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Pharmacy School 2015-16 > Antifungal Agents > Flashcards

Antifungal Agents Flashcards

1
Q

Compared to bacteria, fungi have

A

Different ribosomes

Different cell wall components (chitin, mannoproteins and glucans)

A nuclear membrane

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2
Q

Control of mycotic infections

A

Immunization is not usually effective

Control involves IV amphotericin B, flucytosine, azoles and nystatin

In some cases surgical removal of damaged tissue

Prevention limited to masks and protective clothing to reduce contact with spores

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3
Q

Except for _________________ and _________________, all currently available antifungals target the cell membrane

A

Flucytosine; griseofulvin

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4
Q

Azoles

A

Interfere with ergosterol synthesis by targeting lanosterol demethylase enzyme, leading to defective cell membranes through accumulation of toxic sterol products; used to treat a variety of systemic and localized fungal infections

All are synthetic, show broad activity towards years and molds (no antibacterial action), orally active or topical, and fungistatic or fungicidal

Imidazoles - ketoconazole, miconazole and clotrimazole

Triazoles - fluconazole and itraconazole

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5
Q

Imadazoles

A

COMET - K

Clotrimazole 
Oxiconazole 
Miconazole 
Econazole 
Tioconazole 
Ketoconazole
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6
Q

Triazoles

A

FIT VIP

Fluconazole 
Itraconazole 
Terconazole 
Voriconazole 
Isavuconazole 
Posaconazole
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7
Q

Echinocandins

A

MAC

Micafungin
Anidulafungin
Caspofungin

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8
Q

Allylamines

A

ANT

Amorolfin
Naftifine
Terbinafine

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9
Q

Clotrimazole

A

Topical imidazole (cream, ear drops) - OTC

Troche - throat lozenge

Treats vaginal yeast, ringworm, athlete’s foot, jock itch and thrush

Side effects include skin irritation, rash, hives, burning, itching, redness, est.

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10
Q

Ketoconazole

A

Imidazole

Tablet, cream, shampoo

Oral administration, requires low pH for absorption

Numerous dose-limiting side effects: hepatotoxic, teratogenic, GI disturbances, disruption of mammalian steroid hormone biosynthesis

Largely replaced by the newer triazoles

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11
Q

Fluconazole

A

Oral or IV Triazole - good absorption and distribution; also for topical use

Oral and esophageal candidiasis in AIDS patients

Cryptococcal meningitis

Better tolerated than ketoconazole

Resistance is common, but usually limited to AIDs patients and after long-term therapy

Potential adverse effects: rash, nausea, hepatotoxicity

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12
Q

Itraconazole

A

Oral Triazole

Similar to ketoconazole in structure but can’t form the same toxic metabolites

Better specificity for fungal cyp450, decreasing toxicity

Broader spectrum than fluconazole, but not as well tolerated as fluconazole

Often drug of choice for non-life-threating mycoses

99% protein bound; no cerebrospinal fluid penetration

Many potential side effects

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13
Q

New Generation Triazoles

A

Some have excellent in vitro activity against a wide variety of fungal pathogens

MIC values lower against most Candid spp.

Have in vitro activity against Aspergillus sp. that is comparable or better than that of amphotericin B and itraconazole

Voriconazole, Posaconazole

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14
Q

Voriconazole

A

New generation triazoles

Approved for acute invasive aspergillosis and salvage therapy for several other rare mycoses

Outperformed amphotericin B in trials

IV or oral

Side effects include visual disturbances and increased liver enzymes

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15
Q

Posaconazole

A

New generation triazole

Similar to itraconazole but better activity and broader spectrum; may cause more serious side effects

Side effects include fever, diarrhea, nausea, increased liver enzymes

Oral only; slow absorption (3-5 hours) and has a long half life (35 hours)

Used to treat invasive infection of Candida, Mucor, and Aspergillus in immunocompromised patients

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16
Q

Azole resistance

A

The broad use of fluconazole and other azoles resulted in isolated Candida species resistant to azoles

