Herpesvirus antivirals

Guanosine Analogs - The 'Clovir' Crew

• Acyclovir, Valacyclovir (prodrug of acyclovir), Famciclovir (prodrug of penciclovir).

• Mechanism: Guanosine analogs that are selectively phosphorylated by viral thymidine kinase. This initial step traps the drug inside infected cells. Host cell kinases complete the conversion to a triphosphate form, which inhibits viral DNA polymerase and causes DNA chain termination.
• Clinical Use: Active against HSV-1, HSV-2, and VZV. Used for herpes labialis, genital herpes, herpes zoster (shingles), and varicella (chickenpox).
• Adverse Effects: Generally well-tolerated.
  • Most common: Headache, nausea, diarrhea.
  • Serious: Acyclovir-induced crystalline nephropathy, neurotoxicity (confusion, delirium).
  • 📌 Mnemonic (ACV): Acute kidney injury, Confusion (neurotoxicity), Vomiting/nausea.

⭐ High-Yield: Acyclovir-induced crystalline nephropathy risk is highest with rapid IV infusion and in dehydrated or renally-impaired patients. Prevent with adequate pre-hydration and slow infusion rates.

CMV Agents - Cytomegalovirus Crushers

• Ganciclovir (IV) and its prodrug Valganciclovir (oral).
• Mechanism of Action:
  • A guanosine analog that requires a viral touch to activate.
  • Initial phosphorylation is uniquely handled by the CMV-specific protein kinase UL97.
  • Cellular kinases then complete the process, forming a triphosphate that competitively inhibits viral DNA polymerase.
• Primary Indications:
  • Treatment of CMV retinitis, colitis, and esophagitis, especially in immunocompromised individuals.
  • Prophylaxis for CMV in transplant recipients.
• Adverse Effects:
  • ⚠️ Myelosuppression is the major dose-limiting toxicity, causing neutropenia and thrombocytopenia.
  • 📌 Mnemonic: Gan-cyc-low-vir makes your cell counts go low.

⭐ Ganciclovir's dose-limiting toxicity is bone marrow suppression, a key distinction from Acyclovir's primary dose-limiting toxicity, which is nephrotoxicity.

Resistance Line - The Backup Brigade

For acyclovir/ganciclovir-resistant HSV & CMV infections. Key feature: Does not require activation by viral thymidine kinase.

Foscarnet

• Mechanism: Pyrophosphate analog; directly inhibits viral DNA polymerase without incorporation. 📌 FOScarnet = PhOSphate analog.
• Toxicity: Nephrotoxicity, electrolyte disturbances (hypo/hypercalcemia, hypo/hyperphosphatemia, hypokalemia, hypomagnesemia).

Cidofovir

• Mechanism: Cytosine nucleotide analog; competitively inhibits viral DNA polymerase and may incorporate into the DNA chain.
• Toxicity: Severe dose-dependent nephrotoxicity. ⚠️ Always co-administer with probenecid and pre-infusion saline hydration to reduce kidney damage.

⭐ Foscarnet can chelate calcium, leading to significant hypocalcemia that may precipitate seizures.

High‑Yield Points - ⚡ Biggest Takeaways

• Acyclovir, a guanosine analog, needs viral thymidine kinase for activation. It treats HSV/VZV and can cause crystalline nephropathy.
• Ganciclovir treats CMV retinitis and requires CMV kinase UL97. Its main toxicity is myelosuppression.
• Foscarnet directly inhibits DNA polymerase, treating resistant CMV/HSV. It's nephrotoxic and causes electrolyte imbalances.
• Cidofovir also directly inhibits DNA polymerase. Its nephrotoxicity is managed with probenecid and hydration.
• Antiviral resistance often stems from mutated viral kinase enzymes.