I3 Anti-fungals

Question 1

Amphotericin B (polyene)
(Resistance)

Answer 1

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

Question 2

Nystatin (polyene)

Answer 2

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.

Question 3

Caspofungin (Echinocandins)

Answer 3

newest class of antifungal agents 
spectrum of antifungal action of these drugs is limiited to Aspergillus and Candida species

Question 4

Terbinafine

Mechanism of action

Answer 4

Fungicidal
inhibits synthesis by blocking squalene epoxidase. This leads to an accumulation of squalene which is toxic to fungi. More effective than griseofluvin

Question 5

Flucytosine

Mechanism of action

Answer 5

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

Question 6

An antimetabolite (pyrimidine analog).
strong antifungal activity - no activity against tumor cells
not as broad spectrum as amphotericin B

Answer 6

Flucytosine

Question 7

Flucytosine

Resistance

Answer 7

Altered metabolism (activation) of te drug by fungal cells

Question 8

Flucytosine

ADME

Answer 8

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)

Question 9

Flucytosine

Toxicities

Answer 9

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.

Question 10

Used to treat dematophytoses esp. onychomycosis (finger and toe nail issues). Binds to keratin and is deposited in newly growing skin and nails.

Answer 10

Terbinafine (Lamisil)

Question 11

Terbinafine

ADME

Answer 11

A - not in the book
D - not in te book
M - first pass hepatic metabolism
E - not in the book

Question 12

Terbinafine

Toxicities

Answer 12

Well tolerated
minor GI disturbances and headaches
no clinically significant drug interactions

Question 13

Dervived from penicillin. Used exclusively in the treatment of dermatophytosis (microsporum, epidermophyton, trichophyton)

Answer 13

Griseofulvin

Question 14

Griseofulvin

Mechanism of action

Answer 14

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.

Question 15

Grisofulvin

ADME

Answer 15

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)

Question 16

Grisofulvin

Toxicity

Answer 16

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

Question 17

Caspofungin (Echinocandins)

Mechanism of Action

Answer 17

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.

Question 18

Caspofungin (Echinocandins)

Resistance

Answer 18

mutations in one of the genes encoding the glucan synthase enzymes (FKS1)

Question 19

Caspofungin (Echinocandins)

Toxicities

Answer 19

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

Question 20

Caspofungin (Echinocandins)

ADME

Answer 20

A- poor oral absorbtion; IV only
D- can NOT enter CSF
M-hepatic mechanisms
E- hepatic clearence

Question 21

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

Answer 21

Azoles

Question 22

Azole (Itraconazole, Fluconazole, Voriconazole)

Mechanism of Action

Answer 22

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.

Question 23

Azole (Itraconazole, Fluconazole, Voriconazole)

Resistance

Answer 23

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.

Question 24

Azole (Itraconazole, Fluconazole, Voriconazole)

ADME

Answer 24

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

Question 25

Inhibits CYP3A4, CYP2C9, CYP2C19

leading to increased plams [ ] of other drugs that would be metabolized by these enzymes ie. wafarin, omeprazole etc

Answer 25

Fluconazole

Question 26

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)

Answer 26

Voriconazole

Question 27

Inhibits CYP3A4

leading to increased plams [ ] of other drugs that would be metabolized by these enzymes ie. wafarin, omeprazole etc

Answer 27

Intraconazole

Question 28

Itraconazole Toxicity

Answer 28

Drug Interactions !

Pts w/ impaired ventricular fxn it is associated with congestive heart failure.

Question 29

Fluconazole Toxicity

Answer 29

Rash, Steven Johnsons, Nausea, Alopecia (reversible)

Teratogenic

Question 30

Voriconazole Toxicity

Answer 30

prolongedation of QT interval (esp in pts with torsades de pointes)
Visual disturbances (dose dependant and reversible)
Hepatotoxicity
Teratogenic

Question 31

Amphotericin B

ADME

Answer 31

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

Question 32

Amphotericin B

Toxicity

Answer 32

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