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Thera VIII > 02 Anti-Fungal Agents Duncan > Flashcards

02 Anti-Fungal Agents Duncan Flashcards

1
Q

What are the Polyene antibiotics?

A

Amphotericin, Nystatin

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2
Q

What are the Azole derivatives?

A

Miconazole, Fluconazole, Itraconazole

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3
Q

What are the Allylamines, Thiocarbamates?

A

Tolnaftate

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4
Q

What are the Echinocandins?

A

Caspofungin

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5
Q

What are some general characteristics of Amphotericin B?

A

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

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6
Q

How does Nystatins structure differ from Amphotericin B?

A

4 conjugated double bonds (one less double bond on the hydrophobic “rod”), less activity

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7
Q

What happens to Amphotericin B when the COOH (negative group) is esterified to methyl group?

A

Decrease in toxicity. AMB methyl ester is cationic (positive)

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8
Q

What is the solubility of Amphotericin like?

A

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

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9
Q

What are the pharmacokinetic advantages of Lipid Complex AMB (Abelcet)?

A

Comparable Cmax. More rapid blood clearance. Larger volume of distribution. Longer half-life. Slower renal elimination. Increased tissue concentrations

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10
Q

What is the MOA of AMB?

A

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

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11
Q

What is the Sensitivity to AMB like?

A

Bacterial membrane doesn’t contain sterols, not affects. Amphotericin has highest affinity for Ergosterol (human membrane sterol is cholesterol), significantly lower affinity

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12
Q

What is a common side effect with AMB?

A

Nephrotoxicity, probably directly related to MOA

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13
Q

What is the PK of AMB like?

A

Mostly metabolized. Some excreted by kidney. Doesn’t readily pass BBB

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14
Q

What is the Spectrum of Activity for AMB?

A

Useful against most systemic infections. Fungicidal

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15
Q

What is the Clinical Use for AMB?

A

Deep-seated infections. Topical infections

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16
Q

What are the ADRs associated with AMB?

A

Acute: Infusion-related (Chills, fever, dyspnea, N/V, bronchospasm, hypotension, convulsions). Subsequent: Nephrotoxicity, Hepatic damage, Hypokalemia, Hemolytic anemia

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17
Q

What is often given with AMB to help with the adverse effects in kidney function?

A

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

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18
Q

What are the characteristics of Flucytosine?

A

Frequently in combination with Amphotericin (d/t resistance). Synergistic activities. Pore enhances penetration

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19
Q

What is the MOA of Flucytosine?

A

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)

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20
Q

What is the important enzyme that has higher concentrations in fungal cells that convert 5FC to 5-Fluorouracil?

A

Cytosine Deaminase

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21
Q

What is the specificity of Flucytosine like?

A

Flucytosine is a prodrug, requires conversion to 5-Fluorouracil first by Cytosine deaminase (relatively low activity in humans)

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22
Q

What is the PK of Flucytosine?

A

Orally administered. Half-life: 3-6 hrs. Passes BBB. Excreted in urine ~80% unchanged

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23
Q

What is the spectrum of activity for Flucytosine?

A

Systemic fungi, mainly Candida and Cryptococcus. Usually used with AMB. Fungistatic

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24
Q

What is the clinical use of Flucytosine?

A

Cryptoccal meningitis (with AMB). Chromoblastomycosis (with itraconazole)

25
Q

What are the ADRs associated with Flucytosine?

A

N/V, colitis. Bone marrow suppression. Thrombocytopenia. Alopecia. Decreased liver function

26
Q

What are the two main classes of Azoles?

A

Imidazoles (older versions). Triazoles

27
Q

What are the characteristics of Imidazoles?

A

2 Nitrogens in the 5 atom ring. More toxic. Topical, for skin infections (OTC; e.g. Micatin)

28
Q

What are the characteristics of Triazoles?

A

3 nitrogens in the 5 atom ring. Less toxic. Can be used systemically

29
Q

What is the MOA of Azoles?

