DR. KAYS ANTIVIRALS

Question 1

Acyclovir (Zovirax)

Answer 1

1. conversion to active form - acyclovir triphosphate
2. viral thymidine kinase in HSV and VZV converts acyclovir to acyclovir monophosphate. Human cellular kinases convert acyclovir monophosphate to acyclovir diphosphate and then acyclovir triphosphate (active form)
3. MOA: inhibition of viral DNA replication. Acyclovir-TP competitively inhibits viral DNA polymerase -> inhibition of viral replication. Acyclovir-TP is incorporated into viral DNA -> premature chain termination.
4. MOR: absence (TK-deficient) or partial or altered production of viral thymidine kinase. Altered viral DNA polymerase.
5. SOA: HSV-1, HSV-2, VZV
6. adjust for renal dysfunction
7. removed by HD but not PD
8. ADRs: N/V/D, rash, HA, nephrotoxicity (crystalline nephrotoxicity), neurotoxicity, thrombophlebitis, TTP/HUS

Question 2

Valacyclovir (Valtrex)

Answer 2

1. L-valyl ester prodrug of acyclovir with same MOA as acyclovir
2. SOA: same as acyclovir
3. 3-5 times higher bioavailability than acyclovir
4. removed by HD
5. adjust for renal dysfunction

Question 3

Famciclovir (Famvir)

Answer 3

1. diacetyl ester prodrug of penciclovir (nucleoside analog similar to acyclovir). Oral famciclovir undergoes rapid and extensive conversion to penciclovir.
2. MOA: penciclovir is phosphorylated by viral thymidine kinase to penciclovir monophosphate and eventually to penciclovir triphosphate by cellular enzymes -> inhibiting viral replication
3. Penciclovir triphosphate is less potent than acyclovir triphosphate in inhibiting viral DNA polymerase
4. SOA: HSV-1, HSV-2, and VZV
5. dose reduction is recommended in renal dysfunction.
6. no effect of mild to moderate hepatic impairment on penciclovir AUC - no dosage adjustment needed
7. ADRs: HA, N/V/D, acute renal failure in patients with underlying renal disease receiving higher than recommended dosing for renal insufficiency
8. probenecid decreases renal clearance, increases serum concentrations

Question 4

Ganciclovir (Cytovene)

Answer 4

1. SOA: HSV-1, HSV-2, VZV, CMV*, EBV
2. MOA: in cells infected with HSV or VZV, monophosphorylation by viral thymidine kinase -> diphosphorylation -> triphosphorylation (active form). In CMV-infected cells, ganciclovir is monophosphorylated by CMV-encoded protein kinase (UL97 gene), then to the di and triphosphate forms by cellular kinases. GCV triphosphate inhibits viral DNA polymerase and/or incorporation into viral DNA -> inhibits viral replication.
3. MOR: UL97 gene mutation which leads to viral kinase deficiency or altered viral DNA polymerase.
4. penetrates CSF
5. half-life increases as renal function decreases - adjust for renal dysfunction
6. removed by HD
7. ADRs: bone marrow suppression, phlebitis, headache, confusion, rash, fever, N/V, psychosis

Question 5

Labs for ganciclovir

Answer 5

monitor CBC/differential - stop if ANC <500/mm3 or platelet <25,000 mm3

Question 6

Valganciclovir (Valcyte)

Answer 6

1. L-valyl ester of ganciclovir - rapidly converted to ganciclovir by intestinal and hepatic esterases
2. MOA: same as ganciclovir
3. SOA: same as ganciclovir
4. adjust for renal dysfunction
5. HD decreases ganciclovir concentrations by 50% following valganciclovir
6. ADRs: hematologic toxicity - severe neutropenia, thrombocytopenia, anemia, pancytopenia, bone marrow aplasia, aplastic anemia
   - fertility
   - potential for birth defects and cancers in humans

Question 7

Letermovir (Prevymis)

Answer 7

1. MOA: inhibits the pUL56 subunit of the viral terminase complex of CMV. Prevents cleavage of concatemeeric DNA into monomeric genome length DNA, interfering with viral DNA processing and packaging into procapsid = inhibition of CMV replication and prevention of CMV infection
2. SOA: CMV
3. no dosage adjustment for CRCL > 10 mL/min; if CRCL < 50 mL/min monitor SCr due to potential accumulation of the IV vehicle
4. no dosage adjustment for mild-moderate hepatic impairment; not recommended in severe hepatic impairment

Question 8

Foscarnet (Foscavir)

Answer 8

1. directly inhibits viral DNA polymerase
2. DOES NOT REQUIRE PHOSPHORYLATION BY THYMIDINE KINASE OR OTHER KINASES
3. SOA: HSV-1 and HSV-2 (including acyclovir-resistant strains), VZV (including acyclovir-resistant strains), CMV (including ganciclovir-resistant strains)
4. bone sequesters
5. adjust for renal dysfunction
6. removed by HD
7. ADRs:
   - nephrotoxicity - hydrate with 0.75-1 L of NS or D5W prior to the first infusion
   - metabolic: hypocalcemia, decreased ionized calcium, hypo- or hyperphosphatemia, hypokalemia, hypomagnesemia
   - CNS: HA, tremor, irritability, seizures, paresthesias, perioral tingling, numbness in extremities
   - GI: N/V

Question 9

Neuramidase inhibitors

Answer 9

1. Zanamivir (Relenza), Oseltamivir (Tamiflu), Peramivir (Rapivab)
2. MOA: attaches to the virus inside the host cell where replication occurs NA inhibitors prevent the virus from leaving the cell -> halt the spread of virus
3. SOA: Influenza A and influenza B
4. oseltamivir adjustment for renal dysfunction
5. linear PK
6. Oseltamivir removed by HD and CRRT
7. do not administer live attenuated influenza vaccine

Question 10

Baloxavir Marboxil (Xofluza)

Answer 10

1. MOA: inhibits polymerase acidic (PA) endonuclease (influenza-specific enzyme in the viral DNA polymerase complex required for viral gene transcription) -> inhibition of mRNA synthesis and viral replication