Antiviral Agents: Classification and Mechanisms

• Antiviral drugs are used to treat viral infections by targeting the viral replication cycle.
• A virus is an obligate intracellular organism, which relies on the host cell's synthetic processes for replication.
• Viruses are classified based on if the nucleic acid is single or double stranded and how these function at replication.
• Viruses are composed of nucleic acids, a capsid, and sometimes an envelope.
• Viral replication steps include adsorption and penetration, uncoating of viral nucleic acid, synthesis of regulatory and structural proteins, synthesis of RNA or DNA, assembly of viral particles, and release from the host cell.
• Antiviral agents either block entry/exit from the cell or act inside the host cell to selectively prevent viral replication, offering critical targets for antiviral therapy.
• Most antiviral agents are virustatic, affecting only replicating viruses, necessitating combination therapy for some infections.

Classification of Antiviral Agents

• Antiviral drugs are classified based on their therapeutic uses, including anti-herpes, anti-influenza, anti-hepatitis, and anti-retroviral agents, along with biologics and immunomodulators.
• The sites of antiviral drug action is illustrated in a diagram, showing points of intervention such as viral adsorption, penetration, uncoating, nucleic acid synthesis, protein synthesis and processing, and viral release.
• Anti-herpes virus agents include include Acyclovir, Famcyclovir, Gancyclovir, Idoxuridine, Foscarnet, Fomivirsen, Pencyclovir, 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.
• Anti-retroviral agents include NRTIs (Zidovudine, Didanosine, Stavudine, Zalcitabine, Lamivudine, Abacavir, Tenofovir), NNRTIs (Nevirapine, Efavirenz, Delavirdine), and Protease Inhibitors (Saquinavir, Indinavir, Atazanavir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir, Tipranavir).

Anti-Herpes Agents

• Agents that treat Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) Infections.
• Acyclovir, Cidofovir, Valacyclovir, Ganciclovir, Penciclovir, Docosanol and Foscarnet.
• Antiviral mechanisms of antiherpes agents are shown in a diagram, including virus-specified enzymes and host kinases involved in monophosphate, diphosphate, and triphosphate transformations, leading to chain termination and inhibition of viral DNA synthesis.

Acyclovir

• Oral acyclovir bioavailability is 15-20% and unaffected by food, necessitating prodrug formulations like Valacyclovir.
• Peak serum concentrations are reached 2-3 hours after dosing.
• Acyclovir is cleared primarily by glomerular filtration and tubular secretion.
• Acyclovir clearance is affected by renal failure, resulting in a t½ of 20 hours in CRF, it has a half-life of approximately 3 hours in patients with normal renal function and 20 hours in patients with anuria.
• Topical formulations produce high local concentrations in herpetic lesions, but systemic concentrations are undetectable.
• Acyclovir diffuses into most tissues and body fluids, producing concentrations 50-100% of those in serum.
• Acyclovir protein binding is 9-33%.
• It crosses the placenta and breast milk, with concentrations three times higher than in maternal serum.
• Acyclovir is generally well tolerated; adverse effects include nausea, diarrhea, headache with oral use, increased bilirubin and liver enzymes, hematologic changes, neurological effects (lethargy, somnolence, confusion, agitation), and topical effects (skin rashes, stinging, burning).
• IV infusion can cause reversible renal dysfunction or neurologic toxicity, which is uncommon with adequate hydration and slow infusion rates.
• Dose-limiting toxicities involve renal insufficiency and CNS effects.
• Chronic daily suppressive use for over 10 years has not shown untoward effects.
• Resistance can occur via selective mutation of enzyme thymidine kinase.
• Probenecid increases acyclovir's t1/2 due to renal clearance blockade.

Clinical Uses and Dosage Forms

• Dosages are detailed for: first episode and recurrent genital herpes, genital herpes suppression, herpes proctitis, mucocutaneous herpes, varicella, herpes zoster, severe HSV infection, herpes encephalitis and neonatal HSV infection, with separate doses provided for oral or intravenous acyclovir.

Ganciclovir

• Ganciclovir is an acyclic guanosine analog requiring triphosphorylation for activation.
• Monophosphorylation is catalyzed by a phosphotransferase in CMV and by thymidine kinase in HSV cells.
• It is activated by viral kinase to mono-phosphate, then by host cell kinases to di & tri-phosphate, activating drug DNA polymerase & viral division
• Ganciclovir is administered orally, IV, and intra-ocularly, with low oral bioavailability; prodrug is Valganciclovir.
• Ganciclovir plasma t1/2 is 2-4 hours in normal renal function; clearance is affected in renal function.

