STEPTRACKERMICROBIOLOGY + PHARMACOLOGY | ANTIVIRALS | HIGH-YIELD REVIEW

Antiviral Drugs

Each antiviral blocks one viral step — guanosine analogs for herpesviruses, neuraminidase inhibitors for influenza, nucleos(t)ides for HBV, and direct-acting antivirals that cure HCV.

FOCUS ON
Acyclovir/valacyclovir/famciclovir: guanosine analogs activated by viral thymidine kinase → chain termination; HSV, VZV; crystal nephropathy (hydrate); resistance = TK mutation → foscarnet. Ganciclovir/valganciclovir: activated by CMV UL97 kinase → CMV; myelosuppression. Foscarnet: pyrophosphate analog, no activation needed → nephrotoxicity, hypocalcemia/hypomagnesemia (seizures). Cidofovir: nucleotide, no activation → nephrotoxicity (+ probenecid). Influenza: oseltamivir/zanamivir (neuraminidase), baloxavir (cap-dependent endonuclease). HBV: tenofovir, entecavir. HCV: NS5B polymerase (sofosbuvir), NS5A (ledipasvir, velpatasvir), NS3/4A protease (glecaprevir). RSV/COVID: nirmatrelvir-ritonavir, remdesivir, ribavirin (teratogen, hemolysis).
DRUG
MECHANISM
USES
TOXICITY · NOTES
Acyclovir · valacyclovir · famciclovir
Guanosine analog phosphorylated by viral thymidine kinase → host kinases → inhibits viral DNA polymerase, chain termination
HSV (genital, labial, encephalitis, neonatal), VZV (chickenpox, zoster)
Crystalline nephropathy (IV; hydrate), neurotoxicity · no effect on latent virus
Ganciclovir · valganciclovir
Guanosine analog activated by CMV UL97 kinase
CMV retinitis, colitis, transplant prophylaxis
Neutropenia, thrombocytopenia, anemia (more than acyclovir)
Foscarnet
Pyrophosphate analog binds viral DNA polymerase directly (no kinase)
Acyclovir-resistant HSV, ganciclovir-resistant CMV
Nephrotoxicity, hypocalcemia, hypomagnesemia, hypokalemia → seizures
Cidofovir
Nucleotide analog; needs no viral kinase
Resistant CMV, adenovirus, BK, poxvirus
Nephrotoxicity — give probenecid and saline
Letermovir · maribavir
CMV terminase complex · UL97 inhibitor
CMV prophylaxis in transplant · refractory CMV
Less marrow toxicity
Oseltamivir · zanamivir · peramivir
Neuraminidase inhibitors → virions can't leave cell
Influenza A and B treatment (within 48 h) and prophylaxis
Zanamivir inhaled → bronchospasm in asthma
Baloxavir
Inhibits cap-dependent endonuclease (cap-snatching)
Influenza, single dose
—
Amantadine · rimantadine
Block M2 ion channel (uncoating)
No longer used for influenza (resistance)
Amantadine in Parkinson disease
Tenofovir · entecavir
Inhibit HBV reverse transcriptase
Chronic HBV
Tenofovir: kidney (TDF), bone · stopping can cause HBV flare
HCV direct-acting antivirals
NS5B polymerase (sofosbuvir, "-buvir"), NS5A (ledipasvir, velpatasvir, "-asvir"), NS3/4A protease (glecaprevir, "-previr")
8–12 weeks, > 95% cure; all genotypes with pan-genotypic combos
Screen for HBV first (reactivation) · amiodarone + sofosbuvir → bradycardia
Ribavirin
Guanosine analog; ↓ GTP synthesis (IMP dehydrogenase), lethal mutagenesis
RSV (rarely), Lassa, some HCV regimens
Hemolytic anemia, severe teratogen (both partners)
COVID-19 antivirals
Nirmatrelvir (3CL protease) + ritonavir (CYP3A4 booster) · remdesivir (RNA polymerase) · molnupiravir (mutagenesis)
High-risk outpatients · inpatients
Ritonavir drug interactions
Interferon-α
↑ antiviral proteins, MHC I
Historic HBV/HCV; hairy cell leukemia, melanoma
Flu-like symptoms, depression, cytopenias

Mechanism — why acyclovir spares host cells

Acyclovir enters cells
→
Viral TK adds first phosphateOnly in infected cells
→
Host kinases → triphosphate
→
Viral DNA polymerase blocked, chain ends

TK-deficient mutants escape → foscarnet or cidofovir, which need no viral kinase.

Herpes drugs compared

DRUG
ACTIVATION
TARGET VIRUS
TOXICITY
Acyclovir
Viral TK
HSV, VZV
Crystal nephropathy
Ganciclovir
CMV UL97
CMV
Marrow suppression
Foscarnet
None
Resistant HSV, CMV
Kidney, ↓ Ca²⁺, ↓ Mg²⁺
Cidofovir
None
CMV, adeno, BK
Kidney

How it's tested

COMMON CONFUSIONAcyclovir doesn't treat CMV well (CMV lacks the TK); ganciclovir does (UL97) but is far more myelosuppressive.
THE TRAPSeizures in a patient on foscarnet are usually from low ionized calcium and magnesium — check electrolytes.
YOUR APPROACHVirus → step to block → drug → activation requirement (resistance) → toxicity (kidney, marrow, electrolytes, teratogen).

If you see… think…

AKI with crystals during IV treatment for HSV encephalitis → acyclovir
Acyclovir-resistant HSV → thymidine kinase mutation → foscarnet
Neutropenia on CMV retinitis treatment → ganciclovir
Seizure with hypocalcemia on CMV therapy → foscarnet
Antiviral given with probenecid → cidofovir
Influenza drug preventing virion release → oseltamivir
Bronchospasm on inhaled flu drug in an asthmatic → zanamivir
Drug ending in -buvir → HCV NS5B polymerase inhibitor
HBV reactivation during HCV treatment → screen and monitor HBV
Hemolytic anemia, teratogenic antiviral → ribavirin