Antiviral Drugs - Pharmacology

Overview

• Harrison's Principles of Internal Medicine 22E, p. 1528

Classification by Target Virus

1. Anti-Herpesvirus Drugs

A. Acyclovir (Prototype)

1. Acyclovir is a guanosine analogue with no 3'-hydroxyl group on its acyclic sugar moiety.
2. It enters virus-infected cells and is monophosphorylated by viral thymidine kinase - this enzyme phosphorylates acyclovir ~100-fold faster than the host cell enzyme does. Uninfected cells activate very little drug, giving excellent selectivity.
3. Host cell kinases then convert it to the triphosphate (Acyclo-GTP), which:
   • Competes with deoxyguanosine triphosphate (dGTP) for viral DNA polymerase
   • Is incorporated into the growing viral DNA strand
   • Causes premature chain termination (lacks 3'-OH needed for next phosphodiester bond)

Figure: Incorporation of acycloguanosine monophosphate into viral DNA causes chain termination because acyclo-GMP lacks a 3'-hydroxyl group. (Lippincott Pharmacology 7e)

• Available IV, oral, topical (topical is much less effective)
• Distributes well including CSF (useful for HSV encephalitis)
• Excreted by glomerular filtration + tubular secretion; dose adjust in renal failure
• Valacyclovir = valine ester prodrug; oral bioavailability ~4x higher; rapidly hydrolyzed to acyclovir in liver/intestine

• Lippincott Illustrated Reviews Pharmacology, p. 1122-1124
• Harrison's 22E, p. 1528-1529

B. Valacyclovir and Famciclovir/Penciclovir

C. Ganciclovir and Valganciclovir

• Ganciclovir is a guanosine analogue structurally similar to acyclovir, differing by one carboxyl side chain - this gives it ~50x more activity against CMV than acyclovir.
• CMV lacks a true thymidine kinase; instead, ganciclovir is phosphorylated by the UL97 protein kinase encoded by CMV.
• Valganciclovir is the oral prodrug (like valacyclovir for acyclovir) with much better bioavailability.
• Key toxicity: myelosuppression (neutropenia, thrombocytopenia) - limits use; also nephrotoxicity.

D. Foscarnet

• Pyrophosphate analogue - directly inhibits viral DNA polymerase and HIV reverse transcriptase at the pyrophosphate-binding site, without requiring phosphorylation by viral kinase.
• Active against all herpesviruses, including acyclovir-resistant and ganciclovir-resistant strains.
• Used for CMV retinitis and acyclovir-resistant HSV/VZV in immunocompromised patients.
• Key toxicity: nephrotoxicity (most common), electrolyte disturbances (hypocalcemia, hypomagnesemia, hypophosphatemia), genital ulcers.

E. Cidofovir

• Nucleotide analogue (contains phosphonate group) - does not require viral kinase for initial phosphorylation, bypassing TK-based resistance.
• Active against CMV, acyclovir-resistant HSV, adenovirus, poxviruses.
• Severe nephrotoxicity - must be given with probenecid and IV saline pre-hydration to reduce tubular toxicity.
• Long intracellular half-life allows weekly/biweekly dosing.

F. Maribavir (newer)

• Benzimidazole that inhibits the CMV UL97 protein kinase, blocking viral replication and egress of viral particles from the nucleus.
• Approved for posttransplant CMV infection/disease refractory to ganciclovir, cidofovir, or foscarnet.
• Important: antagonizes ganciclovir (both target UL97) - do not co-administer.
• Side effect: taste disturbance (dysgeusia) is most common.

2. Anti-Influenza Drugs

A. Neuraminidase Inhibitors

• Harrison's 22E, Table 196-3

B. Baloxavir Marboxil (newer)

• Cap-dependent endonuclease inhibitor - targets the PA subunit of influenza RNA polymerase, blocking viral mRNA transcription ("cap-snatching" mechanism).
• Active against influenza A and B; single oral dose; active against oseltamivir-resistant strains.
• Dose: 40 mg once (80 mg if >80 kg).

C. Adamantanes (M2 Ion Channel Blockers)

• Amantadine and Rimantadine block the M2 ion channel of influenza A, preventing viral uncoating after endocytosis.
• Only active against influenza A (influenza B has no M2 protein).
• Largely obsolete: most circulating influenza A strains are resistant; use only if confirmed sensitivity.
• Amantadine side effects: CNS (insomnia, confusion, hallucinations - especially in elderly), anticholinergic.

3. Anti-Hepatitis Drugs

Hepatitis B (HBV)

Hepatitis C (HCV)

4. Antiretroviral Drugs (HIV)

A. Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• Most commonly used today: tenofovir/emtricitabine (Truvada) as the NRTI backbone.
• Abacavir - requires HLA-B*5701 screening before use (hypersensitivity reaction in carriers).
• Zidovudine (AZT) - first antiretroviral; causes myelosuppression, mitochondrial toxicity.

B. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Efavirenz - CNS side effects (vivid dreams, dizziness), teratogenic (avoid in first trimester); strong CYP3A4 inducer.
• Rilpivirine - better tolerated; must be taken with a substantial meal; not for high viral loads.
• All NNRTIs have a low barrier to resistance (single K103N mutation confers broad class resistance).

C. Protease Inhibitors (PIs)

• Ritonavir at low dose is a potent CYP3A4 inhibitor used as a pharmacokinetic booster ("ritonavir-boosted" regimens) to increase levels of co-administered PIs.
• Side effects: gastrointestinal, lipodystrophy, dyslipidemia, insulin resistance, hepatotoxicity.

D. Integrase Strand Transfer Inhibitors (INSTIs)

• Dolutegravir and bictegravir - high barrier to resistance; preferred in most guidelines.
• Dolutegravir is the cornerstone of WHO-preferred first-line regimens globally (e.g., TLD = tenofovir + lamivudine + dolutegravir).

E. Entry/Fusion Inhibitors

5. Anti-Respiratory Virus Drugs

Key Pharmacological Principles Summary

• Harrison's Principles of Internal Medicine 22E (2025), Ch. 196 - Antiviral Chemotherapy
• Lippincott Illustrated Reviews: Pharmacology, Ch. 34 - Antiviral Drugs
• Jawetz, Melnick & Adelberg's Medical Microbiology, 28E, Ch. 44 - Antiviral Drugs
• Goldman-Cecil Medicine, International Ed., Ch. 328 - Antivirals for Influenza