Three types of drug-resistance:

(1) replacement of initially susceptible species by intrinsically resistance species of Candida
(2) Replacement of an initially susceptible Candida strain by a more resistant strain of the same species
(3) Development of resistance in a single strain of Candida species

Mechanisms include decreased uptake or increased efflux; altered sterol C14 demethylase or other ergosterol biosynthetic enzymes; amplification of genes encoding for target enzymes

17
Q

Fungicidal polyenes

A

Bind ergosterol forming drug-lipid complexes which intercalate into the fungal cell membrane to form a membrane-spanning channel

This causes cellular ions to leak out of the cell, destroying the proton gradient and culminating in osmotic cellular lysis

18
Q

Amphotericin B

A

Polyene antifungal; polyketide natural product of Streptomuces sp; all have 4-7 conjugated double bonds on one side and multiple hydroxyls on the other side; has free carboxy on the macrolide and is modified with an amino sugar

Creates an amphoteric molecule

Most potent antifungal for systemic infections but is highly nephrotoxic (80% of patients show sign of kidney damage; toxicity is dose dpenedent and usually transient if renal function was normal before therapy)

Administered IV

19
Q

Polyenes

A

NAN

Natamycin
Amphotericin B
Nystatin

20
Q

Echinocandins

A

Act as noncompetitive inhibitors of (1,3)-B-d-glucan synthase (encoded by FKS1) and therby cause a loss of cell wall integrity and severe cell wall stress

21
Q

Caspofungin

A

Echinocandin - lipopeptide antifungal natural product

For treating invasive aspergillosis, also effective towards Candida

Given IV - good solubility to H20 | Long t1/2 allows once a day dosing | Metabolized by acetlyation

Minimal side effects

MOA: Inhibit 1,3,B-glucan synthase, blocking assembly of fungal cell wall; no Cryptococcus neoformans activity due to thick capsule

MOR: Rare but substitutions in FKS1P subunit of 1,3-B-glucan synthase confer reduced susceptibility

22
Q

Micafungin

A

Echinocandin

Approved for candidiasis in person undergoing bone marrow transplant and for esophageal candidiasis

Braod spectrum against Candid spp., including azole-resistant C. albicans

23
Q

Anidulafungin

A

Echinocandin

Semisynthetic - has echinocandin B nucleus with modified terphenyl tail

Approved for esophageal candidiasis, candidemia and peritonitis due to candida infection

24
Q

5-fluorocytosine (Flucytosine)

A

Synthetic | only oral | resistance is common in monotherapy - usually combined with amphotericin B - for severe systemic fungal infection

MOA: Interferes with fungal protein and DNA synthesis; requires metabolic activation

Side effects: Hepatotoxicity, bone marrow depression

25
Q

Griseofulvin

A

Natural product taken orally for dermatophytic infections of hair and nails

MOA: Inhibits fungal mitosis by preventing separation of the chromosomes

Effect is only fungistatic; poor bioavailability which can be increased through micronization of dose

Side effects: Headache, rash, GI pain

26
Q

Allylamines

A

Inhibit squalene epoxidase (first step in synthesis of ergosterol)

Terbinafine, Butenafine

27
Q

Terbinafine

A

Effective topically or systemically, mostly for nail fungus

Inhibits ergosterol biosynthesis

Topical squalene epoxidase inhibitor

28
Q

Butenafine

A

Active vs dermatophytes and C. albicans

Achieves high skin concentrations and remains in skin tissue for prolonged periods

Exerts anti-inflammatory as well as antifungal activity in vivo; beneficial in dermatophytic infections that are accompanied by a marked inflammatory reaction in the infected tissue

Better fungicidal activity than terbinafine

29
Q

Tolnaftate

A

Thiocarbamate

Cream, powder, spray, liquid aerosol

Broad spectrum but no anticandida activity

Used topically for athlete’s foot and jock itch

MOA: inhibits ergosterol biosynthesis (target is squalene epoxidase)

Pharmacy School 2015-16 (34 decks)

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