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antiviral agents Flashcards

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1
Q

Why are viruses so hard to treat?

A
  1. Viral latency in recurrent episodic infection (ie HSV)
  2. Obligate intracellular location/syncytia formation
  3. Usurp host cellular mechanisms of replication (enzymes, ribosomes etc.)
  4. Display host external antigens
  5. Rapid mutation (HIV-1, hep C)
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2
Q

What are the three major categories of antiviral agents?

A
  1. Virucidal: directly inactivate intact viruses
  2. Immunomodulating: augment or modify host response to infection
  3. Antiviral: inhibit viral replication at cellular level
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3
Q

What are virucidal agents?

A
  • Inactivate in single or multiple steps
  • Physical disruption – crude
  • Also kill infected cells
  • Major agents: detergents, organic solvents, ultraviolet light, cautery, cryotherapy, podophyllin
  • Important for environmental sterilization eg. Bleach for Hantavirus in mouse droppings or for HIV or HCV in spilled blood
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4
Q

What are immunomodulating agents?

A

Supplement deficient host immune response
a) Vaccination (prevention is always preferable): produces neutralizing antibodies
b) Passive immunotherapy – exogenous antibody is given to neutralize virus. Prophylaxis or early treatment (RIG, VZIG, HBIG, CMVIG, TIG, RSVIG). May work for Ebola. Renewed interest for HIV.
c) Stimulate Cell Mediated Immunity (CMI) locally: Imiquimod, Resiquimod: induce TNF, IFNα and induce macrophages to produce NO
d) Stimulate CMI systemically (or locally) – interferons
o IFN alpha (leukocytes) – pegylated IFN as well
o IFN beta (fibroblasts)
o IFN gamma (T-lymphs)
o Immunogenic proteins of 160-180 amino acids
o Multiple preparations from mixtures, “purified natural” to recombinant
o Mechanism – complex:
• Binds to cellular receptors to exert direct inhibitor effect on viral replication.
• Also immunomodulates through enhancement of macrophage activity and augmentation of cytotoxic lymphocyte actions.

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5
Q

What are the indications for immunomodulating agents?

A

o Indications:
• Non-infectious (Hairy cell leukemia, idiopathic thrombocytopenic purpura (ITP), Kaposi’s sarcoma (KS)
• Hepatitis B, chronic active
• Hepatitis C, chronic active and maybe acute. Unlikely to be used for HCV in the future due to availability of direct acting agents which are more effective and less toxic.
• Condylomata accuminata
• HIV

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6
Q

What is the toxicity and administration frequency and method for immunomodulating agents?

A

o Toxicity:
• Influenza-like symptoms (fever, myalgia, chills)
• Leukopenia
• Rare renal, hepatic toxicity
• Drowsiness to coma (rare)
• Autoimmune problems (diabetes, hypothyroidism)
• Depression
o Administered once daily or 3x/week IV, SC, IM

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7
Q

What is the spectrum and pharmacology for the specific antiviral agent Amantadine/Rimantadine?

A

Spectrum – influenza A (and Parkinson’s Disease)

Pharmacology - well absorbed

	- Peak levels at 3 to 4 hours
	- Renal excretion
	- T ½ 12 hours: ↑ elderly and renal dysfunction
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8
Q

What is the toxicity and clinical uses for the specific antiviral agent Amantadine/Rimantadine?

A

Toxicity - GI (nausea, ↓appetite)
- CNS (nervousness, insomnia, difficulty concentrating)

Clinical uses - Prevention and treatment influenza A

  • Prophylactic tx indicated for elderly (>65), chronically ill, hospital personnel, household contacts who are unvaccinated and at risk from time of outbreak – 6 weeks (2 weeks if vaccinated)
    - Effective tx if started within 48 hours of symptoms
    - Rimantadine = analogue of amantadine with less CNS side effects
    - Resistance is rampant
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9
Q

What is the spectrum and pharmacology for the neuraminidase inhibitors, osteltamivir and Zanamivir?

A

Spectrum – influenza A and B
Pharmacology - Zanamivir has no oral absorption: aerosol
- Oseltamivir is well-absorbed
- No renal adjustment

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10
Q

What is the toxicity and clinical uses for the neuraminidase inhibitors, osteltamivir and Zanamivir?

A

Toxicity - Zanamavir: bronchospasm rarely
- Oseltamivir: GI (nausea, diarrhea) 10%
Clinical Uses - Prevention and treatment of influenza A and B
- Effective only if started with 36 hour of symptoms
- Use restricted by cost, minimal benefit
- Resistance is increasingly common

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11
Q

What is the spectrum and pharmacology for the capsid protein function inhibition?

