Antiviral Drugs
Pharmacology · Antimicrobials · lean revision notes
Antiviral Drugs
A high-yield, mechanism-driven survey of the antivirals that dominate NEET PG pharmacology: anti-herpes agents, antiretrovirals (HAART), anti-influenza neuraminidase inhibitors, and anti-hepatitis drugs. The exam loves prodrug-activation logic, class-specific toxicities, and combination rationale — so master the why, not just the names.
Viruses are obligate intracellular parasites that hijack host machinery, leaving few unique drug targets. Selective toxicity therefore hinges on virus-specific enzymes (thymidine kinase, reverse transcriptase, protease, integrase, neuraminidase, NS5A/NS5B polymerase). Most antivirals are virustatic — they suppress replication but do not eradicate latent virus, which is why HSV and HIV are lifelong infections.
Classification — the big picture
| Target organism | Major classes / drugs |
|---|---|
| Herpesviruses (HSV, VZV, CMV) | Acyclovir, valacyclovir, famciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir, letermovir |
| HIV (antiretrovirals) | NRTIs, NNRTIs, Protease inhibitors (PIs), Integrase strand-transfer inhibitors (INSTIs), Entry/fusion inhibitors, CCR5 antagonist |
| Influenza | Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir); endonuclease inhibitor (baloxavir); M2 blockers (amantadine — now obsolete) |
| Hepatitis B | Tenofovir, entecavir, lamivudine, telbivudine, adefovir; pegylated interferon-α |
| Hepatitis C | Direct-acting antivirals (DAAs): sofosbuvir (NS5B), ledipasvir/velpatasvir (NS5A), grazoprevir (NS3/4A protease) |
| RSV | Ribavirin; palivizumab (monoclonal); nirsevimab |
| Broad-spectrum / emerging | Remdesivir, molnupiravir, nirmatrelvir-ritonavir (Paxlovid) |
High-yield: Antivirals that need viral thymidine kinase for activation (acyclovir, ganciclovir, valacyclovir) lose efficacy when the virus develops TK-deficient mutants — the commonest mechanism of acyclovir resistance. Foscarnet and cidofovir do not require TK and are the fallback drugs.
Anti-herpesvirus agents
Acyclovir — the prototype prodrug
Acyclovir is a guanosine analogue that undergoes a beautiful three-step activation:
Acyclovir → (viral thymidine kinase) → acyclovir monophosphate → (host kinases) → di- and tri-phosphate → incorporated by viral DNA polymerase → chain termination (lacks 3′-OH) + competitive inhibition of DNA polymerase.
Selective toxicity is built into the chemistry: the first phosphorylation occurs ~3000× faster in infected cells because viral TK is far more efficient than host TK on this substrate. Uninfected cells barely activate the drug.
- Spectrum: HSV-1, HSV-2 (most active); VZV (needs higher doses). Weak against EBV; essentially inactive against CMV (CMV lacks classic TK).
- Uses: Genital/orolabial herpes, herpes encephalitis (IV acyclovir is the drug of choice), herpes zoster, varicella in immunocompromised, neonatal HSV.
- Pharmacokinetics: Oral bioavailability poor (~15-30%). Valacyclovir (L-valyl ester prodrug) gives 3-5× higher bioavailability. Renally excreted.
- Toxicity: Generally safe. Crystalline nephropathy (obstructive crystals in tubules — prevent with hydration and slow infusion) and neurotoxicity (tremor, delirium) with rapid IV dosing or renal impairment.
High-yield: Herpes simplex encephalitis → IV acyclovir, started empirically before confirmation. Do not wait for PCR — early treatment dramatically reduces mortality. Investigation of choice = CSF HSV PCR + MRI showing temporal lobe involvement.
Other anti-herpes drugs
| Drug | Activation | Key niche | Signature toxicity |
|---|---|---|---|
| Valacyclovir | Prodrug of acyclovir | Better oral bioavailability | TTP/HUS (high doses, immunocompromised) |
| Famciclovir | Prodrug of penciclovir | HSV/VZV, longer intracellular t½ | Well tolerated |
| Ganciclovir | Viral kinase (UL97) phosphorylates | CMV retinitis, CMV in transplant | Bone marrow suppression (neutropenia) |
| Valganciclovir | Oral prodrug of ganciclovir | CMV prophylaxis/treatment | Myelosuppression |
| Foscarnet | No phosphorylation needed — pyrophosphate analogue, directly inhibits DNA pol | Acyclovir/ganciclovir-resistant (TK-deficient) HSV/CMV | Nephrotoxicity, hypocalcaemia (chelates Ca²⁺), seizures |
| Cidofovir | Host kinases (TK-independent) | Resistant CMV | Severe nephrotoxicity (give with probenecid + saline) |
| Letermovir | Inhibits CMV terminase complex | CMV prophylaxis in HSCT | Well tolerated, no myelosuppression |
High-yield: Ganciclovir = myelosuppression; Foscarnet = nephrotoxicity + electrolyte derangements (low Ca, Mg, K, phosphate abnormalities); Cidofovir = dose-limiting nephrotoxicity. A classic single-best-answer trap.
