Antimicrobial Pharmacology 2 Flashcards
1
Q
What are the different classes of antifungals?
A
- Agents that work on membrane permeability
- Agents that act on microtubule function
- Agents that act on the beta-glucans
- Agents that act at the level of the nucleic acids.
2
Q
What are the pharmacokinetics and toxicity of azole antifungals?
A
- used in systemic infections
- Variable oral bioavailability
- some are intravenous only
- Inducers of cytochrome p450 such as rifampin may decrease bioavailability
- Toxicity:
- vomiting
- diarrhea
- rash
- hepatotoxicity
- drug interaction and steroid blocking effects
3
Q
What is the mechanism of action and resistance in azole antifungals?
A
- Inhibit ergosterol formation
- Ergosterol is important for the development of cell walls within the fungal organism
- reduces membrane permeability and allows leakage of cations and nutrients out of the fungal cell.
Resistance:
- due to the widespread use
- the enzymes that the azoles act on are becoming reduced or changed.
4
Q
What is the spectrum of activity and therapeutic uses of ketoconazole?
A
Ketoconazole
- Narrow spectrum anti-fungal
- more adverse effects than other azoles
- used in chronic oral candidiasis, patients with dermatological fungal infections
- a strong inhibitor of cytochrome p450 - may increase the level of other drugs
- Inducers like rifampin may reduce ketoconazole
5
Q
What is the spectrum of activity and therapeutic uses of fluconazole
A
- Newer agent
- drug of choice in most esophageal infections and oropharyngeal candidiasis
- used to treat vaginal candidiasis, cryptococcal meningitis
6
Q
What is the spectrum of activity and therapeutic uses of clotrimazole?
A
- Canesten - generic name = clotrimazole
- used topically or vaginally
- not useful for systemic use
7
Q
What is the spectrum of activity and therapeutic uses of itraconazole?
A
- wide-spectrum azole antifungal
- drug of choice for infections like Blastomyces and Sporothrix schenckii
- alternative drug of choice for aspergillosis, coccidiomycoses, cryptococcus, and Histoplasma
8
Q
What is the spectrum of activity and therapeutic uses of voriconazole?
A
- relatively new azole antifungal
- wider spectrum than itraconazole
- maybe better than amphotericin B
- 30% of patients develop visual blurring (unknown cause)
9
Q
What is the spectrum of activity and therapeutic uses of posaconazole?
A
- broadest spectrum triazole
- works against most species - inc. candida and aspergillus
- Only azole with activity against Rhizopus and mucormycosis
10
Q
What is the mechanism of action of Polyenes?
A
- polyenes = prototypical drug used for superficial infections
- used topically to suppress candida infections
- ’ swish and swallow ‘ - oral candidiasis
Mechanism of actions:
- bind to ergosterol and cause artificial pores in the cell membranes
- this causes leakage of hydrogen ions, potassium ions, chloride ions, and sodium ions through the pore.
- also increases free radical formations within the cell itself and causes toxic intermediates inside the cell.
- causes fungal cell death.
11
Q
What is Amphotericin B
A
- polyene that is similar to nystatin.
- bind to ergosterol and cause artificial pores
- leaks hydrogen, potassium, chloride, and sodium ions through the pores.
- free radical formation within the cell that causes toxicity inside the cell and causes cell death.
- intravenously administered (unlike nystatin which is topical)
- used for more serious infections
- eliminated through the slow hepatic metabolism - half life =2 weeks
- minimal renal excretion
- used in systemic mycoses (serious ones usually)
- works against aspergillosis, blastomycosis, candida, cryptococcosis, histoplasmosis, and mucor.
- mycotic corneal ulcers
- keratitis
- rarely used intrathecally
Toxicity: - infusion related chills - nausea - muscle spasms - vomiting shock-like fall in blood pressure - can cause renal tubular acidosis - can cause magnesium and potassium wasting - anaemia ( due to decreased erythropoietin from kidney) - nephrotoxic effects
12
Q
Explain the spectrum of activity, mechanism of action, and toxicity of flucytosine (5-FC).
A
- antimetabolite
- used in cancer chemotherapy
- eliminated in the urine
- relatively narrow spectrum agent
- used almost exclusively in cryptococcus neoformans infections
Mechanism of action:
- included into the cell wall by a membrane permease
- concentration inside the cell is increasing and accumulative.
- converted by cytosine deaminase from flucytosine to 5-FU (which is fluorocytosine)
- 5-FU blocks the production of thymidine by inhibiting thymidylate synthase.
- this interferes with the production of DNA and RNA fragments.
Toxicity:
- reversible bone marrow suppression
- alopecia
- liver dysfunction
13
Q
what are the uses of flucytosine?
A
used almost exclusively in cryptococcus neoformans infections
14
Q
What are Echinocandins?
A
- beta-glucan synthesis blockers or inhibitors
- beta-glucans are the links of the chain that lash together the outer part of the membrane or cell wall of the fungus and the inner wall
- the top layer is made up of proteins, the middle layer is made up of the beta-glucans, the third layer is made up of something called chitin and chitin is bound to the protein wall through these beta-glucans.
- Blocking the beta-glucan synthase enzyme reduces the ability of the fungal organism to build a cell wall.
- The mechanism of action therefore is it inhibits the beta-glucan synthase, this acts kind of like the penicillin of all anti-fungals and you have increased susceptibility to any kind of an osmotic force.
15
Q
What are some side effects of echinocandins?
A
- infusion or local site reactions
- redness on skin or at IV site
- histamine rash especially when infusion is given rapidly
- elevation of liver enzymes - alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase.
