Antifungals Flashcards by Stacey Hansen

Many antifungals are moderate to strong inhibitors of this

CYP3A4

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2 enzymes involved in fungal ergosterol synthesis that are targets for antifungals

Squalene epoxidase
14-alpha-demethylase (a CYP450 molecule)

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Amphotericin B, Azoles, Echinocandins and Flucytosine treat this type of mycoses

Systemic

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Natural polyene antifungal produced by Streptomyces bacteria

Amphotericin B

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Amphotericin B is a natural polyene antifungal produced by this

Streptomyces bacteria

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Streptomyces bacteria produce this antifungal

Amphotericin B

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Antifungal effective against wide range of fungi, including Candida albicans, Coccidioides immitis, and many strains of Aspergillus

Amphotericin B

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Antifungal that binds to fungal membrane component ergosterol
Alters fungal cellular permeability, a pore former mechanism

Amphotericin B

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MOA of Amphotericin B

Binds to fungal membrane component ergosterol
Alters fungal cellular permeability = a pore former

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Amphotericin B binds to this fungal component

Membrane ergosterol

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Primarily administration route of Amphotericin B

IV
(inhalation and oral routes possible)

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Does Amphotericin B penetrate the meninges?

No - poor penetration into most compartmented fluids (meningeal, humoral, etc.)

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Biotransformation rate of Amphotericin B

Slow
Half life can vary considerably

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Common adverse effects of Amphotericin B are related to this

Infusion related
Headache, fever, chills, hypotension, nausea/vomiting and tachypnea

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Infusion related adverse effects of Amphotericin B (headache, fever, chills, hypotension, nausea/comiting and tachypnea) can be managed by premedicating with these 3

Ibuprofen, Antihistamines, Steroids (hydrocortisone)

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Pretreating Amphotericin B with ibuprofen, antihistamines, and steroids is a method of managing this

Infusion related adverse effects (headache, fever, chills, hypotension, nausea/vomiting, tachypnea)

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Severe chills as a result of Amphotericin B can be treated with this

Meperidine

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Meperidine can treat severe chills as a result of this drug

Amphotericin B

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Meperidine can treat this adverse effect of Amphotericin B

Severe chills

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Principle adverse effect associated with long-term treatment of Amphotericin B

Nephrotoxicity

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Nephrotoxicity is the principle adverse effect associated with long-term treatment of this antifungal

Amphotericin B

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Antifungal with a black box that states it should be used in serious invasive fungal infections only and at safe dosages

Amphotericin B

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Formulation of Amphotericin B that reduces nephrotoxicity but prolongs infusion reaction

Liposomal formulations

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Liposomal formulations of this drug reduce nephrotoxicity but prolong infusion reaction

Amphotericin B

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Amphotericin B liposomal formulations reduce this

Reduce nephrotoxicity but prolong infusion reaction

Amphotericin B liposomal formulations reduce nephrotoxicity but prolong this

Infusion reaction

Antifungal indicated for a wide range of fungal infections, commonly for Candida infections, Cryptococcosis, Sporotrichosis and other dangerous systemic fungal infections

Azoles

Antifungals that inhibits fungal lanosterol 14-alpha-demethylase (CYP51A1) thereby inhibiting fungal ergosterol synthesis Increases fungal permeability by same mechanism

Azoles

MOA of Azoles

Inhibits fungal lanosterol 14-alpha-demethylase (CYP51A1) thereby inhibiting fungal ergosterol synthesis (fungistatic) Increases fungal permeability by same mechanism

Azoles inhibit this enzyme

lanosterol 14-alpha-demethylase (CYP51A1) (involved in fungal ergosterol synthesis)

Azoles inhibit fungal lanosterol 14-alpha-demethylase, aka this enzyme

CYP51A1

Azoles inhibit CYP51A1, aka this enzyme

lanosterol 14-alpha-demethylase

Azoles inhibit fungal lanosterol 14-alpha-demethylase (CYP51A1), thereby inhibiting synthesis of this

Ergosterol

Spectrum of Azoles

Broad spectrum antifungal activity; resistance is an emerging problem

Absorption of Azoles require this

Acidic environment (except fluconazole)

Azoles require acid environment for oral absorption, with this exception

Fluconazole

Fluconazole is an exception for this requirement of oral absorption of Azoles

Does NOT require acid environment

Hepatic changes, prolonged QT interval, and endocrine effects are adverse effects of this type of antifungal

Azoles

Prolonged QT interval, leading to possible arrhythmia is a characteristic adverse effect of this type of antifungal

Azoles

High doses of this type of antifungal are linked to endocrine effects linked to disruption of CYP action in steroid synthesis, altered sex hormone levels

Azoles

High doses of Azoles are linked to this adverse effect

Endocrine effects Linked to disruption of CYP action in steroid synthesis, altered sex hormone levels

Endocrine effects as a result of high doses of Azoles are linked to this

Disruption of CYP action in steroid synthesis

Azoles should be avoided with drugs that do this

Decrease gastric acid secretion Will slow azole dissolution and absorption Exception is fluconazole

Antifungals whose use should be avoided with drugs that decrease gastric acid secretion

Azoles

Why should azole use be avoided with drugs that decrease gastric acid secretion?

