechanism of action
Fungicidal
inhibits synthesis by blocking squalene epoxidase. This leads to an accumulation of squalene which is toxic to fungi. More effective than griseofluvin
Flucytosine
Mechanism of action
An inhibitor of nucleic acid synthesis (DNA and RNA) in fungal cells. It enters the cell via cytosine permease and then is metabolized to 5-FU then phosphorylated to 5-fluorodeoxyuridine monophosphate (Fdump) and FUTP. Fdump and FUTP are reverrisble, competitive inhibitors of DNA and RNA synthesis.
*mamalian cells can not convert flucytosine into 5-FU
An antimetabolite (pyrimidine analog).
strong antifungal activity - no activity against tumor cells
not as broad spectrum as amphotericin B
Flucytosine
Flucytosine
Resistance
Altered metabolism (activation) of te drug by fungal cells
Flucytosine
ADME
A - oral only
D - wide including CSF
E - Renal
*monitor/dose reduction in pts with renal impairment
*synergistic activity with amphotericin B and azoles
*not often used as a single agent
used for C neoforms, Candida sp, molds (chromoblastomycosis with itraconazole)
Flucytosine
Toxicities
metabolism of this drug can occur in the intestine by gut microflora. This can lead to systemic exposure to 5-FU and serious bone marrow tox.
Used to treat dematophytoses esp. onychomycosis (finger and toe nail issues). Binds to keratin and is deposited in newly growing skin and nails.
Terbinafine (Lamisil)
Terbinafine
ADME
A - not in the book
D - not in te book
M - first pass hepatic metabolism
E - not in the book
Terbinafine
Toxicities
Well tolerated
minor GI disturbances and headaches
no clinically significant drug interactions
Dervived from penicillin. Used exclusively in the treatment of dermatophytosis (microsporum, epidermophyton, trichophyton)
Griseofulvin
Griseofulvin
Mechanism of action
Binds to keratin and therefore becomes deposited in newly formed skin. Inhibits microtubule fuction (assembly) thereby blocking fungal mitotic replication (fungstatic). It is a mitotic inhibitor.
Grisofulvin
ADME
A- insoluble and delivered orally only in the microcrystalline form. Absorbtion is improved when given with fatty foods.
Becuase it is incorported only into newly growing keratin of skin and nails, treatment must contiue until infected tissue is gone (6-12 months)
Inducer of hepatic P450 enzymes (increase metabolism of co-administered drugs like warfarin, phenobarbital)
Grisofulvin
Toxicity
headache, nervous system effects like peripheral neuritis, confusion, lethargy, fatigue, syncope, vertigo)
GI effects like nausea, vomitting, hepatoxicity
skin reaction like cold/warm uticaria, erythema multiforme, serum sickness
Renal side effects - albuminuria, cylindruria
Caspofungin (Echinocandins)
Mechanism of Action
Becuase the fungal cell wall depends on 1-3-b-D-glucans for structure, this drug inhibits the glucan synthase that is responsible for the 1-3-b-D-glucans. Cell Wall structure is lost and osmotic stability is decreased leading to cell death.
Caspofungin (Echinocandins)
Resistance
mutations in one of the genes encoding the glucan synthase enzymes (FKS1)
Caspofungin (Echinocandins)
Toxicities
GI disturbances
Vasomotor Side Effects - Flushing
w/ cyclosporin liver enzymes can be elevated
w/ hepatic insufficency hepatic enzyme levels may be elevated
drug interactions with tacrolimus and rifampin have been reported
Caspofungin (Echinocandins)
ADME
A- poor oral absorbtion; IV only
D- can NOT enter CSF
M-hepatic mechanisms
E- hepatic clearence
drug class
synthetic nitrogen containing compounds that get broken into triazoles, imidazoles.
Imidazoles are used for topical admin only.
triazoles are used for systemic therpy
Azoles
Azole (Itraconazole, Fluconazole, Voriconazole)
Mechanism of Action
Act by inhibiting ergosterol synthesis. Inhibt a key cytochrome P450 enzyme, 14 -alpha-sterol demethylase, required in ergosterol biosynthesis. Decrease the amount of ergserol in fungal cell membranes. Membrane function and permeability are all dirupted.
*Triazoles are more specific for fungal P450 than imidazoles.
Azole (Itraconazole, Fluconazole, Voriconazole)
Resistance
occurs after prolonged therapy.
mutation of the gene ERG1 encoding the P450 target, 14 alpha demethylase.
fungi may increase the production of the target overcoming inhbition by standard therapeutic doses of azoles.
the expression of drug transprters (Efflux) ABC, ATP-binding-cassette transporter
*Cross Resistance is common.
Azole (Itraconazole, Fluconazole, Voriconazole)
ADME
A- Oral and IV (itraconazole is lipid soluble has the lowest water solubility. fluconazole is highly water soluble)
D- fluconazole - can enter CSF
M- hepatic ?
E- hepatic ?
Azoles are inhibitors of P450 enzymes
Inhibits CYP3A4, CYP2C9, CYP2C19
leading to increased plams [ ] of other drugs that would be metabolized by these enzymes ie. wafarin, omeprazole etc
Fluconazole
Substrate and inhbitor of CYP2C9
Inhibitor of CYP3A4, CYP2C19
(leading to increased plams [ ] of other drugs that would be metabolized by these enzymes ie. wafarin, omeprazole etc)
Voriconazole
Inhibits CYP3A4
leading to increased plams [ ] of other drugs that would be metabolized by these enzymes ie. wafarin, omeprazole etc
Intraconazole
Itraconazole Toxicity
Drug Interactions !
Pts w/ impaired ventricular fxn it is associated with congestive heart failure.
Fluconazole Toxicity
Rash, Steven Johnsons, Nausea, Alopecia (reversible)
Teratogenic
Voriconazole Toxicity
prolongedation of QT interval (esp in pts with torsades de pointes)
Visual disturbances (dose dependant and reversible)
Hepatotoxicity
Teratogenic
Amphotericin B
ADME
A- IV admin. poor oral absorb.
D- large VD, can reach CSF (requires intrathecal injections)
M-not in the book
E- not in the book
Amphotericin B
Toxicity
if given IV: nausea, vomitting, headache, fever, chills, and hypotension
(side effects can be diminished if pre-medicated with antipyretics, opiods, antihistamines, or analgesis )
NEPHROTOXICITY - most serious side effect
reversible renal impairment leads to azotemia, potassium/magnesium loss, tubular acidosis, and reduced renal perfusion
irreversible renal impairment leads to decreased production of erythropoietin that can lead to anemia
