Anti-Fungal Therapy (Zheng) - 5/12/16 Flashcards
(27 cards)
Where are the three locations that fungal infections can occur?
Superficial - localized to the skin, hair, and nails
Subcutaneous - infection confined to dermis, subcutaneous tissue or adjacent structures
Systemic - infections of the internal organs
- HIV epidemic
- Cancer patients
- Organ transplantation patients
- Autoimmune patients
- Widespread use of antibiotics
Drug Classifications? (3)
- Systemic (oral and IV)
- Systemic drugs for mucocutaneous infections
- Topical drugs
Antifungal drug targets in the cell?
Cell membrane (Fungi use ergosterol instead of cholesterol in human cells) [amphotericin B, nystatin, azoles, allylamines]
Cell Wall [Cell wall inhibitor - echinocandins]
DNA Synthesis [Nucleic acid inhibitor - flucytosine]
Drugs for Systemic Infections:
Mode of action?
Amphotericin B
(Nystatin)
Macrolide w/ an amphipathic ring structure
Mode of Action:
- Polar side forms pores for ions to leak out of cells
- Non-polar side binds tightly to ergosterol (lipid) in fungal cell membrane
- Selective for ergosterol containing fungal membrane but not the cholesterol containing human or bacterial cell membrane
- Mycosamine sugar unit = crucial link between amphotericin and ergosterol that enables the formation of ion channel pores
Amphotericin B
Broad anti-fungal spectrum?
Resistance?
Broad anti-fungal spectrum:
- Yeast: Candida albicans, Cryptococcus neoformans
- Endemic fungi: Blastomyces dermatitidis, Histoplasma capsulatum, Coccidioides immitis
- Pathogenic molds: Aspergillus fumigatus, mucor
Resistance:
- Candida lusitaniae and Pseudallescheria boydii (display intrinsic amphotericin B resistance)
- Acquired drug resistance can occur in vitro but clinically not significant (decreased ergosterol, modified ergosterol, drug cannot penetrate cell wall)
Amphotericin B
Clinical uses?
- Drug of choice for nearly all life-threatening systemic infections
- Often used as the initial treatment in critical cases, then followed by triazoles for chronic therapy or prevention of relpase
- Topical drops for mycotic corneal ulcer/keratitis
- Local injection for fungal arthritis
Amphotericin B
Administration and Pharmacokinetics?
Liposomal Preparations?
- Drug is nearly insoluble in water
- Administration by IV as suspension in deoxycholate (50:41 colloid)
- Drug poorly absorbed by GI - oral administration is only for GI infections
- Excreted slowly in urine w/ half life 15 days
- Widely distributed, except for CSF
- Drug levels = insensitive to renal or hepatic dysfunction
Liposomal Preparations:
- Improved drug formulation with package in lipid
- Enables higher doses w/ reduced nephrotoxicity
- Expensive/commonly used when normal amphotericin B colloid causes problems
Amphotericin B
Adverse Effects:
- Infused related toxicity?
- Slower toxicity?
- Drug Interactions?
Infused related toxicity:
- Fever, chills, vomiting, headache, hypotension
- Decreasing dose
- Premedication with antipyretics (oral acetaminophin), antihistamines, meperidine, hydrocortisone may help
Slower toxicity
- RENAL DAMAGE IS THE MOST COMMON PROBLEM
- Variable anemia
- Occasional impaired liver function
Drug Interactions
- Nephrotoxic drugs (e.g. cyclosporine and aminoglycosides)
Drugs for Systemic Infections:
Mode of action?
Flucytosine
Pro drug
Taken up by fungal cytosine permase –> converted to 5-fluorouracil (5-FU) by cytosine deaminase –> 5-FU converted to 5-FUTP that inhibits RNA synthesis –> 5-FU converted to 5-FdUMP that inhibits DNA synthesis
*Cytosine deaminase is only found in fungal cells, not human cells so prodrug can be converted into cytotoxic drug
Flucytosine
Selectivity?
Resistance?
Selectivity?
Mammalian cells poorly convert 5-FC to 5-FU
Resistance?
Loss of 5FC to 5FU conversion, or 5FU to 5FUMP conversion, or loss of 5-FC permease
Flucytosine
Administration?
Clinical Uses?
Administration:
- Oral- absorbed rapidly from GI
- Well distributed (including CSF and aqueous humor)
- Removed by kidney - half life 3-6 hours
- Drug can rise to toxic levels with renal impairment
- Synergy with amphotericin B and itraconazole
ClinicalUses:
- Limited spectrum of actin, limited to Candida and Cryptococcus
- Usually given in combination therapy to avoid drug resistance: used in combo with amphotericin B or azoles
Flucytosine
Toxic Effects?
