02 Anti-Fungal Agents Duncan Flashcards
What are the Polyene antibiotics?
Amphotericin, Nystatin
What are the Azole derivatives?
Miconazole, Fluconazole, Itraconazole
What are the Allylamines, Thiocarbamates?
Tolnaftate
What are the Echinocandins?
Caspofungin
What are some general characteristics of Amphotericin B?
Active against all fungi. Has a hydrophilic “rod” and hydrophobic “rod”, as well as a polar, negative charged and polar positive charged sugar. The hydrophobic “rod” has 7 conjugated double bonds
How does Nystatins structure differ from Amphotericin B?
4 conjugated double bonds (one less double bond on the hydrophobic “rod”), less activity
What happens to Amphotericin B when the COOH (negative group) is esterified to methyl group?
Decrease in toxicity. AMB methyl ester is cationic (positive)
What is the solubility of Amphotericin like?
Amphotericin is insoluble in water (Fungizone: complex with deoxycholate, forms a colloidal suspension). AMB can be formulated as a “Liposome” which decreases toxicity and may allow higher dosing
What are the pharmacokinetic advantages of Lipid Complex AMB (Abelcet)?
Comparable Cmax. More rapid blood clearance. Larger volume of distribution. Longer half-life. Slower renal elimination. Increased tissue concentrations
What is the MOA of AMB?
Membrane targeting agent. “Like-associates-with-like” type mechanism. Amphotericin has high affinity for sterols (Ergosterol interaction provides major binding energy). Amphotericin monomers multimerize to form a “pore”, which “breaks” the membrane (molecules enter that should be kept out), numerous physiological processes are compromised
What is the Sensitivity to AMB like?
Bacterial membrane doesn’t contain sterols, not affects. Amphotericin has highest affinity for Ergosterol (human membrane sterol is cholesterol), significantly lower affinity
What is a common side effect with AMB?
Nephrotoxicity, probably directly related to MOA
What is the PK of AMB like?
Mostly metabolized. Some excreted by kidney. Doesn’t readily pass BBB
What is the Spectrum of Activity for AMB?
Useful against most systemic infections. Fungicidal
What is the Clinical Use for AMB?
Deep-seated infections. Topical infections
What are the ADRs associated with AMB?
Acute: Infusion-related (Chills, fever, dyspnea, N/V, bronchospasm, hypotension, convulsions). Subsequent: Nephrotoxicity, Hepatic damage, Hypokalemia, Hemolytic anemia
What is often given with AMB to help with the adverse effects in kidney function?
Calcium channel blockers or salt loading minimize adverse effects in kidney function. Liposomal formulations minimize adverse nephrotoxic effects by maintaining renal blood flow and GFR
What are the characteristics of Flucytosine?
Frequently in combination with Amphotericin (d/t resistance). Synergistic activities. Pore enhances penetration
What is the MOA of Flucytosine?
5FC acts as a metabolic antagonist, in two ways: 1) Inhibition of DNA synthesis, 2) Inhibition of RNA synthesis. 5FC must first be converted to 5-Fluorouracil by Cytosine Deaminase. 5-Fluorouracil then binds with deoxyribose, inhibiting DNA synthesis (Thymidylate Synthetase is inhibited)
What is the important enzyme that has higher concentrations in fungal cells that convert 5FC to 5-Fluorouracil?
Cytosine Deaminase
What is the specificity of Flucytosine like?
Flucytosine is a prodrug, requires conversion to 5-Fluorouracil first by Cytosine deaminase (relatively low activity in humans)
What is the PK of Flucytosine?
Orally administered. Half-life: 3-6 hrs. Passes BBB. Excreted in urine ~80% unchanged
What is the spectrum of activity for Flucytosine?
Systemic fungi, mainly Candida and Cryptococcus. Usually used with AMB. Fungistatic
What is the clinical use of Flucytosine?
Cryptoccal meningitis (with AMB). Chromoblastomycosis (with itraconazole)
What are the ADRs associated with Flucytosine?
N/V, colitis. Bone marrow suppression. Thrombocytopenia. Alopecia. Decreased liver function
What are the two main classes of Azoles?
Imidazoles (older versions). Triazoles
What are the characteristics of Imidazoles?
2 Nitrogens in the 5 atom ring. More toxic. Topical, for skin infections (OTC; e.g. Micatin)
What are the characteristics of Triazoles?
3 nitrogens in the 5 atom ring. Less toxic. Can be used systemically
What is the MOA of Azoles?
