Although bacitracin has found its widest use in topical preparations for local infections, it is quite effective in several systemic and local infections when administered parenterally. It is not absorbed from the GI tract; accordingly, oral administration is without effect, except for the treatment of amebic infections within the alimentary channel.

Antiviral Agents CLASSIFICATION OF VIRUSES

Viruses are classified on the basis of several features: Nucleic acid content (DNA or RNA) Viral morphology (helical, icosahedral) Site of replication in cell (cytoplasm or nucleus) Coating (enveloped or nonenveloped) Serological typing (antigenic signatures) Cell types infected (B lymphocytes, T lymphocytes, monocytes)

The following lists some virus types together with diseases that they cause: RNA viruses responsible for the following disease.. RNA viruses: polio, hepatitis A, rhinovirus, yellow fever, dengue fever, St. Louis encephalitis, hemorrhagic fever, mumps, measles, retroviruses (HIV) DNA viruses responsible for the following disease.. herpes, cold sores, polyoma, warts, canine, distemper. It has been estimated that viruses cause more than 60% of the infectious diseases that occur in the developing countries. Bacterial infections account for only 15%. provides a synopsis of virus types with their possible therapeutic modalities.

Biochemical Targets for Antiviral Therapy: The development of useful antiviral agents (antibiotics and antiviral agents), in contrast, has historically lagged behind. There are several reasons for this. Unlike bacteria, viruses will not grow in simple synthetic culture media. Another possible reason for the lag in antiviral drug development lies in the comparative biochemical simplicity of viruses vis-à-vis bacteria and their use of the biochemical processes of a host cell. Chemotherapeutic agents are needed, however, to combat viruses that cause severe or chronic infections, such as encephalitis, AIDS, and herpes, particularly in patients with compromised immune systems.

THE INFECTIOUS PROCESS FOR A VIRUS Despite their simplicity relative to bacteria, viruses still possess various biochemical targets for potential attack by chemotherapeutic agents. The process of viral infection can be sequenced in seven stages: 1. Adsorption, attachment of the virus to specific receptors on the surface of the host cells, a specific recognition process. 2. Entry, penetration of the virus into the cell. 3. Uncoating, release of viral nucleic acid from the protein coat. 4. Transcription, production of viral mRNA from the viral genome. 5. Translation, synthesis of viral proteins (coat proteins and enzymes for replication) and viral nucleic acid (i.e., the parental genome or complimentary strand). 6. Assembly of the viral particle. 7.Release of the mature virus from the cell by budding from the cell membrane or rupture of the cell and repeat of the process, from cell to cell or individual to individual.

Chemoprophylaxis is an alternative to active immunization for the prevention of viral infection. With chemoprophylaxis, one uses a chemical agent that interferes with a step in early viral infectivity. The immune system is not directly stimulated by the drug but is required to respond to any active infection. It would seem that the most successful chemoprophylactic agents would be those that prevent penetration of the virus into the host cell. In principle, this can be achieved by blocking any of three steps prior to the start of the replication cycle: (a) attachment of the virion to the host cell via its receptor complex, (b) its entry into the cell via endocytosis, (c) release of the viral nucleic acid from the protein coat. At present, only a single class of agents affects these early stages of replication

Product Chemoprophylaxis Influenza,Amantadine and Rimantadine. Amantadine and rimantadine are both drugs that interfere with penetration of host cells by viruses and block earlystage replication. Amantadine, 1- adamantanamine hydrochloride (Symmetrel), and its α-methyl derivative rimantadine, α-methyl-1- adamantane methylamine hydrochloride (Flumadine), are un usual caged tricyclic amines with the following structures:

Amantadine has been used for years as a treatment for Parkinson disease. Both of these agents will specifically inhibit replication of the influenza type A viruses at low concentrations. Rimantadine is generally 4 to 10 times more active than amantadine. The adamantanamines have two mechanisms in common: (a) they inhibit an early step in viral replication, most likely viral uncoating. (b) in some strains, they affect a later step that probably involves viral assembly, possibly by interfering with hemagglutinin processing. because amantadine is used in the treatment of Parkinson disease. Rimantadine has significantly fewer side effects, probably because of its extensive biotransformation.

