Antiviral Agents and CMV Infections

Antiviral Agents

• Mechanism of Action: Antivirals target viral enzymes and processes to interfere with viral replication. Some common mechanisms include:
  • Nucleosides and Nucleotide Analogues: These drugs get incorporated into viral DNA and/or RNA, leading to faulty and nonfunctional viral components.
  • Enzyme Inhibition: Inhibiting viral enzymes required for viral replication.

Antiviral Agents for Cytomegalovirus (CMV) Infections

• Ganciclovir (Cytovene®):

  • Available in oral, intravenous, and ophthalmic formulations.
  • Indications: CMV infection, certain HSV and VZV infections, and as a special chemotherapy agent.
  • Administered via IV as a special formulation.
  • Black Box Warning (BBW): Myelosuppression, carcinogenic, and teratogenic.
  • Common Side Effects: Fever, nausea, vomiting, diarrhea, and anorexia.
  • Serious Side Effects: Myelosuppression, seizures, increased serum creatinine (Scr).
  • Drug Interactions: Significant interaction with zidovudine, potentially causing myelosuppression.
  • Pregnancy Category: C, but considered teratogenic.
  • Administration: Renal dose adjustments are required. Special chemotherapy handling is needed.

• Valganciclovir (Valcyte®):

  • A prodrug of ganciclovir, converted to active form by GI esterases.
  • Given orally and absorbed better than ganciclovir.
  • Indications: CMV, HSV, and VZV infections.
  • BBW: Similar to ganciclovir.
  • Common Side Effects: Similar to ganciclovir.
  • Serious Side Effects: Myelosuppression (less common than with ganciclovir), but can still occur.
  • Drug Interactions: Limited drug interactions.
  • Pregnancy Category: C, but considered teratogenic.
  • Administration: Renal dose adjustments are required. Special chemotherapy handling is needed.
  • Take with food to improve absorption.

• Cidofovir (Vistide®):

  • Given intravenously.
  • BBW: In addition to BBW for Ganciclovir, dose-related nephropathy should also be watched for.
  • Contraindications: Scr > 1.5 mg/dL and CrCl < 50 mL/min (adjust dose accordingly).
  • Common Side Effects: Similar to ganciclovir & valganciclovir.
  • Serious Side Effects: Nephropathy (dose-related).
  • Administration: Renal dose adjustments are required. Maintain adequate hydration.

Other Antiviral Agents

• Acyclovir (Zovirax®):

  • Available in oral, intravenous, and topical formulations.
  • Mechanism of Action: Inhibits viral DNA polymerase.
  • Indications: HSV and VZV infections, viral encephalitis.
  • Common Side Effects: Rash, nausea, vomiting, abdominal pain, headache, fatigue, transient changes in BUN and Scr.
  • Serious Side Effects: CNS (encephalopathy, confusion, delirium, seizures), crystalluria, renal failure, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, SJS/TENS.
  • Administration: Renal dose adjustments are required. Maintain adequate hydration. Drug is stable in normal saline (not D5W). Dose based on ideal body weight.

• Valacyclovir (Valtrex®):

  • Oral prodrug of acyclovir, metabolized to active form via GI esterases.
  • BBW: None.
  • Common Side Effects: Rash, nausea, vomiting, abdominal pain, headache, fatigue.
  • Serious Side Effects: Thrombotic thrombocytopenic purpura, crystalluria, hemolytic uremic syndrome, seizures, CNS events (encephalopathy, confusion, delirium).
  • Administration: Renal dose adjustments are required. Maintain adequate hydration.

• Famciclovir (Famvir®):

  • Oral prodrug of penciclovir.
  • BBW: None.
  • Common Side Effects: Headache, nausea, vomiting, and diarrhea.
  • Serious Side Effects: Erythema multiforme, SJS, nephrotoxicity (especially at high doses).
  • Administration: Renal dose adjustments are required.

• Penciclovir (Denavir®):

  • Topical cream for treating herpetic lesions on the lips and face.
  • Common Side Effects: Local irritation, headache.
  • Serious Side Effects: None.
  • Important Considerations: Avoid contact with eyes and mucous membranes.

• Trifluridine (Viroptic®):

  • Ophthalmic solution for keratoconjunctivitis.
  • Mechanism of Action: Incorporated into viral DNA in place of thymidine, resulting in faulty viral DNA.
  • Common Side Effects: Burning, edema
  • Serious Side Effects: None.
  • Administration: Refrigerate solution.

