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Pharm Block 3 > 13 - Antivirals > Flashcards

13 - Antivirals Flashcards

1
Q

For many infections, when does viral replication peak? When are drugs most effective?

A

Near the time clinical symptoms appear.

Most effective if given before onset of symptoms (not true to herpesvirus, HIV, or hepatitis because replication continues over long periods of time).

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2
Q

Describe the function of drug treatment of viral infections?

A

Therapy does not eliminate latent (dormant) forms.

Viral eradication requires competent host immune system

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3
Q

What are strategies to inhibit viral adsorption and penetration?

A

Immunization:

  • active: vaccination
  • passive: injection fo immune globulin (antibodies)
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4
Q

What monoclonal antibody prevents severe respiratory syncytial virus (RSV) in high-risk peds patients? What is its MOA?

A

Palivizumab

Binds to fusion protein of RSV to prevent fusion to host cells.

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5
Q

What drug is used as prophylaxis and treatment for influenza A? What drug is used for prophylaxis and treatment of influenza A and B?

A

Influenza A (not B): Amantadine

Influenza A and B: Oseltamivir

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6
Q

What is the benefit of using amantadine for prophylaxis or treatment of influenza A?

A

Reduces fever in 50% of pts and illness duration by 1-2 days if given within first 48 hrs of illness.

Resistance now a common problem

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7
Q

What is the MOA of amantadine? What are side effects?

A

Blocks viral uncoating by interfering with influenza A M2 protein, an ion channel.

CNS side effects.

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8
Q

What is the MOA of oseltamivir? How is it given? When is it given?

A

Prodrug - given orally

Competitively inhibits influenza neuraminidases and interferes with viral release and penetration.

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9
Q

What is the benefit of using oseltamivir? What are side effects?

A

Treats uncom. influenza A and B, greatest benefit within 48 hours of symptom onset. Prophylaxis in pts 1 or older.

Nausea, vomiting, diarrhea, bronchitis.

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10
Q

What drug is a thymidine analog that interferes with DNA synthesis? What are the uses of this drug?

A

Trifluridine

Ophthalmic use

Herpes simplex types 1 and 2

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11
Q

What is the function of Acyclovir?

A

Phosphorylated form make 40-100x faster in infected cells by herpes thymidine kinase.

Inhibits herpes DNA pol 10-30x more effective than host cell DNA pol

Competes with deoxy-GTP for DNA polymerase and terminates DNA chain elongation

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12
Q

What are uses of IV acyclovir?

A
  • Serious systemic herpes simplex virus (HSV)
  • HSV encephalitis
  • Disseminated neonatal HSV
  • Severe initial genital herpes
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13
Q

What are uses of oral acyclovir?

A

Primary genital herpes

Primary herpetic gingivostomatitis

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14
Q

What are topical uses of acyclovir?

A

Primary genital herpes

-may shorten healing time when applied early

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15
Q

What are side effects of Acyclovir?

A

Generally well-tolerated

Rash, itching

Nausea, vomiting, headache, fatigue.

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16
Q

What drug is a prodrug that’s converted to it’s active form, penciclovir-triP? What is its MOA?

A

Famciclovir

Penciclovir-triP inhibits viral DNA polymerase

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17
Q

What are the uses of famciclovir? What is its absorption?

A

Acute herpes zoster and shingles.

Treatment./suppression of recurrent genital herpes.

Better absorbed than acyclovir.

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18
Q

Famciclovir taken daily as suppressive therapy markedly reduces recurrent episodes of ______ _______? What are side effects of famciclovir?

A

Genital herpes

Side effects similar to acyclovir.

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19
Q

What drug has a similar MOA to acyclovir and is used topically to treat recurrent herpes of the lips and face ?

A

Penciclovir.

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20
Q

What family does cytomegalovirus (CMV) belong to?

A

Latent member of hte herpesvirus family.

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21
Q

What is the incidence and important of CMV?

A

The majority of the population is seropositive, but it’s more of a concern for HIV and solid organ transplant patients.

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22
Q

What drugs are use for cytomegalovirus (CMV) prophylaxis and infection?

A

Ganciclovir

Foscarnet

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23
Q

What is the MOA of ganciclovir?

