Questions and Answers
How can antifungals be classified?
There are 4 classifications of antifungals by MOA including __________, __________, __________, and __________.
alter cell membrane permeability, block nucleic acid synthesis, disrupt microtubule function, disrupt fungal cell wall.
Which of the following are ways to classify antifungals by clinical use?
Name 4 systemic drugs used for subcutaneous & systemic mycoses.
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What is the mechanism of action of Amphotericin B?
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Amphotericin B is poorly absorbed from the __________ and thus must be given __________.
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How does Amphotericin B penetrate the CSF?
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Amphotericin B has a __________ spectrum of fungicidal action and is often used as __________ to rapidly reduce fungal burden.
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Amphotericin B is the preferred treatment for deep fungal infections during __________.
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What are the immediate adverse effects (AEs) of Amphotericin B related to?
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What is a slower toxicity associated with Amphotericin B?
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What measures have pharmaceutical companies taken to decrease renal toxicity of Amphotericin B?
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What type of antimetabolite is Flucytosine?
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Flucytosine is taken up by fungal ___________ and is converted to 5-FU, which inhibits __________.
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What is the effect of the combination of Flucytosine and Amphotericin B?
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Flucytosine is used in combination with __________ for the treatment of __________.
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The most common adverse effect of Flucytosine is __________, and is likely a result of __________.
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Which antifungals are relatively nontoxic oral drugs?
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Azoles are divided into 2 categories: __________ and __________.
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Name 3 imidazoles.
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Name 4 triazoles.
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Azoles inhibit __________, thereby reducing __________ and disrupting __________.
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With respect to adverse effects, how are azoles categorized?
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Ketoconazole is an inhibitor of __________, which can lead to decreased plasma __________ causing __________.
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High doses of Ketoconazole may inhibit __________ and decrease plasma __________.
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What does Ketoconazole inhibit that can potentiate the toxicities of certain drugs?
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Ketoconazole is best absorbed at __________, thus these drugs __________ interfere with absorption.
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Study Notes
Antifungal Drug Classification
- Antifungals can be classified by mechanism of action (MOA) and clinical use.
- Classification by MOA includes altering cell membrane permeability, blocking nucleic acid synthesis, disrupting microtubule function, and disrupting the fungal cell wall.
Types of Antifungals by MOA
- Alter cell membrane permeability: Polyenes, Azoles, Allylamines.
- Block nucleic acid synthesis: Flucytosine.
- Disrupt microtubule function: Griseofulvin.
- Disrupt fungal cell wall: Echinocandins.
Clinical Use of Antifungals
- Systemic drugs target subcutaneous and systemic mycoses.
- Drugs for superficial mycoses can be systemic or topical.
Systemic Drugs for Mycoses
- Four key systemic drugs include Amphotericin B, Flucytosine, Azoles, and Echinocandins.
Amphotericin B Mechanism of Action
- Binds to ergosterol in fungal cell membranes, creating pores leading to ion and macromolecule leakage and cell death.
Administration of Amphotericin B
- Poor absorption from the gastrointestinal tract necessitates intravenous (IV) administration.
- Penetration into the central nervous system (CSF) is extremely slow.
Spectrum and Use of Amphotericin B
- Exhibits a broad spectrum of fungicidal action; commonly used as an initial induction treatment to quickly lower fungal burden.
- Preferred for deep fungal infections, particularly during pregnancy.
Adverse Effects of Amphotericin B
- Immediate adverse effects relate to infusion-related toxicity occurring nearly universally but can be reduced by slow infusion or pre-medication with antihistamines, glucocorticoids, antipyretics, or meperidine.
- Slower toxicity primarily involves renal toxicity due to binding with cholesterol in mammalian cells, potentially leading to anemia from decreased erythropoietin (EPO).
Lipid Formulations of Amphotericin B
- Lipid formulations (Amphotec, Abelcet, AmBisome) developed to decrease renal toxicity, though still used as first-line treatment due to higher costs.
Flucytosine Overview
- Flucytosine is a synthetic pyrimidine antimetabolite, acting as an analog of cytosine.
Flucytosine Mechanism of Action
- Taken up by fungal cytosine permease, converted to 5-fluorouracil (5-FU), inhibiting thymidylate synthetase and thereby blocking dTMP formation.
- Disrupts protein synthesis through 5-FUTP.
Combination Therapy
- Flucytosine combined with Amphotericin B exhibits a synergistic effect, effectively treating candidiasis and cryptococcosis.
Adverse Effects of Flucytosine
- Bone marrow toxicity is the most common adverse effect due to conversion of the drug to 5-FU by intestinal flora.
Azoles Overview
- Azoles are relatively nontoxic oral antifungals.
Classification of Azoles
- Azoles are divided into imidazoles (older) and triazoles (newer).
- Common imidazoles include Ketoconazole, Miconazole, and Clotrimazole.
- Common triazoles include Itraconazole, Fluconazole, Voriconazole, and Posaconazole.
Azoles Mechanism of Action
- Inhibit 14-α-sterol demethylase, disrupting ergosterol synthesis, which affects membrane function and increases permeability.
- Triazoles are more specific than imidazoles.
Adverse Effects of Azoles
- Generally considered relatively nontoxic; minor gastrointestinal upset is the most common side effect.
Ketoconazole Effects
- Inhibits mammalian CYP P450 enzymes, potentially decreasing plasma testosterone levels, leading to gynecomastia, decreased libido, and menstrual irregularities.
- High doses may also inhibit adrenal steroid synthesis, reducing cortisol concentrations.
Drug Interactions with Ketoconazole
- Strongly inhibits CYP 3A4, potentially potentiating toxicities of warfarin and cyclosporin.
Absorption of Ketoconazole
- Optimal absorption occurs in low gastric pH; certain drugs may interfere with its absorption.
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Explore the classification of antifungal drugs through this helpful flashcard quiz. Learn about their mechanisms of action and clinical uses to enhance your understanding of antifungal therapy. Perfect for students and healthcare professionals alike!
