Antifungals Flashcards
3 most common systemic antifungals
Candidiasis
Cryptococcus
Aspergillosis
Drugs that alter cell membraine permeability
Polyenes
Azoles
Allylamines
Drugs that block nucleic acid synthesis
Flucytosine
Drugs that disrupt microtubule function
Griseofulvin
Drugs that disrupt the fungal cell wall
Echinocandins
Systemic drugs for subcutaneous and systemic mycoses
Ampotericin B
Flucytosine
Azoles
Echinocandins
Amphotericin B
MOA
RANGE of USE
Polyene antibiotic
- binds ergosterol and forms pores IN CELL MEMBRANE
- leakage of intracellular ions and macromolecules–>cell death
- Broadest spectrum - yeast, endemic mycoses, pathogenic molds
Amphotericin B
PK
What procedure can cause seizures as a side effect?
- highly insoluble:
- IV only (SLOW IV INFUSION)
poorly absorbed from the gut
LOW CSF penetration - INTRATHECAL therapy WARNING can cause seizures!
Amphotericin B USES
- Broad spectrum fungicidal
- Often used as initial induction regimen to rapidly reduce fungal burden.
- patients then continue therapy with an azole.
Amphotericin B prefere treatment for
deep fungal infections during pregnancy!!
Amphotericin B AE:
Infusion related toxicity
- Nearly universal: Fever and chills, muscle spasms, vomiting, headache and hypotension.
- Pre medication with Antiistamines, glucocorticoids, antipyetics or meperidine can be helpful!
Amphotericin B AE SLOWER TOXICITY?
Also binds cholesterol and forms mammalian cell membrane pores, leading to renal toxicity!!
- Renal impairment in all pts
• Azotemia occurs in most patients.
• GFR may be decreased.
• Renal toxicity commonly presents with renal tubular
acidosis with severe magnesium and potassium
wasting.
• Renal damage can be attenuated with sodium
loading: it is common practice to administer SALINE INFUSION with amphotericin B.
Amphotericin B AE SLOWER toxcicty 2?
• Hypochromic normocytic anemia, due to reduced
erythropoietin production.
• Renal function should be monitored frequently
during amphotericin B therapy.
• It is also advisable to monitor liver function, serum
electrolytes (particularly magnesium and
potassium), blood counts, and hemoglobin.
Amphotericin Lipid formulations use?
Package in lipid carriers to reduce interaction with nephron
- Liposomal amphotericin B (L-AMB)
- Amphotericin B Lipid complex (ABLC)
- Amphotericin B colloidal dispersion ( ABCD)
- Nephrotoxicity is less common and less severe with the lipid formulations
Flucytosine analogue of?
Cytosine
- pyramidine antimetabolite
Flucytosine MOA?
Taken up by fungal cells via cytosine permease
- disrupts RNA and DNA synthesis
Flucytosine –> 5-Fluorouracil (intracellular conversion) –> 5-fluorodeoxyuridine monophosphate –> inhibits THYMIDYLATE SYNTHASE thus blocking dTMP.
Flurorouridine triphosphate is also formed, which inhibits protein synthesis (5-FUTP)
Can mammalian cell convert Flucytosine to its active metabolites?
A combo with what drug shows synergism with Flucytosine?
- NO
2. Amphotericin B
Flucytosine spectrum
Fungistatic
Narrow spectrum
Not used as a single agent because of synergy with other agents, and to avoid resistance
Fucytosine USES
• Indicated only for serious infections caused by
susceptible strains of Candida and/or
Cryptococcus.
• Should be used in combination with
amphotericin B for the treatment of systemic
candidiasis and cryptococcosis in order to avoid
resistance.
Flucytosine AE:
Results from metabolism (intestinal flora) to 5-fluorouracil
- Bone marrow toxicity is the mot common.
AZOLES
Non toxic oral drugs
systemic therapy
IMIDAZOLES and TRIAZOLES
Imidazoles
“KMC”
Ketoconazole–> (inhibits 17, 20 desmolase 1st step of steroid synthesis)
Miconazole (my cone)–> tinea infections
Clotrimazole (close trim)–> tinea infections
Triazoles
"VIP Flu" Itraconazole Fluconazole Voriconazole Posaconazole (posaco)
Azoles: MOA
Inhibit CYP 450 enzyme 14 alpha demethylase from converting Lanosterol to ergosterol.
- increases permeability by disrupting membrane function.
CYP 450 enzyme specifity for azoles?
which ones have higher specificity?
High affinity for fungal CYP450 than human
Triazoles
Azoles AE
Relatively non toxic
minor GI upset
Ketoconazole MOA
- Inhibits mammalian CYP450 (CYP3A4) enzymes
- decreases plasma testorsterone levels and causes gynecomastia
- decreaed libido in men and loss of potency
- menstrual irregularities in womne
- high doses may inhibit adrenal steroid synthesis and decrease plasma cortisol concentrations
Ketoconazole is a CYP3A4 inhibitor what drugs can it potentiate toxcicities?
when is it best absorbed?
