Pharmacology
Summary
A variety of drugs and treatments may be used for cytomegalovirus (CMV) infections, particularly in the setting of advanced immunosuppression or post organ transplantation. Ganciclovir is a guanisine analog, first converted into ganciclovir monophosphate by a CMV-encoded protein kinase, followed by additional phosphorylation steps by cellular enzymes. This results in ganciclovir triphosphate, which competes with deoxyguanisine triphosphate for viral DNA polymerase, terminating viral DNA synthesis. Resistance to ganciclovir occurs due to mutations in the CMV protein kinase.
Valganciclovir, a prodrug of ganciclovir with better oral bioavailability, is also used for prevention and treatment of CMV diseases, especially in high risk organ and bone marrow transplant recipients. Side effects of both include myelosuppression, necessitating monitoring for hematologic toxicity during treatment. Foscarnet and cidofovir are two drugs effective against resistant strains of CMV. Foscarnet is a pyrophosphate analog, inhibiting viral DNA polymerase directly and may cause electrolyte disturbances, as well as seizures and renal insufficiency. Cidofovir inhibits viral DNA polymerase directly, working against kinase-deficient strains of CMV. The primary adverse effect of cidofovir is nephrotoxicity, mitigated with concomitant administration of probenecid.
Lesson Outline
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FAQs
Ganciclovir is converted to ganciclovir monophosphate by a virus-encoded kinase (UL97), and further converted to ganciclovir triphosphate by cellular kinases. Ganciclovir triphosphate incorporates into replicating viral DNA, halting synthesis. Valganciclovir, which has better oral bioavailability, is a prodrug of ganciclovir, and functions in the same way.
Both ganciclovir and valganciclovir are indicated in high-risk solid organ and bone marrow transplant recipients, as well as in patients with AIDS. They are particularly effective against Cytomegalovirus (CMV) infections, which are more common with a CD4+ count < 50.
The most significant side effect associated with ganciclovir and valganciclovir is bone marrow suppression. Therefore, myelosuppression may be additive in patients receiving zidovudine or other myelosuppressive drugs.
Unlike ganciclovir and valganciclovir, foscarnet does not require phosphorylation by the viral kinase. This makes it active against ganciclovir or acyclovir resistant Herpes Simplex Virus (HSV), CMV, and Varicella Zoster Virus (VZV). It works by directly inhibiting viral DNA polymerase.
Foscarnet may induce renal insufficiency, electrolyte abnormalities such as hypocalcemia, hypomagnesemia, hypokalemia, and may even cause seizures. Cidofovir, like foscarnet, does not require phosphorylation by the viral kinase and is active against acyclovir or ganciclovir resistant HSV, CMV, VZV. However, cidofovir is potentially nephrotoxic, leading to proteinuria, azotemia, and metabolic acidosis. For this reason, probenecid is often used alongside cidofovir treatment to limit its toxic effects.
