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Antivirals Flashcards

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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
CMV in immunocompromised patients ## Footnote HIV patients: Solid organ transplants:
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)
26
Drugs for CMV prophylaxis/infection
Ganciclovir Foscarnet
27
Ganciclovir ## Footnote Mechanism of action: Uses: Side Effects:
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
28
Foscarnet ## Footnote Mechanism of Action: Uses:
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
Foscarnet - Side Effects
* 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
Do anti-CMV drugs cure the disease?
No they can only slow the progression (×̯×)
31
Drugs for Hepatitis and Respiratory syncitial virus ## Footnote Hepatitis B: Hepatitis C: (combo) RSV:
Hepatitis B: * Lamivudine (3TC) * Tenofovir * Interferon-α Hepatitis C: * Ribarvirin + Interferon-α + Boceprevir RSV: Ribavirin
32
Lamivudine (3TC) ## Footnote Mechanism: Use: Administration: Side Effects:
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
Tenfovir ## Footnote Mechanism of Action: Uses: Administration: Side Effects:
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
Ribavirin mechanism of action
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
Uses of Ribavirin ## Footnote Aerosol use: Oral use:
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
Ribavirin Side Effects ## Footnote Aerosol Use: IV/Oral Use:
Aerosol Use: Drug may precipitate in and clog respiratory equipment; pulmonary function deterioration IV/Oral Use: Anemia, bone marrow suppression
37
Alpha-interferons, recombinant - Approved antiviral uses ## Footnote
* Condyloma acuminata (veneral warts) * Hepatitis B and C * PEG-alpha-2a and 2b interferons in combination with ribavirin and boceprevir for hepatitis C
38
Interferon-α side effects
* Flu-like syndrome * Leukopenia, bone marrow suppression * Neurotoxicity, myalgia Side effects are the greatest limit to long term use
39
Boceprevir ## Footnote Mechanism of action: Use:
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
Most effective treatment for hepatitis C genotype 1
3 drug regimen Ribavirin + PEG-inteferon-α + Boceprevir
41
Boceprevir - side effects
* Anemia, neutropenia * Contraindicated with CYP3A substrates or inducers
42
Classes of drugs for HIV therapy
* Reverse transcriptase (RT) inhibitors * nucleoside analogs (NRTIs) * non-nucleoside inhibitors (NNRTIs) * Protease inhibitors (PIs) * Fusion inhibitors * CCR5 antagonists * Integrase inhibitors
43
NRTIs: NNRTIs: Protease Inhibitors: Fusion Inhibitors: CCR5 Antagonists: Integrase Inhibitors:
NRTIs: Zidovudine; Lamivudine; Abacavir; Tenofovir; Emtricitabine NNRTIs: Efavirenz Protease Inhibitors: Lopinavir; Ritonavir (booster) Fusion Inhibitors: Enfuvirtide CCR5 Antagonists: Maraviroc Integrase Inhibitors: Raltegravir
44
Zidovudine (AZT) - First anti-HIV drug Activation:
* Thymidine nucleoside analog * Phosphorylated by cellular kinase (host cell) * AZT-trip inhibits RT and acts as chain terminator
45
Zidovudine Side Effects
* Bone marrow suppression * neutropenia, anemia * Avoid drugs which inhibit glucuronyl transferases (phase II) * Myopathy and myositis (after prolonged use)
46
AZT and Inhibitors of Glucuronyl Transferases
Drugs that inhibit glucuronidation of AZT increase the hematologic toxicity of AZT
47
Mechanism of other NRTIs
* 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
Tenofovir Mechanism ## Footnote Unlike AZT: Similarity to AZT:
Unlike AZT: Nucleotide prodrug Similarity to AZT: Inhibits RT by competinf for incorporation into DNA, causing chain termination
49
Tenofovir ## Footnote Uses: Side Efects:
Uses: Combinatio therapy for HIV Side Effects: Well tolerated - Some nausea/vomiting, diarrhea, flatulence
50
Lamivudine (3TC) - for HIV treament ## Footnote Synergism with AZT: Admnistration: Side Effects:
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
Emtricitabine (fluorinated analog of \_\_\_\_\_\_) Has same mechanism and resistance as \_\_\_\_
Lamivudine; 3TC
52
Abacavir ## Footnote Mechanism of Action: Adverse effect:
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
Other side effects associated with a number of NRTIs
* Lactic acidosis * Hepatic steatosis (fatty liver) * Myopathy * Dilated cardiomyopathy
54
Some differences between NRTIs and NNRTIs
* Non-nucleoside inhibitors of RT * All are active as given; do not require phosphorylation to be active * Bind elsewhere on the enzyme
55
Efavirenz ## Footnote Categorization: Uses: Side Effects:
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
Is Ritonavir a Protease Inhibitor (P.I)?
NO! it is used as a P.I booster, not as a P.I
57
Use of Protease Inhibitors: Mechanism of Protease Inhibitors
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
Toxicities common to a number of protease inhibitors (including Lopinavir)
* Diabetes (insulin resistance) * Alterations in lipid metabolism * Fat redistribution * Alters metabolism of many other drugs (potent CYP3A inhibitors)
59
Ritonavir Use:
* Too toxic to dose as a protease inhibitor * Used to boost levels of other protease inhibitors because it blocks their metabolism by CYP3A
60
Enfuvirtide ## Footnote Class: Use: Advantage: Mechanism of Action:
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
Enfuvirtide Side Effects
* Local injection site reactions (98%) * Diarrhea, nausea, fatigue * Mainly used as a later option when other regimens have failed
62
Maravirok ## Footnote Class: Use: Mechanism of Action:
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
Maraviroc side effects
* Possible hepatotoxicity * Possible cardiovascular events * Most common * Cough, fever, rash, abdominal pain
64
Raltegravir ## Footnote Class: Approved Use: Mechanism:
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
Raltegravir Side Effects:
Generally well-tolerated
66
Current reasons for HIV therapeutic failure
* Failure to maintain adherence to drug regimens (biggest issue) * Restistant strains emerge
67
Drug combinations for treating HIV HAART:
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
DHHS guidelines: There should be urgency in initiating HAART therapy when CD4 count is \< \_\_\_\_
350
69
Occupational risk for HIV and initiation of anti-HIV drugs
* Needlestick transmission (0.3%) * Initiate anti-HIV drugs ASAP * Even 24-36 hours may be too late

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