Antiviral Drugs: Mechanism and Classification

• Antiviral drugs are medications designed to combat viral infections.

Lecture Outline

• The lecture will cover objectives, general introduction, and classification of antiviral agents.
• Specific drugs discussed will include anti-herpes, anti-influenza, anti-hepatitis, and anti-retroviral medications.
• The lecture will also touch on biologics and immunomodulators.

Objectives

• By the end of the lecture, one should understand the viral replication cycle and where antivirals intervene.
• It's important to classify antivirals by their treatment mode and action.
• An understanding of pharmacokinetics and pharmacodynamics of different antivirals is expected.
• The ability to apply relevant clinical practice information is an objective.

Introduction to Viruses

• Viruses are obligate intracellular organisms.
• Viral replication primarily relies on the host cell's synthetic processes.
• Viruses are classified by the nature of their nucleic acid content (DNA or RNA).
• Further subdivision is based on whether the nucleic acid is single or double-stranded and how it functions during replication.

Viral structure

• Viruses are made up of nucleic acids, a capsid, and an envelope.

Viral replication - Steps

• Adsorption and penetration into cell
• Uncoating of viral nucleic acid
• Synthesis of regulatory proteins
• Synthesis of RNA or DNA
• Synthesis of structural proteins
• Assembly of viral particles
• Release from host cell

Antiviral agents - Information

• They can block viral entry / exit from cells or act inside host cells to prevent replication.
• Antivirals should be selective to the virus.
• Viral replication steps offer critical targets for antiviral therapy.
• Most antiviral agents are virustatic, affecting only replicating viruses.
• Combination therapy may be needed for some viral infections to be effective.

Classification of Antiviral Agents

• Antivirals can be classified based on where they act during the viral replication cycle.
• Examples include blocking viral adsorption, penetration, uncoating, nucleic acid synthesis, and viral release.

Antiviral classification by therapeutic use

• Anti-herpes agents include acyclovir, famciclovir, ganciclovir, idoxuridine, foscarnet, fomivirsen, penciclovir, trifluridine, tromantadine, valacyclovir, valgancyclovir, vidarabine, cidofovir, and docosanol.
• Anti-influenza agents include amantadine, oseltamivir, peramivir, rimantadine, and zanamivir.
• Other antiviral agents include fomivirsen, enfuvirtide, imiquimod, interferon, ribavirin, and viramidine.
• Antiretroviral agents can be NRTIs, NNRTIs or Protease inhibitors.
• NRTIs: Zidovudine, Didanosine, Stavudine, Zalcitabine, Lamivudine, Abacavir, Tenofovir -NNRTIs: Nevirapine, Efavirenz, Delavirdine
• Protease Inhibitors: Saquinavir, Indinavir, Atazanavir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir, Tipranavir

Anti-Herpes Agents

• Used to treat Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) Infections.
• Examples: Acyclovir, Cidofovir, Valacyclovir, Ganciclovir, Penciclovir, Docosanol, and Foscarnet.

Anti-Herpes - Mechanism of Action

• Acyclovir, Penciclovir, and Ganciclovir require virus-specified enzymes for monophosphorylation, followed by host kinases for further phosphorylation.
• Trifluridine, Cidofovir, and Foscarnet skip the virus-specified enzyme step.
• The phosphorylated drugs can then be incorporated into viral DNA or competitively inhibit viral DNA polymerase, leading to chain termination or inhibition of DNA synthesis.

Acyclovir Pharmacokinetics

• Oral bioavailability of acyclovir is 15-20% and is unaffected by food.
• Peak serum concentrations are reached 2-3 hours after dosing.
• Acyclovir is cleared primarily by glomerular filtration and tubular secretion.
• Clearance is affected by renal failure; half-life (t ½) is 20 hours in Chronic Renal Failure (CRF).
• The half-life is approximately 3 hours in patients with normal renal function and 20 hours in patients with anuria.
• Topical formulations have high local concentrations in herpetic lesions, but systemic concentrations are undetectable.
• Acyclovir diffuses into most tissues and body fluids to produce serum concentrations that are 50-100%.
• Protein binding is 9-33%.
• Acyclovir crosses the placenta and enters breast milk, with concentrations 3 times higher than in maternal serum.

Acyclovir - Clinical Use and Dosage

• Various dosages and routes of administration are shown for different conditions such as first episode genital herpes and zoster.