A

similar to acyclovir, except mono-phosphorylated by CMV protein kinase (instead of thymidine kinase)

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24
Q

What are the uses of ganciclovir?What are side effectS?

A

Treats CMV retinitis and CMV prophylaxis for transplant recipients.

Side effects: BM suppression - leukopenia (<40%), thrombocytopenia, and anemia.

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25
Q

What drug inhibits CMV DNA pol by binding to its pyrophosphate-binding site? Does it require conversion to be active?

A

Foscarnet

Does not require conversion to triphosphate form to be active.

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26
Q

What are uses of foscarnet?

A

CMV (cytomegalovirus) retinitis)

Acyclovir-resistant herpes simplex (ie those with thymidine kinase mutations)

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27
Q

What are side effects of Foscarnet? How does the severity of side effects differ from that of ganciclovir?

A

Renal damage, electrolyte imbalances, seizures.

Compared to ganciclovir, a higher % of patients on foscarnet must be taken off due to its side effects.

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28
Q

What effect do anti-cytomegalovirus drugs have on CMV retinitis? What is the best strategy to go about treating this?

A

They will slow the progression of CMV retinitis but will not cure it.

Best CMV retinitis strategy is prevention: for HIV pts, effective anti-HIV drug regimens to keep CD4 counts elevated.

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29
Q

What drugs treat Hepatitis B (HBV)? Can it be cured?

A

Lamivudine
Tenofovir
Interferon-alpha

Difficult to cure due to persistent HBV cccDNA in the nucleus. Usually requires life-long therapy.

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30
Q

What drugs treat Hepatitis C?

A 
Ribavirin 
PEG-Interferon-alpha
SimePrevir - Protease inhibitor
Sofosbuvir- NS5B RNA pol inhibitor
Ledipasvir - NS5A protein inhibitor
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31
Q

What drugs treat respiratory syncitial virus (RSV)?

A

Ribavirin

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32
Q

What nucleuside analog converted to the triphosphate form treats HepB by competitively inhibiting the reverse transcriptase domain of the HBV polymerase? What effect does this have and what are side effects?

A

Lamivudine (3TC)

Causes DNA chain termination .

Side effects: nausea and diarrhea

33
Q

What monophosphate prodrug in the triphosphate form treats HepB and competitively inhibits the reverse transcriptase domain of the HBV polymerase? What effect does this have?

A

Tenofovir

Causes DNA chain termination.

Side effects: GI upset

34
Q

What HepB and HepC drug is given with other drugs and can also treat condyloma acuminata (genital warts)? What can increase its activity?

A

alpha-interferons

Pegylation decreases IFN clearance and allows for better kinetics and less frequent dosing.

35
Q

What are side effects of interferon-alpha? What is the greatest limitation to long-term use of interferon-alpha?

A

Flu-like symptoms; leukopenia and BM suppression.

Neurotoxicity, myalgia.

Side effects are the greatest limitation to long-term use.

36
Q

What drug interferes with viral mRNA synthesis by working through two different forms?

A

Ribavirin

37
Q

What are the two forms of ribavirin and how do they interferes with viral mRNA synthesis?

A
  1. Mono-P form inhibits inosine-5’-P dehydrogenase and thus GMP (and GTP) synthesis
  2. Tri-P form inhibits GTP-dependent capping of viral mRNA
38
Q

What are the uses of Ribavirin?

A

Aerosol use: subset of infants/children with severe RSV infections (no longer commonly used)

Oral capsule: for HepC in combo with PEG-interferon-alpha

39
Q

What are the side effects of ribavirin in the aerosolized form and IV/oral form?

A

Aerosol: may precipitate and clog respiratory equiptment; can cause pulmonary function deterioration and rash.

IV or Oral: anemia, BM suppression

40
Q

What are characteristics of the Hepatitis C virus?

A

RNA virus that does NOT integrate into host DNA, which means it can’t go latent.

Theoretically curable.

No vaccine available (there is a vaccine for HepB)

41
Q

What drug reversibly inhibits NS3/NS4A protease and blocks cleavage of polyprotein and thus formation of infectious HepC virus? What are approved uses?