Because these will slow azole dissolution and absorption (except for fluconazole) Azoles require acid environment for absorption

With use of azoles, be alert for possible drug-drug interactions resulting from this

CYP inhibition

MOA of echinocandins

Inhibit Beta-1,3-glucan formation to reduce cell wall integrity

Antifungals that Inhibit Beta-1,3-glucan formation to reduce cell wall integrity

Echinocandins

Echinocandins inhibit formation of this

Beta-1,3-glucan Reduces cell wall integrity

Echinocandins inhibit beta-1,3-glucan formation, which has this effect

Reduce cell wall integrity Results in cell wall instability and death (fungicidal)

Antifungals Indicated for invasive Candidiasis, esophageal Candidiasis, candidemia and others

Echinocandins

Transient hepatotoxicity (monitor liver markers) and flushing are adverse effects of this type of antifungal

Echinocandins

Antifungal that is a prodrug converted by fungal enzymes

Flucytosine

MOA of Flucytosine

Prodrug converted to 5-FU by fungal cytosine deaminase Inhibits protein and DNA synthesis

What provides selective toxicity for flucytosine?

Requirement of fungal cytosine deaminase

Flucytosine is activated by fungal cytosine deaminase to this

5-fluorouracil

Flucytosine is activated by this to 5-fluorouracil

Fungal cytosine deaminase

Antifungal that is activated by fungal cytosine deaminase to 5-FU

Flucytosine

Flucytosine toxicity is mainly due to this

Fungal release of 5-FU

Antifungal whose toxicity is mainly due to fungal release of 5-FU

Flucytosine

Antifungal with black box warning urging caution when used in patients with renal impairment

Flucytosine

Flucytosine black box warning urges caution when used in patients with this

Renal impairment

Flucytosine bone marrow depression occurs from this, a powerful and toxic anticancer drug, released following fungal death

5-fluorouracil

Antifungal with bone marrow depression and hepatotoxicity as adverse effects

Flucytosine

This is an adverse effect of flucytosine that occurs from 5-FU, a powerful and toxic anticancer drug, released following fungal death

Bone marrow depression

Bone marrow suppression is a characteristic adverse effect of this antifungal

Flucytosine

Antifungal combination with synergistic MOA that can be used for severe candida and cryptococcal infections Both drugs can be used at lower concentrations to reduce toxicity of both agents

Flucytosine and Amphotericin B combination

Antifungal indicated for Candida infections of skin, vagina, mouth and esophagus

Nystatin

Antifungal with MOA similar to amphotericin B in that it binds to sterols in the fungal membrane to cause leaks

Nystatin

MOA of nystatin

Similar to that of amphotericin B in that it binds to sterols in the fungal membrane to cause leaks

Antifungal used topically to avoid severe systemic toxicity and does not produce systemic levels of any significance

Nystatin

Antifungal often used in "swish and swallow" treatment of thrush

Nystatin

Systemic or topically administered anti-fungal for dermatophytic infections

terbinafine and Naftifine

Antifungal that inhibits squalene epoxidase, a key enzyme in sterol synthesis in fungal, depleting ergosterol

Terbinafine and Naftifine

MOA of Terbinafine and Naftifine

Inhibits squalene epoxidase, depleting ergosterol

Terbinafine and Naftifine inhbit this

Squalene epoxidase (depleting ergosterol)

Squalene epoxidase is involved in the synthesis of this

Ergosterol

Naftifine uses this administration only

Topical

Terbinafine or Naftifine: Topical only

Naftifine

Terbinafine or Naftifine: Oral and topical formulations

Terbinafine

Antifungals Indicated for Trichophyton skin and nail infections (Tinea pedis)

Terbinafine and Naftifine

Hepatotoxicity (rarely severe) and taste distortion (dysgeusia), rarely severe, are adverse effects of this antifungal

Terbinafine and Naftifine

Taste distortion is a characteristic adverse effect of this antifungal

Terbinafine and Naftifine

Antifungal that inhibits microtubule functions, especially mitotic spindle formation, inhibiting mitosis and increasing production of multinucleate cells

Griseofulvin

MOA of Griseofulvin

Inhibits microtubule functions Inhibits mitosis and increases production of multinucleate cells

Antifungal with oral absorption, limited by poor solubility, improved by microsize or ultramicrosize preparations/tablets and by taken whole or crushed with a fatty meal

Griseofulvin

Oral solubility of Griseofulvin is improved by this

Microsize or ultramicrosize preparations And by taken whole or crushed with a fatty meal

Antifungal that is concentrated in fat and skeletal muscle, but also skin, hair, nails, because it binds to keratinocyte precursor cells and is incorporated into new keratin

Griseofulvin

Why does Griseofulvin concentrate in fat and skeletal muscle, also skin, hair, nails?

Binds to keratinocyte precursor cells and is incorporated into new keratin

Griseofulvin concentrates in fat and skeletal muscle because it binds to these

Keratinocyte precursor cells Is incorporated into new keratin

Elimination of Griseofulvin

Excreted in the urine, feces, and perspiration (sweat carries drug to skin)

Transient headache (~15%), cognitive disruptions, considered teratogenic and carcinogenic, and triggers a disulfiram-like reaction in combination with alcohol are adverse effects of this antifungal

Griseofulvin