Flashcards in Antivirals: Herpes Deck (24):
Most drugs active against herpes virus are antimetabolites bioactivated via viral or host cell kinases to form compounds that?
Inhibit viral DNA polymerases.
--all anti-herpetic drugs have NO effect on the latent form of the virus
First antiviral drug for Herpes is Acyclovir, what are some features?
Synthetic guanosine analog
--used for HSV and varicella zoster (VZV)
--must be converted to acyclovir-triphosphate: this process is initially catalyzed viral thymidine kinase and subsequently by human enzymes
--acyclovir-triphosphate serves as a competitive substrate for viral DNA polymerase
--incorporation into the DNA chain results in termination of viral replication
What is the susceptibility of the herpes virus to Acyclovir?
HSV type 1: most susceptible
followed by HSV type 2 and VZV and then EBV
What are the pharmacokinetics for Acyclovir?
Excellent tissue and fluid penetration (including CSF)
Oral: modest bioavailability
Bioavailability improved with the use of valacyclovir (ester formulation of acyclovir)
Excreted by glomerular formation and tubular secretion
What is the current use of Acyclovir?
Tx of primary and recurrent genital HSV infection
Topical can be used for genital HSV but oral is recommended (oral also reduces the incidence of recurrent genital herpes)
IV acyclovir: 1st line for HSV encephalitis
Acyclovir is used to treat VZV
Used prophylactically in immunocompromised and transplant patients
What are the AE for Acyclovir?
IV = reversible nephrotoxicity in 5-10% of patients due to intra-tubular precipitation of acyclovir crystals
Adequate hydration, slower infusion rate and dosing based on renal function reduces this AE.
What is the resistance for Acyclovir?
Resistance has been reported
--esp in immunocompromised patients
--selection of viral mutant that are deficient in thymidine kinase or that have altered DNA polymerase with reduced affinity to acyclovir-triphosphate
Next drug for the tx of Herpes is Ganciclovir, what are some features?
Acyclic 2'-deoxyguanosine analog used in the management of CMV
--undergoes triphosphorylation to become active
Ganciclovir triphosphate inhibits viral DNA synthesis through competitive incorporation during DNA synthesis
--leads to DNA chain termination
What are the pharmacokinetics for Ganciclovir?
Oral and Parenteral
Oral is poorly absorbed so low bioavailability
Active CMV disease should be tx with IV or the oral prodrug valganciclovir
Ganciclovir is used in the treatment of what?
CMV retinitis in patients with HIV/AIDS
Herpes Simplex Keratitis
CMV prophylaxis in transplant patients (Valganciclovir)
IV ganciclovir for CMV colitis or esophagitis
What are the AE of Ganciclovir?
Reversible bone marrow suppression: most common
What is the resistance for Ganciclovir?
Occurs in severely immunocompromised patients with prolonged exposure to the drug
--most common mechanism: UL97 gene mutation
Next drug used in herpes treatment is Penciclovir, what are some features?
Acyclic Guanine Analog
Only available topically for mucocutaneous herpes
Antiviral activity is similar to acyclovir with efficacy against HSV-1, HSV-2, and VZV and somewhat against EBV
Again action is the same as acyclovir:
--monophosphorylated by thymidine kinase and by cellular kinases into penciclovir-triphosphate, which inhibits DNA polymerase activity by serving as a competitive inhibitor of deoxyguanosine triphosphate
What is the use and AE of penciclovir?
Topical therapy for recurrent herpes labialis
AE: mild dermatological
The next drug used in herpes treatment is Cidofovir, what are some features?
Nucleoside analog used for tx of CMV, other herpes viruses, and other DNA viral infections
--phosphorylated by cellular kinases into cidofovir-diphosphate, a competitive substrate for viral DNA synthesis, thereby halting DNA synthesis
What the pharmacokinetics for Cidofovir?
Eliminated by glomerular filtration and tubular secretion
Probenecid is coadministered to reduce its excretion by blocking tubular secretion
What is the clinical indication for Cidofovir?
Tx of CMV retinitis in HIV infected patients
Rescue therapy for immunocompromised patients with CMV disease resistant or unresponsive to ganciclovir
What is the resistance for Cidofovir?
Activation does not rely on viral kinases, it retains activity
against CMV with the UL97 mutation and HSV with the thymidine kinase mutation
Resistance occurs when the virus develops mutations in the DNA polymerase gene
What are the AE of Cidofovir?
Nephrotoxicity is common and serious
The incidence is reduced by hydration and probenecid
The next drug in the tx of herpes is Foscarnet, what are some features?
Non-nucleoside pyrophosphate analog
--give IV for the tx of herpes
High incidence of nephrotoxicity and deposition and release from bone
Inhibits pyrophosphate binding on viral DNA polymerases
--suppressing HSV-1, HSV-2, and CMV replication
--also active against VZV and HSV-6
DOES NOT REQUIRE INTRACELLULAR CONVERSION TO ACTIVE TRIPHOSPHATE (so mutations to thymidine kinase does not matter)
Foscarnet is approved for tx in whom?
CMV retinitis in patients with AIDS
Other CMV diseases in immunocompromised esp those unable to tolerate ganciclovir and those with ganciclovir resistance
used for treating acyclovir-resistant mucocutaneous HSV or VZV in immunocompromised patients
What are the AE of Foscarnet?
Most serious is Nephrotoxicity
--foscarnet crystals in the glomerular capillary lumen
Patients should be hydrated to prevent nephrotoxicity and electrolyte abnormalities (hypokalemia, hypomagnesemia and hypophosphatasemia) should be corrected
The last drug in the treatment of herpes is Trifluridine, what are some features?
Thymidine analog that interferes with viral replication by inhibiting thymidylate synthetase and incorporating into viral DNA in place of thymidine