• Idoxuridine (Herplex®):

  • Ophthalmic solution for keratoconjunctivitis.
  • Common Side Effects: Photophobia, local irritation.
  • Serious Side Effects: None.
  • Important Considerations: Not currently available in the United States.

• Vidarabine (Vira-A®):

  • Topical ointment for keratoconjunctivitis.
  • Common Side Effects: Photophobia, local irritation.
  • Serious Side Effects: None.
  • Important Considerations: Not currently disponível nos Estados Unidos.

Anti-Influenza Agents

• Inhibitors of Viral Uncoating prevent influenza A viruses from uncoating inside host cells by blocking M2, a proton channel that acidifies the interior of the virus. This is necessary for the dissociation of the viral matrix protein from the viral ribonucleic protein (RNA).
• Rimantadine and Amantadine are drugs that work by inhibiting viral uncoating. They are both administered orally and metabolized differently; Rimantadine is metabolized in the liver, while Amantadine is excreted by the kidneys.
• Both drugs are used to treat or prevent influenza A but not influenza B infections.
• Amantadine can increase the risk of neurologic effects and greater dose adjustments are necessary with lower creatinine clearance (CrCl), a measure of kidney function.
• Rimantadine is a common drug but can be difficult to use due to the need to adjust dosages in patients with impaired liver function.

Inhibitors of Viral Release

• Inhibitors of Viral Release prevent influenza viruses from spreading by inhibiting neuraminidase, an enzyme that enables newly synthesized virions to detach from host cells.
• Oseltamivir is the most common inhibitor of viral release, and is a prodrug (a substance that becomes active in the body) that gets activated via ester hydrolysis.
• Zanamivir is a well-established inhibitor of viral release, with low bioavailability (~4-17%). It is administered via a diskhaler device.
• Peramivir is also a well-established inhibitor of viral release that requires a single 600-mg dose.
• Oseltamivir, Zanamivir, and Peramivir are all recommended for use in influenza A and B infections.

Endonuclease Inhibitor

• Baloxavir marboxil is a prodrug that is converted to baloxavir, which inhibits influenza virus replication. Baloxavir inhibits the endonuclease activity of the polymerase acidic (PA) protein, which is essential for the replication of influenza virus.
• Baloxavir marboxil has an 80-hour half-life and is administered orally.

Agents for Human Papillomavirus (HPV)

• Immune Modulating agents for HPV infections work by interacting with Toll-like receptor 7 to boost innate immunity and interferon secretion.
• Imiquimod is the most common immune modulating agent for HPV infections. It is applied topically and is effective against a variety of HPV-related conditions, including condyloma acuminatum, actinic keratosis, and basal cell carcinoma.

Agents for Herpes Simplex Virus (HSV) and Varicella-Zoster Virus (VZV)

• Fusion Inhibitors prevent the fusion of the HSV membrane with the plasma membrane of the host cell, preventing the virus from entering the cell and replicating.
• Docosanol is a topical agent that is used to treat herpetic lesions on lips and face.

Nucleoside and Nucleotide Analogues

• Nucleoside and Nucleotide Analogues are used to treat HSV and VZV infections. These drugs work by inhibiting DNA polymerase, which slows viral replication.
• Nucleoside and Nucleotide Analogues are phosphorylated by viral kinases, which leads to inhibition of DNA polymerase.

Influenza Viral Release Inhibitors

• Mechanism of Action: Prevents release of newly formed virus particles by inhibiting the enzyme neuraminidase, leaving the virus attached to the host cell.

• Oseltamivir (Tamiflu®)

  • Pharmacokinetics: PO (oral) prodrug that is activated in the liver via ester hydrolysis to the active form.
  • Clinical Uses: Recommended by the CDC for both treatment and prophylaxis of Influenza A and B infections.
  • Timing: Begin taking within 48 hours of symptom onset for optimal efficacy.
  • Administration: Take with food.
  • Adverse Effects:
    • Common: Nausea, vomiting, abdominal pain.
    • Serious: Rash (Stevens-Johnson syndrome (SJS)/Toxic epidermal necrolysis (TEN), neuropsychiatric events (e.g., delirium, hallucinations, seizures).
  • Drug Interactions: Avoid concurrent administration with live influenza vaccine.

This quiz covers antiviral agents, focusing on their mechanisms of action, specifically for cytomegalovirus (CMV) infections. Learn about ganciclovir, its formulations, indications, and potential side effects. Test your knowledge on how these agents function in combating viral replication.