Ganciclovir

Chemical nature and mechanism of action

In its structure, the drug is a guanine derivative. It differs from natural deoxyguanosine by an open (acyclic) chain, and from its related acyclovir by the presence of an additional hydroxymethyl group.

For the drug to start working, it must undergo activation (phosphorylation) inside the infected cell:

1. Initial phosphorylation. In cells infected with herpes simplex virus, this process is triggered by viral thymidine kinase. However, cytomegalovirus (CMV) lacks this enzyme. In the case of CMV, activation is carried out by a specific viral phosphotransferase, which is encoded by the UL97 gene. This specific nuance makes the drug effective against cytomegalovirus.
2. Further activation. Conversion to di- and triphosphate occurs through the enzymes (kinases) of the host cell itself.

The resulting ganciclovir triphosphate is the active form. It competes with the natural substrate (deoxyguanosine triphosphate), incorporates into the growing chain of viral DNA, and blocks its further elongation. The drug accumulates in infected cells at concentrations 10–30 times higher than in healthy tissues and retains its activity for several days.

Pharmacokinetics: the absorption problem

Ganciclovir itself is extremely poorly absorbed when taken orally — its bioavailability is only about 10%. Because of this, it must be administered intravenously or taken orally strictly with meals, accepting its low absorption efficiency.

To solve this problem, a prodrug was created — valganciclovir. It is a valyl ester of the base substance. When taken orally, it is absorbed very well (bioavailability reaches 60%) and is transformed into active ganciclovir during the first pass through the liver.

Indications for use

The drug has a fairly broad spectrum of action: it is active against herpes simplex viruses, Epstein-Barr virus, and Varicella-zoster. However, in practice, it is used exclusively for the treatment of cytomegalovirus infection, since other, less toxic agents (e.g., acyclovir) are practically powerless against CMV.

Main indications include severe lesions against the background of immunodeficiency states (including in AIDS):

• CMV retinitis (damage to the retina of the eye);
• gastrointestinal lesions (colitis, esophagitis);
• CMV pneumonia;
• generalized forms of infection.

The drug is also prescribed for the prevention of cytomegalovirus disease in newborns and in patients after organ and tissue transplantation.

Toxicity and adverse effects

The limited use of the drug is associated with its ability to partially incorporate into the DNA of healthy human cells, suppressing cellular polymerase. The active metabolite persists in the host organism longer and in larger quantities than acyclovir metabolites.

The most formidable complication is myelotoxicity (suppression of bone marrow functions). This manifests as severe hematopoiesis disorders:

• decrease in neutrophil levels (neutropenia);
• drop in platelet count (thrombocytopenia);
• anemia;
• pancytopenia (simultaneous deficiency of all blood cells).

In addition, systemic reactions are possible: neurological disorders (ataxia, paresthesias), arrhythmias, diarrhea, liver and kidney dysfunction, as well as retinal detachment. Local phlebitis frequently develops with intravenous administration.

Resistance issue

During treatment, cytomegalovirus is capable of developing resistance to therapy. Most often, this occurs due to mutations in the UL97 gene encoding phosphotransferase. Without this enzyme, the drug simply cannot undergo the initial phosphorylation stage and remains inactive. Mutations of the viral DNA polymerase itself are less common, resulting in reduced affinity for the drug.

If resistance develops, the patient is prescribed drugs that do not require viral enzymes for activation (e.g., foscarnet or cidofovir).

Class and exam questions

What else to study on this topic

• Biochemical mechanisms of the drug's competition with deoxyguanosine triphosphate
• Alternative treatment regimens for UL97 gene mutation (use of foscarnet)
• Features of prophylactic use in organ transplant recipients
• Pathogenesis of pancytopenia development during antiviral therapy
• Specifics of treating CMV retinitis in patients with AIDS

Other topics in the "Antivirals" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.