A

Simeprevir

HepC genotype 1 and in combination with other drugs.

42
Q

What drug combo is used to markedly improve outcomes for HCV (HepC) genotype 1?

A

Simeprevir + Ribavirin + PEG-interferon-alpha

43
Q

What are side effects of simeprevir?

A

Rash
Nausea, itching.

CYP3A interactions: metabolized by CYP3A (avoid with other inducers of or inhibitors of CYP3A which would significantly alter simeprevir levels).

44
Q

What nucleoside (uridine) analog prodrug is converted to the triphosphate form and inhibits HCV NS5B RNA pol? What does this result in?

A

Sofosbuvir

Causes chain termination

45
Q

What can Sofosbuvir treat? What are contraindications?

A

All hepatitis C genotypes; given with other anti-HCV drugs to cover all HepC we see in this country.

Avoid with inducers of P-glycoprotein, an efflux pump which can decrease blood levels by pumping it out into the intestinal lumen.

46
Q

What drug inhibits NS5A phosphoprotein and is given with sofosbuvir? What HCV genotypes do these cover together? What is a contraindication?

A

Ledipasvir

With sofosbuvir covers 1, 4, 5, and 6.

Should avoid use with potent inducers of P-glycoprotein.

47
Q

What are important properties of HCV drug combinations?

A

Give 2 or more drugs with different mechanisms.

Avoid IFN-alpha when possible.

Genotype appropriate therapy and consider side effect. tolerance

48
Q

What are the classes of drugs used for HIV therapy?

A
  1. Reverse transcriptase (RT) inhibitors - NRTIs and NNRTIs)
  2. Protease inhibits (PIs)
  3. Fusion inhibitors
  4. CCR5 antagonists
  5. Integrase inhibitors
49
Q

What drug is a nucleoside analog that is phosphorylated by thymidine kinase to an active form that competitively inhibits RT and acts as a chain terminator?

A

Zidovudine (AZT)

Active phosphorylated form is AZT-trophosphate.

NRTA - nucleotide reverse transcriptase inhibitor

50
Q

What are side effects of zidovudine (AZT)?

A

BM suppression: neutropenia and anemia

Avoid drugs which inhibit glucuronyltransferases

Myopathy

51
Q

Why shouldnt AZT be used with inhibitors of glucuronyl transferases?

A

Drugs that inhibit glucuronidation of AZT increase the hematologic toxicity of AZT.

When glucuronyl transferase is inhibited this minor product becomes a major product that damages the bone marrow

52
Q

What are mechanisms of other NRTIs?

A

Nucleoside analogs that must be phosphorylated to tri-phosphate forms to be active.

Competitive inhibits of RT

Cause DNA chain termination when incorporated into DNA

53
Q

What drug is a monophosphate prodrug that’s triphosphate form competitively inhibits RT, causing DNA chain termination? What can it treat? What are the side effects?

A

Tenofovir (also used for HepB)

Used for combination therapy for HIV, also used for HepB

Overall, well-tolerated.

54
Q

What nucleoside analog is made into the triphosphate form and competitively inhibits RT, causing DNA chain termination and is used on AZT-resistant strains? How is it used?

A

Lamivudine (3TC)

3TC-resistant strains are AZT sensitive and vice versa

Synergistic with AZT against HIV.

55
Q

What are side effects of Lamivudine (3TC)?

A

Nausea, diarrhea, rash.

56
Q

What drug is a analog of lamivudine and has the same MOA and resistance as 3TC?

A

Emtricitabine (FTC)

57
Q

What drug is a nucleoside analog thats triphosphorylated form inhibits RT and causes DNA chain termination but has a side effect of hypersensitivity reaction? Describe the hypersensitivity.

A

Abacavir

Hypersensitivity associated with HLA-B*5701 allele

If hypersensitivity occurs, stop drug immediately and NEVER restart.

58
Q

What are side effects associated with NRTIs asa group?

A

Increased risk of lactic acidosis and hepatic steatosis (fatty liver)

59
Q

What is a non-nucleoside inhibitor of RT? Describe the activity of this class of drugs.

A

Efavirenz

Active as given; does not require phosphorylation to be active.

