Antifungals Flashcards
Different mechanisms of antifungals?
- alter cell membrane permeability
- block nucleic acid synthesis
- disrupt microtubule functions
Antifungals that alter cell membrane permeability?
Azoles (ketoconazole), polyenes (Nystatin), Terbinafine
Antifungals that block nucleic acid synthesis?
Flucytosine
Antifungals that disrupt microtubule functions?
Griseofulvin
What topical drugs are used for cutaneous fungal infections?
azoles and polyenes
What are the systemic drugs used for superficial fungal infections?
Griseofulvin, Terbinafine, and Itraconazole (azole)
Systemic drugs used for systemic fungal infections?
*Bad systemic infections
Amphoteracin B (Amphoterrible -> don’t use)
Azoles
Flucytosine (5-FC)
What are the topical azalea antifungals and their MOA?
clotrimazole, ketoconazole, miconazole
- fungicidal, impairs the formation of fungal cell membranes therefore increasing permeability (so intracellular contents leak out leading to cell death)
Clinical uses of Topical azole antifungals
tinea corporis (body), tinea cruris (jock itch), tinea pedis (athletes foot), cutaneous candidiasis (yeast infection)
*Tinea=condition caused by dermatophytes
CIs of topical azole antifungals (c,k,m)
pregnancy, lactation
- caution w/ liver failure
- don’t use ketoconazole if hx of sulfa allergy
Application of topical azole antifungals
lotion or powder ->
apply 2x daily for 2-4 weeks
continue for 1 week after lesions clear
MOA of topical azole antifungals
inhibit CYP450, inhibit synthesis of ergosterol (cell membrane of fungi)
SE: pruritis, irritation, burning or stinging
Clotrimazole
Names: Gyne-Lotrimin, Mycelex 3&7, Trivagizole 3
Indications:
- cutaneous candidiasis (topical)
- vulvovaginal candidiasis (topical)
- oropharyngeal candidiasis (thrush -> oral formulation)
CI: hypersensitivity to clotrimazole or any other component of formula
Oropharyngeal candidiasis dosing
troche dissolved slowly 5x / day for 14 days
Clotrimazole MOA
binds to phospholipids in the fungal cell membrane altering permeability and loss of intracellular elements
- very little systemic absorption from topical
- oral: inhibitory concentrations in saliva for up to 3 hours post dissolution of troche
Drug interactions for clotrimazole
topical= none
oral drug interactions similar to other azaleas due to inhibition of P450 enzymes
Adverse effects of Clotrimazole
Topical: vulvovaginal burning
oral: abn. LFTs, pruritus, N/V
monitor: periodic LFTs
Ketoconazole (topical)
formula: cream, foam, gel or shampoo
indications: tinea corporis, tinea cruris, tinea pedis, cutaneous candidiasis, + seborrheic dermatitis and tinea versicolor
Topical azoles: miconazole (micatin, monistat, desenx, lotrimin AF)
formulations: aerosol, powder aerosol, intravaginal supp, cream, ointment, lotion
indications: tinea corporis, tinea cruris, tinea pedis, cutaneous candidiasis, tinea versicolor + vulvovaginal candidiasis
- intravaginal sups may interfere with warfarin
Topical Polyene: Nystatin (mycostatin)
Indications: cutaneous and mucocutaneous infections caused by candida
-oral and intestinal candidia infections
CIs: hypersensitivity reaction
Mycostatin MOA
binds to sterols in fungal cell membrane and changes the cell wall permeability leading to the leakage of intracellular contents
Mycostatin dosing
cream, ointment and powder:100,000 U/g 2-3x daily
oral suspension - 400,000-600000 U QID
intestinal infections: tablets- 500000-1,000,000 U po q8H
Mycostatin pharmokinetics/dynamics
onset of action -> relief of sxs: w/in 24-72 hours
systemic absorption- none (why its used to tx intestinal infections)
-no drug interactions
Adverse effects of mycostatin
contact dermatitis - develop blisters
- SJS
- oral: N/V/D
Systemic drugs for superficial fungal infections
Griseofulvin, terbinafine, itraconazole
-for hair, skin and nails
Griseofulvin indications
used to tx tine infections of skin, hair and nails
-most commonly used for tx of tine capitis (scalp)
Griseofulvin MOA
inhibits fungal cell division
binds to himan keratin making it resistant to fungal invasion (goes down into hair follicles as hair grows out, takes a long time to work)
Duration fo Griseofulvin therapy
tinea corporis: 2-4 weeks tinea cruris: 2-6 weeks tinea capitis: 4-6 weeks tinea pedis: 4-8 weeks tinea unguium (nails): 4-6 months or longer
administration: fatty meal (PB or ice cream) may increase GI absorption
- with food or milk to decrease GI upset
CIs and precautions with administration of Griseofulvin
- liver failure
- porphyria (porphyrin accum)
- preg (X)
- caution if hx of pcn allergy
- breast feeding not recom.
