Saidala 24: Antiviral agents

Introduction

Antiviral agents are pharmacological substances designed to prevent or treat viral infections by inhibiting viral replication at specific stages of the viral life cycle.
They can be virus-specific (targeting a particular virus or group) or broad-spectrum (active against multiple viruses).
Unlike antibiotics, antivirals must act selectively against viral components without harming host cells, making development challenging.
Used in prophylaxis, acute treatment, and chronic suppression of viral infections.

General Principles of Antiviral Therapy

Selectivity: Drugs target viral proteins or enzymes absent in host cells or sufficiently different to minimize toxicity.
Timing: Most antivirals are most effective when given early in infection, before extensive viral replication.
Resistance: Viral mutations can reduce drug susceptibility, especially with monotherapy in chronic infections.
Combination therapy: Often used to enhance efficacy, reduce resistance, and target multiple replication steps.

Mechanisms of Action

1. Inhibition of Viral Entry/Attachment

Block viral binding to host cell receptors or fusion with the host membrane.
Examples:
- Enfuvirtide (HIV fusion inhibitor).
- Maraviroc (HIV CCR5 co-receptor antagonist).
- Palivizumab (monoclonal antibody against RSV F protein).

2. Inhibition of Uncoating

Prevent release of viral genome into the host cell cytoplasm.
Examples:
- Amantadine, Rimantadine (influenza A M2 ion channel blockers – largely obsolete due to resistance).

3. Inhibition of Viral Genome Replication

Nucleoside/nucleotide analogues: Incorporate into viral nucleic acids and terminate chain elongation or cause faulty replication.
Non-nucleoside inhibitors: Bind viral polymerase and inhibit activity without incorporation.
Examples:
- Acyclovir, Ganciclovir, Zidovudine, Sofosbuvir, Remdesivir.

4. Inhibition of Viral Integration

Block integration of viral DNA into host genome (retroviruses).
Example:
- Raltegravir, Dolutegravir (HIV integrase strand transfer inhibitors).

5. Inhibition of Viral Protein Processing

Protease inhibitors prevent cleavage of viral polyproteins into functional proteins.
Examples:
- Lopinavir, Darunavir (HIV).
- Glecaprevir (HCV).

6. Inhibition of Viral Assembly and Release

Neuraminidase inhibitors prevent release of newly formed influenza virions.
Examples:
- Oseltamivir, Zanamivir, Peramivir.

7. Immunomodulatory Antivirals

Enhance host immune response against viruses.
Examples:
- Interferon alfa, Interferon lambda.

Major Classes of Antiviral Agents and Examples

1. Anti-Herpesvirus Agents

Targets: HSV-1, HSV-2, VZV, CMV, EBV.
Nucleoside analogues:
- Acyclovir, Valacyclovir, Famciclovir (HSV, VZV).
- Ganciclovir, Valganciclovir (CMV).
Pyrophosphate analogue:
- Foscarnet (HSV, CMV, acyclovir-resistant strains).
Nucleotide analogue:
- Cidofovir (CMV retinitis, resistant HSV).

2. Anti-HIV Agents (Antiretrovirals)

NRTIs: Zidovudine, Tenofovir, Lamivudine.
NNRTIs: Efavirenz, Nevirapine, Rilpivirine.
Protease inhibitors: Lopinavir, Darunavir, Atazanavir.
Integrase inhibitors: Raltegravir, Dolutegravir, Bictegravir.
Entry inhibitors: Maraviroc, Enfuvirtide.

3. Anti-Hepatitis Agents

HBV: Entecavir, Tenofovir, Peginterferon alfa-2a.
HCV: Sofosbuvir, Ledipasvir, Velpatasvir, Glecaprevir, Pibrentasvir.

4. Anti-Influenza Agents

Neuraminidase inhibitors: Oseltamivir, Zanamivir, Peramivir.
Cap-dependent endonuclease inhibitor: Baloxavir marboxil.

5. Anti-Respiratory Syncytial Virus (RSV)

Ribavirin (aerosolized or systemic).
Monoclonal antibodies: Palivizumab, Nirsevimab.

6. Anti-Ebola Virus

Monoclonal antibody cocktails (Inmazeb, Ebanga).

7. Broad-Spectrum Antivirals

Ribavirin: RSV, Lassa fever, some viral hemorrhagic fevers.
Favipiravir: Investigational for influenza, Ebola, emerging viruses.

Pharmacokinetic Considerations

Many antivirals require intracellular activation (e.g., phosphorylation by viral or host kinases).
Some have poor oral bioavailability, necessitating prodrug forms (e.g., valacyclovir from acyclovir, valganciclovir from ganciclovir).
Metabolism: hepatic (CYP450) or renal excretion; dose adjustment often needed in renal impairment.
Half-lives vary widely; pegylation (as in interferons) can prolong action.

Adverse Effects – General Patterns

Gastrointestinal: Nausea, diarrhea, abdominal pain.
CNS: Headache, dizziness, insomnia.
Hematologic: Anemia, neutropenia, thrombocytopenia (notably with ganciclovir, zidovudine).
Renal: Nephrotoxicity (foscarnet, cidofovir).
Hepatic: Elevated liver enzymes, hepatotoxicity (some NRTIs, NNRTIs, protease inhibitors).
Metabolic: Lipid abnormalities, insulin resistance (protease inhibitors).

Contraindications and Precautions

Known hypersensitivity to active drug or formulation components.
Significant pre-existing organ dysfunction (renal, hepatic) without dose adjustment.
Pregnancy and lactation: Some antivirals are contraindicated or require careful benefit–risk assessment.
Concomitant use with interacting drugs that can cause severe toxicity or loss of efficacy.

Resistance Considerations

Mutations in viral enzymes targeted by antivirals can confer resistance (e.g., thymidine kinase mutations in HSV, reverse transcriptase mutations in HIV).
Cross-resistance can occur within a drug class.
Resistance testing is standard in HIV and increasingly used in HBV and HCV.

Special Populations

Immunocompromised patients: May require higher doses or prolonged therapy.
Pediatrics: Age-specific dosing and formulations needed.
Pregnancy: Certain antivirals safe (e.g., tenofovir, lamivudine), others contraindicated.
Renal/hepatic impairment: Dose adjustment or drug selection based on clearance pathways.

Future Directions in Antiviral Development

Broad-spectrum agents targeting conserved viral structures.
Long-acting injectable formulations for HIV, HBV, HCV.
Host-targeted antivirals to reduce risk of resistance.
CRISPR-based antivirals for genome editing of latent viruses.
mRNA-based antiviral therapeutics.

Saidala 24

الصفحات

Monday, August 11, 2025

Antiviral agents