60
Q

What is the MOA of efavirenz? What is this drug used for?

A

Binds at different site than NRTIs and disrupts active site of RT; active as given.

Used as part of a multi-drug therapy for HIV; in 2005 it was the #1 anti-HIV drug in the US.

61
Q

What are the side effects of Efavirenz?

A

Rash.

CNS/psychiatric symptoms such as nightmares and vivid dreams - these occur in about 50% of patients, particularly in the first month of treatment.

62
Q

What drugs are protease inhibitors used to treat HIV?

A

Lopinavir

Ritonavir (used as a PI booster, not as a PT (protease inhibitor)

63
Q

What are the uses of protease inhibitors for HIV?

A

In combo with inhibitors of RT.

Significantly decreases viral blood load.

64
Q

What is the mechanism of action of protease inhibitors for treating HIV?

A

Prevents viral aspartic protease from cleaving Gag-pol polypeptide into separate functional proteins.

Competitive inhibitor.

Results in non-infectious viral particles.

65
Q

What are toxicities common to a number of protease inhibitors, including lopinavir?

A
  1. Diabetes
  2. Alterations in lipid metabolism: increased triglycerides and cholesterol
  3. Fat redistribution
  4. Alters metabolism of other drugs - potent CYP3A inhibitors
66
Q

How do the uses of lopinavir and ritonavir differ?

A

Lopinavir: used as a protease inhibitor

Ritonavir: used to boost levels of other protease inhibitors because it blocks their metabolism by CYP3A (avoid other drugs metabolized by CYP3A).

67
Q

What fusion inhibitor is used to treat HIV-1 only? When is it used?

A

Enfuvirtide

Used to treat patients who have failed multiple HIV treatment regimens.

68
Q

What is the MOA of Enfuvirtide?

A

Binds to gp41 subunit of HIV glycoprotein and blocks membrane fusion to CD4+ cells.

69
Q

What are side effects of Enfuvirtide? When is it used?

A

Local injection site reactions (these are bad).

Diarrhea, nausea, and fatigue.

Used as a later option when other regimens have failed.

70
Q

What HIV drug treats CCR5-tropic HIV-1? What is this drug effective on/when does it work?

A

Maraviroc - effective for strains resistant to other drugs.

CCR5-tropic strains tend to predominate early in infection.

71
Q

What is the MOA of Maraviroc and what effect does it have? What is special/unique about this HIV drug?

A

It’s an antagonist of the chemokine co-receptor CCR5

Blocks entry of HIV into cells.

The only anti-HIV drug that targets a human protein.

72
Q

What are side effects of Maraviroc?

A

Hepatotoxicity and CV events.

73
Q

What drug is an inhibitor of HIB integrase and prevents integration of HIV-1 DNA into the genome? What is it used to treat?

A

Raltegravir - common first line use

Treats HIV-1 in new and treatment-experienced pts.

Works on virus that is resistant to other drugs.

74
Q

What are the adverse effects of Raltegravir?

A

Potential for severe/fatal skin and hypersensitivity rxns.

75
Q

What are current reasons for HIV therapeutic failure?

A

Failure to adhere to drug regimens.

Resistant strains emerge (replication not stopped) - test initially and when changing regimens.

76
Q

Describe the effectiveness of HIV treatment? What is the best way to prevent infections in anti-HIV therapy?

A

Available drugs are very effective at suppressing viral replication when selected and used properly.

Best way to prevent opportunistic infections is anti-HIV therapy to stop HIV replication, keeping CD4+ counts higher.

77
Q

What should be considered when selecting drug combinations for HIV?

A

Viral resistance profiles

Compliance/ease of administration

Tolerance of side effects

Co-morbid conditions

78
Q

How many drugs should be used to treat HIV?

A

3 (or more) drugs per patient with 2 or more drug classes. (Usually always use an NRTI)

This keeps replication at zero to prevent resistance.

HAART (highly active anti-retroviral therapy) - combo of drugs of 2 or more classes)

79
Q

What are indications for starting HAART?

A

Initiate treatment in all HIV-infected individuals as soon as possible.

If someone has an occupational risk for HIV: initiate anti-HIV drugs ASAP

Pharm Block 3 (15 decks)

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