Antivirals Flashcards
Why is antiviral therapy difficult?
At what point in illness are antivirals most effective?
Most viruses have intracellular phases, use host enzymes, and can go latent.
Like many drugs, antivirals are more effective in relieving illness early on–before viral replication occurs.
Are antivirals broad or narrow spectrum?
Are antivirals virustatic or virucidal?
Most antivirals are quite narrow-spectrum. Many can only target one phase of a virus’s replication cycle.
Most antivirals are virustatic, relying on the immune system to do the clearing.
How does immunization compare to antiviral treatment in terms of efficacy?
Distinguish between active and passive immunization (from a therapeutic perspective).
Immunization provides much better defense, especially since it is “always-on”.
Active immunization eg Vaccination, immune system recognizes and produces antibodies against the virus.
Passive immunization eg IVIG, protective and lasts for weeks, but expensive and potentially immunogenic.
Amantadine
What is its mechanism of action?
What are its indications?
What are its side effects?
Amantadine
Blocks the M2 influenza protein, stopping acidification and activation (uncoating).
For prophylaxis and treatment of Influenza A.
Low incidence of CNS effects (anxiety, confusion, headache…)
Amantadine
What is the current status of its resistance?
Compare it with rimantadine.
Amantadine
Some strains of Influenza A (especially H3N2) exhibit resistance, which took only a few years to develop…
Rimantadine has milder side effects and it metabolized by the liver. It is also more expensive.
Oseltamivir
What is its mechanism of action?
What are its indications?
What are its side effects?
Oseltamivir
It is an orally-administered prodrug, which is activated by esterases to oseltamivir carboxylate and inhibits viral neuraminidase, blocking release/penetration.
For treatment and prophylaxis of Influenza A & B. Recipients should be at least 1 year old and receive it within 48 hours of symptoms.
N/V/D, bronchitis/cough.
What mechanism of treatment is best for treating Herpesvirus? Why?
Since herpes encodes many of its own DNA enzymes, inhibiting nucleic acid synthesis is an effective method to block it.
Trifluridine
What is its mechanism of action?
What are its indications?
What are its side effects?
Trifluridine
It is a thymidine analog that interferes with DNA synthesis (doesn’t require activation).
As an ophthalmic solution, it treats ocular herpes simplex infections.
Burning, stinging, hypersensitivity.
Acyclovir
What is its mechanism of action?
What are its indications?
What are its side effects?
Acyclovir
Upon phosphorylation by viral & host enzymes, it forms a dGTP analog that blocks DNA chain elongation (no 3’-OH; affects mostly viral DNA pol).
IV (serious HSV; encephalitis & neonatal), Oral (primary genital herpes and gingivostomatitis), topical (primary genital herpes).
Although it is well-tolerated, some experience rash/itching, N/V, headache, fatigue.
Famciclovir
What is its mechanism of action?
What are its indications?
What are its side effects?
Famciclovir
Same as acyclovir: triphosphorylation >> block DNA chain elongation.
For shingles, latent chickenpox, and treatment/suppression of recurrent genital herpes.
Same as acyclovir: Rash, N/V, etc. Note that it is better absorbed.
Penciclovir
What is its mechanism of action?
What are its indications?
What are its side effects?
Penciclovir
Same as acyclovir: triphosphorylation >> block DNA chain elongation.
For recurrent herpes of face and lips (topical).
Same as acyclovir: Rash/irritation (no N/V since not ingested).
How widespread are CMV infections?
Who is especially at risk?
How effective are CMV antivirals in treating them?
Hugely; 50-85% of US popuilation is seropositive and/or latently infected.
Reactivation can occur in the immunocompromised; the infection is generally serious in HIV patients and transplant recipients on immunosuppression.
They slow the progression of CMV, but do not cure it.
Ganciclovir
What is its mechanism of action?
What are its indications?
What are its side effects?
Ganciclovir
SIMILAR to acyclovir. However, mono-phosphorylated by a CMV kinase (not a host kinase!)
For CMV retinitis and CMV prophylaxis in transplant recipients.
Bone marrow suppression (causing leukopenia, thrombocytopenia, anemia), made worse with AZT.
Foscarnet
What is its mechanism of action?
What are its indications?
What are its side effects?
Foscarnet
It is a pyrophosphate analog that inhibits CMV DNA pol. Doesn’t require activation.
Used for CMV retinitis, and for HSV that resists acyclovir.
Renal damage, electrolyte imbalances, and seizures. Worse than ganciclovir!
Lamivudine (3TC)
What is its mechanism of action?
What are its indications?
What are its side effects?
Lamivudine (3TC)
It is a nucleoside analog that is phosphorylated to inhibit reverse transcriptase (an NRTI)
Approved for hepatitis B (which apparently has an RT domain) and HIV (good against AZT-resistant strains and vice versa–synergistic).
Well tolerated, with some N/V/D and rash.
Tenofovir
What is its mechanism of action?
What are its indications?
What are its side effects?
Tenofovir
AMP analog, hydrolased & phosphorylated to block reverse transcriptase (NRTI).
For hepatitis B and HIV (a preferred drug).
Just some GI upset, otherwise well-tolerated.
Ribavirin
What is its mechanism of action?
What are its indications?
What are its side effects?
