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Flashcards in Antiviral Agents Deck (17):
1

What drugs might one use to combat influenza?

Amantadine, Rimantadine, Oseltamivir, Zanamivir

2

Amantadine:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

-Blocks virally encoded H+ ion channel (M2 protein) preventing changes in intracellular pH necessary for uncoating. This prevents the subsequent release of the virion ribonucleoprotein and RNA genome for replication in the cytosol.
-Effective orally with accumulation in lungs. Excreted unchanged in urine (90%) requiring dosage adjustment if impaired renal function.
-Not recommended if breast feeding → urinary retention, vomiting, skin rash in the infant.Insomnia, concentration difficulty, lightheadedness / dizziness, headache. Teratogenic.
-For prophylaxis and treatment of influenza A infections (B lacks M2 protein target). Can be given for 2-3 weeks in along with flu vaccine in high risk populations. If given 1-2 days prior to and 6-7 days during infection - incidence and severity of symptoms reduced. If given 48 hours after, only slight therapeutic effect seen.In 2009, most seasonal A H3N2 and A H1N1 isolates were resistant limiting current use.

3

Rimantadine:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Blocks virally encoded H+ ion channel (M2 protein) preventing changes in intracellular pH necessary for uncoating. This prevents the subsequent release of the virion ribonucleoprotein and RNA genome for replication in the cytosol.Effective orally with accumulation in lungs. Hepatic elimination for rimantidine (t1/2 ∼ 12 hrs, 1-2 daily doses. Not recommended if breast feeding → urinary retention, vomiting, skin rash in the infant.Better tolerated than Amantadine due to poor CNS penetration (more highly protein bound). TeratogenicFor prophylaxis and treatment of influenza A infections (B lacks M2 protein target). Can be given for 2-3 weeks in along with flu vaccine in high risk populations. If given 1-2 days prior to and 6-7 days during infection - incidence and severity of symptoms reduced. If given 48 hours after, only slight therapeutic effect seen.In 2009, most seasonal A H3N2 and A H1N1 isolates were resistant limiting current use.

4

Oseltamivir (Tamiflu):Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Inhibition of the enzyme neuraminidase (NA) that cleaves N-acetyl neuraminic acid (sialic acid) from host cell receptors for the influenza virus (A and B). Egress of new virions are stuck to the plasma membrane. Such aggregation decreases both intracellular viral translocation and viral budding = ↓ viral infectivity. Also ↓ viral penetration through mucin secretions = ↓ the infection of other respiratory epithelial cells.Administered po as prodrug. Eliminated via renal tubular secretion with plasma. t1/2 = 6-10 hours (given twice daily)Minor, occasional nausea and vomiting (reduced by taking with food).Started within 48 hours of symptom onset can decrease the severity and duration by 1-2 days. Influenza A or B, adults and children.Effective (80-90%) as prophylactic measure in contacts; indicated to control influenza institutional outbreaks and protect high-risk individuals until vaccination effective.

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Zanamivir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Inhibition of the enzyme neuraminidase (NA) that cleaves N-acetyl neuraminic acid (sialic acid) from host cell receptors for the influenza virus (A and B). Egress of new virions are stuck to the plasma membrane. Such aggregation decreases both intracellular viral translocation and viral budding = ↓ viral infectivity. Also ↓ viral penetration through mucin secretions = ↓ the infection of other respiratory epithelial cells.Poor oral bioavailability, administered via inhalation. Renal elimination.Bronchospasm reported uncommonly in patients with asthma or COPD.Started within 48 hours of symptom onset can decrease the severity and duration by 1-2 days. Influenza A or B, adults and children.Effective (80-90%) as prophylactic measure in contacts; indicated to control influenza institutional outbreaks and protect high-risk individuals until vaccination effective.

6

What drugs might one use to combat herpes?

