Flashcards in Week 2 - Antifungal Drugs & Fungal Skin Infections Deck (35)
What are the 6 antifungals we need to know?
1. Polyenes - Amphotericin & Nystatin
2. Azoles - Fluconazole, Itraconazole, Ketoconazole
3. Allylamines - Terbinafine
6. Echinocandins - Caspofungin
What is the mechanism of Polyenes (Amphotericin B & Nystatin)?
It binds ergosterol, creating holes in the membrane allowing leakage of electrolytes. It's fungicidal!
What is the spectrum of Polyenes? What types of patients are they commonly used for?
Broad spectrum. Used for invasive systemic fungal infections in immunocompromised patients. Active against yeast and molds.
How are Polyenes distributed through out the body?
A small fraction of drug is excreted and has a long tissue half life. Liposomal form can cross blood-brain barrier.
Resistance is rare in polyenes. How does a fungi become resistant to a Polyene?
It has a decreased amount of ergosterol in its membrane.
What are the adverse effects of Polyenes?
TOXIC because they're able to bind cholesterol. This decreases renal blood flow and leads to permanent destruction of the basement membrane. About 80% of patients have nephrotoxicity. Nystatin does NOT have these effects. Nystatin is a topical used for Candida.
What are the three Azoles?
Fluconazole, Itraconazole, Ketoconazole
What is the mechanism of azoles?
They bind fungal P-450 enzyme (Erg11) and block the production of the membrane protein ergosterol and causes accumulation of lanosterol. It's fungistatic.
What is the spectrum of Azoles?
They're the most widely used antifungal and the spectrum varies by the agent used.
How are Azoles distributed in the body?
They have better oral availability when taken with cola/acid. Cola helps facilitate absorption of itraconazole and ketoconazole.
What kind of toxicity do Azoles cause?
Drug-drug interactions, hepatotoxicity, neurotoxicity, alters hormone synthesis - AVOID DURING PREGNANCY (pregnancy class C)
How can fungi become resistant to Azoles?
Altered cytochome P-450, upregulation of efflux transporters
What is the drug in the Allylamines class?
What is the mechanism of Terbinafine (Lamisil)?
It inhibits squalene epoxidase, which leads to the toxic accumulation of squalene. This drug is fungicidal.
What is the spectrum of Allylamines (Terbinafine - Lamisil)?
What type of toxicity does Terbinafine cause?
It's almost always used topically. It can cause drug interactions with CYP2D6 substrates.
How can a fungi become resistant to Terbinafine (Lamisil)?
Resistance is rare in human pathogens, but it could include (1) Decreased uptake, (2) Mutant binding site, and (3) Substrate for efflux transporters
What is the fungal nucleic acid synthesis inhibitor?
What is the mechanism of Flucytosine?
It's an antimetabolite selectively taken up and converted to 5-fluorouracil in fungi, interfering with DNA and RNA synthesis. It's fungistatic.
What is the spectrum of Flucytosine?
Narrow spectrum, mostly yeast. (Candida albicans & Cryptococcus)
How is Flucytosine taken?
Orally, it penetrates the CNS when distributed in the body.
What is the toxicity of Flucytosine?
It is only partially selective for yeast so it can lead to bone marrow suppression - need to follow a patient's cell counts closely
How do fungi become resistant to Flucytosine?
They loose the converting enzyme or transporters.
How do we compensate for the resistance some fungi have developed against Flucytosine?
It is rarely used as a monotherapy, often its cotreated with Amphotericin B to increase uptake and minimize the likelihood of developing resistance.
What is the mechanism of Griseofulvin?
It binds microtubules and inhibits spindles leading to multinucleate cells. It's fungistatic.
What is the spectrum of Griseofulvin?
How is griseofulvin distributed in the body?
Lipids increase the oral absorption.
Then the medication concentrates in the dead keratinized layer of the skin.
What toxicity does griseofulvin cause?
It is teratogenic, it's able to disturb the growth & development of an embryo or fetus.
How do fungi gain resistance for griseofulvin?
It changes beta-tubulin.
How long does a patient need to take Griseofulvin?
They need to take it for months orally, so if the patient is not adherent, resistance mutations are more likely to develop.
What is the mechanism of Echinocandins (Caspofungin)?
Its a cell wall inhibitor that blocks the synthesis of Beta (1,3)-d-glucan polysaccharide. It's fungicidal - Candida and Fungistatic- aspergillus.
What is the spectrum of Caspofungin?
Candida albicans, systemic
How is caspofungin given to the patient?
It's given through IV. The large molecular weight prohibits CNS penetration.
What toxicity does Caspofungin cause?
Limited - fever, rash at site of injection