Antimicrobial Pharmacology 2 Flashcards
What are the different classes of antifungals?
- 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.
What are the pharmacokinetics and toxicity of azole antifungals?
- 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
What is the mechanism of action and resistance in azole antifungals?
- 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.
What is the spectrum of activity and therapeutic uses of ketoconazole?
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
What is the spectrum of activity and therapeutic uses of fluconazole
- Newer agent
- drug of choice in most esophageal infections and oropharyngeal candidiasis
- used to treat vaginal candidiasis, cryptococcal meningitis
What is the spectrum of activity and therapeutic uses of clotrimazole?
- Canesten - generic name = clotrimazole
- used topically or vaginally
- not useful for systemic use
What is the spectrum of activity and therapeutic uses of itraconazole?
- wide-spectrum azole antifungal
- drug of choice for infections like Blastomyces and Sporothrix schenckii
- alternative drug of choice for aspergillosis, coccidiomycoses, cryptococcus, and Histoplasma
What is the spectrum of activity and therapeutic uses of voriconazole?
- relatively new azole antifungal
- wider spectrum than itraconazole
- maybe better than amphotericin B
- 30% of patients develop visual blurring (unknown cause)
What is the spectrum of activity and therapeutic uses of posaconazole?
- broadest spectrum triazole
- works against most species - inc. candida and aspergillus
- Only azole with activity against Rhizopus and mucormycosis
What is the mechanism of action of Polyenes?
- 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.
What is Amphotericin B
- 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
Explain the spectrum of activity, mechanism of action, and toxicity of flucytosine (5-FC).
- 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
what are the uses of flucytosine?
used almost exclusively in cryptococcus neoformans infections
What are Echinocandins?
- 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.
What are some side effects of echinocandins?
- 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.
What is the activity of antiviral agents in mammalian hearts?
1) attachment of the virus to the membrane of the cell —> Entry + fusion inhibitors act by inhibiting viral attachment and entry.
2) viral penetration —–> this is where interferon alpha is effective
3) Uncoating of the virus particle —-> inhibitors of viral uncoating e.g., amantadine and rimantadine
4) Early protein synthesis
5) nucleic acid synthesis —-> inhibit a reverse transcriptase
6) late protein synthesis —-> blocked by protease inhibitors
7) Packaging and assembly —> blocked by maturation inhibitors
8) Viral release —-> neuraminidase inhibitors
what are the drugs that block viral entrance and attachment?
1) attachment of the virus to the membrane of the cell —> Entry + fusion inhibitors act by inhibiting viral attachment and entry.
Which drugs block virus-cell uncoating?
3) Uncoating of the virus particle —-> inhibitors of viral uncoating e.g., amantadine and rimantadine
Which antiviral drugs block nucleic acid synthesis and early protein synthesis?
5) nucleic acid synthesis —-> inhibit a reverse transcriptase
Which drugs block viral packaging and assembly?
7) Packaging and assembly —> blocked by maturation inhibitors
Which drugs interfere with the viral release?
8) Viral release —-> neuraminidase inhibitors
Describe the classification of antiviral agents by their target organism.
- Anti-HIV drugs
- anti-herpetic drugs
- anti-influenza drugs
- anti-hepatitis drugs
What is the structure of the human immunodeficiency virus (HIV) particle and the active sites of the anti-HIV agents?
- Lipid membrane
- matrix protein
- Capsid
- nucleocapsid
- Tat- trans-activator of transcription
- viral RNA genome
- reverse transcriptase
- integrase
- protease
- glycoprotein complex - gp120 and gp41
What is a CCR5 receptor?
- integral membrane protein
- looks like a column or tube
- a protein on the cell surface of T-cells, macrophages, dendritic cells, and some eosinophils.
- provides entry port for the HIV
How is the CCR5 molecule essential for the spread of 1 of the types of the human immunodeficiency virus (HIV)?
- the Gp120 of the virus binds to CCR5 or CXCR4 (cousin of CCR5) at the same time it binds to the CD4 complex.
- the Gp41 subunit spans the membrane
- If Gp120 binds to CD4 without binding to CCR5 - you won’t get viral binding and won’t be able to initiate the fusion properly -> virus gets thrown away and shed off
- Entry inhibitor if you can’t bind to both
- the CCR5 molecule is essential for the spread of HIV-1
What are the entry inhibitor anti-HIV agents?
- Gp41 inhibitors
- CCR5 inhibitors
- Gp120 binders
- CD4 binders
What are the mechanism of action and adverse effects of the Gp41 inhibitor enfuvirtide?
- very effective drugs
- prototypical drug = Enfuviritide
- Incredible expensive (in America)
- Injectable
Mechanism of action;
- binds to the gp41 molecule and interferes with the ability to create an entry pore for the virus or for the capsid.
- active against HIV-1 only
Adverse effects:
- injection site reactions
- cough
- dyspnoea
- arthralgia
What are the mechanism of action, development of resistance, and side effects of CCR5 inhibitors?
-CCR5 is a transmembrane receptor that’s involved in the fusion or binding of the HIV envelope to the mammalian cell membrane.
Drugs = maraviroc, vicriviroc, cenicriviroc
- bind to CCR5
- if the cell binds to gp120 and is unable to bind to CCR5 - the virus can’t get in
- (cenicriviroc targets another receptor complex called CCR2 -)
- if an HIV particle binds to a CXCR4 receptor (CXCR4 looks like CCR5) - the agents won’t work
- CCR5 antagonist only work against CCR5
- have to do a trofile assay on particles of the patient’s blood to see if these agents work
Resistance:
- not a lot of cross-resistance between these agents and others
- sometimes resistance of the virus through a mutation in the env gene can happen
Maraviroc side effects: - hepatitis
- allergic reactions
What is the structure and mechanism of action of Gp120 binders?
- protein that is on the surface of HIV particle
- Fostemsavir
What is the mechanism of action of CD4 binders?
- CD4 antagonists
- using monoclonal antibodies to target very specific receptors either on the HIV particle or on the cell.
- Ibalizumab
