ANTIVIRAL AGENTS

CLASSIFICATION AND MECHANISM OF ACTION

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What is an antiviral

• Antiviral drugs are medicines that cure or control virus infections.
• Unlike antibacterial drugs, which may cover a wide range of pathogens, antiviral agents tend to be narrow in spectrum and have limited efficacy.

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Facts to know

• Antivirals target a specific viral protein, most often an enzyme involved in viral nucleic acid synthesis(polymerase, or transcriptase) or a viral processing protein(protease).

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• Single-nucleotide changes leading to critical amino acid substitutions in a target protein often can cause resistance to antiviral drugs.

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• Clinical failures of antiviral therapy may occur with drug sensitive virus in immunocompromised patients or following emergence of resistant variants

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• Most drug-resistant viruses are recovered from immunocompromised patients or those with chronic infections (HBV) with high viral loads and repeated or prolonged courses of antiviral treatment.

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Classification of antivirals

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1. Anti-influenza A drugs

Amantadine

• Trade name : generic, Symmetrel.
• Drug class : anti-influenza-A virus, Parkinson’s medication
• Mechanism of action
• Blocks the M2 proton ion channel of virus particles and this interferes with uncoating of the viral RNA of influenza A within infected host cells, thus preventing viral replication.

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Indications

• A prophylactic DOC for influenza-A virus
• Is not as effective if taken after viral infection.

Contraindications

• In pregnancy due to teratogenic effects

Side effects

• CNS toxicity – excitability, insomnia and anorexia.

Pharmacokinetics

• Orally administered.
• Excreted unchanged(90%) in the urine (half life – 12-18hrs)
• Adjust dosage in patients with impaired renal function.

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Major drug interactions

• Anticholinergic drugs.
• Hydrochlorothiazide and triamterene (which reduce the clearance of amantadine.

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Rimantidine

• Trade name : Flumadine
• Drug class : Anti-influenza-A

Mechanism of action

• M2 viral proton ion channel inhibitor which interferes with uncoating of virus.

Indications

• Prophylactic for influenza-A virus.
• Preferred over amantadine due to lower CNS toxicity & increased metabolism.

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Contraindications

• Contraindicated in pregnancy due to teratogenicity

Side effects

• Anorexia and GI side effects similar to amantadine.

Pharmacokinetics

• Orally administered.
• Extensively metabolized before renal excretion, so dose reductions are not needed until creatinine clearance falls below 10ml/min.

Drug interactions

• Anticholinergic drugs, hydrochlorothiazide & triamterene.

Note

• Influenza A viruses cross-resistant to both amantadine and rimantadine can emerge.

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2. Anti-influenza A & B drugs ( Inhibitors of viral packaging & Release)

Zanamivir.

• Trade name : Relenza.
• Drug class : Antiviral,anti-influenza virus A & B.

Mechanism of action

• Inhibits influenza neuraminidase which blocks the cellular release of the virus particle.

Indications

• Treatment of acute uncomplicated influenza A & B ( oral inhalation).

Contraindications

• Hypersensitivity

Side effects

• Nasal and throat discomfort
• Bronchospasm in patients with reactive airway disease.

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Pharmacokinetics

• Inhalation every 12 hrs.No systemic absorption.

Drug interactions

• Is not a P450 substrate and does not affect CYP 450 isoenzymes.

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Oseltamivir

• Trade name : Tamiflu
• Drug class : anti influenza virus ( A& B)

Mechanism of action.

• A prodrug activated by carboxylesterase (HCE 1)
• Inhibition of influenza neuraminidase to block virus particle release and aggregation.

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Indications

• Treatment of acute uncomplicated influenza A and B.
• Can decrease the severity and duration of symptoms.
• Must be taken within 2 days of onset of symptoms.

Contraindications

• Known hypersensitivity.

Side effects

Bronchitis, insomnia, nausea, vertigo and vomiting can occur.

Pharmacokinetics

• Oral administration – oseltamivir phosphate is readily absorbed from the GIT.
• It is extensively converted by hepatic esterases to oseltamivir carboxylate.
• At least 75% of an oral dose reaches the systemic circulation as oseltamivir carboxylate.

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Drug interactions

• Not a substrate and does not affect CYP 450 isoenzymes.

Clopidogrel

• Oseltamivir is a prodrug activated by carboxylesterase, which is inhibited by clopidogrel, resulting in decreased levels of the active metabolite.

Probenecid

• Reduces the renal excretion of the active metabolite of oseltamivir.

