The replication of viruses depends on synthetic processes of the host cell. Antiviral drugs can exert their actions at several stages of viral replication including viral entry, nucleic acid synthesis and integration, late protein synthesis, and processing, as well as in the final stages of viral packaging and virion release (Figure 49–1). Most of the drugs active against herpes viruses (HSV) and many agents active against human immunodeficiency virus (HIV) are antimetabolites, structurally similar to naturally occurring compounds. The selective toxicity of antiviral drugs usually depends on greater susceptibility of viral enzymes to their inhibitory actions than host cell enzymes.
One of the most important trends in viral chemotherapy, especially in the management of HIV infection, has been the introduction of combination drug therapy. This can result in greater clinical effectiveness in viral infections and can also prevent, or delay, the emergence of resistance.
The major sites of antiviral drug action. Note: interferon-alfas are speculated to have multiple sites of action on viral replication. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 14th ed. McGraw-Hill, 2018: Fig. 49–1.)
Most drugs active against herpes viruses are antimetabolites bioactivated via viral or host cell kinases to form compounds that inhibit viral DNA polymerases.
A. Acyclovir (Acycloguanosine)
Acyclovir is a guanosine analog active against herpes simplex virus (HSV-1, HSV-2) and varicella-zoster virus (VZV). The drug is activated initially by the viral kinase to form acyclovir triphosphate, which interferes with viral synthesis in 2 ways. It acts as a competitive substrate for DNA polymerase, and it leads to chain termination after its incorporation into viral DNA (Figure 49–2). Resistance of HSV can involve changes in viral DNA polymerase. However, many resistant strains of HSV (TK– strains) lack thymidine kinase, the enzyme involved in the initial viral-specific phosphorylation of acyclovir. Such strains are cross-resistant to famciclovir, ganciclovir, and valacyclovir.
Mechanism of action of antiherpes agents. (Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 12th ed. McGraw-Hill, 2012: Fig. 49–3.)
Acyclovir can be administered by the topical, oral, and intravenous routes. Because of its short half-life, oral administration requires multiple daily doses of acyclovir. Renal excretion is the major route of elimination of acyclovir, and dosage should be reduced in patients with renal impairment.
3. Clinical uses and toxicity
Oral acyclovir is commonly used for the treatment of mucocutaneous and genital herpes lesions (Table 49–1) and for prophylaxis in AIDS and in other immuno-compromised patients ...