Antifungals

Question 1

What are the two groups of antifungals required for this course?

Answer 1

Azoles & Allylamines

Question 2

What are the four azole’s required for the course?

Answer 2

Fluconazole, Itraconazole, Voriconazole, Ketoconazole

Question 3

What is the main Allylamine required for the course?

Answer 3

Terbinafine

Question 4

What is the unique component in fungal cell walls targeted by antifungals?

Answer 4

cholesterol ergosterol

Question 5

What is the MOA of azoles?

Answer 5

Reduce ergosterol production by inhibiting 14-Ademethylase (the fungal CYP450 enzyme)

Question 6

Which major enzyme group is inhibited by the azoles?

Answer 6

CYP450

Question 7

What is the MOA of Allylamines?

Answer 7

They interfere with synthesis of ergosterol through inhibition of squalene epoxide → squalene builds up and causes cell death

Question 8

What are the main organisms targeted by azoles?

Answer 8

-Candida

-Cryptococcus

-Mycoses: blastomycosis, coccidioidomycosis, histoplasmosis

-Dermatophytes

Question 9

Use of Itraconazole is now limited to combat these organisms:

Answer 9

histoplasmosis & blastomycosis

Question 10

Voriconazole has an extended spectrum of coverage & is used to treat:

Answer 10

Most yeasts & molds including fluconazole resistant Candida, Aspergillus and Zygomyces

Question 11

Terbinafine is only approved for the treatment of:

Answer 11

Onychomycosis (fungal infection under nails)

Question 12

Describe Fluconazole’s absorption & distribution:

Answer 12

Well absorbed with a bioavailability of 90%. Wide distribution into CSF, eye, & perineum

Question 13

Itraconazole can be taken as a capsule or solution. which one is preferred and why?

Answer 13

Solution is preferred because bioavailability not affected by food or antacids

Question 14

Describe the PO absorption of Itraconazole

Answer 14

Capsule bioavailability is 55% when taken with food; 30% on empty stomach

Question 15

What instructions should be given to a patient when taking PO Itraconazole?

Answer 15

DO NOT TAKE with H2 Blockers or PPI’s

Question 16

What is the distribution of Itraconazole?

Answer 16

Higher distribution to tissues than plasma. Does not enter CSF; enters breast milk

Question 17

What is Voriconazole’s absorption?

Answer 17

Bioavailability of 90% in adults; 45-64% in children

Question 18

What is Ketoconazole’s absorption?

Answer 18

99% protein bound. 75% bioavailability

Question 19

Describe Terbinafine’s absorption & distribution?

Answer 19

-Bioavailability 70-85%; not affected by food
-Lipophilic & widely distributed: outer layers of skin, hair follicles, skin & nails

Enters breast milk

Question 20

Describe fluconazole’s metabolism:

Answer 20

Inhibits CYP3A4 & 2C9 (BUT, less than the other antifungals)

Question 21

Describe fluconazole’s excretion:

Answer 21

Heavy renal excretion (80% as unchanged drug, ~11% as metabolite)

Question 22

Which parameters should be taken into account before prescribing fluconazole?

Answer 22

Renal impairment; dose adjustment (reduce by 50%) required when CrCl <50mL/min

Question 23

Describe Itraconazole’s metabolism

Answer 23

Extensive metabolism & inhibition of CYP3A4

Question 24

How is Itraconazole excreted?

Answer 24

40% in urine as metabolites; 3-18% in feces

Question 25

Describe Voriconazole's metabolism:

Answer 25

Extensive metabolism by CYP450

Question 26

What is a special consideration for *some* patients taking Voriconazole?

Answer 26

Dose should be adjusted for patients who are poor metabolizers of CYP2C19

Question 27

How is Voriconazole excreted?

Answer 27

almost entirely non-renal

Question 28

How is Ketoconazole metabolized?

Answer 28

Very strong CYP3A4 inhibitor

Question 29

How is Ketoconazole excreted?

Answer 29

85-90% in bile & feces; 10-15% in urine

Question 30

What is unique about Terbinafine's metabolism?

Answer 30

Undergoes extensive first pass metabolism & CYP450 only does about 5% of metabolism

Question 31

Is Terbinafine affected by drugs that undergo CYP450 metabolism?

Answer 31

No; CYP450 only does about 5% of metabolism

Question 32

What are important considerations when prescribing Terbinafine?

Answer 32

Requires dose reduction in liver & renal impairment

Question 33

How is Terbinafine excreted?

Answer 33

80% in urine as metabolites; 20% in feces

Question 34

Describe the blackbox warning for Ketoconazole:

Answer 34

Can cause severe hepatotoxicity that can lead to death or liver transplant; only use this medication if other anti fungal therapies are available

Question 35

What are general precaution for the azoles & allylamines?

Answer 35

-All have been associated with hepatotoxicity -Caution in preexisting liver & renal disease

Question 36

Which antifungals are excreted in breast milk?

Answer 36

Fluconazole Itraconazole Terbinafine

Question 37

Is Voriconazole safe to use in pregnancy?

Answer 37

It should only be used in pregnancy when potential benefits to mom outweigh risk to fetus

Question 38

Can Voriconazole be used in children?

Answer 38

Yes. May be used in neonates with severe fungal infection; higher doses may be required in children <50kg or less than 15 years old

Question 39

Can Fluconazole be used in children?

Answer 39

Yes. Safe & effective for children & infants

Question 40

What are common ADR's for Azoles?

Answer 40

May cause QT prolongation

Question 41

Itraconazole should be used with caution in these patients:

Answer 41

patients with preexisting HF & ventricular dysfunction; has been *Rarely* associated with development of HF

Question 42

ADR for Voriconazole:

Answer 42

Visual disturbances in 19% of patients: -Flashes of light, photophobia, color changes -Neurological symptoms (associated with toxic drug levels) Visual hallucinations, confusion, myoclonus

Question 43

How can you assume a patient has toxic drug levels of Voriconazole?

Answer 43

They would experience neurological symptoms such as visual hallucinations, confusion, myoclonus

Question 44

ADR's for Ketoconazole:

Answer 44

PO tablets may cause hepatotoxicity leading to death

Question 45

ADR's for Terbinafine:

Answer 45

-Hepatoxocity -Loss or change of taste (can require 2-6 months to recover) -Hypersensitivity, hepatitis, blood dyscrasias, Steven Johnson’s

Question 46

To a general extent, we could state that all antifungals inhibit:

Answer 46

CYP3A4

Question 47

Ketoconazole should not be used with these medications:

Answer 47

-Rifampin, Isoniazid -Hepatotoxic drugs -Drugs that increase gastric pH (antacids, PPI's, H-2 Blockers)

Question 48

Fluconazole should not be used concurrently with these meds:

Answer 48

Cimetidine & Hydrochlorothiazides

Question 49

These drugs are contraindicated when taking voriconazole:

Answer 49

Carbamazepine, Rifamycin, St. John’s Worth, Ergot Alkaloids, Rifabutin, Sirolimus

Question 50

Which drugs are contraindicated when taking Terbinafine?

Answer 50

alcohol, hepatotoxins

Question 51

We should avoid concurrent use of these drugs when taking Terbinafine:

Answer 51

phenytoin, rifampin

Question 52

What are indications for fluconazole?

Answer 52

-candidiasis (vaginal, oropharyngeal, esophageal) -other candida infections

Question 53

What is voriconazole indicated for?

Answer 53

Invasive aspergillosis

Question 54

What is Terbinafine indicated for?

Answer 54

Onychomycosis (toenail & fingernail) Off label: Tinea: capitis, corporis or cruris, pedis