Drug Category / Drug
Action Mechanism
Resistance Mechanism
Pharmacokinetics
Adverse Reactions
Clinical uses
1) Anti-Influenza Agents:





M2 Proton Channel Antagonist





Amantadine
1o: Prevents viral uncoating by plugging endosome M2 pore preventing H+ influx & RNP release of viral RNA.
Rare: M2 transmembrane domain mutns. Cross-susceptible w Rimantadine.
po. t1/2= 12-18hrs. Renally excreted unmetabolized.
Well tolerated. Minor GI problems (apetite loss). CNS (light headed, insomnia, nervous).
Prevention & Rx: Influenza A. Rx ↓flu symptoms by 1-2 days.

2o: inhibits hemagglutinin (which tethers virion to plasma membrane), inhibiting virion release.


Greater ability to cross BBB (blood brain barrier).
Rx Parkinson's Disease.
Rimantadine
(same as above, but more potent)
(same as above)
po. t1/2= 24-36hrs. Highly metabolized.
Well tolerated. Minor GI problems (apetite loss). CNS (light headed, insomnia, nervous).
Prevention & Rx: Influenza A. Rx ↓flu symptoms by 1-2 days.
Neuraminidase Inhibitors





Zanamivir
Binds neuraminidase, inhibiting cleavage of host cell sialic acid, & thus viral egress.
Rare: Hemagluttinin (cross-susceptible) or neuraminidase (agent-specific) mutns promoting virion release.
dry inhaled powder. t1/2= 2.5-5hrs. Renally excreted unmetabolized.
Well tolerated. Wheezing/ bronchospasm in COPD/asthma pts.
Rx Influenze A & B.
Oseltamivir
(same as above)
(same as above)
po. t1/2= 2.5-5hrs. (or 6-10?) Prodrug(→active). Renally excreted unmetabolized.
Nausea, vomiting, moderate GI complaints. Tend to resolve if taken w meals.
Rx Influenze A & B.






5) Miscellaneous Antiviral Agents:





For RSV:





Ribavirin
(see below)




Palivizumab
Humanized monoclonal antibody against RSV, inhibiting viral fusion with host cell membranes.

t1/2= 20days.

Prophylaxis for respiratory infections in children.
For Genital Warts:





Imiquimod
TLR-7/8 activ'n→cytokine (IFN α/β/γ, TNF-α, IL-6) synthesis/release→ ↑ innate immune activity.

Topical.
Local rashes, ulcerations, itching, burning, flaking.
~50% of pts clear genital warts w/in 8-10 wks. Relapse common. Better response in women than men. Rx HPVs.






2) Anti-Herpes Agents (simplex/ varicella/ zoster):





Viral DNA Polymerase Inhibitors:





Acyclovir
Cellular PO4'n of drug to TP via viral thymidine kinase (NOTE: selectivity). Incorp'n into viral DNA primer causing replic'n term'n & viral DNA pol suicide inactiv'n.
1:↓viral thymidine kinase expression (most common). 2: ↓thymidine kinase specificity for drug as substrate. 3: Altered viral DNA pol activity. Esp in immunosuppressed pts.
IV, topical. t1/2= 2.5hrs. Renally excreted unmetabolized.
Well tolerated. Nausea, diarrhea, rash, headaches. Limit dosage in co-administration of cyclosporin or zidovudine→renal insuff'y.
Rx recurrent/initial genital herpes virus (HSV) in nml & immunocompromised pts. EBV(mono) & VZV(chickpox).
Valacyclovir
(same as above) L-valyl ester prodrug: once activ'd by GI/hepatic esterases, same as Acyclovir.
(same as above)
po. t1/2= 2.5hrs. Renally excreted unmetabolized.
(same as above) High doses linked to CNS deficiencies (confusion, hallucinations).
(same as above) ↑bioavail'y means↑efficacy against EBV, VZV, & CMV, esp in HIV pts.
Penciclovir
Same as acyclovir, but 3' OH grp inhibits DNA primer termin'n, only DNA pol inhibition.
Same as & predicted by acyclovir. (Mutns in viral thymidine kinase &/or DNA pol.)
not po. t1/2= 2hrs (plasma) & 7-20hrs (in cells). Renally excreted unmetabolized.
(same as acyclovir)
Rx HSV & VZV.
Famciclovir
(Same as above) Prodrug: once activ'd by liver enzymes, becomes penciclovir.
(same as above)
po. (Otherwise, same as above)
Headaches, diarrhea, nausea, rash, confusion.
(Same as above) May also treat HBV.
Vidarabine
Cellular PO4'n of drug → viral DNA pol & DNA replication inhibition.
1: DNA pol mutns. 2: Drug deamin'n to hypoxanthine ↓s potency x10.
Topical. t1/2= unk.
Teratogen (not for use during pregnancy). Formerly w IV use: tremors, nausea, vomiting, leukopenia/ thrombocytopenia.
Rx HSV keratitis. (Opthalmic ointment.)






Docosanol
Inhibits fusion bw viral lipid envelope & host membrane. Prevents entry.
None?
Topical, OTC (over the counter)
None?
Rx orolabial herpes. Efficacy depends on appl'n w/in 12hrs of prodromal (early) symptom onset.






