Pharmacology of antifungal agents Flashcards
(11 cards)
Discuss Polyenes and their MOA, reason for possible toxicity of amphotericin-B to humans?
Therapeutic use and side effects
They include: amphotericin-B, nystatin and natamycin
These drugs are natural products from streptomyces species
Amphotericin B has a broader antifungal spectrum compared to other agents
MOA:
* Amphotericin-B acts by binding to ergosterol on fungi membrane, creating pores or channels.
* The pores disrupts fungal membrane permeability, allows leakage of essential cell contents resulting in cell death.
* Much of the toxicity of amphotericin is attributable to the presence of cholesterol in mammalian cell membranes. When amphotericin binds with cholesterol in mammalian membranes, the effect is similar to that seen in fungi.
Amphotericin B has a much greater affinity for ergosterol than cholesterol
Because amphotericin B is highly insoluble there are four different commercially available formulations of amphotericin B.
The conventional amphotericin B and three lipid formulations.
Pharmacokinetics
Amphotericin is poorly absorbed from the GI tract, and hence oral therapy cannot be used for systemic infection. Rather, amphotericin must be administered IV.
Therapeutic Uses
* Amphotericin B is a drug of choice for most systemic mycoses eg. histoplasmosis, para and coccidiomycosis etc
* opportunistic mycoses eg. aspergillosis
* Amphotericin B is also s drug of choice for leishmaniasis.
* Amphotericin can cause a variety of serious adverse effects which limits its clinical use.
* Patients should be under close supervision, preferably in a hospital.
Adverse effects are divided into three groups:
* immediate systemic reactions,
* renal effects, and
* hematologic effects.
Discuss the Inhibitor of Fungal Nucleic Acid Synthesis: Flucytosine, MOA, uses and adverse effects
Flucytosine is 5-fluorocytosine, related to the chemotherapeutic agent fluorouracil (5-FU) but lacks anticancer activity.
Flucytosine is taken up selectively by fungal cells via cytosine-specific permeases that are only found in fungal membranes.
Mammalian cells are safe because they lack these transporters.
Inhibition of thymidylate synthase results in inhibition of DNA synthesis and cell division
Flucytosine is typically used in combination with amphotericin B to treat systemic mycoses
Resistance occurs when used as a single agent.
Flucytosine has no intrinsic activity against Aspergilliosis
The activity of flucytosine as a single agent is limited to candidiasis, cryptococcosis, chromoblastomycosis
Flucytosine is used in combination with amphotericin B to treat crytococcal meningitis in HIV infected patient
Flucytosine plus itraconazole is used for chromoblastomycosis
Adverse effects
Fungi in the intestinal flora can convert flucytosine to 5-FU resulting in adverse reactions
Bone marrow depression resulting in leukopenia, thrombocytopenia
Others include rash, nausea, vomiting hepatic dysfunction
Discuss the Inhibitors of the Ergosterol Synthesis Pathway (Azoles, Allylamines and Benzylamines)
Inhibitors of Squalene Epoxidase: Allylamines (Terbinafine, Naftinafine) and Benzylamines (Butenafine)
Inhibitors of 14 α-Sterol Demethylase: Imidazoles (Ketoconazole, Clotrimazole, Miconazole) and Triazoles (Itraconazole, Fluconazole, Voriconazole)
Discuss AZOLES: Imidazoles (Clotrimazole) and Triazoles (Itraconazole)
Inhibitors of 14 α-Sterol Demethylase: Imidazoles (Ketoconazole, Clotrimazole, Miconazole) and Triazoles (Itraconazole, Fluconazole, Voriconazole)
Azoles are broad-spectrum antifungals, they are an alternative to amphotericin B for most systemic fungal infections.
Azoles inhibit fungal 14 α-sterol demethylase (required for the conversion of lansterol to ergosterol). The resulting decrease in ergosterol synthesis disrupts fungal membranes.
Destabilization of the fungal membrane leads to dysfunction of membrane-associated enzymes and may ultimately lead to cell death.
Azoles can inhibit hepatic cytochrome P450 drug-metabolizing enzymes and can increase the levels of many other drugs.
Drug– drug interactions are an important consideration whenever an azole antifungal agent is prescribed
Azoles have lower toxicity and can be given by mouth.
Possible Q: Therapeutic use and adverse effcects of Itraconazole
Therapeutic Use.
Itraconazole is active against a broad spectrum of fungal pathogens.