What periodic monitoring is required if pt is on long term tx of griseofulvin
renal fxn, liver fxn, and CBC to watch for granulocytopenia
* get CBC and CMP
Drug interactions of Griseofulvin
many due to its effects on CYP1A2, CYP2C9, CYP3A4
-warfarin, oral contraceptives, alcohol, barbiturates, cyclosporine and others
Adverse reactions of griseofulvin
photosensitivity, SJS, toxic epidermal necrolysis, erythema multiforme, jaundice, elevated LFTs, granulocytopenia, dizziness, fatigue, HA, N/V/D, drug induced lupus like syndrome
Dose adjustments of griseofulvin dependent on?
smaller particle size the greater bioavailability requiring dose adjustments between 2 formulations
- microsize: suspensions, grifulvin V tablets
-ultramicrosize: Gris-PEG tablets
(tablets are spendy)!
Terbinafine (Lamisil)
oral/systemic formula:
- oncychomycosis of toenails and fingernails
- tinea capitis
CIs: Hypersensitivity
Terbinafine MOA
creates ergosterol deficiency within the cell wall leading to cell death
Dosing of Terbinafine
oral: onychomcosis of the fingernails -> 250 mg/day x 6 weeks
oncychomycosis of the toenails: 250 mg day x 12 weeks
Terbinafine pharmacodynamics/kinetics
effective half life 36 h
- distribution to the sebum and skin
- 99% plasma bound (drug interactions)
- hepatic metabolism
drug interactions of Terbinafine
due to inhibition of CYP450 enzymes there are some sig. drug interactions including metoprolol (B blocker), and tramadol - pain med (oral formulation)
Terbinafine SEs
HA, diarrhea, LFTs,
burning, contact dermatitis, dryness, pruritus, rash
Itraconazole (sporanox) indications for superficial infections
**Onychomycosis
Itraconazole (sporanox) CIs
hypersensitivity to intraconazole or other azoles
- concurrent administration with other drugs that act at CYP450 system
- Ventricular dysfunction (negative inotrope)
- CHF
- pregnancy or intend to become pregnant
Itraconazole (Sporanox) Pharmacodynamics/Kinetics
requires gastric acidity for optimal absorption
- better absorbed with food (capsule)
- solution better absorbed on an empty stomach
- 99.*% protein bound
- half life: 21 hours
- metabolized by liver
Itraconazole (Sporanox) drug interactions
significant list of drug interactions:
- proton pump inhibitors, anxiolytics, pain meds, antiplatelet agents, anthypertensives, cholesterol lowering meds
- drug interaction checker is a must when using these drugs
Itraconazole (sporanox) adverse effects
Nausea, diarrhea, edema (from L. ventricular dysfunction), HA, rash, Abnorm. LFTs, heart failure, arrhythmia, hearing loss, and many more
Itraconazole (sporanox) monitoring
baseline LFTs, monthly LFTs (if long term therapy), serum concentrations to assure therapeutic levels (obtain after 2 weeks of therapy, draw anytime during the dosing interval)
Systemic drugs for systemic fungal infections (the worst of the worst)
Amphoteracin B (stay away from), azoles: ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, flucytosine (5-FC)
Amphoteracin B (Amphoterrible!!)
systemic antifungal for use in SEVERE fungal infections
- IV only
indications: severe systemic and CNS infections that are progressive and potentially life threatening.