Azoles are metabolic antagonists. Block biosynthesis of ergosterol. Inhibit Lanosterol Demethylase (removes C14 methyl), a cytochrome P450 enzyme by attaching to its heme group. Membranes become fragile, impaired. Imidazoles can directly interact with cell membranes (contributes to their toxicity)
What is the specificity of Azoles like?
Humans obtain membrane sterols (chlesterol) from their diet. Cytochrome P450 is more active in fungi (Triazoles have lower interaction with human cytochrome P450 (> 100 –> 1000 fold)
What does Ketoconazole cover?
Blastomycosis, Coccidioidomycosis, Ringworm, Candidiasis. Poor activity against CNS infection
What does Itraconazole cover?
Blastomycosis, Histoplasmosis, Sporotrichosis, Aspergillosis
What does Fluconazole cover?
Cryptococcus, Coccidioidomycosis, Candidiasis. Best activity against CNS infection
What does Miconazole, Clotrimazole cover?
Topical dermatophytes such as Trichosporum spp., etc.
What are the ADRs associated with Imidazoles?
Azoles interact with human cytochrome P450s involved in steroid biosynthesis. N/V. Allergic rash. Fluid retention. Teratogen. Inhibits/Interacts with drug metabolism of other agents
What are the ADRs associated with Itraconazole (Triazole)?
N/V. Liver dysfunction. Hypokalemia. Hypertriglyceridemia
What are the ADRs associated with Fluconazole (Triazole)?
HA, rash, alopecia, rarely liver failure. Least effect of all azoles on liver enzymes
What are the ADRs associated with Voriconazole (Triazole)?
Reduced interaction with “off-target” cytochrome P450s
What are some common drugs that Ketoconazole interacts with (increasing their AUC) by inhibiting CYP3A4?
Cyclosporin. Triazolam
What are some common drugs that Itraconazole interacts with?
Properties mirror ketoconazole, but to lesser degree. Also shown to increase statin AUC
What are some common drugs that Fluconazole interacts with?
Interacts with cytochrome P450 2C9. WARFARIN
What are some cross-reactions with Azoles?
Absorption of systemic imidazoles is reduced by H2 antihistamines and omeprazole and antacids
How does Terbinafine work?
Oral use. Blocks the epoxidase step in ergosterol synthesis
What are the Allylamines?
Naftifine (topical). Terbinafine (oral)
What are the Thiocarbamates?
Tolnaftate (topical)
What is the spectrum of activity for Allylamines and Thiocarbamates?
Dermatophytes (either topically applied or systemic). Fungicidal
What is Griseofulvin?
Systemic agent; for treatment of dermatophytes only. Affects microtubules, therefore affects chromosome movements. Requires prolonged treatment courses
What are the ADRs assoicated with Griseofulvin?
HA. Neurotoxicity. Hepatotoxicity. Photo-sensitivity. May be carcinogenic
What are the important structural features of Pentamidine (treatment of Pneumocystis jirovecii)?
Termed diamidineg. Central string of 5 CH2s, sandwhiched between two modified phenols. Each phenol with identical side amide side chains
What are Polyoxins and Nikkomycins?
Pyrimidine linked to peptide. Target cell wall biosynthesis. Block chitin biosynthesis. Agents are structural analogues of UDP-N-Acetylglucosamine. Limited usefulness; poor intracellular penetration to target site
What are Papulacandins and Echinocandins?
Inhibit glucan synthesis. Appear to act synergistically with AMB, polyoxins, nikkomycins
What is the main Glucan Synthase Inhibitor used?
Pneumocandins (Echinocandins): lipopeptide antifungal agent
How are Pneumocandins (Echinocandins) administered?
Very poor oral absorption: parenteral
What are the general structural characteristics of Pneumocandins?
Lipopeptide. Cyclic hexapeptide nucleus
What are the different Pneumocandins used?
Caspofungin. Micafungin. Anidulafungin
What is the MOA of Pneumocandins?
Glucan synthase: multiple subunits (FKS1: largest catalytic subunit)
What are B-Glucans?
Important determinants by which macrophages recognize fungi for elimination. By uncovering them (with Caspofungin) you get better immune surveillance
What is the sensitivity and resistance like for Pneumocandins?
Fungi are uniquely sensitive d/t the unique use of glucan polysaccharide in cell wall. Fungi with little or no glucan in cell wall are resistant (e.g. Cryptococcus neoformans). Mutations in FKS1 gene cause resistance
Look at treatment options summary
On slide 80-81
