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Antivirals Flashcards

1
Q

Virus Replication (General steps)

A
  1. Adsorption
  2. Penetration
  3. Uncoating
  4. Transcription
  5. Translation
  6. Synthesis of virus nucleic acid and production of virus proteins
  7. Assembly of new virus particles
  8. Egress
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2
Q

Problems with antiviral therapy

A
  • Viruses take over cell’s synthetic machinery for their own reproduction
  • Viral latency
  • Intracellular stages afford protection from certain arms of immune system
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3
Q

When do clinical symptoms first appear and what is the significance of this in terms of drug administration?

A

Viral replication peaks near the time clinical symptoms first appear

  • Drugs most effective if administered before the onset of symptoms
  • NOT TRUE for Herpesvirus, HIV, or hepatitis
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4
Q

Therapy does not eliminate _____ forms of viruses

Viral eradication requires a competent ______ _______ ______

A

Latent; host immune system

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5
Q

What is the difference between active and passive immunization?

A

Active - Vaccination

Passive - Injection of immune globulin antibodies

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6
Q

Drugs that can interfere with viral adsorption/penetration

Influenza A prophylaxis/treatment:

Influenza A and B treatment/prophylaxis:

A

Influenza A prophylaxis/treatment: Amantadine

Influenza A and B treatment/prophylaxis: Oseltamivir

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7
Q

Amantadine

Virus:

Mechanism Of Action:

Timing of administration:

A

Virus: Influenza A, NOT influenza B

Mechanism Of Action: Blocks viral uncoating with influenza A M2 protein (an ion channel)

Timing of administration: Reduces fever in 50% of patients and illness duration by 1-2 days if given within 2 days of illness

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8
Q

Amantadine side effects

A

CNS effects

  • Slurred speech, anxiety
  • Confusion depression
  • Headache, hallucinations
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9
Q

Oseltamivir

Mechanism:

Uses:

Timing of administration:

A

Mechanism: Prodrug converted to oseltamivir carboxylate - Competitiively inhibits influenza neuraminidases (interferes with viral release and viral penetration)

Uses: Uncomplicated influenza A and B in patients > 1 year old

Timing of administration: Only effective if given within 48 hours of symptom onset (oral administration - 5 day regimen)

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10
Q

Side effects of Oseltamivir

A
  • Nausea, vomiting Diarrhea
  • Bronchitis (cough)
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11
Q
  • As of 2008/2009, Influenza A (H3N2) was 100% resistant to ________
  • As of 2008/2009, Influenza A (H1N1) was 99% resistant to ________
A

Amantadine; Oseltamivir

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12
Q

Now we mostly use Oseltamivir and zanamivir for influenza due to _______ ________

A

Amantadine resistance

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13
Q

Inhibition of Nucleic Acid Synthesis

A
  • Most viruses encode at least one enzyme involved in replication of viral nucleic acid
  • A preponderance of drugs for herpes family
    • Encodes several of its own enzymes, incl:
      • Thymidine kinase
      • DNA polymerase
      • ribonucleotide reductase
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14
Q

Trifluridine

Mechanism of Action:

Administration:

Use:

Side Effects:

A

Mechanism of Action: Thymidine analog that interferes with DNA synthesis

Administration: Opthalmic use only

Use: Treatment of Herpes simplex types 1 and 2

Side Effects: Burning, stinging, hypersensitivity

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15
Q

Acyclovir Mechanism of Action

A
  • Phosphorylated form is produced 40-100X faster in infected cells
  • Inhibits herpes DNA polymerase 10-30x more effectively than host cell DNA polymerase
  • Competes with deoxy-GTP for DNA polymerase - terminates DNA chain elongation
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16
Q

Acyclovir - Intravenous Uses

A
  • Serious systemic herpes simplex virus (HSV)
  • HSV encephalitis
  • Disseminated neonatal HSV
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17
Q

Acyclovir - Oral Uses

A
  • Primary genital herpes
  • Primary herpetic gingivostomatitis
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18
Q

Acyclovir - Topical Uses

A

Primary genital herpes - may shorten healing time when applied early

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19
Q

Acyclovir - Some Side Effects

A
  • Generally well tolerated
  • Rash-itching
  • Nausea, vomiting, headache, fatigue
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20
Q

