Antifugals

Question 1

bind to ergosterol, alter fungal membrane permeability via pores

Answer 1

polyenes

Question 2

inhibits fungal DNA synthesis

Answer 2

flucytosine

Question 3

inhibit ergosterol fungal membrane synthesis via target site 14-a-demthylase

Answer 3

azole

Question 4

inhibit fungal cell wall synthesis of beta glucan

Answer 4

caspofungin

Question 5

…drugs for superficial/dermatophytic
…drugs for mucocutaneous/serious dermatophytic infections
…adm for systemic infections that primarily occur in those who are immunosuppressed

Answer 5

topical, oral, oral/parenteral

Question 6

block squalene epoxidase

Answer 6

allyamines

Question 7

What is mechanism of amphotericin B?

Answer 7

Macrolide (lactone), binds ergosterol in cell membrane to form leaky pores with loss of ions metabolites; newer MOA suggests that Amp B acts as a sponge ; fungistatic/fungicidal
Prepared as colloidal suspension due to water insolubility. Adm slow IV infusion t1/2 ~ 15 days, intrathecal adm in fungal meningitis

Question 8

What is clinical indication of Amp B

Answer 8

Used primarily for invasive/progressive and potentially fatal fungal infections; Broad spectrum antifungal

Question 9

What are ADRs of Amp B?

Answer 9

flu symptoms, hypotension; use of antipyretics, steroids, antihistamines can prevent
Phlebitis at site of infusion.
Renal dysfunction: dec GFR/creatinine clearance, hypokalemia; prevent with hydration / sodium loading
irreversible renal tubular injury may occur with prolonged admin
Normocytic anemia/dec erythropoietin
Co-admin. with antibiotics is not recommended

Question 10

Why amp B given in liposomal form?

Answer 10

These preparations facilitate the binding of amp B to fungal ergosterol rather than human cholesterol
Adm in higher dosages and produce less nephrotoxicity bc bypass kidneys. However, usu less effective than Amp B deoxycholate due to lower plasma levels. Use in patients intolerant to conventional Amp B

Question 11

WWhat is MOA of nystatin?

Answer 11

Topical / nonsystemic use : topical powder for skin, vaginal tablets, PO swish/ swallow for upper/lower GI tract, or oral lozenge
Natamycin (NATACYN) - ophthalmic suspension for fungal eye infections caused by Candida, Aspergillus, others

Question 12

What are indications for nystatin and ADRs?

Answer 12

Similar structure/mechanism as amp B, but too toxic for systemic use, Main indication candidiasis. Adverse usu local irritation, burning, itching, n/v with PO adm

Question 13

in general increase the bioavailability of many other drugs metabolized by the liver by inhibiting CYPs

Answer 13

azoles

Question 14

What is MOA of flucytosine?

Answer 14

Actively transported into fungi by specific fungal permease system
Activated by fungal cytosine deaminase enzyme to 5-fluorouracil (5-FU) to inhibit thymidylate synthase/DNA synthesis; human cells lack this enzyme, cytosine deaminase; fungistatic

Question 15

What is indications for flucytosine?

Answer 15

Main use in combination with amp B for systemic cryptococcal / candidal infections, esp. meningitis; resistance develops rapidly when flucytosine is used alone

Question 16

What are ADRs of flucytosine?

Answer 16

PO, good distribution to CSF (75% Cp), 90% urinary exc in unmetabolized form; so amp B nephrotoxicity can cause accumulation & inc flucytosine toxicity
GI, liver dysfunction with inc transaminase and alkaline phosphatase
Dec WBCs/platelets (due to GI bacterial conversion to 5-FU), this may inc in AIDS with drug AZT and other bone marrow suppressors

Question 17

What’s MOA of Azoles?

Answer 17

IMIDAZOLES: (two N + azole ring) ketoconazole, miconazole, clotrimazole, others: binds\ inhibits P-450 coenzyme of fungal lanosterol-14-demethylase that dec synthesis of ergosterol and some sex \ steroid hormones in humans
TRIAZOLES: (three N + azole ring) fluconazole, itraconazole, voriconazole; MA same, but more selective for fungal P-450, little if any sex/steroid inhibition

Question 18

What’s clinical indication of azoles?

Answer 18

Current main uses mucocutaneous candidiasis, coccidioidomycosis and invasive aspergillosis

Question 19

What are clinical indications of Miconazole?