Ribavirin
Nucleoside analog that is phosphorylated: Mono-P blocks IMPDH (GMP synthesis), Tri-P blocks GTP-capping of mRNA.
It is one of the few broad antivirals. For RSV in young children (aerosol; declining) and for Hepatitis C (oral; combination).
The aerosol can precipitate in nebulizers. It similarly harms pulmonary function. The oral form can cause anemia/bone marrow suppression.
Alpha Interferon__s
What is their mechanism of action?
What are their indications?
What are their side effects?
Alpha Interferons
Regulates immune response and induces apoptosis of infected cells.
For condyloma accuminata (HPV 6/11), and for Hepatitis B & C.
Flu-like symptoms, leukopenia/bone marrow suppression, neurotoxicity & myalgia.
Boceprevir
What is its mechanism of action?
What are its indications?
What are its side effects?
Boceprevir
Reversibly inhibits NS3 to interfere with virion production.
For Hepatitis C (genotype 1), in combo with ribavirin and a PEG-interferon-a.
Anemia, neutropenia. CYP3A inhibition.
Name 6 classes of anti-HIV drugs, and an example of each one.
What does HAART usually consist of?
NRTIs (Zidovudine), NNRTIs (Efavirenz), Protease inhibitors (Lopinavir), Fusion inhibitors (enfuvirtide), CCR5 antagonists (Maraviroc), Integrase inhibitors (Raltegravir).
3+ drugs from 2+ classes, usually 2 NRTIs and something else.
Zidovudine (AZT)
What is its mechanism of action?
What are its indications?
What are its side effects?
Zidovudine (AZT)
As an NRTI, gets phosphorylated and disrupts DNA chain elongation (like acyclovir) by RT.
For HIV (HAART).
Bone marrow suppression (neutropenia, anemia), myopathy. CYP metabolite is toxic, so avoid glucuronyl inhibitors.
Emtricitabine (FTC)
What is its mechanism of action?
What are its indications?
What are its side effects?
Emtricitabine (FTC)
Same as lamivudine (it’s a fluorinated 3TC), but with longer half-life.
For HIV, maybe Hepatitis B.
Probably the same as lamivudine–mild N/V/D and rash.
Abacavir
What is its mechanism of action?
What are its indications?
What are its side effects?
Abacavir
As an NRTI, is phosphorylated to inhibit RT.
For HIV.
Hypersensitivity, especially in those with HLA-B*5701 (stop and don’t restart!)
What side effects are seen with NRTIs, and why?
How do NNRTIs differ from NRTIs?
Lactic acidosis, steatohepatitis, and other metabolic conditions, probably due to mitochondrial DNA pol inhibition.
They are non-nucleosides, they don’t insert into the chain and don’t require activation by phosphorylation.
Efavirenz
What is its mechanism of action?
What are its indications?
What are its side effects?
1 Anti-HIV drug!
Efavirenz
It binds at an allosteric site on NRTIs and disrupts the active site.
Rash, CNS symptoms (vivid dreams/nightmares in 50% of patients).
Lopinavir
What is its mechanism of action?
What are its indications?
What are its side effects?
Lopinavir
Competitively blocks viral aspartate protease from cleaving gag-pol–results in defective virions.
For HIV-1/2, can decrease viral blood load.
Diabetes (onset & exacerbation), increased triglycerides/cholesterol, truncal fat redistribution, and CYP3A inhibition.
Ritonavir
What is its mechanism of action?
What are its indications?
What are its side effects?
Ritonavir
It is a protease inhibitor, but it’s too toxic to be used as such. Instead, it is used for CYP3A inhibition to potentiate other PIs.
Combination therapy in HIV.
Diabetes (onset & exacerbation), increased triglycerides/cholesterol, truncal fat redistribution, and CYP3A inhibition (kind of the point).
Enfuvirtide
What is its mechanism of action?
What are its indications?
What are its side effects?
Enfuvirtide
It is a 36-aa peptide that binds gp41 to prevent HIV fusion.
For HIV-1 (not 2), in patients who have failed multiple other regimens.
N/D, fatigue. Injection site reactions (98%–it is a protein, after all).
Maraviroc
What is its mechanism of action?
What are its indications?
What are its side effects?
Maraviroc
It is a CCR5 antagonist, preventing it from interacting with gp120 (blocks entry).
It is used to treat early-stage (M-tropic) HIV-1, including resistant strains.
Possible hepatotoxicity, possible CV events. Might increase infection incidence.
Raltegravir
What is its mechanism of action?
What are its indications?
What are its side effects?
Raltegravir
It is an integrase inhibitor; stops HIV from inserting into host genome.
For HIV-1 in new and experienced patients, including resistant strains.
It is well-tolerated.
What are the usual causes for HIV treatment regimens to fail?
What are some criteria to consider when selecting HIV treatment plans?
- Lack of adherence 2. Emergence of resistance.
How resistant the HIV is, and ease of compliance of the regimen (administration & side effects).
What are the current guidelines for when to start HAART?
What is the chance of transmission via needlestick in a healthcare setting? What should you do if it happens to you?
When CD4+ counts drop below 350, or if there are opportunistic infections/pregnancy/HepB and in elderly patients or those requesting HAART.
0.3% (Rule of 3s!). Initiate anti-HIV therapy (PEP) as soon as possible.
