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Antiviral Drugs - KD Tripathi Style

Note: KD Tripathi's Essentials of Medical Pharmacology is not directly in this library, but the content below is sourced from Katzung's Basic and Clinical Pharmacology (16th ed.) - the international equivalent - which covers exactly the same syllabus as Tripathi. The classification and drug details align closely with Tripathi's presentation.

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Key Concept

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Sites of Antiviral Drug Action

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Classification of Antiviral Drugs

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1. Anti-Herpesvirus Drugs (HSV, VZV, CMV)

Acyclovir (Prototype)

• Mechanism: Acyclovir is a guanosine analog. It is selectively phosphorylated by viral thymidine kinase (TK) to acyclovir monophosphate, then by host cell kinases to the triphosphate form, which inhibits viral DNA polymerase and causes chain termination.
• Selectivity: ~3,000 times more active against viral DNA polymerase than host polymerase
• Spectrum: HSV-1, HSV-2, VZV, EBV (less active against CMV)
• Uses: Genital herpes, herpes labialis, herpes encephalitis (IV: 10 mg/kg q8h x 14-21 days), neonatal HSV (IV: 20 mg/kg q8h), VZV (shingles), chickenpox
• ADRs: Crystalluria/nephrotoxicity (IV - maintain hydration), neurotoxicity at high doses; generally well-tolerated orally
• Resistance: Mutation in viral TK (most common) or DNA polymerase

Valacyclovir

• L-valyl ester prodrug of acyclovir; converted to acyclovir after intestinal/hepatic metabolism
• Higher oral bioavailability (~55% vs 15-30% for acyclovir)
• Dosed less frequently (bid vs 5 times/day)

Famciclovir

• Prodrug of penciclovir; similar mechanism to acyclovir
• Longer intracellular half-life than acyclovir

Ganciclovir

• Guanosine analog; phosphorylated by CMV UL97 protein kinase
• Spectrum: CMV (cytomegalovirus) - the key drug here
• Uses: CMV retinitis, CMV colitis, CMV pneumonitis in immunocompromised
• ADRs: Myelosuppression (neutropenia, thrombocytopenia) - major dose-limiting toxicity; also nephrotoxic, teratogenic, gonadotoxic
• Valganciclovir: Oral prodrug with improved bioavailability

Foscarnet

• Pyrophosphate analog; directly inhibits viral DNA polymerase WITHOUT requiring phosphorylation by viral kinase
• Use: CMV retinitis (alternative to ganciclovir); acyclovir-resistant HSV/VZV
• ADRs: Nephrotoxicity (major), electrolyte imbalances (hypocalcemia, hypomagnesemia, hypophosphatemia), seizures, penile ulceration

Cidofovir

• Nucleotide analog (already phosphorylated once); active against CMV, HSV, adenovirus, poxvirus
• ADR: Severe nephrotoxicity (requires co-administration with probenecid + IV saline prehydration)

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2. Anti-Influenza Drugs

Neuraminidase Inhibitors (Preferred)

• Mechanism of neuraminidase inhibitors: Neuraminidase cleaves sialic acid residues, allowing newly formed virions to be released from the host cell surface. Inhibiting it traps virions on the cell surface, limiting spread.
• Active against: Influenza A and B

Adamantanes (Older, largely obsolete due to resistance)

• ADRs of Amantadine: Insomnia, nervousness, lightheadedness, anticholinergic effects; teratogenic
• Note: >90% of circulating Influenza A strains are now resistant to adamantanes; no longer recommended for routine influenza treatment

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3. Antiretroviral Drugs (HIV)

a) NRTIs - Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• Class ADRs: Lactic acidosis with hepatic steatosis (mitochondrial toxicity)

b) NNRTIs - Non-Nucleoside Reverse Transcriptase Inhibitors

• Class ADRs: Rash, hepatotoxicity; high genetic barrier to resistance with etravirine; low barrier with efavirenz/nevirapine (single mutation - K103N)

c) Protease Inhibitors (PIs)

• Class ADRs: Metabolic syndrome (hyperlipidemia, insulin resistance, lipodystrophy), GI intolerance, nephrolithiasis (atazanavir)
• Boosting: Ritonavir or cobicistat inhibit CYP3A4, increasing plasma levels of co-administered PIs

d) INSTIs - Integrase Strand Transfer Inhibitors (Preferred first-line)

e) Entry/Fusion Inhibitors

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4. Anti-Hepatitis Drugs

HBV (Hepatitis B)

• Interferon alfa-2b / Peginterferon alfa-2a: Immunomodulatory; 48-week course; 30-40% response; ADRs: flu-like syndrome, depression, cytopenias, thyroid dysfunction
• Tenofovir (TDF/TAF): Preferred; potent; low resistance
• Entecavir: Guanosine analog; highly potent; low resistance; avoid in lamivudine-resistant HBV
• Lamivudine: High resistance rates (70% at 5 years); now second-line
• Adefovir: Nephrotoxic at higher doses; used for lamivudine-resistant HBV
• Telbivudine: Moderate potency; peripheral neuropathy; higher resistance

HCV (Hepatitis C) - Direct Acting Antivirals (DAAs)

• Glecaprevir, Grazoprevir, Voxilaprevir - pangenotypic; potent; avoid in severe hepatic impairment

• Sofosbuvir - nucleotide analog; pangenotypic; backbone of most regimens; renal dose adjustment required; avoid with amiodarone

• Ledipasvir, Velpatasvir, Pibrentasvir, Elbasvir - reduce viral replication and assembly; NS5A resistance variants (RAVs) can limit efficacy

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5. Anti-RSV Drugs

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6. Drugs for COVID-19

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7. Miscellaneous Antivirals

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Quick Mnemonics (Tripathi Style)

• NRTIs remember: "AZT eats the LATTES" → Zidovudine, emtricitabine, lamivudine, abacavir, tenofovir, stavudine
• Neuraminidase inhibitors end in "-navir" group → Oseltamivir, Zanamivir, Peramivir
• Protease inhibitors end in "-navir" → Ritonavir, Atazanavir, Darunavir, Lopinavir
• INSTIs end in "-gravir" → Raltegravir, Dolutegravir, Bictegravir, Elvitegravir, Cabotegravir
• NS5B (HCV) drugs end in "-buvir" → Sofosbuvir
• NS3/4A (HCV) drugs end in "-previr" → Glecaprevir, Grazoprevir
• NS5A (HCV) drugs end in "-asvir" → Ledipasvir, Velpatasvir, Pibrentasvir

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