FIGURE 49–1 The major sites of antiviral drug action. Note: Interferon alfas are speculated to have multiple sites of action. (Modified and reproduced, with permission, from Trevor AJ, Katzung BG, Masters SB: Pharmacology: Examination & Board Review, 9th ed. McGraw-Hill, 2010. Copyright © The McGraw-Hill Companies, Inc.)
TABLE 49–1 Agents to treat or prevent herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections.
1 Dose adjustment is necessary for renal insufficiency. 2 Higher doses may be necessary in HIV-infected patients. HIV, human immunodeficiency virus; HSV, herpes simplex virus; IV, intravenous; VZV, varicella-zoster virus.
The antiherpes agents significantly decrease the total number of the latter agents were associated with a shorter duration of zosterlesions, duration of symptoms, and viral shedding in patients with associated pain. Since VZV is less susceptible to the antiherpes varicella (if begun within 24 hours after the onset of rash) or cutane-agents than HSV, higher doses are required (Table 49–1). ous zoster (if begun within 72 hours); the risk of post-herpetic neu-The antiherpes agents may also be administered prophylactiralgia is also reduced if treatment is initiated early. In comparative cally for the prevention of HSV or VZV infection in patients trials with acyclovir for the treatment of patients with zoster, rates of undergoing organ transplantation, as well as for the treatment of cutaneous healing with valacyclovir or famciclovir were similar, but these infections should they occur.
Acyclovir is an acyclic guanosine derivative with clinical activity against HSV-1, HSV-2, and VZV, but it is approximately 10 times more potent against HSV-1 and HSV-2 than against VZV. In vitro activity against Epstein-Barr virus (EBV), cytomegalovirus (CMV), and human herpesvirus-6 (HHV-6) is present but weaker.
Acyclovir requires three phosphorylation steps for activation. It is converted first to the monophosphate derivative by the virus-specified thymidine kinase and then to the diand triphosphate compounds by host cell enzymes (Figure 49–2). Because it requires the viral kinase for initial phosphorylation, acyclovir is selectively activated—and the active metabolite accumulates— only in infected cells. Acyclovir triphosphate inhibits viral DNA synthesis by two mechanisms: competition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex; and chain termination following incorporation into the viral DNA.
The bioavailability of oral acyclovir is low (15–20%) and is unaffected by food. Topical formulations produce high concentrations in herpetic lesions, but systemic concentrations are undetectable by this route.
Acyclovir is cleared primarily by glomerular filtration and tubular secretion. The half-life is 2.5–3 hours in patients with normal renal function and 20 hours in patients with anuria. Acyclovir enzymes (eg, thymidine kinase, UL97)
FIGURE 49–2 Mechanism of action of antiherpes agents.
diffuses readily into most tissues and body fluids. Cerebrospinal fluid concentrations are 20–50% of serum values.