A

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)

30
Q

What is the specificity of Azoles like?

A

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)

31
Q

What does Ketoconazole cover?

A

Blastomycosis, Coccidioidomycosis, Ringworm, Candidiasis. Poor activity against CNS infection

32
Q

What does Itraconazole cover?

A

Blastomycosis, Histoplasmosis, Sporotrichosis, Aspergillosis

33
Q

What does Fluconazole cover?

A

Cryptococcus, Coccidioidomycosis, Candidiasis. Best activity against CNS infection

34
Q

What does Miconazole, Clotrimazole cover?

A

Topical dermatophytes such as Trichosporum spp., etc.

35
Q

What are the ADRs associated with Imidazoles?

A

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

36
Q

What are the ADRs associated with Itraconazole (Triazole)?

A

N/V. Liver dysfunction. Hypokalemia. Hypertriglyceridemia

37
Q

What are the ADRs associated with Fluconazole (Triazole)?

A

HA, rash, alopecia, rarely liver failure. Least effect of all azoles on liver enzymes

38
Q

What are the ADRs associated with Voriconazole (Triazole)?

A

Reduced interaction with “off-target” cytochrome P450s

39
Q

What are some common drugs that Ketoconazole interacts with (increasing their AUC) by inhibiting CYP3A4?

A

Cyclosporin. Triazolam

40
Q

What are some common drugs that Itraconazole interacts with?

A

Properties mirror ketoconazole, but to lesser degree. Also shown to increase statin AUC

41
Q

What are some common drugs that Fluconazole interacts with?

A

Interacts with cytochrome P450 2C9. WARFARIN

42
Q

What are some cross-reactions with Azoles?

A

Absorption of systemic imidazoles is reduced by H2 antihistamines and omeprazole and antacids

43
Q

How does Terbinafine work?

A

Oral use. Blocks the epoxidase step in ergosterol synthesis

44
Q

What are the Allylamines?

A

Naftifine (topical). Terbinafine (oral)

45
Q

What are the Thiocarbamates?

A

Tolnaftate (topical)

46
Q

What is the spectrum of activity for Allylamines and Thiocarbamates?

A

Dermatophytes (either topically applied or systemic). Fungicidal

47
Q

What is Griseofulvin?

A

Systemic agent; for treatment of dermatophytes only. Affects microtubules, therefore affects chromosome movements. Requires prolonged treatment courses

48
Q

What are the ADRs assoicated with Griseofulvin?

A

HA. Neurotoxicity. Hepatotoxicity. Photo-sensitivity. May be carcinogenic

49
Q

What are the important structural features of Pentamidine (treatment of Pneumocystis jirovecii)?

A

Termed diamidineg. Central string of 5 CH2s, sandwhiched between two modified phenols. Each phenol with identical side amide side chains

50
Q

What are Polyoxins and Nikkomycins?

A

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

51
Q

What are Papulacandins and Echinocandins?

A

Inhibit glucan synthesis. Appear to act synergistically with AMB, polyoxins, nikkomycins

52
Q

What is the main Glucan Synthase Inhibitor used?

A

Pneumocandins (Echinocandins): lipopeptide antifungal agent

53
Q

How are Pneumocandins (Echinocandins) administered?

A

Very poor oral absorption: parenteral

54
Q

What are the general structural characteristics of Pneumocandins?

A

Lipopeptide. Cyclic hexapeptide nucleus

55
Q

What are the different Pneumocandins used?

A

Caspofungin. Micafungin. Anidulafungin

56
Q

What is the MOA of Pneumocandins?

A

Glucan synthase: multiple subunits (FKS1: largest catalytic subunit)

57
Q

What are B-Glucans?

A

Important determinants by which macrophages recognize fungi for elimination. By uncovering them (with Caspofungin) you get better immune surveillance

58
Q

What is the sensitivity and resistance like for Pneumocandins?

A

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

59
Q

Look at treatment options summary

A

On slide 80-81

Thera VIII (24 decks)

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