Resistance

• Influenza A & B resistance in about 5% of children.
• H1N1 resistance in 2008 – 09 was over 98%, however over

99% of pandemic influenzae A ( H1NI ) during the 2009 pandemic were sensitive.

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3. Anti – herpes simplex topical medications (Thymidine analogs )

Idoxuridine

• Trade name : Herplex.
• Drug class : anti – Herpes Simplex Virus (HSV)

Mechanism of action

• Iodinated thymidine analog, activated intracellularly to tri-phosphate which can inhibit DNA polymerases required for incorporation of thymidine into viral DNA.
• Idoxuridine, instead of thymidine, is incorporated into viral DNA, resulting in faulty DNA and the inability of the virus to infect tissue or reproduce.

Indications

• Alternate drug for topical use against HSV keratitis.

Contraindications

Hypersensitivity, severe systemic toxicity.

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Side effects

• Irritation, pruritis, inflammation.

Pharmacokinetics

• Administered in eye drops, no systemic absorption.

Drug interactions

• Boric acid containing solutions.

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Trifluridine

• Trade name : Viroptic
• Drug class : anti – Herpes simplex virus ( HSV-1 and -2 ) and anti-vaccinia virus

Mechanism of action

• Tri-fluoro thymidine analog, activated intracellularly to tri-phosphates which then inhibit DNA polymerase.

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Indications

• A DOC for topical treatment of HSV keratitis.
• Also effective in treating cutaneous infections by acyclovir resistant strains of HSV.

Contraindications

• Hypersensitivity and chemical intolerance

Side effects

• Severe systemic toxicity

Pharmacokinetics

• Used topically in eye drops and ophthalmic preparations. No systemic absorption.

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4. VZV (Varicella zoster virus), HSV & CMV ( Cyto-megalo virus ) – Guanosine analogs.

Acyclovir

• Trade name : generic, Zovirax
• Drug class : Ant-herpes and varicella zoster virus (HSV and VZV )

Mechanism of action

• A guanosine derivative that causes DNA chain termination.
• Activated by viral thymidine kinase ( TK) to a monophosphate form.
• Host enzymes then convert the monophosphate to di- and then tri-phosphate (active ) which inhibits the viral DNA polymerase causing chain termination due to the lack of a 3’ –OH group.

Indications

• A DOC for parenteral treatment of herpes zoster(shingles), oral therapy for recurrent genital herpes (HSV-2).

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• Also indicated for HSV encephalitis and Varicella zoster (chickenpox).

Contraindications

• Hypersensitivity or chemical intolerance.

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Side effects

• Inflammation or phlebitis, malaise, nausea and headache.
• Encephalopathic changes may occur.
• Renal function impairment may occur.

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Pharmacokinetics

• Can be given orally, i.v. or topically.
• Low bioavailability (15 – 20%), but sufficient to achieve therapeutic plasma levels.
• Renal excretion with half-life of 2.5hrs (15% metabolized, 85% excreted unchanged)
• Only 50% of plasma levels penetrate into the CSF, hence dose escalation is required for HSV encephalitis.

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Drug interactions

• Probenecid inhibits acyclovir elimination
• Zidovudine --- drowsiness and fatigue.

Resistance

• Not effective against CMV because CMV-TK cannot activate the drug.

Valacyclovir.

• Trade name : Valtrex
• Drug class : anti-herpes simplex and varicella zoster and cold sores (herpes labialis)

Mechanism of action

• Valine ester of acyclovir (a prodrug form of acyclovir)
• Stomach acid converts it to acyclovir.

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• Activated by viral thymidine kinase and host enzymes, inhibits viral DNA polymerase.
• Produces DNA chain termination.

Indications

• Herpes zoster ( shingles ), recurrent genital herpes, cold sores (herpes labialis).

Drug interactions

• Cimetidine, Probenecid

Ganciclovir

• Drug class : Anti-cytomegalo virus (CMV)

Mechanism of action

• Structure similar to acyclovir but with an additional side group.
• Activated by viral thymidine kinase (TK) and host enzymes, which inhibits the viralDNA polymerase.
• Produces DNA chain termination

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Indications

• A DOC for CMV retinitis in immunocompromised patients
• For CMV retinitis it can be administered by intravitreal injection or by intraocular implant(vitrasert)

Side effects

• Bone marrow toxicity (significant myelosuppression, neutropenia and thrombocytopenia)
• Possible teratogen.

Valganciclovir

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5. Resistant HSV, VZV, & CMV (Pyrophosphate analog)

Foscarnet

Trade name : Foscavir

Drug class : anti-cytomegalo virus.