Acyclovir adverse effects

• Acyclovir is generally well tolerated, with nausea, diarrhea, and headache associated with oral formulations.
• It can cause increased bilirubin and liver enzymes and hematologic changes.
• Neurological effects can occur, such as lethargy and confusion.
• Topical effects may include skin rashes and stinging.
• IV infusion may be associated with reversible renal dysfunction due to crystalline nephropathy or neurologic toxicity.
• Renal insufficiency and CNS effects are dose-limiting toxicities.
• Long-term suppressive use hasn't been associated with untoward effects.
• Resistance can occur through selective mutation of the enzyme thymidine kinase.
• Drug interactions can occur with probenecid, increasing acyclovir's half-life.

Ganciclovir

• Its an acyclic guanosine analog that requires triphosphorylation for activation.
• Monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells.

Ganciclovir - Mechanism of Action

• Similar to Acyclovir in which it is activated by viral kinase to mono-phosphate and then is activated by host cell kinases to di and tri phosphate.
• It then activates drug DNA polymerase and viral division.

Ganciclovir - Pharmacokinetics

• Administered orally, IV, and intra-ocularly.
• There is a low oral bioavailability
• Administered intraveneously.
• The prodrug is Valganciclovir.
• Plasma half life is 2-4 hours in normal renal function, affected if there is affected renal function.

Ganciclovir - Clinical uses

• Used in treatment of CMV retinitis and prevention of CMV retinitis in transplant patients.
• For CMV retinitis, a dosage of 1000mg tds for oral ganciclovir or 900mg bd for 21 days with oral valaganciclovir can be used, with reduction to 900mg od.
• Intravitreal ganciclovir injections have been used and an intraocular sustained-release ganciclovir implant (VITRASERT) is more effective than systemic dosing in suppressing retinitis progression

Ganciclovir - Adverse effects

• Bone marrow suppression, leukopenia, and thrombocytopenia.
• Nausea, diarrhea, fever, rash, headache, insomnia, peripheral neuropathy and retinal detachment in patients with CMV retinitis.

Valganciclovir

• Used for CMV retinitis in patients with AIDS.
• It's an oral dosage form with 450 mg capsules.

Valganciclovir - Pharmacokinetics

• Well absorbed and rapidly metabolized in the intestinal wall and the liver to ganciclovir.
• Absolute bioavailability is 60%.
• Major route of elimination is renal through glomerular filtration and tubular secretion.

Cidofovir

• Cidofovir is a cytosine nucleoside analog with in vitro activity against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses and human papillomavirus

Cidofovir - Indications

• Treatment of CMV retinitis, given IV.
• Treatment of polyomaviruses-associated progressive multifocal leukoencephalopathy in AIDS patients.
• Post-exposure prophylaxis against small pox.
• Topical treatment of molluscam contagiosam.

Cidofovir - Dose

• Intravenous
• For CMV retinitis induction, use 5 mg/kg every 7 days, and for maintenance, use 5 mg/kg every 14 days.

Cidofovir - Contraindications

• Renal insufficiency
• Concurrent administration of potentially nephrotoxic agents e.g. amphotericin B, aminoglycosides, NSAIDs, pentamidine, etc.

Cidofovir- Adverse reactions

• Dose-dependent nephrotoxicity
• Uveitis
• Decreased intraocular pressure
• Probenecid related hypersensitivity reactions
• Rare neutropenia and metabolic acidosis

Fosarnet

• Foscarnet is a direct inhibitor of DNA Polymerase and Reverse Transcriptase.
• It is used in the treatment of CMV retinitis and CMV infection resistant to Ganciclovir.
• It's available as topical and intravenous formulations because of its poor aqueous solubility.

Other Anti-Herpes Agents

• Idoxuridine and Trifluridine are topical agents used for hepatic keratitis, CMV, and keratoconjuctivitis by herpes simplex II.
• Formulations are topical, ocular
• Adverse reactions include pain, pruritus and inflammation
• Topical agents are unlikely to cause allergic reactions
• Famiciclovir is an alternative to Acyclovir for genital/orolabial herpes and Herpes Zoster.
• Most contraindications are renal insufficiency.

Anti-Influenza Agents

• Used in treatment of acute uncomplicated influenza and for preventive purposes.
• The drug activity depends on the type of influenza specie.
• The agents are classified into 2 categories: Adamantes (Amantadine, Rimantadine) and Neuraminidase Inhibitors (Oseltamivir and Zanamivir).