Antiretroviral therapy (HAART)
HIV is a retrovirus; its replication cycle offers multiple drug targets. HAART = at least 3 active drugs from ≥2 classes to suppress viral load, restore CD4 counts, and prevent resistance.
The replication cycle and where drugs act
- Attachment/entry — gp120 binds CD4 + co-receptor (CCR5/CXCR4) → blocked by maraviroc (CCR5 antagonist) and enfuvirtide (fusion inhibitor, blocks gp41) and fostemsavir (attachment).
- Reverse transcription — RNA → DNA by reverse transcriptase → blocked by NRTIs and NNRTIs.
- Integration — viral DNA into host genome by integrase → blocked by INSTIs.
- Maturation — Gag-Pol polyprotein cleaved by HIV protease → blocked by PIs.
NRTIs (Nucleoside/nucleotide reverse transcriptase inhibitors)
Require intracellular phosphorylation to triphosphate form; act as chain terminators lacking 3′-OH and competitively inhibit RT.
- Examples: Zidovudine (AZT), lamivudine (3TC), emtricitabine (FTC), abacavir, tenofovir (TDF/TAF), stavudine, didanosine (older).
- Class toxicity = MITOCHONDRIAL TOXICITY. NRTIs inhibit DNA polymerase-γ → impaired mitochondrial DNA replication → lactic acidosis, hepatic steatosis, peripheral neuropathy, lipoatrophy, pancreatitis.
| NRTI | Distinctive adverse effect |
|---|---|
| Zidovudine (AZT) | Anaemia, megaloblastic marrow, neutropenia; myopathy |
| Abacavir | Hypersensitivity reaction — fatal on rechallenge; screen HLA-B*5701 |
| Tenofovir (TDF) | Nephrotoxicity, Fanconi syndrome, decreased bone density; TAF is gentler on kidney/bone |
| Stavudine (d4T) | Severe peripheral neuropathy, lipoatrophy (now avoided) |
| Didanosine | Pancreatitis, peripheral neuropathy |
| Lamivudine/Emtricitabine | Very well tolerated; also active against HBV |
High-yield: Before starting abacavir, test for HLA-B*5701 — positive patients must NOT receive it (risk of severe, potentially fatal hypersensitivity). Mnemonic: "AB-acavir → AB-stain if B*5701."
High-yield: NRTI-induced lactic acidosis with hepatic steatosis is the dreaded class effect from polymerase-γ inhibition. Stavudine and didanosine were the worst offenders.
NNRTIs
Bind a non-substrate allosteric pocket on RT (no phosphorylation needed). Active against HIV-1 only.
- Examples: Efavirenz, nevirapine, etravirine, rilpivirine, doravirine.
- Toxicities: Efavirenz → CNS effects (vivid dreams, dizziness, psychiatric symptoms; historically teratogenic concern — neural tube). Nevirapine → hepatotoxicity + severe rash/Stevens-Johnson. All can cause rash and are CYP450 substrates/inducers → drug interactions.
Protease inhibitors (PIs)
Inhibit HIV protease → immature, non-infectious virions. Names end in "-navir" (ritonavir, atazanavir, darunavir, lopinavir).
- Class effects: Metabolic syndrome — hyperlipidaemia, insulin resistance/hyperglycaemia, lipodystrophy (central fat accumulation, buffalo hump), GI intolerance.
- Ritonavir is a potent CYP3A4 inhibitor used as a pharmacokinetic booster ("boosted PI") to raise levels of co-administered PIs — the basis of Paxlovid (nirmatrelvir + ritonavir) for COVID-19.
- Atazanavir → indirect hyperbilirubinaemia (jaundice, harmless), nephrolithiasis. Indinavir → crystalluria/stones.
Integrase strand-transfer inhibitors (INSTIs)
Names end in "-tegravir" (dolutegravir, raltegravir, bictegravir, elvitegravir). Block integration of proviral DNA.
- Now first-line backbone of preferred regimens (e.g. dolutegravir + tenofovir + lamivudine, "TLD" — WHO/NACO preferred adult regimen in India).