A

Spectrum - Enteroviruses, Rhinoviruses
Pharmacology - Orally bioavailable
- Good blood/brain barrier penetration
- Compresses and makes rigid the viral capsid

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12
Q

What is the toxicity and clinical use for the capsid protein function inhibition?

A

Toxicity - Appears minimal
Clinical uses - Preliminary studies, not licenses
- Treatment and prevention of colds
- Treatment of enteroviral meningitis

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13
Q

What is the nucleotide/nucleoside analogue Idozuridine for?

A
  • Iodinated thymidine analogue
    • Inhibits viral DNA synthesis
    • Mainly used for HSV keratitis
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14
Q

What is the nucleotide/nucleoside analogue trifluridine for?

A
  • Fluorinated thymidine analogue
    • Inhibits viral DNA synthesis
    • Mainly used for HSV keratitis
    • Greater activity than Idoxuridine
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15
Q

What is the nucleotide/nucleoside analogue acylovir (valacyclovir, famciclovir too) spectrum and action as well as resistance?

A

Spectrum - Active HSV-1, HSV-2, VZV, some EBV

		- Twice as active HSV over VZV
		- ?Not against CMV

Action		- Inhibits viral DNA synthesis
		Acyclovir	Thymidine		Acyclovir – monophosphate
				→				↓
				Kinase				↓	host
								↓	enzymes
							Acyclovir triphosphate
							Blocks viral DNA polymerase
							Chain terminator
	Resistance	- TK deficient viruses
			- Altered DNA polymerase
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16
Q

What is the nucleotide/nucleoside analogue acylovir (valacyclovir, famciclovir too) pharmacology, toxicity?

A

Pharmacology - T ½ 3 hours

		- Oral acyclovir 30% absorbed
		- Almost no systemic absorption with topical
		- Levels 10 to 20 ug/mL with doses 5 to 10 mg/kg
		- Renal excretion

Toxicity	- Generally well tolerated

		- Phlebitis may occur with IV use
		- Uncommon – rash, headache, nausea
		- Renal failure due to crystal deposition
		- Reversible renal dysfunction 5%
		- ?Bone marrow suppression
		- Confusion
17
Q

What is the nucleotide/nucleoside analogue acylovir (valacyclovir, famciclovir too) clinical uses?

A

a. HSVI and II (Herpes Simplex) and VZV (Varicella Zoster Virus):
- High dose IV (45-60 mg/kg/d, divided q8h) for encephalitis, neonatal infection, zoster
- Low dose IV (15-30 mg/kg/d, divided q8h) for primary genital
- Oral low dose (400 mg tid) for HSV, genital or orolabial, treatment or prophylaxis
- Oral famciclovir or valacyclovir for all HSV, VZV low dose indications
- Indications for treatment generally:
- severe disease, even if self-limited
- immune compromised host
- higher dose for VZV and CNS HSV

b. CMV (Cytomegalovirus)
- Prophylaxis in marrow and solid organ transplantation
- Treatment is ineffective

c. EBV (Epstein Barr Virus)
- No indications for use
- Famciclovir (penciclovir prodrug), valacylovir (acyclovir prodrug) have improved absorption through addition of valerate ester

18
Q

What is the nucleotide/nucleoside analogue ribavirin for?

A
  • Guanosine analogue
  • Inhibits wide array or TNA/DNA viruses in vitro
  • Especially active vs influenza A, B, and RSV (respiratory syncytial virus) plus hepatitis C
  • Interferes with guanine nucleotide
  • RSV: for selected infants, aerosolized only for 20 hr/d X 3-6 d
  • HCV: orally (with IFN) – mechanism may be directly antiviral or immune
  • SARS, Hanta: IV or p.o. with little evidence
19
Q

What is the nucleotide/nucleoside analogue Ganciclovir spectrum, action and pharmacology?

A

Spectrum - Nucleoside analogous of guanine
- Active vs all in HSV family but potent inhibition of CMV

Action - Similar mechanism of action as acyclovir
- Inhibition of viral DNA synthesis

Pharmacology - Not absorbed well orally: p.o. valganciclovir now available. IV usually used.

	- T ½ = 3 to 4 hours
	- 90% renal excretion unchanged
20
Q

What is the nucleotide/nucleoside analogue Ganciclovir toxicity and clinical use?

A

Toxicity - Bone marrow suppression – 20 to 40%
- CNS – behaviour changes, seizures 5 to 15%

Clinical Use - Life or sight-threatening CMV infections

	- Induction of 10 mg/kg/d x 2 weeks
	- Main stay of tx CMV retinitis in AIDS
	- Maintenance therapy needed to prevent relapse
	- Prophylaxis in marrow/solid organ transplant
21
Q

What is the nucleotide/nucleoside analogue antiretroviral nucleoside analogue for?

