Antiherpetics

Question 1

How does Acyclovir work?

Answer 1

1. Monophosphorylated by viral thymidine kinase (TK), then further bioactivated by host-cell kinases to triphosphate
2. Acyclovir-triphosphate is both a substrate for and inhibitor of viral DNA polymerase (when incorporated into the DNA molecule it acts as a chain terminator*)

*lacks the equivalent of a ribosyl 3’ hydroxyl group

Question 2

How many HSV strains are resistant to acyclovir?

Answer 2

>50% because they lack thymidine kinase (i.e., do not activate the prodrug)

Question 3

Activity and Clinical Uses of Acyclovir

Answer 3

1. Active against HSV and VZV
2. Topical, oral, and IV (short half-life)

Reduces viral shedding in genital herpes and decreases acute neuritis in shingles. Reduces syptoms if used early in chickenpox.

Question 4

Side effects of Acyclovir

Answer 4

Side effects are minor with oral use, but more obvious with IV

Crystalluria (maintain full hydration) and neurotoxicity (agitation, headache, confusion–seizures in OD)

NOT hematoxic

Question 5

Can Acyclovir be used to treat dormant cells infected with HSV or VZV?

Answer 5

No.

Two points to remember:

1. Only HSV and VZV contain thymidine kinase
2. Drug only works when viruses are replicating

Question 6

Famciclovir and Valacyclovir

Answer 6

Newer drugs approved for HSV infection and are similar to Acyclovir in mechanism, but with a longer half-life. They may have activity against strains resistant to acyclovir, but not TK- strains.

Question 7

How does Ganciclovir work?

Answer 7

Similar to acyclovir:

1. First phosphorylation step is viral-specific; involves thymidine kinase in HSV and a phosphotransferase (UL97) in CMV
2. Triphosphate form inhibits viral DNA polymerase and causes chain termination

Resistance = changes in DNA polymerase OR decreased TK activity

Question 8

Activity and Clinical Uses of Ganciclovir

Answer 8

1. Active against HSV, VZV, and CMV
2. Mostly used in prophylaxis and treatment of CMV infections (NOT A CURE b/c cannot kill dormant cells)

Question 9

Side effects of Ganciclovir

Answer 9

Dose-limiting hematotoxicity (leukopenia, thrombocytopenia), mucositis, fever, rash, and crystalluria

-Seizures occur in overdoes

Question 10

How does Foscarnet work and what is it used for?

Answer 10

• NOT an antimetabolite, but still inhibits viral DNA and RNA polymerases
• Uses identical to Ganciclovir PLUS greater activity versus acyclovir-resistant strains of HSV

Question 11

Side effects of Foscarnet

Answer 11

1. Dose-limiting nephrotoxicity with acute tubular necrosis
2. Electrolyte imbalance with hypocalcemia (tremors and seizures)

Question 12

What antiherpetic would you give a HIV patient who could not withstand bone marrow suppression?

Answer 12

Foscarnet (not an antimetabolite)

NOTE: avoid pentamidine–which is used to treat PCP–because it increases risk for nephrotoxicity and hypocalcemia (side effects of foscarnet)