02 Anti-Fungal Agents Duncan

Question 1

What are the Polyene antibiotics?

Answer 1

Amphotericin, Nystatin

Question 2

What are the Azole derivatives?

Answer 2

Miconazole, Fluconazole, Itraconazole

Question 3

What are the Allylamines, Thiocarbamates?

Answer 3

Tolnaftate

Question 4

What are the Echinocandins?

Answer 4

Caspofungin

Question 5

What are some general characteristics of Amphotericin B?

Answer 5

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

Question 6

How does Nystatins structure differ from Amphotericin B?

Answer 6

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

Question 7

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

Answer 7

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

Question 8

What is the solubility of Amphotericin like?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

What is the MOA of AMB?

Answer 10

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

Question 11

What is the Sensitivity to AMB like?

Answer 11

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

Question 12

What is a common side effect with AMB?

Answer 12

Nephrotoxicity, probably directly related to MOA

Question 13

What is the PK of AMB like?

Answer 13

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

Question 14

What is the Spectrum of Activity for AMB?

Answer 14

Useful against most systemic infections. Fungicidal

Question 15

What is the Clinical Use for AMB?

Answer 15

Deep-seated infections. Topical infections

Question 16

What are the ADRs associated with AMB?

Answer 16

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

Question 17

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

Answer 17

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

Question 18

What are the characteristics of Flucytosine?

Answer 18

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

Question 19

What is the MOA of Flucytosine?

Answer 19

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)

Question 20

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

Answer 20

Cytosine Deaminase

Question 21

What is the specificity of Flucytosine like?

Answer 21

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

Question 22

What is the PK of Flucytosine?

Answer 22

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

Question 23

What is the spectrum of activity for Flucytosine?

Answer 23

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

Question 24

What is the clinical use of Flucytosine?

Answer 24

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

Question 25

What are the ADRs associated with Flucytosine?

Answer 25

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

Question 26

What are the two main classes of Azoles?

Answer 26

Imidazoles (older versions). Triazoles

Question 27

What are the characteristics of Imidazoles?

Answer 27

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

Question 28

What are the characteristics of Triazoles?

Answer 28

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

Question 29

What is the MOA of Azoles?

Answer 29

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)

Question 30

What is the specificity of Azoles like?

Answer 30

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)

Question 31

What does Ketoconazole cover?

Answer 31

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

Question 32

What does Itraconazole cover?

Answer 32

Blastomycosis, Histoplasmosis, Sporotrichosis, Aspergillosis

Question 33

What does Fluconazole cover?

Answer 33

Cryptococcus, Coccidioidomycosis, Candidiasis. Best activity against CNS infection

Question 34

What does Miconazole, Clotrimazole cover?

Answer 34

Topical dermatophytes such as Trichosporum spp., etc.

Question 35

What are the ADRs associated with Imidazoles?

Answer 35

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

Question 36

What are the ADRs associated with Itraconazole (Triazole)?

Answer 36

N/V. Liver dysfunction. Hypokalemia. Hypertriglyceridemia

Question 37

What are the ADRs associated with Fluconazole (Triazole)?

Answer 37

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

Question 38

What are the ADRs associated with Voriconazole (Triazole)?

Answer 38

Reduced interaction with "off-target" cytochrome P450s

Question 39

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

Answer 39

Cyclosporin. Triazolam

Question 40

What are some common drugs that Itraconazole interacts with?

Answer 40

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

Question 41

What are some common drugs that Fluconazole interacts with?

Answer 41

Interacts with cytochrome P450 2C9. WARFARIN

Question 42

What are some cross-reactions with Azoles?

Answer 42

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

Question 43

How does Terbinafine work?

Answer 43

Oral use. Blocks the epoxidase step in ergosterol synthesis

Question 44

What are the Allylamines?

Answer 44

Naftifine (topical). Terbinafine (oral)

Question 45

What are the Thiocarbamates?

Answer 45

Tolnaftate (topical)

Question 46

What is the spectrum of activity for Allylamines and Thiocarbamates?

Answer 46

Dermatophytes (either topically applied or systemic). Fungicidal

Question 47

What is Griseofulvin?

Answer 47

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

Question 48

What are the ADRs assoicated with Griseofulvin?

Answer 48

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

Question 49

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

Answer 49

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

Question 50

What are Polyoxins and Nikkomycins?

Answer 50

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

Question 51

What are Papulacandins and Echinocandins?

Answer 51

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

Question 52

What is the main Glucan Synthase Inhibitor used?

Answer 52

Pneumocandins (Echinocandins): lipopeptide antifungal agent

Question 53

How are Pneumocandins (Echinocandins) administered?

Answer 53

Very poor oral absorption: parenteral

Question 54

What are the general structural characteristics of Pneumocandins?

Answer 54

Lipopeptide. Cyclic hexapeptide nucleus

Question 55

What are the different Pneumocandins used?

Answer 55

Caspofungin. Micafungin. Anidulafungin

Question 56

What is the MOA of Pneumocandins?

Answer 56

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

Question 57

What are B-Glucans?

Answer 57

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

Question 58

What is the sensitivity and resistance like for Pneumocandins?

Answer 58

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

Question 59

Look at treatment options summary

Answer 59

On slide 80-81