Given its broad spectrum of activity, itraconazole has largely replaced oral ketoconazole for the treatment of many mycoses
It is a drug of choice for blastomycosis, histoplasmosis, paracoccidioidomycosis, and sporotrichosis and is an alternative to amphotericin B for aspergillosis, candidiasis, and coccidioidomycosis.
Itraconazole may also be used for superficial mycoses
Adverse effect.
Itraconazole is well tolerated.
Gastrointestinal reactions (nausea, vomiting, diarrhea) are most common.
Other reactions include rash, headache, abdominal pain, and edema.
Itraconazole may also cause cardiac suppression and liver injury
Discuss the Inhibitors of Squalene Epoxidase: Terbinafine, Naftinafine, Butenafine
Therapeutic use and adverse effects?
Terbinafine works through inhibition of squalene epoxidase with resultant inhibition of ergosterol synthesis.
It accumulates extensively in the skin, nails, and fat.
The drug is highly active against dermatophytes and less active against Candida species.
Terbinafine is available in topical and oral formulations. Topical therapy is used for ringworm infections (e.g., tinea corporis, tinea cruris, tinea pedis).
Oral therapy is used for ringworm and onychomycosis (fungal infection of the nails), tinea corporis, tinea cruris, tinea pedis, and tinea capitis.
Terbinafine is not recommended in patients with renal or hepatic failure or in pregnant women.
Adverse reaction:
Very rarely, the oral form of terbinafine can lead to hepatotoxicity, Stevens-Johnson syndrome, neutropenia, and exacerbation of psoriasis or subacute cutaneous lupus erythematosus.
Possible Q: Therapeutic use and adverse effcects of Ketoconazole
Ketoconazole is available in both oral and topical formulations.
It is broad spectrum antifungal agent.
The pharmacokinetic and adverse effect profiles of ketoconazole limit its clinical utility. (Infact, oral ketoconazole has been replaced by itraconazole for the treatment of many mycoses.
Ketoconazole potently inhibits hepatic P450 enzymes and therefore affects the metabolism of many other drugs.
At therapeutic doses, it also inhibits enzymes in the adrenal gland and gonads, thereby decreasing steroid hormone synthesis.
Persistent adrenal insufficiency has been reported in association with ketoconazole therapy; at high doses significant inhibition of androgen synthesis can result in gynecomastia and impotence.
Discuss the Inhibitor of Fungal Mitosis: Griseofulvin
Griseofulvin kills fungi by inhibiting fungal mitosis by binding to components of microtubules, the structures that form the mitotic spindle.
Because griseofulvin acts by disrupting mitosis, the drug affects only fungi that are actively growing.
Therapeutic Uses
Griseofulvin is employed orally to treat dermatophytic infections of the skin, hair, and nails.
The drug is not active against Candida species, nor is it useful against systemic mycoses.
Dermatophytic infections of the skin respond relatively quickly (in 3 to 8 weeks).
Infections of the palms may require 2 to 3 months of treatment, and a year or more may be needed to eliminate infections of the toenails.
Discuss the Inhibitors of Fungal Wall Synthesis: Echinocandins (Caspofungin, Micafungin, Anidulafungin)
Pharmacokinetics and adverse effects of caspofungin?
Echinocandins are a class of antifungal agents that target fungal cell wall synthesis by noncompetitively inhibiting the synthesis of β-(1,3)-D-glucans.
Disruption of cell wall integrity results in osmotic stress, lysis of the fungal cell, and ultimately fungal cell death.
Caspofungin is approved for IV therapy of, invasive aspergillosis in patients unresponsive to or intolerant of traditional agents (e.g., amphotericin B, itraconazole) and systemic Candida infections.
The drug is better tolerated than amphotericin B and appears to be just as effective.
Caspofungin is generally well tolerated. The most common adverse effects are fever and phlebitis at the injection site, headache, rash, nausea, and vomiting.
It is contraindicated in pregnancy.
PQ: MOA Therapeutic use and adverse effcects of Fluconazole
What is the classification and mechanism of action of antifungal agents?
- Damage to fungal cell membrane
Azoles: fluconazole, itraconazole, ketoconazole
Allylamines: terbinafine
Polyenes: nystatin, amphotericin B - Inhibition of cell wall synthesis
Echinocandins: caspofungin, micafungin - Inhibition of protein synthesis
Pyrimidines: 5-flucytosine