Famciclovir

Mechanism of Action:

Uses:

Administration:

A

Mechanism of Action: Prodrug activation (famciclovir → penciclovir → penciclovir-triP) - similar mechanism to acyclovir

Uses: Acute herpes zoster (shingles); treatment and suppression of recurrent genital herpes

Administration: Oral administration (better absorbed than acyclovir)

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21
Q

_______ (Famiclovir analog) - can reduce genital herpes transmission risk

A

Valacyclovir

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22
Q

Side effects of famiciclovir

A

Similar to acyclovir

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23
Q

Penciclovir

Mechanism of action:

Use:

Administration:

Side effects:

A

Mechanism of action: similar to acyclovir (not technically a chain terminator due to -OH group)

Use: Recurrent herpes of the lips and face

Administration: Topical

Side effects: Skin irritation, rash

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24
Q

CMV - Cytomegalovirus

A

Latent member of the herpesvirus family

Reactivation occurs in those with compromised immune systems

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25
Q

CMV in immunocompromised patients

HIV patients:

Solid organ transplants:

A

HIV patients:

  • Most common cause of retinitis and visual loss (80% of CMV disease)
  • Other organs infected include GI, CNS, respiratory

Solid organ transplants:

  • SIngle most common viral infection after solid organ transplantation
  • 20-60% of organ recipients (from organ donor)
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26
Q

Drugs for CMV prophylaxis/infection

A

Ganciclovir

Foscarnet

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27
Q

Ganciclovir

Mechanism of action:

Uses:

Side Effects:

A

Mechanism of action: Similar to acyclovir, except mono-phos. by CMV protein kinase

Uses: CMV retinitis (in AIDS patients); CMV prophylaxis for transplant recipients

Side Effects: Bone marrow suppression

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28
Q

Foscarnet

Mechanism of Action:

Uses:

A

Mechanism of Action: Selectively inhibits CMV DNA polymerase by binding to its pyrophosphate-binding site; Does not require conversion to triphosphate form to be active

Uses: CMV (cytomegalovirus) retinitis in immunocompromised; Acyclovir-resistant herpes simplex (thymidine kinase mutations)

29
Q

Foscarnet - Side Effects

A
  • Renal damage (30-50%) - reversible
  • Electrolyte imbalances (binds calcium and magnesium)
  • Seizures
  • Compared to ganciclovir, higher % of patients on foscarnet must be taken off due to side effects
30
Q

Do anti-CMV drugs cure the disease?

A

No they can only slow the progression (×̯×)

31
Q

Drugs for Hepatitis and Respiratory syncitial virus

Hepatitis B:

Hepatitis C: (combo)

RSV:

A

Hepatitis B:

  • Lamivudine (3TC)
  • Tenofovir
  • Interferon-α

Hepatitis C:

  • Ribarvirin + Interferon-α + Boceprevir

RSV: Ribavirin

32
Q

Lamivudine (3TC)

Mechanism:

Use:

Administration:

Side Effects:

A

Mechanism: Nucleoside analog phosphorylated by cell enzymes to the active form - inhibits the reverse transcriptase domain of the hepatitis B DNA polymerase

Use: Hepatitis B (Also HIV)

Administration: Oral (85% bioavailable)

Side Effects: Generally well tolerated

  • Nausea; Diarrhea
33
Q

Tenfovir

Mechanism of Action:

Uses:

Administration:

Side Effects:

A

Mechanism of Action: Adenosine monophosphate analog phosphorylated by cell enzymes to the active form - Inhibits the reverse transcriptase domain of the hepatitis B DNA polymerase

Uses: Approved for hepatitis B (also HIV)

Administration: Oral (25% bioavailability)

Side Effects: GI upset

34
Q

Ribavirin mechanism of action

A

Interferes with viral mRNA synthesis by:

  • Mono-P form inhibits inosine-5’-P dehydrogenase and thus GMP (and GTP) synthesis
  • Tri-P form inhibits GTP dependent capping of viral mRNA
35
Q

Uses of Ribavirin

Aerosol use:

Oral use:

