Anti-fungal drugs Flashcards Preview

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Flashcards in Anti-fungal drugs Deck (15):
1

Fungal cell structure and targets

1. fungal cell wall

- most medically relevant fungi have a cell wall composed of proteins and carbs including mannoproteins, chitin, glucan polymers

2. cell membrane

- major sterol for mamals cells: cholesterol

- major sterol for fungal cells: ergosterol

3. metabolism

- diferences in nucleotise metabolism from mammalian cells

2

polyene antifungal agents

 

structure:

mech:

prep:

Amphotericin B

Nystatin (too neprotoxic for systemic use, often used topically)

structure: multiple conjugated double bonds, internal ester, glcoside side chain

mech: moles form channel allowing loss of intracellular cations

original prep of amphotericin: solubilized with deoxycholate as micellar suspension

3

Amphotericin B

spectrum

extremely broad

- active against most medically related fungi

 

4

5

Antifungal triazoles

absorption:

distribution:

mech:

drug interactions:

apsorption:

- excellent for fluconazole

- poor for itraconazole tablets (esp in high pH)

- antacids decreased absorption of itraconazole

distribution: variable

- excellent CSF penetration by fluconazole and voriconazole

- poor CSF penetration by posaconazole and itraconazole

MEch of action:

- inhibition or ergosterol synthesis by interfering with Iansterol 14alpha demethylase, a funglal CYP450 molecule

Interfere with our CYP450 metabolism of many other drugs:

- durg-drug interations much be careful

- ex. inhibit metabolism of warfarin, increasing anticoagulant effect

- Rifampin enhances metabolism of azoles 

 

6

terbinafine

inhibits squalene epoxidase step in erosterol biosyn

oral and topical formulations

indicated for onychomycosis, tinea

Gi upset, hepatotoxicity

7

Griseofulvin

inferferes with microtubule assembly

well tolerated, inexpensive, but useful only for tx of skin infections

rare, peds cases

being replaced by itraconazole and terbinafine for many uses

8

classes of anti-fungal agents

1. disruption of fungal cell wall

2. disruption of fungal cell membrane

3. antimetabolites

4. microtubule assembly inhibitor

1. disruption of fungal cell wall

- Echinocandins: caspofungin, anidulafungin, micafungin

2. diruption of fungal cell membrane

- allylamine: terbinafine

- azoles: ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole

- polyenes: ampho B, including lipid formulations

3. antimetabolite

- pryimidine analogue: 5-flucytosine (5-FC)

4. microtubule assembly inhibitor

- griseofulvin

9

Amphotericin B

admin:

major toxicities:

administration:

- IV only for systemic use

- topical for sinus use

- unilaminar liposomes with Ampho B

- Major toxicities

- infusion- related rxns (75%): fever, chills, myalgias, nausea, vomiting, headache

- can be minimized by slow infusion, pretreatment with acetaminophen, hydrocortisone

nephrotoxicity

- tubular injury

- azotemia (increased blood urea nitrogen, creatine), hypomagnesemia and hypokelemia

- nephrogenic diabetes insipidus

- can be minimized by "saline loading", avoid other nephrotoxic agents

- patient with worst infection- use AMpho B

10

Azoles

spectrum:

ketaconazole- modestly effective- candida, aspergillus, not well absorbes, multiple doses needed

fluconazole- candida, cocciodes, cryptococcal pneumonia

itraconazole- expanded to aspergillus, durg of choise for histoplasmosis

voriconazole- expnaded and enhanced pharmacokinetics for molds, aspergillus

posaconazole- same as vori + zygomycosis 

11

anti fungal 

spectrum slide, admin route

fluconazole:

itraconazole and voriconazole:

posaconazole:

fluconazole

- active against most cryptococcus, candida sps (C.krusei resistant)

- aspergillus sps are resistant

- IV and PO

itraconazole and voriconazole

- active against most candida sps

-active against more aspergillus sps

- voriconazole is tx of choice for most invasive aspergillus

- itra PO only, vori IV and PO

posaconazole

- active against most candida, aspergillus, many molds, zygomycosis

- PO only

12

Echinocandins

- caspofungin, anidulafungin, micafungin

Mech:

toxicities:

admin:

spectrum:

mech:

-inhibit beta glucan synthetase activity, interfering with synthesis of cell wall component

toxicitites:

- well tolerated compared to polyenes

- fewer toxicities and drug interactions that triazoles, but casofungin alters metabolism of tacrolimus

admin:

IV only

Relative clinical efficacy compared to triazoles and plyenes not certain

spectrum: 

FDA approved for invasive infections due to aspergillus and candida

 

13

5-flucytosine

mech:

toxicities:

admin:

mech:

- taken up by fungal cells, converted in cytoplasm by cytosine deaminase to 5-fluoruracil, phophorylated, then inhibiting DNA, RNA synthesis

Toxicities:

- Gi intolerance, bone marrow suppression, rashe,s eosinophilia

admin:

PO only

Used synergistically with AmphoB for certain candida infections, cryptococcal meningitis

14

Topical antifungals

polyenes: amphotericin, nystatin

azoles: ketaconazole, butoconazole, clotrimazole, econazole, miconazole

allylamine: terbinafine, naftifine

antimetabolites: ciclopirox, tolnafte...

15

Dermatophyte (tinea) infections

most common

tinea coporis, crusis, pedis- topical antifungals

- clotrimazole, econazole

- avoid use of product with corticosteroids

tinea capitis (hair follicles)- systemic therpy needed

- terbinafine, itraconazole, griseofulvin, fluconazole

onychomycosis (nail infections due to fungi), systemic therapy needed

- terbinafine, itraconazole, grisefulvin, fluconazole