Antiherpesvirus Agents

Antivirals

Antiherpesvirus Agents

Acyclovir

Acyclovir is a synthetic purine nucleoside analogue which was first approved for use in 1982. Valacyclovir is the L-valyl ester prodrug of acyclovir. The latter acts (after being converted to acyclovir triphosphate by intracellular phosphorylation medi-ated by thymidine kinase), by inhibiting viral reverse transcrip-tase, thereby terminating viral DNA synthesis. Valacyclovir is converted to acyclovir in the body after oral administration. It serves to increase relative oral bioavailability of acyclovir. Penciclovir and famciclovir are related drugs which are similar to acyclovir in action and toxicity.

Acyclovir and related drugs are antiviral agents indicated for the treatment of herpes simplex-1 and -2, herpes simplex encephalitis, herpes zoster, varicella zoster, and prophylaxis of cytomegalovirus.

Acyclovir is generally well tolerated at recommended doses. Oral administration sometimes causes vomiting and headache. Intravenous use may result in phlebitis, renal dysfunction (due to precipitation of acyclovir crystals in renal tubules), and encephalopathy. The latter is associated with high-dose administration and manifests as lethargy, confusion, hallucinations, delirium, and convulsions. Hallucinations may occur. Topical use may cause occasional burning on applica-tion, with erythema on drying.

A few cases of acute overdose have been reported with acyclovir in adults as well as infants, but serious toxicity was not evident in any of them, though renal dysfunction occurred in one which was rectified by appropriate treatment. The risk of nephrotoxicity is primarily related to high serum levels following bolus IV injections or overdose and is usually revers-ible. The incidence of renal toxicity may be greatly decreased by administering acyclovir slowly in a concentration less than 7 mg/ml. Adequate hydration and high urine output should be maintained throughout treatment to minimise nephrotoxicity. Myoclonus, agitation, tremor, and convulsions have also been reported in overdose.

Treatment: Any patient suspected of a toxic oral orintravenous exposure to acyclovir, famciclovir or penciclovir should be monitored in a controlled setting until all signs and symptoms of toxicity have subsided. The amount contained in a 15-gram tube of ointment (750 mg) of acyclovir is unlikely to produce toxicity and is within the daily recommended oral dose in adults. Penciclovir is poorly absorbed after oral admin-istration, so ingestion is unlikely to cause significant toxicity. Monitoring hepatic enzymes, renal function and urinalysis may be of value in evaluating the seriousness of acyclovir overdose.

o     Decontamination: Gastric lavage can be done if the patient is seen within 2 hours of ingestion. Acyclovir is adsorbed well by activated charcoal.

o     Intravenous fluid hydration may aid in solubilising crystals and therefore prevent or minimise crystal deposits in renal tubules and collecting ducts.

o     Haemodialysis has been shown to be beneficial in acyclovir overdose. Due to the low molecular weight, water solubility, and low protein binding of acyclovir, it is anticipated that continuous haemodialysis would be effective in removal of acyclovir from plasma. Famciclovir and penciclovir are also removed by haemodialysis. Exchange transfusion, haemoperfusion, and peritoneal dialysis are not efficacious.

o     Supportive measures: Patients should be carefully moni- tored for signs of neurotoxicity (encephalopathy) and renal dysfunction, and appropriate measures instituted if they are evident.

Foscarnet

Foscarnet is trisodium phosphonoformate, and acts by inhib-iting viral nucleic acid synthesis through direct interaction with herpesvirus DNA polymerase or HIV reverse transcriptase. It is effective against HSV, VZV, HIV, and CMV (cytomegalovirus) infections. Foscarnet is administered intravenously, but has serious potential for nephrotoxicity and hypocalcaemia. Other toxic effects include convulsions, paraesthesias, hallucinosis, vomiting, hepatic damage and painful genital ulcerations.

Treatment involves haemodialysis and supportive measures.

Ganciclovir

Ganciclovir is a nucleoside analogue which is structurally similar to acyclovir but is 50 times more active against CMV. It utilises cellular kinases for conversion to its active triphosphate form which inhibits viral DNA replication. Ganciclovir is a synthetic guanine derivative and acts as an acyclic nucleoside analogue of 2’-deoxyguanosine that inhibits replication of herpes viruses (sensitive viruses include cytomegalovirus). It is however quite toxic and produces haematologic abnormali-ties (leukopenia, anaemia and thrombocytopenia), and chronic renal failure. Other adverse effects include vomiting, diar-rhoea, liver damage, convulsions, vertigo, torsades de pointes, cardiac arrest, cardiac conduction abnormalities, ventricular tachycardia, gastrointestinal perforation, multiple organ failure, pancreatitis, and sepsis. Pneumonia, dyspnoea, and cough have also been reported. Pruritus, rash, and sweating were the most frequent dermatologic complaints associated with intravenous or oral ganciclovir.

Since ganciclovir has been almost exclusively evaluated in immunocompromised patients with infections, the adverse events reported may be confounded by underlying disease processes and concomitant drug therapies. Irreversible pancy-topenia, persistent bone marrow suppression, hepatitis, haema-turia, elevated creatinine, convulsions, neutropenia, anaemia, leukopenia, and thrombocytopenia have been reported after intravenous overdose as well as with intravenous or oral thera-peutic doses. Retinal damage and permanent visual loss have been reported after overdose by intravitreal injection.

Valganciclovir is the l-valyl ester of ganciclovir. It is a prodrug, being rapidly hydrolysed to ganciclovir in plasma following oral administration; it was developed to improve the bioavailability of oral ganciclovir.

Ganciclovir has been shown to be carcinogenic and tera-togenic in animal studies. Ganciclovir may be teratogenic or embryotoxic at dose levels recommended for human use.

Treatment of overdose involves gut decontamination (induc-tion of emesis is contraindicated because of the potential for convulsions, cardiovascular instability, and CNS depression), and institution of elimination procedures such as haemodialysis or CAVH (continuous arteriovenous haemodialysis). Treatment of convulsions and cardiac arrhythmias require special atten-tion.

Idoxuridine

It is an iodinated thymidine analogue which inhibits the in vitro replication of various DNA viruses such as herpes viruses and pox viruses. Idoxuridine is however only recommended for topical treatment (HSV keratitis), and may occasionally cause allergic reactions resulting in pruritis and inflammation.

Vidarabine

Vidaribine is an adenosine analogue which is recommended for use in HSV encephalitis, neonatal herpes, and zoster or varicella in immunocompromised patients. It is administered intravenously. Toxic effects include vomiting, diarrhoea, weakness, hypokalaemia, haematological abnormalities, and CNS disturbances.