Warfarin and cyclosporine
At low gastric levels
- antacids, H2 blockers or proton pump inhibitots interfere w/ absorption
-poor CSF penetration
Ketoconazole is rarely used for?
Why?
still used for?
due to narrow spectrum and AE
used for cutaneous mycoses
Flucanazole PK?
GOOD CSF PENETRATION**
High oral bioavailability
IV and Oral
Moderate inhibitor of CYP3A4
Strong inhibitor of CYP2C9 –> increases plasma phenytoin, zidovudine and warfarin!
Fluconazole DOC
DOC in esophageal, oropharyngeal, vulvovaginal or urinary candidiasis
DOC for Candidemia
DOC for coccidoidomycosis
DOC for consolidation and maintenance of crytpococcal meninigitis after induction w/ amphotericin B
- alternative to amphotericin B for non-severe criptococcal meningitis
DOC for initiial and secondary prophylaxis against cryptococcal meningitis!
Fluconazole USES:
is ineffective against?
Aspergillus or other filamentous fungi!
Itraconazole: Metabolizes and inhibits? causes what fatal problem when administered w/ what 2 drugsl? PK? Can penetrate? what reduces absorption?
CYP3A4 arryhthmias when adminisitered w/ cisapride and quinidine Poor bioavaibility Penetrates poorly in CSF Antacids, H2 blockers and PPIs
Itraconazole uses?
butterfly is dimorphic
• Preferred azole for mycoses due to the
dimorphic fungi Blastomyces, Sporothrix and
Histoplasma.
• Effective against Aspergillus, but has been
replaced by voriconazole for this indication.
• Used for dermatophytoses and onychomycosis
Voriconazole DOC
DOC invasive ASPERGILLLOSIS
-spectrum similar to itraoncazole
Voriconazole AE
• Transient visual disturbances occur in up to 30% of patients.
• metabolized by and inhibits
CYP2C19, CYP2C9 and CYP3A4.
• The significant number of drug interactions due
to its metabolism through the various hepatic
enzymes may limit its use.
Posaconazole USES
inhibits?
used against zygomycetes (MUCOR)
- inhibits CYP3A4
ECHINOCANDINS: CASPOFUNGIN
spectrum of activity
• Active against candida and aspergillus but
not Cryptococcus neoformans.
• Only available IV.
ECHINOCANDINS: CASPOFUNGIN MOA?
• Inhibit synthesis of β(1-3)-D-glucans in the
fungal cell wall.
• This results in disruption of the fungal cell wall
and cell death
Systemic drugs for superficial mycoses
"FIT Keys onto Surface": • Griseofulvin • Terbinafine • Ketoconazole • Fluconazole • Itraconazole
Griseofulvin
whats its only use?
Absorbs best with?
MOA
- Only use: treatment of severe dermatophytosis of skin, hair and nails
- Absorption improved when given with fatty foods.
MECHANISM OF ACTION
• Disrupts mitotic spindle and inhibits mitosis.
Griseofulvin has been replaced w/?
Is an inducer of?
- newer antifungal drugs like
itraconazole and terbinafine.
• Induces P450 enzymes: increases metabolism
of a number of drugs, including warfarin.
Terbinafine
what type of antifungal is it?
PK?
- Allylamine.
* Available in oral formulation
Terbiafine MOA
inhibits squalene epoxidase!!
prevents synthesis of ergosterol.
• It also causes
accumulation of toxic
levels of squalene in the
fungal cell.
Terbinafine like griseofulvin accumulates in?
Its more effective in?
Keratin!
Much more effective in onychomycosis!!
what Azoles are commonly used in the treatment of dermatophytoses?
“KIt Fits the skin (derm)”
Ketoconazole
Itraconazole
Fluconazole
Topical drugs for superficial mycoses?
- Nystatin
- Amphotericin B
- Clotrimazole
- Miconazole
- Ketoconazole
- Terbinafine
NYSTATIN
• Polyene macrolide.
• Structurally similar to amphotericin B.
• Same mechanism of action.
68
NYSTATIN
• Too toxic for IV administration.
• Used only for candidiasis.
• Supplied in preparations for cutaneous,
vaginal, or oral administration.
• Not absorbed from the GI tract, skin, or
vagina.
• As a result it has little significant toxicity
What is topical amphotericin B used for?
Cutaneous candidiasis
The two azoles most commonly used
topically?
CLOTRIMAZOLE
MICONAZOLE
-available over the counter
Terbanafine effective against?
- Available as topical creams.
* Effective for tinea cruris and tinea corporis.
WHAT FUNGUS DOES NOT RESPOND TO ANTIFUNGALS?
Pneumpcystis Jirovecii Penumonia (PCP)
DOC for PCP, also DOC for prevention of PCP n immunocompromised individuals?
Co-trimoxazole
PNEUMOCYSTIS JIROVECII PNEUMONIA
Therapies:
• Alternative therapies are: • Clindamycin + primaquine • Dapsone + trimethoprim • Atovaquone • Pentamidine • Patients with moderate-to-severe disease should also be given prednisone.