Clinical Uses of Ganciclovir

• Clinical use includes treatment of CMV retinitis(main stem use) and prevention of CMV retinitis in transplant patients.
• CMV retinitis dosage: 1000mg tds for oral ganciclovir, 900mg bd for 21 days with oral valaganciclovir with reduction to 900mg od
• Intravitreal ganciclovir injections and intraocular sustained-release implants (VITRASERT) are effectively used to suppress retinitis progression.
• Adverse effects include myelosuppression, leukopenia, thrombocytopenia, nausea, diarrhea, fever, rash, headache, insomnia, peripheral neuropathy, and retinal detachment.

Valganciclovir

• It is indicated for the treatment of CMV retinitis in patients with AIDS.
• Available in oral dosage forms, 450 mg capsules.
• Valganciclovir is well absorbed and rapidly metabolized in the intestinal wall and liver to ganciclovir.
• Valganciclovir absolute bioavailability is 60%.
• Valganciclovir is eliminated mainly renally via glomerular filtration and tubular secretion.

Cidofovir

• Cidofovir is active in vitro against CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses and human papillomavirus.
• It is indicated for the treatment of CMV retinitis and polyomaviruses-associated progressive multifocal leukoencephalopathy in AIDS patients
• Post exposure prophylaxis against small pox and topical treatment of molluscam contagiosam
• Cidofovir is administered intravenously, induction: 5 mg/kg every 7 days, maintenance: 5 mg/kg every 14 days.
• Contraindications include renal insufficiency and concurrent administration of nephrotoxic agents like amphotericin B, aminoglycosides, NSAIDs, pentamidine, foscarnet, tacrolimus, and neomycin.
• Adverse reactions: dose-dependent nephrotoxicity, uveitis, decreased intraocular pressure, probenecid-related hypersensitivity, rare neutropenia, and metabolic acidosis.

Foscarnet

• It is a direct inhibitor of DNA Polymerase and Reverse transcriptase.
• It is used to treat CMV retinitis and Ganciclovir-resistant CMV infections.
• Foscarnet formulations are topical and intravenous due to poor aqueous solubility.

Idoxuridine and Trifluridine

• These are topical agents used for hepatic keratitis, CMV and keratoconjuctivitis caused by herpes simplex II.
• Formulations are topical and ocular
• Adverse reactions include pain, pruritus, inflammation, and edema involving the eye or lids, with rare allergic reactions.

Famciclovir

• It is an alternative to Acyclovir for treating genital/orolabial herpes and Herpes Zoster.

Anti-Influenza Agents

• These are used to treat acute uncomplicated influenza and for preventive purposes.
• Their activity depends on the type of influenza species.
• It is classified into Adamantanes (Amantadine, Rimantadine) and Neuraminidase Inhibitors (Oseltamivir and Zanamivir).
• Permavir is an investigational agent in the U.S. and approved in Japan at a dose of 600 mg intravenously once daily in adults.

Adamantanes Mechanism

• Tricyclic amines inhibit uncoating of viral RNA of influenza A within infected host cells, preventing replication.
• This works by blocking the M2 ion channel, which inhibits uncoating of viral RNA and viral disassembly within infected host cells.
• Amantadine is well absorbed, with 67% protein bound, while Rimantadine is 40% protein bound.
• The plasma half-life of Amantadine is 12-18 hours and of Rimantadine is 24-36 hours, depending on renal function for Amantadine and hepatic function for Rimantadine.

Adamantanes Indications

• Administrate for Type A infections: 100mg bd or 200mg od if no resistance is present, preventing illness in 70-90% of cases.
• Rimantadine is 4-10 times more active than Amantadine.
• Adverse effects are usually dose-dependent and may lapse within the 1st week of treatment. Rimantadine has less neurotoxic side effects.
• Gl intolerance-Nausea and Anorexia
• CNS complaints (nervousness, difficulty concentrating, light headedness).
• Concomitant use of Amantadine with antihistamines, anticholinergic drugs, hydrochlorothiazide, and trimethoprim-sulfamethoxazole increases CNS toxicity.
• High plasma concentrations of amantadine (1-5 ug/ml) can produce serious neurotoxic reactions.
• Dose reductions are needed in the elderly and in those with renal insufficiency when using both agents.
• There is caution with Rimantadine in cases of hepatic insufficiency.
• May cause birth defects due to teratogenicity and embryotoxicity.