- Well tolerated; can cause weight gain, insomnia; dolutegravir has small neural-tube defect signal (early data) and raises creatinine by blocking tubular secretion (not true nephrotoxicity).
Entry inhibitors
- Maraviroc — CCR5 antagonist; needs a tropism assay (only works on R5-tropic virus).
- Enfuvirtide — gp41 fusion inhibitor; subcutaneous, injection-site reactions.
High-yield first-line ART (India/NACO): TLD = Tenofovir + Lamivudine + Dolutegravir, single fixed-dose pill. INSTI-based regimens are globally preferred for potency, high genetic barrier to resistance, and tolerability.
IRIS — Immune Reconstitution Inflammatory Syndrome
After starting HAART, the recovering immune system mounts an exaggerated inflammatory response to pre-existing (often subclinical) opportunistic infections — paradoxical clinical worsening despite falling viral load and rising CD4.
- Commonest with TB, cryptococcal meningitis, MAC, CMV.
- Highest risk when ART started at very low CD4 and when started soon after an OI diagnosis.
- Management: continue ART, treat the underlying OI, add corticosteroids/NSAIDs for severe inflammation.
High-yield: IRIS = clinical deterioration because the immune system is recovering. Do not stop ART. Most classic with cryptococcal meningitis and TB.
Post-exposure & pre-exposure prophylaxis
- PEP (post-exposure): Start within 72 hours (ideally < 2 hours; sooner is better), continue 28 days. Preferred regimen = tenofovir + lamivudine/emtricitabine + dolutegravir (3-drug).
- PrEP (pre-exposure): Daily tenofovir + emtricitabine for high-risk HIV-negative individuals; long-acting injectable cabotegravir is newer.
- PMTCT: ART to all pregnant women (triple therapy) + infant prophylaxis (nevirapine/zidovudine).
High-yield: PEP window = within 72 hours of exposure; duration = 28 days. A perennial favourite. The earlier, the better — efficacy falls sharply after 72 h.
Anti-influenza drugs
Neuraminidase inhibitors
Influenza neuraminidase cleaves sialic acid, releasing budding virions from the infected cell surface. Inhibiting it traps new virions → halts spread.
- Oseltamivir — oral; drug of choice for influenza A and B (including H1N1).
- Zanamivir — inhaled (avoid in asthma/COPD — bronchospasm).
- Peramivir — IV (single dose).
- Must start within 48 hours of symptom onset for benefit; reduces illness duration by ~1 day and complications.
- Oseltamivir adverse effects: nausea/vomiting; rare neuropsychiatric events (especially reported in Japanese children).
Baloxavir marboxil
Inhibits the viral cap-dependent endonuclease (PA subunit of polymerase) — blocks mRNA synthesis. Single oral dose.
M2 inhibitors (amantadine, rimantadine)
Block the M2 ion channel (uncoating). Active only against influenza A; now obsolete due to near-universal resistance. Amantadine survives in neurology (Parkinson's, dopaminergic).
High-yield: Oseltamivir = oral neuraminidase inhibitor, start within 48 h. Zanamivir = inhaled, avoid in reactive airway disease. Amantadine is no longer recommended for influenza (resistance).
Anti-hepatitis agents
Hepatitis B
Goal: suppress HBV DNA, prevent cirrhosis/HCC (cure is rare — cccDNA persists).
- First-line oral: Tenofovir (TDF/TAF) and Entecavir — high potency, high genetic barrier to resistance.
- Lamivudine, telbivudine, adefovir — older, high resistance rates, now less preferred.
- Pegylated interferon-α — finite course, immunomodulatory; flu-like symptoms, depression, cytopenias, autoimmune flare.
High-yield: Patients with HIV-HBV co-infection benefit from tenofovir + lamivudine/emtricitabine, since these NRTIs are active against both viruses.
Hepatitis C — the DAA revolution
HCV is now curable (>95% SVR) with all-oral, interferon-free DAA regimens. Target three viral proteins:
| DAA class | Suffix | Examples |
|---|---|---|
| NS3/4A protease inhibitor | -previr | grazoprevir, glecaprevir, voxilaprevir |
| NS5A inhibitor | -asvir | ledipasvir, velpatasvir, pibrentasvir |
| NS5B polymerase inhibitor | -buvir | sofosbuvir (nucleotide) |
- Pan-genotypic regimens: sofosbuvir + velpatasvir; glecaprevir + pibrentasvir.
- Cure = sustained virologic response (SVR12) — undetectable HCV RNA 12 weeks after therapy.
- Ribavirin (guanosine analogue) — adjunct in some regimens; causes dose-dependent haemolytic anaemia and is teratogenic (Category X — avoid in pregnancy, contraception for both partners).