Adamantanes - Mechanism of action

• Tricyclic amines inhibit uncoating of viral RNA influenza A within infected host cells, preventing its replication.
• They exert their effect by blocking the M2 ion channel, which inhibits uncoating of viral RNA and viral disassembly within infected host cell.

Adamantanes - Pharmacokinetics

• Amantadine well absorbed, with 67% being protein bound.
• Rimantadine is 40% protein bound.
• Plasma half-life is 12-18 hours for Amantadine and 24-36 hours for Rimantadine.
• Varies with renal function for Amantadine and hepatic function for Rimantadine.

Adamantanes - Indications

• Treatment of Type A infections
• Administered as 100mg bd or 200mg od if no resistance is present.
• 70-90% effectiveness to prevent illness
• Rimantadine is 4-10 times more active than Amantadine.

Adamantanes- Adverse effects

• Usually dose dependent and may lapse in 1st week of treatment.
• Rimantadine has less neurotoxic side effects
• GI intolerance-Nausea, Anorexia
• CNS complaints include nervousness, difficulty in concentrating, and light-headedness.
• Concomitant use of Amantadine with antihistamines, anticholinergic drugs, hydrochlorothiazide, trimethoprim-sulfamethoxazole increases CNS toxicity.

Adamantanes - Precautions

• High plasma concentrations of amantadine (1-5 ug/ml) results into neurotoxic reactions.
• Dose reductions for both agents in the elderly and in renal insufficiency.
• Exercise caution with Rimantadine in hepatic insufficiency.
• May cause birth defects due to teratogenicity and embryotoxicity.

Neuraminidase Inhibitors

• The first line agents in type A and B Influenza, including Oseltamivir and Zanamivir.
• As analogs of sialic acid, they interfere with release of progeny influenza virus from infected host cell.
• Neuraminidase cleaves sialic acid residues and destroys receptors recognized by viral hemagglutinin (present on cell surface in progeny virions).
• This action is essential for virus release from infected cell.
• The drugs interact with neuraminidase causing a conformational change within enzyme active site thus inhibits activity.
• Competitive inhibition and reversible interaction with the active enzyme site prevents viral neuraminidase activity at low concentrations, leading to clumping of newly released influenza virions to each other and to membranes of infected cells.
• The carboxylate form of Oseltamivir is active, and the ethyl ester prodrug lacks antiviral activity.

Neuraminidase Inhibitors - Indication

• To treat acute uncomplicated influenza infections, Oseltamivir dose is 75 mg bd for 5 days.
• Children's doses are weight-adjusted, shown to reduce illness duration, speed recovery, and reduce complications.
• The preventive dose is 75mg od
• Zanamivir is administered as 10mg inhalation powder bd for 5 days and the preventive dose is 10mg od.
• Oseltamivir (Tamiflu) is available as 75 mg capsule and powder to reconstitute as suspension (12 mg/ml).

NIs - Adverse effects

• Oseltamivir-Nausea, Abd pain and Vomiting, Headache, fatigue, diarrhoea and transient neuropsychotic events, usually resolve with time.
• Zanamivir-Cough and bronchospasm, reversible decrease in pulmonary function and transient nasal and throat discomfort, and is not recommended with airway disease

Neuraminidase Inhibitors - Drug Interactions

• Probenecid doubles plasma half life of carboxylate, decreasing clearance by 50%.
• Caution in pregnancy!
• Check dose adjustment in renal pts.
• Resistance is associated with point mutations in viral neuraminidase/hemagglutinin.

Anti-Hepatitis Drugs

• Agents are used in the treatment of Hepatitis B and HCV infections.
• Include Interferon Alfa, PEGylated Interferon Alfa, Lamivudine, Adefovir, Tenofovir, Cidofovir, Ribavirin, and Entecavir.

Interferon Alpha

• They're naturally occurring small proteins that exert complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic synthesis of both RNA and protein.
• Synthesized by host cell in response to various inducers, causing biochemical changes that lead to an antiviral state in cells.
• Interferons belong to the large class of glycoproteins known as cytokines. There are different classes-alpha, beta and gamma.