Neuraminidase Inhibitors

• These are the first-line agents in type A and B Influenza, including Oseltamivir and Zanamivir.
• As analogs of sialic acid, they interfere with the release of progeny influenza virus from infected host cells.
• Neuraminidase cleaves sialic acid residues and destroys receptors recognized by viral hemagglutinin (present on cell surface in progeny virions), essential for viral release from infected cells.
• They interact with neuraminidase, causing a conformational change within the enzyme active site, inhibiting activity.
• The competitive inhibition and reversible interaction with the active enzyme site prevents viral neuraminidase activity at low concentrations. This leads to clumping of newly released influenza virions to each other and to membranes of infected cells.
• The carboxylate form of Oseltamivir is active; the ethyl ester prodrug lacks antiviral activity.
• These are indicated for treatment of acute uncomplicated influenza infections as the Oseltamivir dose is p.o 75 mg bd for 5 days for adults.
• Adjust Oseltamivir dose for children according to weight, it reduces illness duration, speeds recovery, and reduces complications; preventive dose is 75mg od.
• Zanamivir is administered as 10mg inhalation powder bd for 5 days, preventive dose is 10mg od.
• Available dosage forms: Zanamivir (Relenza) is administered via oral inhalation of dry powder (5 mg), with a breath-actuated device; IV infusion is 200mg.
• Zanamivir dose includes dry powder 5 mg with breath actuated device and IV infusion 200mg.
• Oseltamivir (Tamiflu) is available in oral capsules of 75 mg.

Neuraminidase Inhibitors Side Effects

• Oseltamivir related side effects: Nausea, Abd pain, and Vomiting (usually resolve), Headache, fatigue, diarrhoea, and transient neuropsychotic events.
• Zanamivir related side effects cough, bronchospasm (potentially severe), reversible impairment of pulmonary function, transient nasal and throat discomfort and is not recommended for patients with underlying airway disease.
• Probenecid doubles the plasma half-life of the carboxylate, decreasing clearance by 50%, indicating tubular secretion by anionic pathway
• Caution is advised during pregnancy.
• Adjust dose carefully in renal pts, carboxylate serum levels increase with declining renal fn.
• Resistance is associated with point mutations in viral neuraminidase/hemagglutinin.

Anti-Hepatitis Drugs

• Used in the treatment of Hepatitis B and HCV infections.
• Hepatitis drugs act differently; treatments include Interferon Alfa, PEGylated Interferon Alfa, Lamivudine, Adefovir, Tenofovir (Nucleoside Reverse Transcriptase Inhibitor (NRTI)), Cidofovir, Ribavirin and Entecavir.

Interferon Alpha

• Naturally occurring small proteins with complex antiviral, immunomodulatory, and antiproliferative activities through cellular metabolic processes involving RNA and protein synthesis.
• Synthesized by host cells in response to various inducers, causing biochemical changes that induce an antiviral state.
• Belong to the large class of glycoproteins known as cytokines, with classes including alpha, beta, and gamma.
• They bind specific ganglioside receptors on host cell membranes, inducing enzyme production that inhibits translation of viral mRNA into viral protein, halting viral replication.
• Intrefereon also stimulates the cytotoxic activity of lymphocytes, natural killer cells, and macrophages, via increasing host cell expression of MHC complex antigens, as well as increased phagocytic activity of macrophages.
• Interferon has antiviral activities via inhibition of viral penetration, uncoating, and mRNA synthesis.
• Maximum serum concentrations occur approximately 4 hours after IM administration and 7 hours after SC 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.

