Antiviral Drugs

Learning Objectives

• Describe the general characteristics of pathogenic viruses.
• Recognize the general targets of antiviral drugs.
• List the major classes of antiviral drugs and their mechanisms of action.
• List common indications, major side effects, contraindications, and drug interactions of antiviral drug classes and individual drugs.
• Explain potential causes and processes involved in resistance to antivirals.

Antiviral Drug Targets

• Attachment to the host cell and entry is a target.
• Viral uncoating is a target.
• Nucleic acid synthesis is a target.
• Viral protein synthesis is a target.
• Assembly and release of viral particles is a target.

Antiviral Drug Classification

• Inhibitors of cell penetration.
• Inhibitors of viral uncoating.
• Nucleic acid synthesis inhibitors.
  • Inhibitors of viral DNA and RNA synthesis.
  • Reverse transcriptase inhibitors.
    • Nucleoside RTIs (NRTIs).
    • Non-nucleoside RTIs (NNRTIs).
• Integrase strand transfer inhibitors.
• Assembly and release of viral particles.
  • Protease inhibitors (HIV).
  • Neuraminidase inhibitors (Influenza).

Inhibitors of Cell Penetration: Enfuvirtide (Fuzeon®)

• Enfuvirtide is a fusion inhibitor.
• It's a 36 amino acid protein.
• Administered subcutaneously.
• Indicated as an antiretroviral agent, combined with other antiretroviral drugs, for patients with persistent HIV-1 replication.
• Adverse drug reactions include: fatigue, insomnia, GI upset, injection site reactions, and hypersensitivity.
• Binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational change required for fusion with the host cell membrane.

Inhibitors of Viral Uncoating: Amantadine (Symmetrel®) and Rimantadine (Flumadine®)

• Active against influenza A virus.
• Inhibit viral uncoating within the host cell.
• Drugs interfere with the ion channel function of the viral membrane M2 protein and inhibit the late stage of virion uncoating.
• Influenza B virus lacks the M2 protein, so these drugs aren't effective against it.

Nucleic Acid Synthesis Inhibitors

• Inhibit viral DNA and RNA synthesis.
• Reverse transcriptase inhibitors (RTIs) are included
  • Nucleoside RTIs (NRTIs).
  • Non-nucleoside RTIs (NNRTIs).

Inhibitors of Viral DNA and RNA Synthesis

• DNA synthesis inhibitors: Acyclovir, Ganciclovir, Valacyclovir, and Famciclovir.
• DNA and RNA synthesis inhibitors: Foscarnet.

Acyclovir (Zovirax®)

• Acyclovir is a synthetic guanosine analog.
• Prototype of anti-herpesvirus drugs.
• It is distributed in most tissues and fluids, including CSF.
• Excreted renally.
• Is indicated for infections by HSV (e.g., cold sores), Varicella zoster virus (chicken pox), and HZV (shingles), and can be administered orally, intravenously, or topically.
• ADRs: well-tolerated, but can cause malaise, headache, GIT disturbances, and reversible renal dysfunction with IV infusion.
• Can diminish the therapeutic effect of the Zoster Vaccine.
• Discontinue use 24 hours prior and 14 days after a live attenuated zoster vaccine.

Acyclovir MOA

• Conversion to monophosphate (MP) derivative by herpes virus thymidine kinase.
• Acyclovir-MP is then phosphorylated to acyclovir-DP and acyclovir-TP by cellular enzymes.
• Uninfected cells do convert little to no drug to phosphorylated derivatives.
• Acyclovir is selectively activated in cells infected with herpes viruses that code for appropriate thymidine kinases.
• Incorporation of acyclovir-TP into the primer strand during viral DNA replication leads to chain termination and formation of an inactive complex with the viral DNA polymerase.

Reverse Transcriptase Inhibitors (RTIs)

• Nucleoside RTIs (NRTIs).
• Non-nucleoside RTIs (NNRTIs).

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

• NRTIs are nucleoside analogs and competitive inhibitors of HIV reverse transcriptase.
• Require conversion in the host cytoplasm to a triphosphate form to become active.
• Viral reverse transcriptases are more sensitive to NRTIs compared to host cell polymerases, making them less toxic to host cells.

Zidovudine or Azidothymidine or AZT (Retrovir®)

• Antiretroviral drug.
• Deoxythymidine analog inhibitor of RT.
• Prototype of NRTIs.
• Well absorbed from the GIT.
• Distributed to most tissues and CSF.
• Glucuronidated in the liver and excreted in urine.
• Slows disease progression and prolongs survival in HIV patients.
• Used as a prophylactic agent in cases like needle stick injury and unprotected sex and prevents mother-to-child transmission.
• ADRs: myelosuppression is most common. GIT and CNS effects usually resolve during therapy. Avoid other myelosuppressants like ganciclovir and ribavirin.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• Non-nucleoside compounds don’t have to be phosphorylated.
• Cause conformational changes in the HIV-1 RT enzyme by binding to it at a site distant from the catalytic site.
• Used with NRTIs in combination therapy, since they bind to a different site.
• There is no cross-resistance between NRTIs and NNRTIs.