Acyclovir, Valacyclovir, Penciclovir, Famciclovir, Docosanol

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Acylovir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Cellular uptake and initial phosphorylation is mediated by viral thymidine kinase (mechanism of selectivity - 200x difference in affinity). Cellular protein kinases convert acyclovir-MP to its TP form. Acyclovir-TP competes with cellular dGTP for viral DNA polymerase, which incorporates the nucleotide analog into replicating viral DNA strands. Incorporation of A-TP terminates further DNA replication and strand elongation. A-TP DNA irreversibly binds and inactivates viral DNA polymerase (suicide).Oral absorption poor (15-30%); not affected by food. Also available in topical and intravenous formulations. Renally excreted. Neonatal (< 1 yr) clearance only 1/3 of adultsMinor toxicities include headache, nausea, vomiting, reversible renal dysfunction (rare with adequate hydration). IV acyclovir associated with encephalopathy including tremors, hallucinations, seizures, and coma. Category B for pregnancy.HSV: ORAL acyclovir shortens symptom duration of primary and recurrent genital herpes and reduces mean duration of pain (not time to healing) in recurrent herpes labialis. Topical therapy much less effective. Also effective in secondary prevention (lower daily dose. IV Treatment of choice for herpes simplex encephalitis, neonatal HSV infections, and serious HSV or VZV infections, especially in immunocompromised patients.VSV: ORAL acyclovir decreases number of lesions and duration of varicella (chicken pox) and zoster (shingles) but higher doses are required. Suppression with oral acyclovir reduces VZV reactivation in immunocompromised patients.

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Valacylovir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Cellular uptake and initial phosphorylation is mediated by viral thymidine kinase (mechanism of selectivity - 200x difference in affinity). Cellular protein kinases convert Valacyclovir-MP to its TP form. Valacyclovir-TP competes with cellular dGTP for viral DNA polymerase, which incorporates the nucleotide analog into replicating viral DNA strands. Incorporation of V-TP terminates further DNA replication and strand elongation. V-TP DNA irreversibly binds and inactivates viral DNA polymerase (suicide).Valyl ester prodrug of acyclovir; given orally achieves plasma levels 3-5 times higher than acyclovir (equivalent to IV administration)Generally well tolerated, Pregnancy Cat B.Herpes (orolabial or genital)

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Penciclovir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Cellular uptake and initial phosphorylation is mediated by viral thymidine kinase (mechanism of selectivity - 200x difference in affinity). Cellular protein kinases convert Peniciclovir-MP to its TP form. Peniciclovir-TP competes with cellular dGTP for viral DNA polymerase, which incorporates the nucleotide analog into replicating viral DNA strands. Incorporation of P-TP terminates further DNA replication and strand elongation. P-TP DNA irreversibly binds and inactivates viral DNA polymerase (suicide).topical, renalGenerally well tolerated, may burn at site of administration, Pregnancy Cat B.Herpes orolabial

10

Famciclovir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Cellular uptake and initial phosphorylation is mediated by viral thymidine kinase (mechanism of selectivity - 200x difference in affinity). Cellular protein kinases convert Famciclovir-MP to its TP form. Famciclovir-TP competes with cellular dGTP for viral DNA polymerase, which incorporates the nucleotide analog into replicating viral DNA strands. Incorporation of F-TP terminates further DNA replication and strand elongation. F-TP DNA irreversibly binds and inactivates viral DNA polymerase (suicide).Oral (F = 70%), renalGenerally well tolerated, Pregnancy Cat B.Herpes

11

Docosanol:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Long chain saturated alcohol that inhibits replication of many lipid-enveloped viruses (including HSV). Acts via prevention of fusion between cellular and viral envelop membranes that blocks viral entry into cell.Topical cream.Appears to be well tolerated.Topical treatment (5X daily to lips or face) begun within 12 hours of prodromal symptoms or lesion onset reduces healing time about one day (4.8 days to 4.1 days, similar to penciclovir). Administration at papular or later stages fails to elicit therapeutic responses.

12

What drugs might one use to combat Cytomegalovirus (CMV)?

