Antifungals

Question 1

What are the classes of azoles?

Answer 1

Imidazoles and Triazoles

Question 2

Azole MOA?

Answer 2

impairs the synthesis of ergosterol resulting in:
increased cellular permeability
leakage of cellular contents
inhibition of fungal growth

Question 3

Azole Side Effects

Answer 3

GI: nausea, vomitting, diarrhea
Hepatotoxicity - CYP450 metabolism
Rash

Question 4

Imidazole drugs

Answer 4

Ketoconazole
Clotrimazole
Miconazole
KCM

Question 5

KCM formulations and role

Answer 5

creams, lotions, shampoos, vaginal tablets, lozenges, and solutions
Tx: vaginal and epidermal candidiasis

Question 6

Ketoconazole Formulations

Answer 6

Only imidazole to come in oral form in addition to other forms

Question 7

Ketoconazole Treats what?

Answer 7

Tx:
Candida sp
Malassezia furfur
Blastomyces dermatitidis
Coccidioides sp

Question 8

Ketoconazole DI and BBW

Answer 8

Many drug-drug interactions from CYP metabolism

BBW: hepatotoxicity -> use triazoles first

Question 9

Triazoles

Answer 9

Fluconazole
Itraconazole
Terconazole
Voriconazole
Posaconazole

Question 10

Fluconazole Facts

Answer 10

broad spectrum of activity
oral dosage
Does not undergo 1st pass metab. –> >90% bioavail.
Half-life ~ 30 hrs

Question 11

Fluconazole Spectrum of Activity

Answer 11

Cadida sp., Cryptococcus neoformans
Some dimorphic fungi - coccidioidomycosis
M. furfur
Prototheca sp.
Some molds and dermatophytes

Question 12

Fluconazole DOC for what?

Answer 12

For susceptible fungal infections:
Invasive and noninvasive candidiasis and cryptococcal inf
When topical azoles not enough
Can give prophylactically in immunocompromised
Not all candida species susceptible

Question 13

Fluconazole CYP interactions

Answer 13

Inhibits 2C9, 2C19, 3A4

Question 14

Itraconazole

Answer 14

Oral or IV
Similar to ketocon. – also covers aspergillus sp, sprothix schenckii, and histoplasmosis
Potent CYP INHIBITOR
DOC for dimorphic fungal infx like histoplasmosis

Question 15

Itraconazole SE

Answer 15

20% have transient visual disturbances - photophobia, blurred vision, color changes
15% have dose related hallucinations

Question 16

Itraconazole BBW

Answer 16

avoid in patients with systolic heart failure due to inotropic effects
especially oral doses over 400 mg

Question 17

Voriconazole

Answer 17

Oral or IV
Extended/Broad spectrum of activity: resistant aspergillus or candida
Superior to amphotericin B for aspergillus

Question 18

Voriconazole Metabolism

Answer 18

CYP450 metabolism w/ many drug-drug interaction

Adjust dose for renal failure

Question 19

Posconazole

Answer 19

Expanded spectrum of activity - resistant Candida
Active against zygomycetes**
Oral suspension only

Question 20

Posconazole PK/PD

Answer 20

Poor bioavailability - high-fat meal increases bioavail 400%

SE: GI disturbances, elevation of LFTs

Question 21

Posconazole Indication

Answer 21

prophylaxis of fungal infections in neutropenic patients

Treatment of oropharyngeal candidiasis

Question 22

Polyenes

Answer 22

Amphotericin B and Nystatin
MOA: bind to ergosterol and disrupt fungal cell membrane
Causes increased cell permeability and leakage of intracellular contents

Question 23

Amphotericin B

Answer 23

Polyene
IV for systemic infections
DOC for cryptococcal meningitis

Question 24

Amphotericin B Spectrum of Activity

Answer 24

The majority of invasive fungi

Candida sp, Aspergillus sp, dimorphic fungi, cryptococcus

Question 25

Amphotericin B Toxicities

Answer 25

``` Nephrotoxicity Hematologic toxicitiy Infusion related reactions Thrombophlebitits Monitor for toxicities - use clinical pharmacist ```

Question 26

Amphotericin B premedication regimens

Answer 26

Acetaminophen: prevent fever, headache Heparin: prevent thrombophlebitis NS: decreases nephrotoxicity Correct electrolyte disturbances

Question 27

Nystatin

Answer 27