Clinical Uses of Interferon Alpha

• Treats both HBV and HCV virus infections with Interferon alpha 2a (5MU/day or 10MU in adults 3 times for 4-6 weeks; 6MU/m2 children's dosage).
• Interferon alfa-2b is the only product licensed to treat chronic HBV and HCV weekly; a monotherapy dose is 3MU three times/week.
• Other Uses
• Treatment of Hairy cell leukemia
• Treatment of clinically aggressive follicular lymphoma
• Treatment of AIDS-Related Kaposi's Sarcoma
• Administer Alpha2a 180micrgms S.C weekly for 48 weeks while Alpha 2b is 5microgms/kg/week for 1 year, either via combination Oral Ribavirin, given as a once weekly dose.
• Adverse effects include a flu-like syndrome within 6 hours after dosing in >30% of patients, resolving upon continued administration
• Additional adverse effects, after high does, include thrombocytopenia, granulocytopenia, neurotoxicity (fatigue, sleepiness, confusion, seizures), cardiotoxicity, and interstitial nephritis
• Rare hypersensitivity reactions and impairment of fertility

Contraindications

• Pregnancy (abortifacient)
• Hepatic decompensation
• Autoimmune diseases
• Hx of cardiac arrhythmias
• Psychiatric dx, epilepsy, thyroid dx, ischemic heart disease, renal insufficiency and cytopenias.

Adefovir Mechanism and Indication

• A nucleotide analog of adenosine monophosphate that competitively inhibits viral DNA polymerase and reverse transcriptase, also terminating DNA synthesis.
• High HBV DNA polymerase affinity for selectivity, used to treat chronic HBV infection.
• Results to complete seroconversion, used in patients that are resistant to Lamivudine
• Available in oral tablets: 10 mg, for chronic HBV 10 mg od orally.
• prodrug is rapidly absorbed and hydrolyzed, increasing BA to approximately 30-60%
• The serum half life is approximately 7.5 hours, and is increased to 5-18 hours in the diphosphate form for o.d dosing
• Adefovir is secreted unchaged in the kidneys for treatment by treatment glomerular filtration and tubular reabsorption
• Reduce dosage in levels below 50ml/min
• It is also haemodialysable
• It genotoxic and high doses cause renal tubular nephropathy, hepatotoxicity and lymphoid tissue toxicity.
• Adverse effects include dose-dependent nephrotoxicity and tubular dysfunction-azotemia, hypophosphatemia, acidosis, glycosuria and proteinuria (monitor every 3 months)
• Other adverse effects are headache, abdominal discomfort, asthenia, diarrhoea,
• Hepatomegaly with steatosis: withdraw if there's a rapid increase in aminotransferases with steatosis or lactic acidosis.
• Check liver enzymes cautiously to understand if its in response to medication toxicity
• Acute heptic exacerbations has occurred in patients stopping treatment, close monitoring with necessary resumption needed
• Ibuprofen increases bioavailability by adefovir by 23%
• Caution and increased risk of lactic acidosis and steatosis are needed when given with nucleoside analogs

Ribavirin

• A guanosine analogue is phosphorylated intracellularly by the host cell enzyme and interacts with synthesis of guanosine triphosphate to inhibit viral RNA and DNA polymerase activity in the DNA polymerases.
• Indication for chronic Hepatitis C in combination with SC interferon alfa-2b, is also useful in influenza A and B & parainfluenza infections and for treatment of Respiratory Syncytial Virus and Viral hemorrhagic fever
• Available as oral tablets in 600mg and 800mg doses
• It interferes with synthesis of guanosine triphosphate, to inhibit capping of viral messenger RNA and to inhibit viral RNA dependent RNA polymerase.
• Dosing is dependent on weight for the Treatment of HCV is dependent on weight- 800 mg - 1400mg max.
• The normal BA is about 45% to 64%. Increases with fatty meals and reduces with antacids
• Primarialy eliminated in urine that is monitored via creatinine

Side Effects of Ribavirin

• Dependant causes dose hemolitic, caused by extravascular hemolysis, and bone marrow suppression
• Additional related side effects: fatigue, irritability, rash , insomnia, cough and pruritus.
• Dose reduction to prevent hemolytic anemia-associated with increase in reticulocyte count. High triphosphate levels coz oxidative damage to membrane-Erythrophagocytosis by RES.
• Contraindications of anemia, end-stage renal failure, ischemic heart failure, pregnancy

Other Antiviral Agents

• Tenofovir is active against Lamivudine and Entecavir-resistant hepatitis and used to treat chronic HBV infection.
• Lamivudine, use in HBV is based on prolonged intracellular t1/2(17-19hrs)than in HIV (10.5-15.5) that leads to chain resistant.
• It can be prescribed to treat for chronic suppression and in rapid and potent viral therapy. It has an ecxellent safter profile
• Etecair competitively inhibits the functions of the HBV DA polymersere, best taken of the somtche with little sid effects
• It high BA and to the kidney
• dont't co administrer with druges that competer in tubular secretation