NUCLEOSIDE ANTIMETABOLITES: INHIBITING VIRAL REPLICATION Inhibitors of DNA Polymerase Idoxuridine

Idoxuridine, (Stoxil, Herplex), was introduced in 1963 for the treatment of herpes simplex keratitis. The drug is an iodinated analog of thymidine that inhibits replication of several DNA viruses in vitro.

Idoxuridine enters the cell and is phosphorylated at O-5 by a viral thymidylate kinase to yield a monophosphate, which undergoes further biotransformation to a triphosphate. The triphosphate is believed to be both a substrate and an inhibitor of viral DNA polymerase, causing inhibition of viral DNA synthesis and facilitating the synthesis of DNA that contains the iodinated pyrimidine. The ability of idoxuridylic acid to substitute for deoxythymidylic acid in the synthesis of DNA may be a result of the similar van der Waals radii of iodine (2.15 Å) and the thymidine methyl group (2.00 Å).

The use of idoxuridine is limited because the drug lacks selectivity; low, subtherapeutic concentrations inhibit the growth of uninfected host cells. The compound is a weak acid, with a pKa of Aqueous solutions are slightly acidic, yielding a pH of about 6.0. Idoxuridine is light and heat sensitive.

Acyclovir Acyclovir, 9-[2-(hydroxyethoxy)methyl]-9H-guanine (Zovirax), is the most effective of a series of acyclic nucleosides that possess antiviral activity. The clinically useful antiviral spectrum of acyclovir is limited to herpesviruses. It is most active (invitro) against HSV type 1, about two times less against HSV type 2, and 10 times less potent against varicella–zoster virus (VZV). An advantage is that uninfected human cells are unaffected by the drug.

Guanosine

The ultimate effect of acyclovir is the inhibition of viral DNA synthesis. Transport into the cell and monophosphorylation are accomplished by a thymidine kinase that is encoded by the virus itself. The affinity of acyclovir for the viral thymidine kinase is about 200 times that of the corresponding mammalian enzyme.

Enzymes in the infected cell catalyze the conversion of the monophosphate to acyclovir triphosphate, which is present in 40 to 100 times greater concentrations in HSV-infected than uninfected cells. Acyclovir triphosphate competes for endogenous deoxyguanosine triphosphate (dGTP); hence, acyclovir triphosphate competitively inhibits viral DNA polymerases. The triphosphorylated drug is also incorporated into viral DNA, where it acts as a chain terminator. Because it has no 3 – -hydroxyl group, no 3 –,5 – - phosphodiester bond can form. Two dosage forms of acyclovir are available for systemic use: oral and parenteral. Oral acyclovir is used in the initial treatment of genital herpes and to control mild recurrent episodes.

Intravenous administration is indicated for initial and recurrent infections in immunocompromised patients and for the prevention and treatment of severe episodes. The drug is absorbed slowly and incompletely from the GI tract, and its oral bioavailability is only 15% to 30%. Nevertheless, acyclovir is distributed to virtually all body compartments. Less than 30% is bound to protein. Most of the drug is excreted unchanged in the urine, about 10% excreted as the carboxy metabolite. Acyclovir occurs as a chemically stable, white, crystalline solid that is slightly soluble in water. Because of its amphoteric properties (pKa values of 2.27 and 9.25),

solubility is increased by both strong acids and bases. The injectable form is the sodium salt, which is supplied as a lyophilized powder, equivalent to 50 mg/mL of active acyclovir dissolved in sterile water for injection. Because the solution is strongly alkaline (pH ~ 11), it must be administered by slow, constant intravenous infusion to avoid irritation and thrombophlebitis at the injection site.

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