## Mechanism of Action of Antiviral Agents ### Correct Statements (Options 0, 1, 2) **Option 0 — Acyclovir activation:** - Acyclovir is a nucleoside analogue that requires **viral thymidine kinase (TK)** for initial phosphorylation to acyclovir monophosphate - Cellular kinases then convert it to the active triphosphate form - The triphosphate inhibits viral DNA polymerase and causes chain termination - This selectivity for viral TK is why acyclovir has low toxicity to uninfected cells **Option 1 — Foscarnet mechanism:** - Foscarnet is a **pyrophosphate analogue** that does NOT require viral enzyme activation - It directly inhibits viral DNA polymerase by chelating Mg²⁺ ions at the active site - This makes it effective against TK-deficient and acyclovir-resistant strains - Used primarily for CMV and severe HSV/VZV in immunocompromised patients **Option 2 — Valacyclovir:** - Valacyclovir is the L-valine ester prodrug of acyclovir - Rapidly hydrolyzed by first-pass hepatic metabolism to acyclovir - Achieves **3–5 times higher plasma acyclovir levels** than oral acyclovir - Better oral bioavailability (54% vs 15–20% for acyclovir) ### Incorrect Statement (Option 3 — THE ANSWER) **Penciclovir activation — the trap:** - Penciclovir (and its prodrug famciclovir) also requires **viral thymidine kinase** for initial phosphorylation, just like acyclovir - It does NOT rely on cellular kinases alone - Therefore, penciclovir is **equally susceptible to TK-deficient resistance** as acyclovir - The statement falsely claims penciclovir works in TK-deficient strains — this is incorrect ### High-Yield Comparison Table | Agent | Activation | Mechanism | Resistance Pattern | Use | | --- | --- | --- | --- | --- | | Acyclovir | Viral TK + cellular kinases | DNA polymerase inhibition | TK-deficient strains | HSV, VZV (oral/IV) | | Valacyclovir | Viral TK + cellular kinases (after hydrolysis) | DNA polymerase inhibition | TK-deficient strains | HSV, VZV (oral, better bioavailability) | | Penciclovir | Viral TK + cellular kinases | DNA polymerase inhibition | TK-deficient strains | HSV, VZV (topical as cream) | | Foscarnet | **None — direct action** | Mg²⁺ chelation, DNA polymerase inhibition | **NOT TK-dependent** | CMV, acyclovir-resistant HSV/VZV | **Key Point:** - All nucleoside/nucleotide analogues (acyclovir, valacyclovir, penciclovir, ganciclovir) require viral TK for activation - Foscarnet is the exception — it is a pyrophosphate analogue that acts directly without requiring viral enzyme activation - This is why foscarnet is the drug of choice for TK-deficient resistant strains **Clinical Pearl:** - Acyclovir-resistant HSV/VZV strains are usually TK-deficient or have altered DNA polymerase - Foscarnet is reserved for immunocompromised patients (e.g., HIV/AIDS with CD4 <50) with resistant infections because of its nephrotoxicity and electrolyte disturbances **High-Yield:** - The distinction between TK-dependent (nucleoside analogues) and TK-independent (foscarnet) activation is a classic NEET PG exam question - Penciclovir's mechanism is identical to acyclovir regarding TK dependence — the only difference is lower CNS penetration and topical availability
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