Antiviral Agents: Ribavirin

Ribavirin

Ribavirin is a synthetic guanosine analogue that pos-sesses broad antiviral inhibitory activity against many viruses, including influenza A and B, parainfluenza, RSV, HCV, HIV-1, and various herpesviruses, arenaviruses, and paramyxoviruses. Its exact mechanism of action has not been fully elucidated; however, it appears to inhibit the synthesis of viral mRNA through an effect on nu-cleotide pools. Following absorption, host cell enzymes convert ribavirin to its monophosphate, diphosphate, and triphosphate forms. Ribavirin monophosphate inhibits the guanosine triphosphate (GTP) synthesis pathway and subsequently inhibits many GTP-depend-ent processes. Ribavirin triphosphate inhibits the 5 cap-ping of viral mRNA with GTP and specifically inhibits influenza virus RNA polymerase. Ribavirin may also act by increasing the mutation rate of RNA viruses, lead-ing to the production of nonviable progeny virions. Ribavirin resistance has not been documented in clinical isolates.

Absorption, Metabolism, and Excretion

Ribavirin can be administered as an aerosol using a small-particle aerosol generator. When administered by this route, the drug has only minimal systemic ab-sorption, with drug concentrations in respiratory tract secretions approximately 100 times as high as those found in plasma. Oral absorption is rapid, and first-pass metabolism is extensive; ribavirin’s oral bioavailability is 64% and can be increased by administration with a high-fat meal. Steady-state levels are reached after 4 weeks.

Ribavirin is reversibly phosphorylated by all nucle-ated cells. It is also metabolized in the liver to a triazole carboxylic acid metabolite that is eliminated in the urine along with the parent compound. The plasma half-life of ribavirin is 9.5 hours when it is administered by aerosol (2.5 hours/day for 3 days), whereas its half-life is around 12.5 days at steady state. The drug accumulates in erythrocytes, with a half-life of 40 days.

Clinical Uses

Ribavirin aerosol (Virazole) is indicated in the treat-ment of high-risk infants and young children with se-vere bronchiolitis or pneumonia due to RSV infection. Treatment is most effective if begun within 3 days of the onset of symptoms.

Although ribavirin monotherapy is ineffective against HCV, oral ribavirin in combination with inter-feron- (Rebatron) is approved for this indication and is effective in patients resistant to interferon therapy alone. Intravenous ribavirin may be useful in the ther-apy of Hantaan virus infection, Crimean or Congo virus hemorrhagic fever, Lassa fever, and severe adenovirus infection.

Adverse Effects, Contraindications, and Drug Interactions

Most adverse effects associated with aerosol ribavirin are local. Pulmonary function may decline if aerosol rib-avirin is used in adults with chronic obstructive lung dis-ease or asthma. Deterioration of pulmonary and cardio-vascular function has also been seen in severely ill infants given this preparation. Rash, conjunctivitis, and rare cases of anemia have been reported. Health care workers exposed to aerosol ribavirin during its administration have reported adverse effects including head-ache, conjunctivitis, rash, and rarely, bronchospasm.

Oral and intravenous ribavirin are associated with additional adverse effects. When given via these routes, ribavirin can produce hemolytic anemia that is re-versible following dosage reduction or cessation of ther-apy. When given in combination with interferon- , rib-avirin increases the incidence of many of its side effects, such as fatigue, nausea, insomnia, depression, and ane-mia, and may cause fatal or nonfatal pancreatitis. Ribavirin is mutagenic, teratogenic, and embryotoxic in animals at doses below the therapeutic level in humans. It is contraindicated in pregnant women and in the male partners of pregnant women. Women of childbearing potential and male partners of these women must use two effective forms of contraception during ribavirin treatment and for 6 months post therapy. Pregnant women should not directly care for patients receiving ribavirin.

Ribavirin is contraindicated in patients with sickle cell anemia and other hemoglobinopathies because of its propensity to cause anemia. Similarly, persons with coronary disease should not use ribavirin, because anemia may cause deterioration of cardiac function. Oral ribavirin should not be given to individuals with severe renal impairment; no dosage adjustment is nec-essary for the inhaled formulation. However, patients with hepatic impairment may require dosage adjust-ment.

Little information on the drug interactions of rib-avirin is available. In vitro, ribavirin inhibits the phos-phorylation reactions that are required for activation of zidovudine and stavudine.