Pharmacology- Antifungals Flashcards
What class of antifungals does amphotericin B belong to?
Polyenes
What class of antifungals does nystatin belong to?
Polyenes
How is amphotericin B administered?
Topical or (slow) IV
What is the spectrum of action of amphotericin B?
Effective against Candida albicans (Candidiasis), Histoplasma (Histoplasmosis), Cryptococcus and many species of Aspergillus (Asperigillosis)
Is amphotericin B able to penetrate the CSF?
Poor but improves w inflammation
Liposomal formulations are better at penetrating
How is amphotericin B excreted?
Low levels of parent & metabolites appear in the urine over a long period of time, and some also eliminated by bile
What are the adverse reactions associated with amphotericin B?
- Fever and chills - usually 1-3h after starting IV infusion, but usually subside w repeated admin of the drug
- Nephrotoxicity - low levels in urine but conventional formulation causes renal vasoconstriction, reducing GFR by more than half. Avoid concurrent Tx w other nephrotoxic agents. Ensure adequate hydration
- Hypotension w hypokalaemia: may need K supplementation, be cautious w K fluctuation causing drugs
- Thrombophlebitis - can add heparin to the infusion to alleviate
- Bone marrow suppression, anemia
How is nystatin administered?
PO/Topical
Not used parenterally due to systemic toxicity (acute infusion-related adverse effects and nephrotoxicity)
What is the spectrum of action of nystatin?
Effective against Candida albicans (Candidiasis), Histoplasma (Histoplasmosis), Cryptococcus and many species of Aspergillus (Asperigillosis)
What is nystatin used for?
Oropharyngeal candidiasis
Vulvovaginal candidiasis
Cutaneous candidiasis
What are the adverse effects associated with nystatin?
PO: rare to have adverse effects
Topical/Vaginal: skin irritation
What is the mechanism of action of azoles?
Inhibit C-14 a-demethylase (CYP450 enzyme), thereby blocking the demethylation of lanosterol to ergosterol.
Results in disrupted membrane structure and function, inhibits fungal cell growth
What is the difference in the use of triazoles vs imidazoles?
triazoles - used IV/PO
imidazoles - used topically or slow IV (v low PO absorption)
List the triazoles.
Fluconazole, Posaconazole, Itraconazole, Voriconazole
List the imidazoles.
Clotrimazole, miconazole
What is the spectrum of action of fluconazole?
- Candida infections and most forms of mucocutaneous candidiasis
- Cryptococcal meningitis (but not 1st line)
- Histoplasmosis
- Single, small dose PO Tx for vulvovaginal candidiasis
- Most types of fungal meningitis
What is the spectrum of action of posaconazole?
Coverage against multiple infections: Candida, Aspergillus, some species of Fusarium and zygomycetes
What is the spectrum of action of itraconazole?
Broad spectrum compared to fluconazole
Tx of histoplasmosis, blastomycosis, aspergillosis in pts intolerant to amphotericin B
Tx of onychomycosis in non immunocompromised pts
Oral solution used for esophageal & oropharyngeal candidiasis
What is the spectrum of action of voriconazole?
Broad-spectrum antifungal
For invasive apergillosis and candida infections
Which of the triazoles can penetrate the CSF?
Small molecule triazoles can - fluconazole, voriconazole
Large molecule triazoles cannot - posaconazole, itraconazole
How is fluconazole excreted?
Renal, unchanged
How is posaconazole excreted?
Mainly by faeces
How is itraconazole excreted?
Hepatic metabolism, parent drug and inactive metabolites excreted in faeces and urine
How is voriconazole excreted?
Metabolised by CYP450s, inactive metabolites excreted by urine
What are the adverse reactions associated with triazoles?
- N/V
- Headache
- Skin rashes
- Hepatotoxicity
- QT prolongation
How should itraconazole capsules be taken?
Take after a full meal
How should itraconazole solution be taken?
Take on an empty stomach
What does voriconazole interact with?
Don’t take with PPIs - Voriconazole is metabolized by CYP2C19 and proton-pump inhibitors are enzymatic inhibitors of CYP2C19.
What is the spectrum of action of imidazoles?
Wide range of activity against Epidermophyton, Microsporum, Trichophyton, Candida and Malassezia (depending on agent)
Generally used for Tinea and candidiasis
What indications are clotrimazole used for?
Dermatophyte infections
Cutaneous candidiasis
Vulvovaginal candidiasis
Oral and pharyngeala candidiasis (troches)
What indications are miconazole used for?
Tinea pedis, tinea cruris, tinea versicolor, vulvovaginal candidiasis
What are the adverse effects associated with the imidazoles?
Topical use associated w contact dermatitis, vulvar irritation and edema
Oral admin may result in GI disturbances
Name the echinocandins.
Caspofungin, Micafungin, Anidulafungin
What is the mechanism of action of echinocandins?
Inhibits activity of glucan synthase complex, so that synthesis of glucans to make up fungal cell wall is inhibited, to result in loss of structural integrity of cell wall and thus cell lysis
How are the echinocandins administered?
IV
What is the spectrum of action of the echinocandins?
Potent activity against Aspergillus and most Candida species, incl azole resistant species
1st line for invasive candidiasis, 2nd line for invasive aspergillosis in pts that have failed or cannot tolerate amphotericin B or an azole
Are the echinocandins able to penetrate the CSF?
No.
How are the echinocandins excreted?
Metabolised slowly by hydrolysis and N-acetylation, not metabolised by CYP450 but DDI observed for micafungin
Non-renally cleared
What are the adverse reactions associated with the echinocandins?
Minimal, rarely lead to drug discontinuation
1. GIT Sx
2. Fever, chills
3. Rashes
4. Skin flushing
5. Thrombocytopenia
What is the mechanism of action of terbinafine?
Inhibit squalene epoxidase to block conversion of squalene to lanosterol and biosynthesis of ergosterol
Accumulation of toxic amounts of squalene results in inc membrane permeability and death of the fungal cell
How is terbinafine administered?
PO/Topical
What is the spectrum of action of terbinafine?
Active against Trichophyton
PO used to treat nail fungal infections and tinea capitis (needs to accumulate in keratin to exert effect)
Topical used to treat tinea pedis, tinea corporis and tinea cruris
In what groups of patients should PO terbinafine be avoided in?
Moderate-severe renal impairment or hepatic dysfunction
How is PO terbinafine excreted?
PO extensively metabolised by several CYP450s
Excreted mainly by urine
What are the adverse reactions associated with terbinafine?
- GI disturbances
- Headache
- Rash
- Elevated liver enzymes