SEs: anaphylaxis, infusion reaction, leukoencephalopathy (damage to brain white matter), nephrotoxicity
Amphotericin B MOA
bind to ergosterol and alters cell membrane permeability and may also stimulate the macrophages
monitor: renal and liver fxn (CMP), electrolytes, PT/PTT, CBC
Drug interactions with Amphotericin B
aminoglycosides, antifungal agents, corticosteroids, cyclosporine
Itraconazole (Sporanox) indications - for systemic infections
(for superficial -> onychomycosis)
systemic: aspergillosis, blastomycosis, esophageal and oropharyngeal candidiasis (oral soln), coccidioidomycosis, histoplasmosis
Itraconazole (sporanox) CIs
hypersensitivity to intraconazole or other azoles
- concurrent admin with other drugs that act at CYP450 system
- ventricular dysfunction (negative inotrope)
- CHF
- pregnancy or intend to become pregnant
Itraconazole (sporanox) pharmodynamics/kinetics
requires gastric acidity for optimal absorption
- better absorbed with food (capsule) but soln is better absorbed on an empty stomach,
- 99.8% protein bound, half life: 21 hours
- metabolized by the liver
Itraconazole (Sporanox) drug interactions
sig. list of drug interactions
- proton pump inhibitors, anxiolytics, pain meds, antiplatelet agents, antihypertensives, cholesterol lowering meds
- drug interaction checker is a must when using these drugs (same as for topical infections -same drug)
Itraconazole (sporanox) adverse effects (for systemic use)
Nausea, diarrhea, edema, HA, rash, Abnorm. LFTs, Heart failure, arrhythmia, hearing loss, and many others
Itraconazole (sporanox) monitoring
Baseline LFTs, monthly LFTs (if long term therapy), serum concentrations to assure therapeutic levels: obtain after 2 weeks of therapy, draw anytime during dose interval
Fluconazole (diflucan) indications
- Blastomycosis (CNS disease)
- candidiasis: candidemia, endocarditis, orpharyngeal, prophylaxis, vaginal and more
- coccidioidomycosis: meningitis, pneumonia, prophylaxis
- crypococcosis: meningitis, pneumonia
Fluconazole (Duflucan) CIs
hypersensitivity to fluconazole or other azaleas
-coadmin. of CYP3A4 substrates which may lead to QT prolongation (cisapride, primozide, or quinidine)
FLuconazole (Diflucan) route and dose
IV and oral
dose dep. in disease process
Fluconazole (diflucan) pharmacokinetics/dynamics
distribution: widely thoughout the body, good penetrate into CSF, eye, peritoneal fluid, sputum, skin and urine,
protein binding: 11-12% in plasma
Half life:w/ normal renal function about 30 hours
Fluconazole (Diflucan) Drug interactions
Extensive list: Most commonly used drugs that fluconazole interacts with: -statins (cholesterol) - sildenafil (viagra) -warfarin -sulfonylureas (antidiabetic meds) - proton pump inhibitors -Ca channel blockers, B blockers (antiHTNs) -Diclofenac (NSAID) -Fentanyl, benzodiazepines -macrolides
Fluconazole (Diflucan) Adverse effects
pregnancy: C/D HA, dizziness N/V/D elev LFTs QT prolongation
Fluconazole (Diflucan) monitoring
Baseline LFTs
periodic LF, RF and K
Systemic ketoconazole (Nizoral) FDA warning
Rare cases of serious hepatotoxicity including hepatic failure and death associated with ketoconazole. Occurred in pts receiving high doses for short tx durations and in pts receiving low doses for long durations
- risk of decreased adrenal corticosteroid secretion at doses >/= 400 mg/day
- risk of QT prolong. if on other drugs known to prolong QT
- significant inhibitor of CYP450 enzymes: statins,, Ca channel blockers, antidepressants, macrocodes, and b-blockers
Ketoconazole indications (oral) for systemic infections
use restricted only for tx of systemic life threatening fungal infections when other safer agents cannot be used:
-blastomycosis, coccidiomycosis, histoplasmosis, chromomycosis, paracoccidiodmycosis
*shouldnt be used for candida or dermatophyte infections
Monitoring of ketoconazole for systemic infections
close monitoring warranted
-baseline and weekly monitoring of liver function
SEs: mult. serious drug interactions
-edema, orthostatic hypotension, fatigue, insomnia, pruritus, hot flashes, nausea, vomiting, myalgia, weakness, and more
Voriconazole and posaconazole (systemic infections)
newer systemic tri-azole antifungals
- oral or IV for aspergillosis
- may be used for oral pharyngeal candidiasis resistant to other txs
Flucytosine (5-FC) (systemic infections)
class: pyrimadines (diff. class diff. coverage), for severe systemic fungal infections