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Mechanism of action

• An inorganic pyrophosphate compound that specifically inhibits viral DNA polymerase, RNA polymerase and HIV reverse transcriptase by competing for the pyrophosphate binding site.

Indications

• Use is restricted to immunocompromised patients with CMV retinitis and mucocutaneous acyclovir-resistant HSV infection.
• A DOC for acyclovir resistant HSV or VZV infections.

Side effects

• Renal impairment as the major toxicity causing problems such as hypokalemia, which can cause seizures.
• Frequent monitoring of serum creatinine
• Adequate hydration while on foscarnet is imperative.
• Hematologic dysfunctions.

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Pharmacokinetics

• Poorly absorbed orally, given i.v.
• Excreted unchanged in urine.

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Major drug interactions.

• Nephrotoxic drugs e.g. aminoglycosides, amphotericin B.
• RSV(Respiratory syncytial virus) & HCV (Riboside analog)

Ribavirin

• Trade name : Virazole
• Drug class : Anti-respiratory syncytial virus (RSV)

Mechanism of action

• A triazine riboside analog.
• Converted intracellularly to a 5- triphosphate derivative that inhibits viral RNA polymerase and capping of viral mRNA.

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Indications

• Respiratory syncytial virus (RSV) in hospitalized infants (aerosol)
• Young children with severe lower respiratory tract infections (aerosol)
• Hepatitis C virus infection.
• Not indicated for use in adults.

Contraindications

• Hypersensitivity
• Teratogenicity and embryo toxicity.

Side effects

• Sudden deterioration of respiratory function (esp. in infants)
• Hemolytic anemia, cough, pruritus and rash
• Teratogen

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Pharmacokinetics

• Administered orally, by aerosol inhalation or & i.v.
• Aerosol is absorbed systemically.
• Plasma half life is 9.5 hrs.
• Accumulation occurs in RBC. ( T ½ = 40 days.)

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7. HBV Drugs

Adefovir

• Trade name : Hepsera
• Drug class : Anti- Hepatitis B Virus medication.

Mechanism of Action

Blocks HBV’s Reverse Transcriptase.

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Indications

• Chronic hepatitis B – for patients with clinical evidence of Lamivudine-resistant HBV with compromised liver function.

Side effects

• Asthenia (weakness)
• Dose- related nephrotoxicity
• Transaminase elevation.
• Headache, abdominal pain, diarrhea, nausea.

Pharmacokinetics

• Bioavailability is 59% after oral absorption(unaffected by food).

Entecavir

Trade name : Baraclude

Drug class : Anti-hepatitis B virus medication.

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Mechanism of action

• A guanosine nucleotide analogue that selectively blocks the HBV polymerase ( Entecavir has a 300 – 1300 fold higher affinity for HBV vs human DNA polymerase)

Indications

• Chronic hepatitis B infection in adult patients.

Side effects

• Similar to lamivudine.
• Low likelihood of lactic acidosis
• Acute exacerbations of hepatitis B
• Development of resistance to HIV reverse transcriptase inhibitors in HIV positive patients.

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Pharmacokinetics

• Food decreases absorption by – 20%
• Intracellular half-life is 15hrs.
• Renal elimination.

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7. HBV & HCV (Recombinant Cytokine)

Interferon a-2b

• Trade name : Roferon-A
• Drug class : Anti-hepatitis virus B and C

Mechanism of action

• A recombinant cytokine, with a host of anti-viral properties including inhibition of viral replication ( both RNA and DNA virus) and augmentation of anti-viral immune responses.

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• Activates ribonucleases that degrade viral mRNA.
• Blocks protein synthesis by inhibiting the translation initiative complex.

Indications

• Broad spectrum activity against both DNA and RNA viruses.
• Primarily indicated as a drug of choice against Hepatitis-B and C infections
• Used in combination with ribavirin for RSV.
• Used to treat AIDS-related kaposis sarcoma, and malignant melanoma.

Contraindications

• Hypersensitivity to IFN-alpha-2b or any of the components of the formulation.

Side effects

• Cardiovascular abnormalities such as hypotension, arrhythmia, tachycardia, cardiomyopathy.

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• Thyroid dysfunction.
• Flu like symptoms
• Hepatotoxicity
• Photosensitivity
• High doses can cause bone marrow suppression (standard hemological tests should be performed prior to beginning treatment).

Pharmacokinetics

• Administered i.m. or s.c.
• Kidney may be the main site for IFN catabolism
• Elimination half-life is approx. 2hrs.
• Pegylated interferons have a longer half-life, less frequent dosing and are more effective.

Drug interactions

• Aminophylline and Zidovudine.

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