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.
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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
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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.
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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
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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
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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
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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
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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)
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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
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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.
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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
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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
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13
Q

what are the uses of flucytosine?

A

used almost exclusively in cryptococcus neoformans infections

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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.
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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.
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16
Q

What is the activity of antiviral agents in mammalian hearts?

A

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

17
Q

what are the drugs that block viral entrance and attachment?

A

1) attachment of the virus to the membrane of the cell —> Entry + fusion inhibitors act by inhibiting viral attachment and entry.

18
Q

Which drugs block virus-cell uncoating?

A

3) Uncoating of the virus particle —-> inhibitors of viral uncoating e.g., amantadine and rimantadine

19
Q

Which antiviral drugs block nucleic acid synthesis and early protein synthesis?

A

5) nucleic acid synthesis —-> inhibit a reverse transcriptase

20
Q

Which drugs block viral packaging and assembly?

A

7) Packaging and assembly —> blocked by maturation inhibitors

21
Q

Which drugs interfere with the viral release?

A

8) Viral release —-> neuraminidase inhibitors

22
Q

Describe the classification of antiviral agents by their target organism.

A
  • Anti-HIV drugs
  • anti-herpetic drugs
  • anti-influenza drugs
  • anti-hepatitis drugs
23
Q

What is the structure of the human immunodeficiency virus (HIV) particle and the active sites of the anti-HIV agents?

A
  • Lipid membrane
  • matrix protein
  • Capsid
  • nucleocapsid
  • Tat- trans-activator of transcription
  • viral RNA genome
  • reverse transcriptase
  • integrase
  • protease
  • glycoprotein complex - gp120 and gp41
24
Q

What is a CCR5 receptor?

A
  • 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
25
Q

How is the CCR5 molecule essential for the spread of 1 of the types of the human immunodeficiency virus (HIV)?

A
  • 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
26
Q

What are the entry inhibitor anti-HIV agents?

A
  • Gp41 inhibitors
  • CCR5 inhibitors
  • Gp120 binders
  • CD4 binders
27
Q

What are the mechanism of action and adverse effects of the Gp41 inhibitor enfuvirtide?

A
  • 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
28
Q

What are the mechanism of action, development of resistance, and side effects of CCR5 inhibitors?

A

-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
29
Q

What is the structure and mechanism of action of Gp120 binders?

A
  • protein that is on the surface of HIV particle

- Fostemsavir

30
Q

What is the mechanism of action of CD4 binders?

A
  • CD4 antagonists
  • using monoclonal antibodies to target very specific receptors either on the HIV particle or on the cell.
  • Ibalizumab