Antifungals

Question 1

Key targets for antifungals

Answer 1

The fungal cell wall is rigid and essential for survival of the fungal cell; if this rigidity is lost, the cell dies

Fungal lipid envelope contains ergosterol, not cholesterol; key for drug targeting

Question 2

Structure of Amphotericin B and envrionement it can work in

Answer 2

Ampho B is macrocyclic, amphoteric (meaning, soluble only at extremes of pH, which is key to clinical use limitations) with a lipid tail

Question 3

Ampho B MOA

Answer 3

Ampho B works by forming complexes with ergosterol in cell membrane, causing membrane damage and leaking of cellular contents.

Question 4

What causes resistance to Ampho B

Answer 4

Replacement of ergosterol in membrane with another lipid

Question 5

Amphotericin B toxicities

Answer 5

Infusion reactions (give with acetaminophen and steroids)

Nephrotoxicity

hypokalemia, hypomagnesemia, and renal tubular acidosis (inability of kidney to hold onto bicarbonate) causing a bicarbonate deficiency, which is also called a non-anion-gap metabolic acidosis (NAGMA)

Anemia

Question 6

MOA of flucytosine (5-fluorocytosine)

Answer 6

It is activated by fungi via enzymatic deamination to 5-FU, an antimetabolite drug also used in cancer chemotherapy.

The enzyme (cytosine deaminase) that converts prodrug to 5-FU is only found in fungi, making it specifically active against those species of cells only.

As an antimetabolite, 5-FU blocks action of thymidylate synthetase and halts production of fungal DNA.

Question 7

It is the only antifungal drug that acts on DNA reproduction

Answer 7

flucytosine

Question 8

Can flucytosine be taken orally

Answer 8

Yes, Absorbs well from GI tract, making it an orally effective systemic antifungal drug

Question 9

Flucytosine toxicities

Answer 9

Toxicity of the drug is theorized to be due to conversion of drug to 5-FU by gut bacteria and thus looks like cancer chemotherapy toxicity on rapidly dividing cells; hair loss, bone marrow suppression, mucositis/enterocolitis.

Question 10

When does flucytosine resistance occur

Answer 10

When used as monotherapy, so usually coupled with Ampho B

Question 11

Azole antifungals MOA

Answer 11

Block Cyt p450-dependent production of ergosterol precursor in fungi.

Fungal cyt p450 enzymes are 100-1000x more sensitive to azoles than mammalian p450’s.

Question 12

Administration of azole antifungals

Answer 12

These drugs are orally absorbable with good tissue penetration and lower toxicity than Ampho B

Can be topical or systemic

Question 13

What is important about azole antifungals and drug interactions

Answer 13

They cause competitive inhibition of metabolism of other drugs as well as toxic levels of azole drug if cyt 450 inhibitors also given with these drugs.

drug toxicity will usually look like toxic effects of the second drug, ie bleeding with warfarin, toxicity of any p450-metabolized drug as would be seen in overdose, due to higher than desired serum levels.

Question 14

Azole toxicities

Answer 14

Liver dysfunction, related to the effect on mammalian enzyme systems, and estrogenization, including gynecomastia, due to inhibition of estrogen breakdown by p450 enzymes.

Question 15

Azole antifungal that inhibits sterol synthesis so used in cushing’s

Answer 15

Ketoconazole

Question 16

What is important about voriconazole

Answer 16

Has a nonlinear metabolism, and is a teratogen so must take contraception

Causes QTc prolongation, arrythmia and sudden death risk esp with other QTc prolonging drugs, causes transient visual or auditory hallucinations, usually reserved for resistant infections

Question 17

Itraconazole specific toxicities

Answer 17

causes worsening CHF in patients who already have heart failure as well as hepatic toxicity and death

Question 18

Echinocandins MOA

Answer 18

Echinocandins are derived from products of fungal fermentation. They prevent synthesis of glucans, which are required for cross-linkage with chitin to maintain cell wall rigidity and structure. The enzyme inhibited = glucan synthetase, only found in fungi!

Question 19

Best use for echinocandins

Answer 19

Only given IV and can’t penetrate CSF, so good for non-CSF invasive infections

Question 20

Example of echinocandin

Answer 20

Caspofungin

Question 21

Griseofulvin MOA

Answer 21

Inhibits microtubule formation by binding to alpha/beta tubulin in the mitotic spindle and microtubule-associated protein, disrupting the fungal mitotic spindle.

FUngi becomes multinucleated

Question 22

Use of griseofulvin and why

Answer 22

This drug is very useful for dermatophyte infections because it deposits in precursors of keratin-producing cells, with almost no drug deposition in any other tissue. When these epidermal cells differentiate, the drug stays tightly bound to keratin. This drug is thus used only for infection of keratin-structure-producing tissue.

Question 23

Instructions for taking griseofulvin

Answer 23

It is very lipophilic and should be taken with fatty foods (PB, ice cream) so it can be absorbed in the stomach

Question 24

Griseofulvin toxicities

Answer 24

Serious side effects are rare, but can cause headaches, rashes, some estrogenic effects in children.

Induces Cyt p450 so makes warfarin less effective

Question 25

Terbinafine MOA

Answer 25

Terbinafine inhibits squalene epoxidase, blocking ergosterol synthesis.

Question 26

Bioavailability of Terbinafine

Answer 26

It has good bioavailability and is given orally. 99% of the drug is protein bound. Like griseofulvin, the drug accumulates in skin, nails, fat and thus is used only for dermatophyte infections. It is metabolized by CYP3A4 and can interact with multiple medications as a result.

Question 27

Topical drugs from allyamines class

Answer 27

Naftifine, butenafine (Lotrimin Ultra)

Question 28

MOA and use of nystatin

Answer 28

This drug is structurally similar to Ampho B, complexing with ergosterol in the membrane, but is not absorbed systemically from any mucosal surface, including the GI tract. Because it is not absorbed systemically, it cannot be used for invasive fungal infections.

Question 29

Tavaborole use

Answer 29

topical treatment of onchomycosis