3) Cytomegalovirus (CMV):





Viral DNA Polymerase Inhibitors:





Ganciclovir
(Same as Acyclovir for HSV, but for CMV, viral protein kinase UL97 PO4's to TP.) Also, not a viral DNA chain terminator, but incorp'n slows & ceases elongation.
1: UL97 mutns (most common). 2: viral DNA pol mutns. Cross susceptible to Cidofovir/Foscarnet resistance in CMV & to Acyclovir in HSV.
IV. t1/2= 2-4hrs. Renally excreted unmetabolized.
Myelosuppression. Neutro & thrombocyto-penia. GI disturbances & nausea. Teratogen.
Rx CMV retinitis chronic suppression in immuno-compromised/tx pts. Opthalmic gel: HSV keratitis. Orally: HBV.
Valganciclovir
(same as above) L-valyl ester prodrug: once activ'd by GI/hepatic esterases, same as Ganciclovir.
(same as above)
po. t1/2= 2-4hrs. Renally excreted unmetabolized.
Myelosuppression. Neutro & thrombocyto-penia. GI: nausea,etc. CNS: headache, confusion, convulsion, coma.
(same as above)
Cidofovir
Cytosine nucleotide uptake & PO4'n to DP by cellular protein kinases. (NOTE: less selective.) Like acyclovir, competes w cell dCTP for viral DNA pol activity. Also, not a viral DNA chain terminator, but incorp'n slows & ceases elongation.
Viral DNA pol mutns. Cross susceptible to Ganciclovir resistance.
IV. t1/2= 2.5hrs (plasma, but longer inside cell). Renally excreted unmetabolized.
Nephrotoxicity: Manage w probenecid (reducing CL) & saline prehydration.
Rx 1: CMV retinitis in HIV pts. 2: acyclovir-resistant HSV. 3: ganciclovir-resistant (UL97 mutns) CMV.
Foscarnet
Unique structure, not requiring cellular activ'n. Noncompetitive binding to pyrophosphate DNA/RNA pol site, blocking viral replication.
DNA pol mutns.
IV. t1/2= 4-8hrs (initially), then 3-4 days. Renally excreted unmetabolized.
Nephrotoxicity & hypocalcemia, potentially fatal. CNS: headache, tremor, seizures, hallucinations. Rash, fever, nausea.
Rx 1: CMV retinitis in immuno-compromised pts. 2: acyclovir-resistant HSV/VZV. 3: ganciclovir-resistant CMV.






4) Anti-Hepatitis B/C Agents:





Adefovir
Phosphonate nucleotide. Prodrug. Cellular protein kinases PO4 to DP, competing w dATP for DNA pol activity. Also antagonizes reverse transcriptases.
Rare: mutns in HBV DNA pol.
po/IV. t1/2= 5-7.5hrs. Renally excreted unmetabolized.
Nephrotoxicity. Lower doses: headache, GI abnormalities.
Rx HBV
Entacavir
Cellular protein kinases PO4 to TP, competing w dGTP for viral DNA pol activity. Inhibits DNA pol priming, reverse transcrip'n, & DNA replic'n.
No resistance to date.
po. t1/2= 24hrs. Renally excreted unmetabolized.
Same as Lamuvidine: headache, cough, fatigue, minor GI.
RX HBV (most potent & effective).
Ribavirin
Cellular protein kinases PO4 to TP, inhibiting 5' viral mRNA capping, ↓stability. MP↓dGTP production. May↑viral mutagenesis →viral suicide.
No resistance to date.
po/IV/aerosol. t1/2= 43hrs, @Cpss t1/2=40days (in RBCs). Food↑s po bioavail'y. Hepatic metabolism. Renal excretion.
Anemia. Bone marrow suppression. Aerosol: lung irritation. Teratogenic.
HCV: w Interferon-α-2a/α-2b. Aerosol: Rx RSV, pneumonia. Severe viral flu infections. Many viral infections in immunocompromised pts.
Interferon-α [α-2a, α-2b, α-n3, αcon-1 , peginterferon α-2a, peginterferon α-2b]
Recombinant INF-α binds cell surface receptors, activates JAK/STAT signaling→antiviral gene expression: 1) blocks transcrip/transl'n(via PKR protein kinase eIF-2α PO4'n/inactiv'n AND via 2’5’-oligoadenylate synthetase expression cleaving viral mRNA.) 2) Protein processing/ maturation inhibition: ↓trans-golgi glycosylation rxns, ↓viral assembly. 3) signaling also regulates host adaptive and innate immune responses.
No resistance to date.
IM/SC. t1/2=4-8hrs. Elimin: cellular uptake, hepatic & renal. Polyethylene glycol slows absorption & ↓excretion.
Flu-like symptoms, resolving after 12 hrs. Myelosuppression, granulo/thrombo-cytopenia→mjr dose limit'ns. CNS: depression, drowsiness, confusion.
HBV. HCV (w Ribavirin). Some efficacy against: HPV, genital HSV, localized VZV, CMV in tx pts.