High-yield: DAA suffix mnemonic — "-previr (protease/NS3), -asvir (NS5A), -buvir (NS5B polymerase)." Sofosbuvir-based regimens give >95% cure.
Broad-spectrum & COVID-era antivirals
- Remdesivir — adenosine analogue, inhibits RdRp; IV; used in COVID-19 and Ebola trials.
- Molnupiravir — induces lethal mutagenesis (error catastrophe) in viral RNA.
- Nirmatrelvir-ritonavir (Paxlovid) — Mpro (3CL protease) inhibitor boosted by ritonavir; many CYP3A4 drug interactions.
Complications & monitoring pearls
- NRTIs → lactic acidosis (check lactate, anion gap), hepatic steatosis, peripheral neuropathy.
- Zidovudine → monitor CBC for anaemia/neutropenia.
- Tenofovir (TDF) → monitor renal function, phosphate, bone density.
- Ganciclovir → CBC (neutropenia).
- Foscarnet → serum calcium, magnesium, renal function; ECG (hypocalcaemia).
- Acyclovir IV → hydrate to prevent crystal nephropathy.
- Protease inhibitors → lipid profile, glucose.
- Ribavirin → haemoglobin (haemolysis); pregnancy test.
Key differentials & quick discriminators
- Acyclovir vs Ganciclovir: Both need viral kinase; acyclovir for HSV/VZV (safe), ganciclovir for CMV (myelosuppressive).
- Foscarnet vs Cidofovir: Both TK-independent for resistant herpesviruses; foscarnet → hypocalcaemia/nephrotoxicity, cidofovir → severe nephrotoxicity (give probenecid).
- NRTI vs NNRTI: NRTI = phosphorylation-dependent chain terminator (mitochondrial toxicity); NNRTI = allosteric, no phosphorylation, CYP interactions + rash/hepatotoxicity.
- Oseltamivir vs Amantadine: Neuraminidase inhibitor (A+B, current) vs M2 blocker (A only, obsolete).
Recently asked / exam angle
- Acyclovir activation — "Which viral enzyme phosphorylates acyclovir first?" → viral thymidine kinase (commonest resistance = TK deficiency).
- HSV encephalitis DOC → IV acyclovir, started empirically.
- Abacavir + HLA-B*5701 — pharmacogenomic screening before initiation.
- NRTI mitochondrial toxicity / lactic acidosis via DNA polymerase-γ inhibition.
- First-line ART (NACO) = TLD (Tenofovir + Lamivudine + Dolutegravir).
- PEP timing — within 72 hours, duration 28 days.
- IRIS — paradoxical worsening after starting HAART; continue ART.
- Ganciclovir → neutropenia; Foscarnet → hypocalcaemia/nephrotoxicity matching questions.
- Oseltamivir mechanism (neuraminidase) and 48-hour window.
- HCV DAA suffixes (-previr/-asvir/-buvir) and SVR concept.
- Ritonavir as a booster (CYP3A4 inhibition) — basis of boosted PIs and Paxlovid.
- Ribavirin — haemolytic anaemia + teratogenicity.
Rapid revision
- Acyclovir is activated by viral thymidine kinase → chain terminator; resistance = TK-deficient mutants.
- IV acyclovir is the drug of choice for herpes simplex encephalitis — start empirically.
- Ganciclovir treats CMV and causes myelosuppression; valganciclovir is its oral prodrug.
- Foscarnet = pyrophosphate analogue, no TK needed, causes hypocalcaemia + nephrotoxicity; cidofovir = severe nephrotoxicity (use probenecid).
- NRTI class toxicity = mitochondrial (lactic acidosis, steatosis, neuropathy) via DNA polymerase-γ inhibition.
- Zidovudine → anaemia/neutropenia; Abacavir → HLA-B*5701 hypersensitivity; Tenofovir → renal + bone.
- Efavirenz → CNS/psychiatric; Nevirapine → hepatotoxicity + SJS; PIs (-navir) → lipodystrophy + dyslipidaemia.
- Ritonavir boosts other PIs via CYP3A4 inhibition; basis of Paxlovid.
- INSTIs (-tegravir) are first-line; India's preferred regimen = TLD.
- PEP: start within 72 h, continue 28 days; PrEP = tenofovir + emtricitabine.
- IRIS = worsening because of immune recovery — don't stop ART; classic with TB/cryptococcus.
- Oseltamivir (oral neuraminidase inhibitor) within 48 h; HCV curable with sofosbuvir-based DAAs (>95% SVR); ribavirin → haemolysis + teratogenic.