A

Aerosol use: Infants and young children with documented severe RSV infections (no longer commonly used)

Oral use: Hepatitis C (in combination with PEG-interferon-α)

36
Q

Ribavirin Side Effects

Aerosol Use:

IV/Oral Use:

A

Aerosol Use: Drug may precipitate in and clog respiratory equipment; pulmonary function deterioration

IV/Oral Use: Anemia, bone marrow suppression

37
Q

Alpha-interferons, recombinant - Approved antiviral uses

A
  • Condyloma acuminata (veneral warts)
  • Hepatitis B and C
  • PEG-alpha-2a and 2b interferons in combination with ribavirin and boceprevir for hepatitis C
38
Q

Interferon-α side effects

A
  • Flu-like syndrome
  • Leukopenia, bone marrow suppression
  • Neurotoxicity, myalgia

Side effects are the greatest limit to long term use

39
Q

Boceprevir

Mechanism of action:

Use:

A

Mechanism of action: Reversible inhibitor of NS3 protease of hepatitis C, blocks formation of infectious virus

Use: Approved for hepatitis C genotype 1; Boceprevir + PEG-interferon-α + ribavirin

40
Q

Most effective treatment for hepatitis C genotype 1

A

3 drug regimen

Ribavirin + PEG-inteferon-α + Boceprevir

41
Q

Boceprevir - side effects

A
  • Anemia, neutropenia
  • Contraindicated with CYP3A substrates or inducers
42
Q

Classes of drugs for HIV therapy

A
  • Reverse transcriptase (RT) inhibitors
    • nucleoside analogs (NRTIs)
    • non-nucleoside inhibitors (NNRTIs)
  • Protease inhibitors (PIs)
  • Fusion inhibitors
  • CCR5 antagonists
  • Integrase inhibitors
43
Q

NRTIs:

NNRTIs:

Protease Inhibitors:

Fusion Inhibitors:

CCR5 Antagonists:

Integrase Inhibitors:

A

NRTIs: Zidovudine; Lamivudine; Abacavir; Tenofovir; Emtricitabine

NNRTIs: Efavirenz

Protease Inhibitors: Lopinavir; Ritonavir (booster)

Fusion Inhibitors: Enfuvirtide

CCR5 Antagonists: Maraviroc

Integrase Inhibitors: Raltegravir

44
Q

Zidovudine (AZT) - First anti-HIV drug

Activation:

A
  • Thymidine nucleoside analog
  • Phosphorylated by cellular kinase (host cell)
  • AZT-trip inhibits RT and acts as chain terminator
45
Q

Zidovudine Side Effects

A
  • Bone marrow suppression
    • neutropenia, anemia
  • Avoid drugs which inhibit glucuronyl transferases (phase II)
  • Myopathy and myositis (after prolonged use)
46
Q

AZT and Inhibitors of Glucuronyl Transferases

A

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

47
Q

Mechanism of other NRTIs

A
  • Specific chemistry differs, but general mechanism is analogous to AZT
    • Nucleoside analogs that must be phosphorylated to be active
    • Competitive inhibitors of RT
    • Cause DNA chain termination when incorporated into DNA
48
Q

Tenofovir Mechanism

Unlike AZT:

Similarity to AZT:

A

Unlike AZT: Nucleotide prodrug

Similarity to AZT: Inhibits RT by competinf for incorporation into DNA, causing chain termination

49
Q

Tenofovir

Uses:

Side Efects:

A

Uses: Combinatio therapy for HIV

Side Effects: Well tolerated - Some nausea/vomiting, diarrhea, flatulence

50
Q

Lamivudine (3TC) - for HIV treament

Synergism with AZT:

Admnistration:

Side Effects:

A

Synergism with AZT: Nucleoside analog inhibitor of RT

  • AZT resistant strains are 3TC sensitive and 3TC resistant strains are AZT-sensitive

Admnistration: 85% oral availability

Side Effects: Well tolerated - Nausea; diarrhea; rash

51
Q

Emtricitabine (fluorinated analog of ______)

Has same mechanism and resistance as ____

A

Lamivudine; 3TC

52
Q

Abacavir

Mechanism of Action:

Adverse effect:

