Antiviral Drugs Study Notes

ANTI-VIRAL DRUGS


PRINCIPLES OF ANTIVIRAL THERAPY

  • Antiviral drugs available are relatively small compared to bacterial infection treatments.

  • Selectivity Challenge: Obtaining selective toxicity against viruses is difficult due to their replication processes being similar to normal cellular processes.

  • Despite difficulties, some specific viral replication steps have been identified as sites for effective antiviral drug action (see Table 35-1).

  • Emergence of Drug-Resistant Mutants: Drug-resistant mutants (e.g., in HIV) necessitate changes in drug regimens. Combining drugs from different classes is common in HIV treatment to maintain effectiveness.

  • Timing of Treatment Limitation: Antiviral drugs may be ineffective as many viral replication cycles occur during the incubation period, often before symptoms present. By the time a patient exhibits systematic viral disease, the virus may have widely spread, limiting treatment efficacy.

  • Some viruses, such as herpesviruses, can become latent in host cells, and current antiviral options do not eradicate these latent infections.

  • The chapter concludes with a discussion of oncolytic viruses, which preferentially target and kill cancer cells. This topic, though slightly different, is included for relevance.

INHIBITION OF EARLY EVENTS

  • Amantadine (a-adamantanamine, Symmetrel)

    • Description: A three-ring compound that inhibits the replication of influenza A virus.

    • Mode of Action: Blocks uncoating of the virus by inhibiting the ion channel activity of the M2 protein in the virion.

    • Effect: Prevents transcription by the virion RNA polymerase; absorption and penetration occur normally.

    • Specificity: Specifically inhibits influenza A virus; does not affect influenza B and C viruses.

    • Resistance: Most strains of influenza virus have become resistant to amantadine.

    • Side Effects: Mainly central nervous system alterations (dizziness, ataxia, insomnia).

    • Rimantadine (Flumadine): A derivative of amantadine with the same action but fewer side effects.

INHIBITION OF VIRAL NUCLEIC ACID SYNTHESIS
Inhibitors of Herpesviruses

  • Nucleoside Inhibitors: Nucleoside analogues that inhibit DNA polymerase in herpesvirus types.

  1. Acyclovir (acycloguanosine, Zovirax)

    • Description: A guanosine analogue containing a three-carbon fragment.

    • Mechanism of Action:

      • Activated preferentially within virus-infected cells by virus-encoded thymidine kinase.

      • Phosphorylated to acyclovir monophosphate (ACV-MP) and then to acyclovir triphosphate (ACV-TP), resulting in inhibition of viral DNA polymerase and chain termination due to lack of a hydroxyl group in the 3' position.

    • Selective Toxicity: Acyclovir is preferentially activated in herpes-infected cells due to more effective phosphorylation by viral kinases versus cellular kinases.

    • Therapeutic Uses: Effective in treating primary genital herpes and preventing systemic infections in immunocompromised patients.

    • Resistance: Acyclovir-resistant strains can emerge due to mutations in the viral thymidine kinase gene.

    • Side Effects: Well tolerated, but possible CNS toxicity with prolonged use.

    • Derivatives:

      • Valacyclovir (Valtrex): Oral prodrug that converts to acyclovir, effective against herpes genitalis and herpes zoster.

      • Penciclovir (Denavir): Used topically for recurrent orolabial herpes simplex.

      • Famciclovir (Famvir): Oral treatment converted to penciclovir, effective for herpes zoster and simplex infections.

  2. Ganciclovir (dihydroxypropoxymethylguanine, DHPG, Cytovene)

    • Description: Nucleoside analogue of guanosine with a four-carbon fragment.

    • Activation: Requires a CMV-encoded phosphokinase for phosphorylation.

    • Therapeutic Uses: Effective in treating CMV retinitis in patients with AIDS and can be used for disseminated infections.

    • Resistance: Resistance primarily due to mutations in the UL97 gene, impacting ganciclovir's effectiveness.

    • Side Effects: Can lead to leukopenia and thrombocytopenia, particularly in treated patients.