Nevirapine (Viramune®)

• Non-nucleoside compound that does not need to undergo phosphorylation.
• Causes conformational change to RT.
• Oral bioavailability is excellent and distributes to CSF.
• Antiretroviral drug active against HIV-1 and a component of HIV combination therapy.
• ADR's include dangerous nevirapine-associated ADRs that may cause an abrupt onset of flu-like symptoms, abdominal pain, jaundice, or fever, with or without rash.
• May have progression to hepatic failure with encephalopathy and skin rash, increase in cholesterol.
• Boxed warnings: Severe hepatotoxicity and severe life-threatening skin reactions.
• Is a strong inducer of CYP3A4, which decreases plasma levels of carbamazepine, clozapine, dronedarone, ketoconazole, nifedipine, ranolazine, rivaroxaban, etc. (Cat X interaction).

Baloxavir marboxil (Xofluza®)

• Approved in 2018.
• Converted to baloxavir (mainly by UGT1A3), inhibiting endonuclease activity of a selective polymerase acidic (PA) protein required for viral gene transcription.
• Treats acute uncomplicated influenza in patients ≥12 years old who have been symptomatic for no more than 48 hours.
• Common adverse effects include diarrhea and nasopharyngitis.
• It's not effective in bacterial infections.
• Drug-drug and drug-food interactions.
• Contraindicated in hypersensitivity cases.
• Metallic ions (Fe, Mg, Se, Ca, Zn) and vitamins (ADEK) reduce serum concentrations.
• Avoid anti-influenza antivirals 48 hours before and 2 weeks after a live influenza virus vaccine administration period.

Integrase Strand Transfer Inhibitors

• A type of antiviral drug classification

Raltegravir (Isentress®)

• First integrase strand transfer inhibitor.
• Viral cDNA strand made by reverse transcriptase is processed and inserted into the human genome by the enzyme HIV-1 integrase.
• Inhibits the catalytic activity of integrase, preventing integration of the proviral gene into human DNA.
• Indicated for treatment of HIV-1 infection in combination with other antiretroviral agents.
• Adverse drug reactions: Increased ALT, insomnia, headache, increase in blood glucose.
• Pregnancy category: C.
• Aluminum hydroxide and Magnesium hydroxide reduces plasma levels. (Category X).

Drugs Affecting Assembly and Release of Viral Particles

• Assembly of Virions: Protease inhibitors (HIV).
• Release of Virions: Neuraminidase inhibitors (Influenza).

HIV Protease Inhibitors

• HIV-1 protease is a dimeric aspartyl protease, essential for viral proliferation.
• Encoded in the HIV genome, absent in uninfected CD4 cells.
• Autocatalyzed proenzyme product into the active protease enzyme attacks the precursor protein to generate necessary viral proteins.
• Protease inhibitors bind reversibly to the protease's active site, preventing its function and leads to the assembly of nonfunctional virions.

Saquinavir (Fortovase®)

• Selectively toxic, inhibiting HIV-encoded proteases, but not host-encoded aspartyl proteases.
• Binds reversibly to the active site of HIV protease, preventing polypeptide processing and subsequent virus maturation.
• Virus particles are produced in the presence of saquinavir, but are noninfectious.
• Treatment of HIV infection in combination with two or more other antiretroviral agents.
• Common adverse effects include nausea, chest pain and fatigue.
• Contraindications include congenital or acquired QT prolongation, AV Block, and Hepatic impairment.
• It's a strong inhibitor of CYP3A4 and protease and will therefore increase the plasma concentration of several drugs.
• Saquinavir bioavailability is better from a soft gelatin capsule dosage form.

Neuraminidase Inhibitors

• Influenza A and B viruses possess neuraminidase enzyme that are highly conserved in these viruses
• Neuraminidase (NA) is a viral glycoprotein that cleaves sialic acid residues that are linked to glycoproteins and glycolipids
• This action is essential for the release of the virus from infected cells
• Neuraminidase inhibitors prevent the release of virions, leading to virus aggregation on the cell surface, and reduce the spread in the respiratory tract

Oseltamivir (Tamiflu®)

• Is a pro-drug that's administered orally.
• Indicated for uncomplicated acute illness due to influenza (A or B) infection in children ≥2 weeks and adults who have been symptomatic for no more than 2 days.
• Used for prophylaxis against influenza (A or B) infection in children ≥1 year of age and adults.
• Excreted renally and increases plasma levels of oseltamivir.
• Adverse effects include nausea and abdominal discomfort.
• It may diminish the therapeutic effect of the influenza virus vaccine, so avoid anti-influenza antivirals during the period beginning 48 hours before and ending 2 weeks after vaccine administration.
• Individuals receiving it within 2 weeks of an intranasal spray vaccine should receive a repeat vaccine dose.
• Pregnancy category: C.

HAART (Highly Active Antiretroviral Therapy)

• Involves a combination or “cocktail” of several antiretroviral medicines to slow the rate at which HIV makes copies of itself in the body.
• Consists of three or more antiretroviral medicines combined.
• Highly effective in treating HIV when compared to monotherapy.
• Commonly used drugs include: NRTs, NNRTIs, protease inhibitors, fusion and entry inhibitors, and integrase inhibitors.

Potential Targets for SARS-CoV-2

• Camostat mesylate is a protease inhibitor that blocks the entry of SARS-CoV-19 in the cell by blocking transmembrane protease serine 2 (TMPRSS2).
• ACE2 inhibitors could also block entry.