Antivirals+Chart


 * ~ 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. ||
 * 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. ||