Overview of Antiviral Agents
The conventional approach to control of viral diseases is to develop effective vaccines, but this is not always possible. The objective of antiviral activity is to eradicate the virus while minimally impacting the host and to prevent further viral invasion. However, because of their method of replication, viruses present a greater therapeutic challenge than do bacteria.
Viruses comprise a core genome of nucleic acid surrounded by a protein shell or capsid. Some viruses are further surrounded by a lipoprotein membrane or envelope. Viruses cannot replicate independently and, as such, are obligate intracellular parasites. The host’s pathways of energy generation, protein synthesis, and DNA or RNA replication provide the means of viral replication. Viral replication occurs in five sequential steps: host cell penetration, disassembly, control of host protein and nucleic acid synthesis such that viral components are made, assembly of viral proteins, and release of the virus.
Drugs that target viral processes must penetrate host cells; further, because viruses often assume direction of cell division, drugs that negatively impact a virus are also likely to negatively impact normal pathways of the host. For these reasons, particularly compared with antibacterial drugs, antiviral drugs are characterized by a narrow therapeutic margin. Nephrotoxicity is emerging as an adverse reaction to antiviral drugs in human medicine. Therapy is further complicated by viral latency, ie, the ability of the virus to incorporate its genome in the host genome, with clinical infection becoming evident without reexposure to the organism. In vitro susceptibility testing must depend on cell cultures, which are expensive. More importantly, in vitro inhibitory tests do not necessarily correlate with therapeutic efficacy of antiviral drugs. Part of the discrepancy between in vitro and in vivo testing occurs because some drugs require activation (metabolism) to be effective.
Only a few antiviral drugs are reasonably safe and effective against a limited number of viral diseases, and most of these have been developed in people. Few have been studied in animals, and widespread clinical use of antiviral drugs is not common in veterinary medicine. The advent of human immunodeficiency virus (HIV) and the development of the cat as a model of HIV infection has somewhat increased the animal knowledge base. Only a selection of the more promising agents and their purported attributes are briefly discussed.
Most antiviral drugs interfere with viral nucleic acid synthesis or regulation. Such drugs generally are nucleic acid analogues that interfere with RNA and DNA production. Other mechanisms of action include interference with viral cell binding or interruption of virus uncoating. Some viruses contain unique metabolic pathways that serve as a target of drug therapy. Drugs that simply inhibit single steps in the viral replication cycle are virustatic and only temporarily halt viral replication. Thus, optimal activity of some drugs depends on an adequate host immune response. Some antiviral drugs may enhance the immune system of the host. Dosages of Antiviral Drugs lists the dosage rates for some commonly used antiviral drugs.
Dosages of Antiviral Drugs
A variety of pyrimidine nucleosides (both halogenated and nonhalogenated) effectively inhibit the replication of herpes simplex viruses with limited host-cell toxicity. The exact mechanism of action of these compounds appears to reflect substitution of pyrimidine for thymidine, causing defective DNA molecules. Idoxuridine is effective for treatment of herpesvirus infection of the superficial layers of the cornea (herpesvirus keratitis) and of the skin but is toxic when administered systemically.
Trifluridine, also an analogue of deoxythymidine, is currently the agent of choice for treatment of herpesvirus keratitis in people. The other antiviral pyrimidine nucleosides have not been used clinically to any notable extent.