A

Mechanism of Action: Nucleoside analog inhibitor of RT

Adverse effect: Hypersensitivity

  • Associated with HLA-B*5701 allele
  • If hypersensitivity occurs, stop drug immediately and never restart
53
Q

Other side effects associated with a number of NRTIs

A
  • Lactic acidosis
  • Hepatic steatosis (fatty liver)
  • Myopathy
  • Dilated cardiomyopathy
54
Q

Some differences between NRTIs and NNRTIs

A
  • Non-nucleoside inhibitors of RT
  • All are active as given; do not require phosphorylation to be active
  • Bind elsewhere on the enzyme
55
Q

Efavirenz

Categorization:

Uses:

Side Effects:

A

Categorization: NNRTI

Uses: Part of multi-drug therapy for HIV (#1 anti HIV drug in USA)

Side Effects:

  • Rash
  • CNS/psychiatric symptoms (various)
    • Nightmares, vivid dreams
    • 50% of patients, especially early in Tx
56
Q

Is Ritonavir a Protease Inhibitor (P.I)?

A

NO! it is used as a P.I booster, not as a P.I

57
Q

Use of Protease Inhibitors:

Mechanism of Protease Inhibitors

A

Use of Protease Inhibitors:

  • In combination with inhibitors of RT
  • Significantly decrease viral blood load

Mechanism of Protease Inhibitors

  • Prevents viral aspartic protease from cleaving Gag-pol polypeptide into separate functional proteins
  • Competitive inhibitor of protease active site
  • Results in non-infectious viral particles
58
Q

Toxicities common to a number of protease inhibitors (including Lopinavir)

A
  • Diabetes (insulin resistance)
  • Alterations in lipid metabolism
  • Fat redistribution
  • Alters metabolism of many other drugs (potent CYP3A inhibitors)
59
Q

Ritonavir Use:

A
  • Too toxic to dose as a protease inhibitor
  • Used to boost levels of other protease inhibitors because it blocks their metabolism by CYP3A
60
Q

Enfuvirtide

Class:

Use:

Advantage:

Mechanism of Action:

A

Class: Fusion inhibitors

Use: for HIV-1 only - experienced patients who have failed multiple regimens

Advantage: 2x daily injections

Mechanism of Action: Binds to gp41 subunit of HIV glycoprotein; blocks conformational change required for membrane fusion to CD4+ cells

61
Q

Enfuvirtide Side Effects

A
  • Local injection site reactions (98%)
  • Diarrhea, nausea, fatigue
  • Mainly used as a later option when other regimens have failed
62
Q

Maravirok

Class:

Use:

Mechanism of Action:

A

Class: CCR5 antagonist

Use: Treatment of CCR5-tropic HIV-1 - Effective in strains resistant to other drugs

Mechanism of Action: Antagonist of chemokine co-receptor CCR5, preventing interaction with HIV gp120

  • Blocks entry of HIV into cells
63
Q

Maraviroc side effects

A
  • Possible hepatotoxicity
  • Possible cardiovascular events
  • Most common
    • Cough, fever, rash, abdominal pain
64
Q

Raltegravir

Class:

Approved Use:

Mechanism:

A

Class: Integrase inhibitor

Approved Use: Treatment of HIV-1 in new and treatment experienced patients

  • Works on virus that is resistant to other drugs

Mechanism: Inhibits HIV-1 integrase activity preventing integration of HIV-1 DNA into the genome

65
Q

Raltegravir Side Effects:

A

Generally well-tolerated

66
Q

Current reasons for HIV therapeutic failure

A
  • Failure to maintain adherence to drug regimens (biggest issue)
  • Restistant strains emerge
67
Q

Drug combinations for treating HIV

HAART:

A

3 or more drugs per patient (2 or more drug classes)

HAART: Highly active anti-retroviral therapy

  • Combination of drugs of 2 or more classes
68
Q

DHHS guidelines: There should be urgency in initiating HAART therapy when CD4 count is < ____

69
Q

Occupational risk for HIV and initiation of anti-HIV drugs

A
  • Needlestick transmission (0.3%)
  • Initiate anti-HIV drugs ASAP
    • Even 24-36 hours may be too late

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