``` Polyenes Oral and topical forms No significant drug interactions Poorly absorbed from gut Well tolerated - high dose causes GI issues ```

Question 28

Nystatin Indications

Answer 28

cutaneous and mucocutaneous infections from candida Oral and intestinal Candida infections 1-10% have GI diarrhea, nausea, stomach pain, vomiting

Question 29

Nystatin Formulations

Answer 29

Cream 100,000 U/g - 2-3/day Ointment 100,000 U/g - 2-3/day Powder 100,000 U/g - 2-3/day Oral suspension for thrush - 400,000-600,000 U/day QID Tablets - Intestinal Infx 500,000-1mil U po q8H

Question 30

Allylamines

Answer 30

Terbinafine (Lamsil) | oral and topical

Question 31

Terbinafine MOA, SOA, Indications

Answer 31

MOA: inhibits squalene monooxygenase used in ergosterol synthesis SOA: dermatophytes - does not treat candida or mold Indications: 1st line for onychomycosis 4-12 wk therapy

Question 32

Terbinafine Monitoring, PK/PD

Answer 32

``` Monitoring: check LFTs, CBC (decreased ALC) 36 hr half-life Distribution to sebum and skin 99% plasma protein bound Hepatic metabolism ```

Question 33

Echinocandins

Answer 33

``` Glucan synthesis inhibitors Caspofungin Micafungin Anidulafungin Only available IV ```

Question 34

Echinocandin Indications

Answer 34

Invasisve aspergillosis Esophageal candidiasis Intraabdominal abscesses Peritonitis Pleural space infx from candida sp Cryptococcus does not have glucan = resistant Can treat aspergillosis but not -cidal or -static

Question 35

Echinocandin MOA

Answer 35

inhibits synthesis of 1,3-beta-d-glucan synthase (component of fungal cell walls) Results in intracellular leakage and cell death

Question 36

Echinocandin

Answer 36

Good safety profile - no CYP interactions | Good for treatment of invasive candidiasis and esophageal candidiasis

Question 37

Antimetabolite All

Answer 37

5-flurocytosine - flucocytosine MOA: inhibits DNA and RNA synthesis of fungal cells For: cryptococcus and candida With Amphotericin B to treat cryptococcal meningitis SE: GI and BM depression

Question 38

Griseofulvin Indications and Administration

Answer 38

Grifulvin V, Gris-PEG For tinea capitis and tinea of skin, hair and nails Tablet or suspension Take with fatty meal to increase absorption Food or milk decrease GI upset

Question 39

Griseofulvin MOA

Answer 39

Inhibits fungal cell division | Binds to human keratin making it resistant to fungal invasion

Question 40

Griseofulvin CI and Precautions and monitoring

Answer 40

Liver failure - LFT elevation Porphyria Pregnancy Category X Breast feeding not recommended Use with caution if PCN allergy due to cross reactivity Monitor: renal and liver fxn, and CBC for granulocytopenia

Question 41

Griseofulvin DI and Adverse Reactions

Answer 41

``` CYP 1A2, 2C9, 3A4 metabolism warfarin, OCP, alcohol, barbituate, cyclosporine interactions AR: photosensitivity, stevens-johnson, toxic epidermal necrolysis, erythema multiforme Jaundice Granulocytopenia dizziness, fatigue, HA diarrhea, nausea, vomiting drug induced lupus like syndrome ```

Question 42

Griseofulvin Bioavailability

Answer 42

The smaller the particle size, the greater the bioavailability Microsize: suspension - grifulvin V tablets - cheaper Ultramicrosize: Gris-PEG tablets - smaller = greater bioavailability and smaller dose needed