Interferon alpha - Mechanism of action

• Interferons bind specific ganglioside receptors on the host cell membrane, inducing enzyme production that inhibits translation of viral mRNA into viral protein, leading to viral replication halt.
• Increase host cell expression of MHC complex antigens and increase phagocytic activity of macrophages, augmenting proliferation and survival of T cells.
• The antiviral activity is via inhibition of viral penetration, uncoating, and mRNA synthesis.

Interferon Alpha Pharmacokinetics

• Maximum serum concentrations occur approximately 4 hours after IM administration and approximately 7 hours after SC administration.
• Elimination half-life is 2-5 hours depending on the route of administration.
• Alfa interferons are filtered at the glomeruli and undergo rapid proteolytic degradation during tubular re-absorption, such that detection in the systemic circulation is negligible

Interferon Alpha - Clinical Uses

• Used in the treatment of both HBV and HCV virus infections with Interferon alpha 2a.
• Administered as 5MU/day or 10MU in adults for 3 times for 4-6 weeks; children dosage is 6MU/m2 for the same duration.
• Interferon alfa-2b is the only preparation licensed for treatment of chronic HBV and HCV infections weekly.
• A dose of 3MU three times a week is used if monotherapy is instituted.
• Other Uses include treatment of Hairy cell leukemia, adjuvant to surgical treatment of malignant melanoma, clinically aggressive follicular lymphoma, and AIDS-Related Kaposi's Sarcoma.
• A PEGylated moiety (polyethylene glycol complexed) shows more effectiveness with increased proportion of HbeAg seroconversion, with a steadier half life thus less dosing, especially in HCV.
• The moiety is the standard treatment for chronic HCV infection, administered as alpha 2a-180micrograms S.C weekly for 48 weeks. Alpha 2b is 5micrograms/kg/week for 1 year, in combination with oral Ribavirin, once weekly dose.

Interferon Alpha - Adverse effects

• A flu-like syndrome within 6 hours after dosing in more than 30% of patients that tends to resolve upon continued administration
• Thrombocytopenia and granulocytopenia
• Neurotoxicity
• Cardiotoxicity
• Hepatotoxicity
• Interstitial nephritis
• Hypersensitivity reactions (rare)
• Impairment of fertility

Interferon Alpha - Contraindications

• Pregnancy
• Hepatic decompensation
• Autoimmune disease
• Hx of Cardiac Arrhythmias
• Exercise caution for Psychiatric dx, epilepsy, thyroid dx, ischemic heart disease, renal insufficiency and cytopenias

Adefovir

• Nucleotide analog of adenosine monophosphate
• Competitively inhibits viral DNA polymerase and reverse transcriptase
• Terminates DNA synthesis
• Used to treat HBV

Adefovir - Indications

• Treatment of chronic HBV infection can result in complete seroconversion & used in Lamivudine resistant patients.
• Is administered orally tablets.

Adefovir - Pharmacokinetics

• Low oral BA and drug is rapidly absorbed and hydrolyzed in intestine and blood
• Increased half life, and excreted changed in kidneys

Adefovir - Adverse Effects

• Dose dependent nephrotoxicity and tubular dysfunction
• Monitor every 3 months
• Can occur with lower doses (headache, discomfort)
• Can cause kidney damage

Ribavirin

• Guanosine analogue that is phosphorylated intracellularly by host cell enzyme
• Interferes with synthesis of guanosine triphosphate, to inhibit capping of viral messenger RNA and inhibit viral RNA-dependent RNA polymerase of certain viruses.

Ribavirin - Indications

• Treats chronic hepatitis and is useful in influenza

Ribavirin- adverse effects/cautions/contraindications

• Can cause hemolytic anemia, depression, fatigue and reduce creatinine clearance.
• Should not be taken when pregnant, or anemic.

Other Anti-Hepatitis Drugs

• Tenofovir is active against Lamivudine and Entecavir-resistant hepatitis, licensed in treatment of chronic HBV infection and is more effective than Adefovir.
• Lamivudine use in HBV is based on prolonged intracellular half-life and inhibits HBV DNA polymerase, leading to chain termination.
• Useful in initial rapid and potent viral suppression, and chronic therapy can lead to resistance with an excellent safety profile.
• Entecavir inhibits all functions of HBV DNA polymerase, its oral has a high BA, and its best taken on an empty stomach.
• Generally well tolerated.
• Should not be co-administered with drugs that reduce kidney function.