Ganciclovir, Valganciclovir, Cidofovir, Foscarnet

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Ganciclovir / Valganciclovir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Cellular uptake and initial phosphorylation is mediated by the viral protein kinase UL97 in CMV (or by viral thymidine kinase in HSV). This is the primary mechanism of viral vs. host selectivity. Cellular protein kinases then convert ganciclovir-MP to its TP form, which is 10-fold higher than in non-CMV infected cells. Ganciclovir-TP competes with cellular dGTP for viral DNA polymerase, which then incorporates the nucleotide analog into replicating viral DNA strands. G-TP incorporation into replicating DNA slows and ceases further viral DNA chain elongation.Ganciclovir has poor oral bioavailability, but exhibits good distribution in bodily fluids; usually administered intravenously. Valganciclovir prodrug is rapidly deesterified and converted to ganciclovir by GI and hepatic esterases. Ganciclovir is primarily excreted unchanged via the urine (clearance related to renal function) with a t1/2 of 4 hours (intracellular half-life of 16-24 hours).Myelosuppression with neutropenia and thrombocytopenia is the major side effect and concern (20-40%). Can be reversed by drug cessation. GI disturbances and nausea. Rarely, CNS toxicity (headache, mental status changes, seizures) and abnormal liver function. Category C (risk cannot be ruled out) for use in pregnancy.Effective for treatment and chronic suppression of CMV retinitis in immuno-compromised patients. Also effective in controlling CMV in transplant patients. Ophthalmic gel is effective in treating HSV keratitis. Some activity against HBV when administered orally.

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Cidofovir:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Cellular uptake and phosphorylation of cidofovir is mediated by cellular protein kinases, not viral protein kinases. Thus, cidofovir concentrations are equivalent between normal and viral-infected cells. Cidofovir-DP competes with cellular dCTP for viral DNA polymerase activity and incorporation into replicating DNA slows and ceases further viral DNA chain elongation.Cidofovir has poor oral bioavailability due to the phosphate group already present on prodrug, thus, cidofovir is primarily administered via IV infusion. Cidofovir primarily eliminated via excretion of unchanged drug by the kidney with a plasma t1/2 of 2.5 hours; however, phosphorylated cidofovir has a long intracellular half- life (17-65 hours).Primary side effect is nephrotoxicity. Nephrotoxicity can be partially offset by administration of probenecid, which blocks renal anion transporter activity and reduces renal clearance of cidofovir, and saline prehydration. Category C (risk cannot be ruled out) for use in pregnancy.Primarily used for managing CMV retinitis in HIV-infected individuals. Treatment of acyclovir-resistant HSV and ganciclovir-resistant (UL97 mutants) CMV.;

15

Foscarnet:Mechanism of Action,Pharmacokinetic Properties,Adverse Drug Reactions,Role in Pharmacotherapy

Foscarnet does not require cellular activation. Nononcompetitively binds to the pyrophosphate binding site of RNA and DNA polymerases. Appears to inhibit cleavage of pyrophosphate from deoxy-TPs resulting in a block of viral replication. Resistance. Resistant strains exhibit alterations in DNA polymerase. Combined use of ganciclovir and foscarnet can benefit some CMV patients, but strains resistant to both agents have been reported.Oral bioavailability is poor; primarily administered via IV infusion. Primarily eliminated unchanged in the urine. Plasma half-life is bimodal and complex – initial t1/2 is 4-8 hours, while the terminal t1/2 is 3-4 days.Major side effect is nephrotoxicity and hypocalcemia, can be quite severe or even fatal. CNS abnormalities also have been reported and include headache, tremor, seizures, and even hallucinations. Other reported side effects include rash, fever, and nausea.Effective against CMV retinitis, particularly in immunocompromised patients. Also effective against ganciclovir-resistant CMV infections and acyclovir resistant HSV and VZV infections.

16

How do antivirals attain selective toxicity? (2)

2 ways to get selective toxicity: have a degree of selectivity b/w viral DNA polymerase and human DNA polymerase. The other way is that only cells infected with the virus will express viral thymadine kinase in order to activate the drugs.

17

What can you tell me about intracellular half life versus plasma half life for some of the antiviral drugs?

Nucleoside analogues that are phosphorylated intracellularly often have a longer half life in the cell versus in the plasma.