Drug Interactions?
Toxic Effects:
- Decrease function of bone marrow (leukopenia, thrombocytopenia)
- Rash and GI effects
- Side effects: due to conversion to 5FU by bacteria in intestinal tract
Drug Interactions
- Drugs that suppress bone marrow
Drugs for Systemic Infections:
Anti-fungal azoles
Classification?
Imidazole compounds (2 Ns in five member rings): Ketoconazole, clotrimazole, Miconazole
Triazole compounds (3 Ns in five member rings): Itraconazole, Fluconazole, Voriconazole
Drugs for Systemic Infections:
Anti-fungal azoles
Mode of action?
Inhibit ergosterol synthesis: target third step (binds to active site)
cause accumulation of toxic methylsterols that inhibit membrane enzymes
Drugs for Systemic Infections:
Anti-fungal azoles
Selectivity?
Adverse effects?
Bind less efficiently to mammalian p450s, offering some specificity toward fungal cells
Minor effect:
- Minor GI distress
- Liver enzyme abnormality, causing rare drug-induced hepatitis
Drugs for Systemic Infections:
Anti-fungal azoles
Broad Spectrum?
Candida spp., Cryptococcus neoformans, endemic mycosis, dermatophytes, aspergillus, pseudollescheria boydii (amphotericin B resistant strain)
Drugs for Systemic Infections:
Anti-fungal azoles
Drug Interactions?
Affect many drugs metabolism through P450 (cyclosporine, warfarin, buspirone, dihydropyridine)
Imidazoles?
Ketoconzole:
Miconazole and clotrimazole:
Ketoconzole: first oral azole but has generally been replaced by newer triazole compounds, though this drug is much cheaper
Miconazole and clotrimazole: only used topically
Triazoles: Itraconazole
Description?
Administration?
Metabolism?
Toxicity?
Drug Interaction?
Description:
- Most potent azole
- Itraconzole is favored over ketoconazole because: wider spectrum of action, fewer side effects (more specific than imidazoles)
- Used on when infection is severe
Administration:
- Oral-absorption is increased by gastric acid and food
- Widely distributed, except for CSF
- Limited bioavailability, but improved with cyclodextrin formulations
Metabolism:
- Lipid soluble
- Metabolism in liver through the cytochrome CYP3A4 isoenzyme
- Primary metabolite, hydroxyitraconazole, also has anti-fungal activity
Half life = 30-40 hrs
Toxicity:
- GI distress, teratogenic
Drug Interaction:
- H2 and proton pump blockers that decrease gastric acidity
- Drugs metabolized by P450 enzymes
Triazoles: Fluconazole
(Voriconazole, Posaconazole)
Description?
Administration?
Metabolism?
Toxicity?
Drug Interaction?
Fluconazole:
- Oral and well absorbed, no problem with gastric acidity
- Widely distributed, including CSF
- Least affects hepatic microsomal enzymes (fewer drug interactions)
- Wide therapeutic index
- Long half life (25-30 hrs)
Voriconazole, Posaconazole:
- Newest triazoles with improved bioavailability
- Posaconazole has the broadest spectrum
Echinocandins?
- Newest anti-fungal agents
- Water soluble semi-synthetic lipopeptide derivative of pneumocandin B
- Include caspofungin, micafungin, and anidulafungin
- Caspofungin = first candin to market
How do caspofungins work?
Disrupt cell wall
Caspofungin inhibits beta (1,3)-glucan synthase (FKS1)
Context:
Cell wall has 3 layers made up of mannoproteins, beta (1,6)-glucan/beta (1,3)-glucan, and chitin
Clinical uses
- Candida infections
- For invasive aspergillosis that fails amphotericin B
- Is taken parenterally
- Minor adverse effects include-fever, nausea, flushing, and vomiting
- Resistance due to mutation in FKS1
Systemic drugs for mucocutaneous infections:
Terbinafine?
- Synthetic allylamine
- Inhibits squalene epoxidase to block ergosterol biosynthesis (step 1) and thus ergosterol biosynthesis
- Inhibition leads to tox accumulation of sterol squalene
- Drug accumulates in skin, nail, and fat to prevent nail beds and skin infections
- Must be used continuously until infection is cleared
- Synergistic with triazole compounds
- No significant drug interactions to date and minimal side effects-GI distress and headache
