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Chapter: Modern Pharmacology with Clinical Applications: Antiviral Drugs

Antiherpesvirus Agents: Acyclovir and Valacyclovir

Acyclovir (Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the L-valine ester prodrug of acyclovir.

Acyclovir and Valacyclovir


Acyclovir (Zovirax) is a guanine nucleoside analogue most effective against HSV-1 and HSV-2, but it has some activity against VCV, CMV, and EBV. Valacyclovir (Valtrex) is the L-valine ester prodrug of acyclovir. Acyclovir is converted to its active metabolite via three phosphorylation steps. First, viral thymidine kinase con-verts acyclovir to acyclovir monophosphate. Next, host cell enzymes convert the monophosphate to the diphos-phate and then to the active compound, acyclovir triphosphate. Because viral thymidine kinase has a much greater affinity for acyclovir triphosphate than does mammalian thymidine kinase, acyclovir triphosphate ac-cumulates only in virus-infected cells.


The active metabolite of acyclovir inhibits her-pesvirus DNA replication in two ways. Acyclovir triphos-phate acts as a competitive inhibitor for the incorpora-tion of deoxyguanosine triphosphate (dGTP) into the viral DNA. In addition, acyclovir that is incorporated into viral DNA acts as a chain terminator because it lacks the 3 -hydroxy group necessary for further chain elonga-tion. Viral DNA polymerase becomes irreversibly bound to an acyclovir-terminated DNA chain and is unavailable for further replicative activity. The effect of acyclovir on host cell DNA synthesis is much smaller than its effect on the viral enzyme. Concentrations of acyclovir signifi-cantly beyond the therapeutic range are required to in-hibit host cell growth.


In HSV and VZV, the most common mechanism of resistance to acyclovir involves mutations that result in decreased thymidine kinase activity. Therefore, these vi-ral mutants exhibit cross-resistance to other antiviral agents that require thymidine kinase activation, such as famciclovir, ganciclovir, and valacyclovir. Less com-monly, thymidine kinase mutations result in altered substrate specificity. A rare mechanism of acyclovir re-sistance involves decreased affinity of viral DNA poly-merase for the drug.


Absorption, Metabolism, and Excretion


Valacyclovir is rapidly and completely converted to acy-clovir by intestinal and hepatic first-pass metabolism. The bioavailability of acyclovir following oral valacy-clovir dosing is three to five times that resulting from oral acyclovir administration and is comparable to that of intravenous acyclovir.


Acyclovir absorption is variable and incomplete fol-lowing oral administration. It is about 20% bound to plasma protein and is widely distributed throughout body tissues. Significant amounts may be found in am-niotic fluid, placenta, and breast milk. Acyclovir is both filtered at the glomeruli and actively secreted. Most of the dose is excreted in the urine as unchanged drug; a small portion is excreted as an oxidized inactive metabolite. The plasma half-life of acyclovir is 3 to 4 hours in patients with normal kidney function and up to 20 hours in patients with renal impairment.


Clinical Uses


Oral acyclovir is useful in the treatment of HSV-1 and HSV-2 infections, such as genital herpes, herpes en-cephalitis, herpes keratitis, herpes labialis, and neonatal herpes. In initial episodes of genital herpes, oral acy-clovir has been found to reduce viral shedding, increase the speed of healing of lesions, and decrease the dura-tion of pain and new lesion formation. Acyclovir ap-pears to be less effective in the treatment of recurrent herpes genitalis but may be used for the long-term sup-pression of recurrent HSV.


Intravenous acyclovir is used in the treatment of herpes simplex encephalitis, neonatal HSV infection, and mucocutaneous HSV infection in immunocompro-mised individuals. Acyclovir ointment is used in the treatment of initial genital herpes but is not effective for recurrent disease. Ophthalmic acyclovir formulations, although not available in the United States, are effec-tive in the treatment of herpes keratoconjunctivitis.


Acyclovir reduces the extent and duration of VZV lesions in adults and children, although higher doses are required than for the treatment of HSV infection. Although not recommended for the routine treatment of uncomplicated varicella in children, acyclovir may be used for chickenpox treatment and prophylaxis in high-risk individuals. Acyclovir accelerates healing in pa-tients with herpes zoster (shingles), but it does not af-fect postherpetic neuralgia.


Immunocompromised individuals and patients re-ceiving immunosuppressive drugs or cancer chemotherapy have a high incidence of severe reactivated HSV and VZV infections. In these patients, acyclovir has been shown to be effective for the prophylaxis and ther-apy of HSV and VZV.


Valacyclovir demonstrates efficacy similar to that of acyclovir but requires less frequent oral dosing. While indicated for the treatment of herpes zoster and the treatment and suppression of HSV, it is not approved for use in immunocompromised individuals or for the therapy of disseminated herpes zoster.


Adverse Effects, Contraindications, and Drug Interactions


The adverse effects of valacyclovir and acyclovir are similar. Toxicity is generally minimal, consisting largely of headache, nausea, and diarrhea. Less frequently ob-served are skin rash, fatigue, fever, hair loss, and de-pression. Reversible renal dysfunction (azotemia) and neurotoxicity (tremor, seizure, delirium) are dose-limiting toxicities of intravenous acyclovir. Adequate hydration and slow drug infusion can minimize the risk of renal toxicity.


Aside from drug hypersensitivity, there are no ab-solute contraindications to the use of acyclovir and valacyclovir. Adjustment of drug dosage is required in patients with renal impairment. A potentially fatal disorder, thrombotic thrombocytopenic purpura– hemolytic uremic syndrome (TTP–HUS), has been re-ported in immunocompromised individuals. Animal studies have demonstrated no teratogenic or embryo-toxic effects of valacyclovir and acyclovir. Although there are no large, controlled studies of the safety of these drugs in pregnant women, a prospective epidemi-ological registry of acyclovir use during pregnancy showed no increase in the incidence of common birth defects.


The potential for drug interactions, particularly with other drugs that are actively secreted by the proximal tubules, should be considered. Probenecid has been shown to inhibit the renal clearance of acyclovir. Cyclosporine and other nephrotoxic agents may in-crease the risk of renal toxicity of acyclovir.


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