14. antiviral drugs

Anti Viral

Introduction to Viruses

• Viruses are composed of nucleic acid, protein capsid, and host membrane containing virus proteins.

• Virus are obligate parasiteMammalian Mammalian virusInsect arbovirusPlant Plant virusBacteria Bacteriophage

• Viruses live inside host cells and use many host enzymes.

• viruses have core genome of nucleic acid either DNA or RNA.

• DNA viruses Adenoviruses (upper respiratory infections)

Hepadnaviruses

Herpes virus(HSV-1,HSV-2,VZV,CMV)

Poxvirus ( small pox)

Papilloma viruses (warts)

• RNA virusesArborvirus-yellow fever

Arenaviruses- meningitis

Bunya viruses- encephalitis

Coronaviruses- URI

Influenza A and B

Paramyxoviruses – Measles, mumps

Rhabdoviruses- Rabbies

Human immunodeficiency virus (HIV)

Viral Replication(DNA)

RNA viruses replicationRNA viruses replication in the

cytoplasam.

Own enzyme to synthesis mRNA

mRNA translated as Viral proteins

genomic RNA

RNA virus replication (Influenza)

Anti viral therapy

• Restricted spectrum• No standardized in-vitro susceptibility tests• Most inhibit replication. • Cure depends on host immune system to

eradicate. • If patients are immunocompromized, may

have recurrences.• Drugs need to be activated by viral and

cellular enzymes before exerting antiviral effect.

• Activity of enzymes and concentration of substrates will influence the efficacy.

Mechanisms of Action of Antiviral Drugs

• Targets include• Viral penetration• uncoating• Nucleoside analogs• Non-nucleoside polymerase

inhibitors• Neuraminidase inhibitors

• DNA polymerase inhibitors―Purine Nucleoside Analogues:

Acyclovir Ganciclovir FamiciclovirValacyclovirPenciclovir Cidofovir

– Pyrimidine Nucleoside Analogues:Idoxuridine

– Non nuclosideFoscarnet

• Inhibitors of viral penetration, uncoatingAmantadine Rimantadine

• m-RNA Synthesis inhibitorsRibvirin Fomivirsen

• Neuraminidase InhibitorsZanamivir Oseltamivir

• ImmunomodulatorsImmunoglobulins Interferns Palivizumab Imiquimod

Classification

Nucleoside AnaloguesGeneral Mechanism of Action

1. Taken up by cells2. Converted by viral and cellualr

enzymes to the triphosphate form3. The triphosphate form inhibits:

• DNA polymerase• Reverse transcriptase• RNA polymerase

4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.

Antiviral DrugsNucleoside and Nucleotide Analogs

Figure 20.16b, c

Analogs Block DNA Synthesis

Acyclovir and Valacyclovir (prodrug, better availability)

A Guanine analogue Acyclovir AcycloGMP AcycloGTP

Thymidine kinase Cellular kinases

Viral 200x affinityof mammalian

1. Inhibits viral DNA polymerase selectively2. Incorporated into DNA and terminates synthesis

Resistance:1. ↓ activity of thymidine kinase2. altered DNA polymerase

Toxicity:1. Encephalopathy2. Renal Insuficiency

Use:1. H. simplez I and II2. H. zoster and Varicella, not good for CMV

Pharacokinetics

• Oral• 20-30% BV highly susceptible

infection• Wide distribution• 20% plasma binding• 90% excreted in unchange from in

urine• T ½-3-4hr, but in renal failure-

20hrs.

Spectrum and clinical use

Highly effective against • HSV-1• HSV-2 genital herpes• Varicella zoster (Chickenpox)Parenteral mucocutaneous HSV

VZV, H.Simplex encephalitis

Ointment early genital herpesOphthalmic herpes

keratoconjunctivitis

Adverse effects

• Oral 3-6months use headache, diarrhoea, nausea, vomiting.

• IV – Phelbitis, rash, mild hypotension

• renaltoxicity• DI- Cyclosporine nephro toxicity• Probencid inhibits renal excretion

Guanine

Acyclovir Ganciclovir

Ganciclovir:• Hydroxy methylated analogue of

acyclovir • Poor BV, IV , t ½- 3-4hrs• Use parenteral serious CMV (accu.100

folds)

• ADR:- Myelosupression, neutropenia, anaemia, Teratogenic , carcinogenic

Valacyclovir

• L- Valine ester of acyclovir• Mechanism and clinical use same• It require less oral dose• More effective than acyclovir

Zoster• No IV formulation

Idoxuridine

• First pyrimidine antimetabolite, used as antiviral drug.

• MOA –incorporate in DNA →formed faulty DNA which breaks down easily →synthesis of wronge viral protein.

Use • Only topical ophthalmic use• H. simplex keratoconjunctivitis.• Dose – one drop of 0.1% solution

hourly during day time and two hourly during night time.

• In acute stage- 0.5% eye ointment four hourly for 3 weeks.

• Side effect – ocular irritation, lid odema, photophobia.

Foscarnet• An inorganic pyrophosphate analog• Active against Herpes (I, II, Varicella ,

CMV), including those resistant to Acyclovir and Ganciclovir.

• Direct inhibition of DNA polymerase and RT• Nephrotoxicity (25%) most common ADR• Hypocalcemia (chelates divalent cations)• Others: hypokalemia, hypomagnesemia• Use: CMV retinitis and other CMV infections

instead of ganciclovir. H simplex resistant to Acyclovir.

NON-SELECTIVE ANTIVIRAL DRUG

RIBAVIRIN-• Has broad spectrum antiviral activity.• Oral bioavailability-50%• MAO: Inhibits viral RNAp• USE- 1. Influenza –A,B

2. Measles in immunocompramised pt.,

• Route aerosol to treat Respiratory syncitial virus

• DOSE- 200MG/QID

ADVERSE EFFECT

• ANAEMIA• HAEMOLYSIS.• IRRITATION TO MUCOSA &

BRONCHOSPASM DUE TO AEROSOL.

Inhibitors of viral penetration and uncoating

• Amantadine and Rimantadine • Synthetic tricyclic amines• Active against Influenza-A• MAO:- Inhibit viral M2 protein • t ½- 17-25hr.

Neuraminidase inhibitors

• Oseltamivir, Zanamivir• Oral Oseltamivir carboxylate• 80% BV• t ½- 8hrs.• Effective against influenza • ADR: Zanamivir- bronchospasm,

Nasal discomfort

Immunomodulators

• Interferons:-• Enhanced production of cytokines• Glycoprotiens produced by body

cells after viral infections.• TYPES :

1. ALPHA (α)Leucocytes2. BETA (β) fibroblasts 3 . GAMMA (γ) T-

lymphocytes

• IFN- α, β potent anti viral effects

• IFN- γ antiviral & immuno modulatory

• IFNs Bind to cell surface receptors viral penetration , m-RNA synthesis, assembly of virions.