Antifungals Flashcards
What are the two groups of antifungals required for this course?
Azoles & Allylamines
What are the four azole’s required for the course?
Fluconazole, Itraconazole, Voriconazole, Ketoconazole
What is the main Allylamine required for the course?
Terbinafine
What is the unique component in fungal cell walls targeted by antifungals?
cholesterol ergosterol
What is the MOA of azoles?
Reduce ergosterol production by inhibiting 14-Ademethylase (the fungal CYP450 enzyme)
Which major enzyme group is inhibited by the azoles?
CYP450
What is the MOA of Allylamines?
They interfere with synthesis of ergosterol through inhibition of squalene epoxide → squalene builds up and causes cell death
What are the main organisms targeted by azoles?
-Candida
-Cryptococcus
-Mycoses: blastomycosis, coccidioidomycosis, histoplasmosis
-Dermatophytes
Use of Itraconazole is now limited to combat these organisms:
histoplasmosis & blastomycosis
Voriconazole has an extended spectrum of coverage & is used to treat:
Most yeasts & molds including fluconazole resistant Candida, Aspergillus and Zygomyces
Terbinafine is only approved for the treatment of:
Onychomycosis (fungal infection under nails)
Describe Fluconazole’s absorption & distribution:
Well absorbed with a bioavailability of 90%. Wide distribution into CSF, eye, & perineum
Itraconazole can be taken as a capsule or solution. which one is preferred and why?
Solution is preferred because bioavailability not affected by food or antacids
Describe the PO absorption of Itraconazole
Capsule bioavailability is 55% when taken with food; 30% on empty stomach
What instructions should be given to a patient when taking PO Itraconazole?
DO NOT TAKE with H2 Blockers or PPI’s
What is the distribution of Itraconazole?
Higher distribution to tissues than plasma. Does not enter CSF; enters breast milk
What is Voriconazole’s absorption?
Bioavailability of 90% in adults; 45-64% in children
What is Ketoconazole’s absorption?
99% protein bound. 75% bioavailability
Describe Terbinafine’s absorption & distribution?
-Bioavailability 70-85%; not affected by food
-Lipophilic & widely distributed: outer layers of skin, hair follicles, skin & nails
Enters breast milk
Describe fluconazole’s metabolism:
Inhibits CYP3A4 & 2C9 (BUT, less than the other antifungals)
Describe fluconazole’s excretion:
Heavy renal excretion (80% as unchanged drug, ~11% as metabolite)
Which parameters should be taken into account before prescribing fluconazole?
Renal impairment; dose adjustment (reduce by 50%) required when CrCl <50mL/min
Describe Itraconazole’s metabolism
Extensive metabolism & inhibition of CYP3A4
How is Itraconazole excreted?
40% in urine as metabolites; 3-18% in feces
Describe Voriconazole’s metabolism:
Extensive metabolism by CYP450
What is a special consideration for some patients taking Voriconazole?
Dose should be adjusted for patients who are poor metabolizers of CYP2C19
How is Voriconazole excreted?
almost entirely non-renal
How is Ketoconazole metabolized?
Very strong CYP3A4 inhibitor
How is Ketoconazole excreted?
85-90% in bile & feces; 10-15% in urine
What is unique about Terbinafine’s metabolism?
Undergoes extensive first pass metabolism & CYP450 only does about 5% of metabolism
Is Terbinafine affected by drugs that undergo CYP450 metabolism?
No; CYP450 only does about 5% of metabolism
What are important considerations when prescribing Terbinafine?
Requires dose reduction in liver & renal impairment
How is Terbinafine excreted?
80% in urine as metabolites; 20% in feces
Describe the blackbox warning for Ketoconazole:
Can cause severe hepatotoxicity that can lead to death or liver transplant; only use this medication if other anti fungal therapies are available
What are general precaution for the azoles & allylamines?
-All have been associated with hepatotoxicity
-Caution in preexisting liver & renal disease
Which antifungals are excreted in breast milk?
Fluconazole
Itraconazole
Terbinafine
Is Voriconazole safe to use in pregnancy?
It should only be used in pregnancy when potential benefits to mom outweigh risk to fetus
Can Voriconazole be used in children?
Yes. May be used in neonates with severe fungal infection; higher doses may be required in children <50kg or less than 15 years old
Can Fluconazole be used in children?
Yes. Safe & effective for children & infants
What are common ADR’s for Azoles?
May cause QT prolongation
Itraconazole should be used with caution in these patients:
patients with preexisting HF & ventricular dysfunction; has been Rarely associated with development of HF
ADR for Voriconazole:
Visual disturbances in 19% of patients:
-Flashes of light, photophobia, color changes
-Neurological symptoms (associated with toxic drug levels)
Visual hallucinations, confusion, myoclonus
How can you assume a patient has toxic drug levels of Voriconazole?
They would experience neurological symptoms such as
visual hallucinations, confusion, myoclonus
ADR’s for Ketoconazole:
PO tablets may cause hepatotoxicity leading to death
ADR’s for Terbinafine:
-Hepatoxocity
-Loss or change of taste (can require 2-6 months to recover)
-Hypersensitivity, hepatitis, blood dyscrasias, Steven Johnson’s
To a general extent, we could state that all antifungals inhibit:
CYP3A4
Ketoconazole should not be used with these medications:
-Rifampin, Isoniazid
-Hepatotoxic drugs
-Drugs that increase gastric pH (antacids, PPI’s, H-2 Blockers)
Fluconazole should not be used concurrently with these meds:
Cimetidine & Hydrochlorothiazides
These drugs are contraindicated when taking voriconazole:
Carbamazepine, Rifamycin, St. John’s Worth, Ergot Alkaloids, Rifabutin, Sirolimus
Which drugs are contraindicated when taking Terbinafine?
alcohol, hepatotoxins
We should avoid concurrent use of these drugs when taking Terbinafine:
phenytoin, rifampin
What are indications for fluconazole?
-candidiasis (vaginal, oropharyngeal, esophageal)
-other candida infections
What is voriconazole indicated for?
Invasive aspergillosis
What is Terbinafine indicated for?
Onychomycosis (toenail & fingernail)
Off label: Tinea: capitis, corporis or cruris, pedis