Answer 19

Topical\ GI use for candidiasis, vaginal suppository (MONISTAT 3 & 7)
Athlete’s foot (Tinea pedis), Jock itch (Tinea cruris), Ringworm (Tinea caporis, MICATIN) cream/powder/spray, Tinea versicolor
Infrequent IV alternative to Amphotericin B in some severe infections (MONISTAT-IV)

Question 20

What are some AdRs of miconazole?

Answer 20

Topical irritation, itching, rash
IV: anaphylactoid rxs, cardiorespiratory arrest, arrhythmias, hyponatremia, CNS disturbances; considered highly toxic; therefore IV use very limited

Question 21

What are indictions and ADRs of clotrimazoles?

Answer 21

Oral/GI (MYCELEX TROCHE), skin (LOTRIMIN, MYCELEX)), vaginal (GYNE-LOTRIMIN)
Main indication candidiasis, can cause Topical irritation
Other imidazoles: Butoconazole (FEMSTAT), Tioconazole (VAGISTAT)

Question 22

What is indication of itraconazole (triazole)?

Answer 22

Very broad antifungal activity; aspergillosis, blastomycosis (nonCNS), coccidiomycosis (preferred over Amp B), histoplasmosis, sporotrichosis, nail infections (onychomycosis)

Question 23

What is PK of itraconazole?

Answer 23

PO, take with food. low CNS penetration but does penetrate meninges
Drug interactions due to inhibition P-450 (CYP 3A4) metabolizing enzymes in liver by active metabolite hydroxy-itraconazole

Question 24

What are some ADRs of itraconazole?

Answer 24

dose-dependent effects (>400 mg/d): GI, rash, hepatitis/ hepatoxicity, hypokalemia, hypertension

Question 25

What are indications of fluconazole (triazole)?

Answer 25

Good PO, good CNS
For serious mucocutaneous/systemic candidiasis, alternative to Amp B in cryptococcal meningitis, DOC for coccidioidal meningitis, prophylaxis pts undergoing organ transplantation/those @ risk serious infections

Preferred drug for chronic suppressive therapy cryptococcal meningitis

Question 26

What are some ADRs of fluconazole (triazole)?

Answer 26

GI, rash, liver dysfunction, dec platelets
Reduced Inhibition of P-450 (CYP 3A4) drug enzymes compared to other azoles
Does not inhibit human gonadal / steroid hormone synthesis

Question 27

What are indications, PK, and ADRs of vorionazole (triazole)?

Answer 27

Broad spectrum. Inc activity against candida resistant to other drugs and DOC for invasive aspergillus, esp. in bone marrow transplantation/ cancer patients
2nd generation derivative of fluconazole
Adm PO or IV.
ADRs: inhibits CYP 450, N/V, inc liver enzymes, rash, visual disturbances/photophobia

Question 28

Whats MOA, Indication, and ADR of terbinafine?

Answer 28

Synthetic allylamine, inhibits fungal squalene epoxidase, accumulating squalene > toxic to fungi, fungicidal
PO for dermatophytoses/ringworm, esp. onychomycosis (nail infections) adm daily 12 weeks
ADRs: headache, GI upset, inc liver enzymes (due to liver metabolism), rash
Also topical 1% cream

Question 29

What’s MOA, Clinical indication, and ADRs of griseofulvin?

Answer 29

Binds to keratin esp infected tissue and to fungal microtubules to inhibit mitosis
Dermatophytic, for ringworm infections/tineas, Usu requires prolonged therapy 2-6w
Adm PO, with food (fats); t1/2: 24-36 h, largely replaced by terbinafine/itraconazole, but is still used.
ADRs: GI, CNS ( headache, dizziness, insomnia), rash/hypersensitivity/photosensitivity, teratogenic/carcinogenic in animals, Microsomal enzyme inducer of P-450s

Question 30

What is MOA of echinocandins (Caspofungin, Micafungin, Anidulafungin)?

Answer 30

generally well tolerated, i.v. use only, metabolize by liver. Inhibits synthesis of B(1,3)-glucan, an essential component of fungal cell wall

Question 31

What are clinical indications of Echinocandins?

Answer 31

Mucocutaneous candida infections
Invasive aspergillosis in pts not responding to amp B or voriconazole - (Caspofungin)
Prophylaxis of candida infections in bone marrow transplant patients- (Micafungin)
Esophageal and invasive candidiasis - (Anidulafungin)

Question 32

What are ADRs of echinocandins?

Answer 32

ADRs: histamine-mediated rash/facial flushing/swelling/pruritus/allergic rxs, increase in liver enzymes when caspofungin/cyclosporine are combined