A
  • Thymidine analogues: AZT, d4T, tenofovir
  • Inosine analogue: ddI
  • Ceftidine analogue: ddC
  • Guanosine analogue: abacavir
  • Others: 3TC, emtricitabine
  • Mechanism: reverse transcriptase competitive inhibition: chain termination
  • HCV-directed RNA dependent RNA polymerase inhibitors. Sofosbuvir is the first.
22
Q

What is the nucleotide/nucleoside analogue antiretroviral non-nucleoside reerse transcriptase inhibitor for?

A
  • Efavirenz, nevirapine, etravirine, rilpivirine

- Reverse transcriptase inhibition only

23
Q

What is the nucleotide/nucleoside analogue antiretroviral protease inhibitor for?

A
  • Saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir, tipranavir
  • Darunavir, lopinavir, atazanavir
  • Bind irreversibly to viral proteases, inhibiting cleavage of polymeric protein to functional subunits
  • HCV protease inhibitors bocepravir, telaprevir and soon simeprevir
  • Sofosbuvir
24
Q

What is the nucleotide/nucleoside analogue antiretroviral fusion inhibitor for?

A
  • T-20 fusion inhibitor: subcutaneous injection

- Prevents HIV internalization by binding to gp41 on the viral surface and preventing folding

25
Q

What is the nucleotide/nucleoside analogue antiretroviral integrase inhibitor for?

A
  • Raltegravir and others

- Binds Integrase, preventing insertion of DNA transcript into host cell DNA

26
Q

What is the nucleotide/nucleoside analogue antiretroviral chemokinase receptor blockers for?

A
  • Maraviroc and others

- Bind to CCR5 to prevent HIV binding and entry

27
Q

What are the indications for IFN alpha?

A 
Indications for IFN alpha:
HBV chronic infection.
HCV chronic infection.
HPV infection.
HIV?
Non-infectious: ITP, Kaposi’s sarcoma, Hairy cell leukemia.
28
Q

What are interferon alpha side effects?

A
  1. Influenza-like Sx: fever, myalgias, etc.
  2. ‘Cytopenias: leukopenia, thrombocytopenia, anemia.
  3. Autoimmune: thyroiditis, pancreatitis, DM, vasculitis, glomerulonephritis.
  4. Weight loss, depression.
  5. Renal or hepatic toxicity.
29
Q

How is HIV as a model for antiviral therapy?

A

Six classes of antiretrovirals available.

  1. Nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs or ‘Nukes’)
  2. Non-NRTIs (‘Non-nukes’).
  3. Protease inhibitors.
  4. Fusion inhibitors.
  5. Entry inhibitors.
  6. Integrase inhibitors.
30
Q

What are nucleotide/nucleoside analogues/

A

Defective nucleotides bind to DNA Polymerase or similar enzymes.
Must bind more avidly and with more affinity than to host polymerases to avoid toxicity.
May act also as chain terminators.
Constructed as anti-cancer agents, antivirals and antibacterials.

31
Q

What are the nucleotide antivirals acyclovir, valacyclovir, and famcyclovir good for?

A

All useful against HSV and VZV.
Less useful vs CMV, EBV and other Herpes viruses.
Resistance due to altered thymidine kinase, viral enzyme responsible for acyclovir monophosphorylation.
Resistance due to altered DNA polymerase.
Treatment of primary and recurrent HSV 1 and 2 infections anywhere.
Prophylaxis of HSV 1 and 2 infections.
Treatment of VZV infections, chicken pox and shingles.
EBV related oral hairy leukoplakia (only).
CMV prophylaxis (but no thymidine kinase)

32
Q

What are the nucleotide antivirals acyclovir, valacyclovir, and famcyclovir side effects?

A

allergy
CNS toxicity: confusion to coma.
Renal crystal mediated nephropathy at high doses.
Not OTC due to resistance issues.

33
Q

What is the nucleoside antiviral Ganciclovir for?

A

Prophylaxis of CMV infection in malignant hematology.
CMV retinitis in HIV.
Neonatal CMV infection?
Toxicity: bone marrow suppression.
Guanine analogue.
Active vs all herpes viruses but reserved dfor CMV (cytomegalovirus).
Mechanism of action: DNA polymerase inhibitor and chain terminator.
IV or oral (valganciclovir).

34
Q

What is the other nucleoside antiviral ribavirin for?

A

Inhibits many different RNA and DNA.
RSV (Respiratory Syncytial Virus) with limited use.
HCV: more an immune modulator?
Toxicity: hemolytic anemia by intracellular accumulation.

Microbiology (13 decks)

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