C.4. Antifungal agents Flashcards
list 2 Polyenes
Amphotericin B and Nystatin
mechanism of action of Amphotericin B and Nystatin
- interact with ergosterol in fungal membranes to form ‘pores’, which disrupt membrane permeability
- Fungicidal effect
what is the basis of Amphotericin and Nystatin resistance?
strains that have low ergosterol content in their cell membranes are resistant
spectrum and clinical use of Amphotericin B
broadest antifungal spectrum.
systemic infections: Aspergillosis, Blastomyces, candida, Cryptococcus, Histoplasma, Mucor, Sporthrix
clinical use of Nystatin
topical for candidiasis
*systemic use is limited due to toxicity
how is Amphotericin given?
IV or orally (poor availability)
what is the T1/2 of Amphotericin B?
up to 2 weeks
does Amphotericin B have CNS penetration?
poor
an intrathecal injection is required against cryptococcal or candida meningitis
clearance of amphotericin
hepatic metabolism and renal elimination
adverse effects of Amphotericin infusion-related
fever, chills
muscle spasm
injection site phlebitis
hypotension (due to histamine release)
adverse effects of Amphotericin dose-dependent
- nephrotoxicity (↓ GFR, RTA, K and Mg² wasting, ↓EPO)
- CNS toxicity (seizures)
- Anemia
what are the means to reduce infusion-related toxicity with Amphotericin administration (4)?
- anti-histamines
- NSAID’s
- Meperidine- opioid
- Corticosteroids
what are the means to reduce dose-dependent toxicity with Amphotericin administration (4)?
- liposomal formulation of Amphotericin B
- Co-administration with flucytosine
- volume expansion with IV saline
- K and Mg² supplementation
mechanism of action of azoles
- interfere with the synthesis of ergosterol
2. Fungicidal effect
resistance mechanism of azoles
develops with long term use via ↓ intracellular accumulation and altered sensitivity of target enzymes
what are ketoconazole, clotrimazole and Miconazole?
Imidazoles
what is Fluconazole and Itraconazole?
1st generation Triazoles
what is Voriconazole?
2nd generation Triazole
how are azoles given?
oral, parenteral, topical
which azole can penetrate the CSF and cross the BBB?
fluconazole
are azoles inhibitors of CYP450 enzymes?
yes
what azoles are cleared by hepatic metabolism?
ketoconazole
itraconazole
voriconazole
which azole is cleared by renal elimination?
fluconazole
side effects of azoles
GI symptoms, skin rash
hepatotoxicity (rare)
visual disturbances (voriconazole)
↓ synthesis of steroid hormones cortisol and testosterone –> ↓ libido, gynecomastia (ketoconazole)
clinical use of ketoconazole
- Mucocutaneous candidiasis (topical)
- Dermatophytosis (topical)
- Cushing’s disease ( ↓ cortisol synthesis)
* systemic use is limited cause of side effects
clinical use of clotrimazole and Miconazole
topical: dermatophytes, superficial & vaginal candidiasis
OTC drug
clinical use of fluconazole
- esophageal, oropharyngeal, vaginal and invasive candidiasis
- Coccidiodes infections
- Cryptococcus meningitis- treatment and prophylaxis
clinical use of Itraconazole
- Dimorphic fungi, Blastomyces and Sporothrix infections
2. 2nd line agent for Aspergillus, Coccidioides, Cryptococcus, Histoplasma
clinical use of Voriconazole
Aspergillus infections
invasive candida infections (including sepsis)
what is Flucytosine?
Antimetabolite
mechanism of action of Flucytosine (5-FC)?
5-FC is converted to 5-FU by fungal cytosine deamiase —> 1. tri-phosphorylation, incorporated into fungal RNA
2. 5-FU forms 5-Fd-UMP –> inhibits thymidylate synthase–> thymine ↓ (inhibits DNA synthesis )
when does resistance to Flucytosine (5-FC) emerge?
when used alone and not in combination with Amphotericin B
Flucytosine is used in combination with….
Amphotericin B or triazole
used to treat Cryptococcal meningitis and invasive candidiasis
how is Flucytosine given?
orally
can Flucytosine enter the CNS?
yes
what type of elimination does Flucytosine have?
renal
side effects of Flucytosine (5-FU)
- bone marrow dysfunction (reversible)
- alopecia
- liver dysfunction
what is Caspofungin and what the mechanism?
an Echinocandin
inhibit the synthesis of β (1-3)-glucan, a critical component of the fungal cell wall.
how is Caspofungin given and what is it’s T1/2?
IV
T1/2 9-12 h’
metabolism of Caspofungin
hepatic
clinical uses of Caspofungin
- candida infections failed to respond to amphotericin B (disseminated and mucocutaneous infections)
- mucor infection
- Aspergillus infection
side effects of Caspofungin
- GI distress
- fever, headaches, flushing, skin rash
- hepatotoxic (rarely)
what are Griseofulvin and Terbinafine?
systemic drugs for superficial fungal infections (cutaneous mycoses- dermatophytosis, onychomycosis)
which systemic drug is an inducer of CYP450 enzymes?
Griseofulvin
↑ warfarin metabolism
mechanism of action of Griseofulvin
- fungistatic effect
- accumulates in keratin-rich tissues
- interfere with microtubules function in dermatophytes
resistance mechanism of Griseofulvin
↓ drug uptake
clinical use of Griseofulvin
Dermatophytosis of the skin and hair
*not commonly used!
how is Griseofulcin given?
orally
how is Terbinafine given?
topically and orally
side effects of Griseofulvin
GI distress headaches, mental confusion photosensitivity hepatotoxicity Disulfiram-like reaction teratogenic carcinogenic
mechanism of action of Terbinafine
- fungicidal effect
2. inhibits squalene epoxidase–> interfering with ergosterol synthesis
clinical use of Terbinafine
- Onychomycosis
2. Dermatophytosis of the skin and hair
side effects of Terbinafine
GI distress
Headache, rash
hepatotoxicity
taste disturbances
