Antiviral Drugs Medical Students

7/30/2019 Antiviral Drugs Medical Students

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Antiviral Drugs

basicsDr.T.V.Rao MD

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Understanding Viruses

They are different from other Microbes

Viral replication

A virus cannot replicate on its own

It must attach to and enter a host

cell

It then uses the host cells energy tosynthesize protein, DNA, and RNA

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Understanding Viruses

Viruses are

difficult to kill

because they liveinside the cells

Any drug that kills

a virus may also kill

cells

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Antiviralsavailable for many viral infections

Viruses controlled by current antiviral therapy

Cytomegalovirus (CMV)

Hepatitis viruses Herpes viruses

Human immunodeficiency virus (HIV)

Influenza viruses (the flu)

Respiratory syncytial virus (RSV)11/17/2012 Dr.T.V.Rao MD 5


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Anti-viral drugs

Viruses have no cell wall and made up ofnucleic acid components

Viruses containing envelope antigenic innature

Viruses are obligate intracellular

parasite They do not have a metabolic machinery

of their own uses host enzymes

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Anti-viral drugs

Certain virusesmultiply in thecytoplasm but

others do in thenucleus

Most multiplication

take place beforediagnosis is made

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Anti-Viral drugs Many antiviral drugs arePurine or

Pyrimidine analogs.

Many antiviral drugs are Prodrugs.

They must be phosphorylated by viralor cellular enzymes in order tobecome active.

Anti-viral agents inhibits activereplication so the viral growth

resumes after drug removal.11/17/2012 Dr.T.V.Rao MD 8


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Antivirals how they actKey characteristics of antiviral drugs

Able to enter the cells infected with virus

Interfere with viral nucleic acid synthesis and/or regulation

Some drugs interfere with ability of virus to bind to cells

Some drugs stimulate the bodys immune system

Best responses to antiviral drugs are in patients withcompetent immune systems

A healthy immune system works synergistically with the

drug to eliminate or suppress viral activity11/17/2012 Dr.T.V.Rao MD 9


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Antiviral Medications

Antiviral drugsUsed to treat infections caused by viruses other than HIV

Antiretroviral drugs

Used to treat infections caused by HIV, the virus thatcauses AIDS

Herpes-Simplex Viruses

HSV-1 (oral herpes)

HSV-2 (genital herpes)

Varicella Zoster Virus

Chickenpox

Shingles11/17/2012 Dr.T.V.Rao MD 10


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Antiviral Drugs: Nonretroviral

Mechanism of action

Inhibit viral replication

Used to treat non-HIV viral infections

Influenza virusesHSV (herpes simplex virus), VZV (vericella zoster virus)

CMV (cytomegalovirus)

Hepatitis A, B, C (HAV, HBV, NCV)

Adverse EffectsVary with each drug

Healthy cells are often killed also, resulting in serious toxicities

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Anti-viral drugs

Current anti-viral agents do not eliminatenon-replicating or latent virus

Effective host immune response remainsessential for the recovery from the viralinfection

Clinical efficacy depends on achievinginhibitory conc. at the site of infectionwithin the infected cells

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Anti-viral drugs

Stages of viral replication

Cell entry attachment

- penetration Uncoating

Transcription of viral genome

Translation

Assembly of virion components

Release

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Anti-viral drugsAnti-herpes virus agents

Acyclovir / Valacyclovir

Famciclovir / Penciclovir

Ganciclovir / Cidofovir

Foscarnet Trifluridine / Idoxuridine /Vidarabine

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Anti-viral drugsAcyclovir & Congeners : Valacyclovir is a prodrug of Acyclovir with

better bioavailability.

Famciclovir is hydrolyzed to Penciclovirand has greatest bioavailability.

Penciclovir is used only topically whereas

Famciclovir can be administered orally.

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Anti-Viral drugs

PHARMACOLOGY OFACYCLOVIR ANDCONGENERS

Acyclovir, Valacyclovir,Ganciclovir,Famciclovir,Penciclovir all are

guanine nucleosideanalogs.

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Anti-viral drugs

Mechanism of action of Acyclovir andcongeners :

All drugs are phosphorylated by a viralthymidine-kinase, then metabolized byhost cell kinases to nucleotide analogs.

The analog inhibits viral DNA-polymerase

Only actively replicating viruses are

inhibited11/17/2012 Dr.T.V.Rao MD 18


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Anti-viral drugs

Acyclovir is thusselectively

activated in cellsinfected withherpes virus.

Uninfected cellsdo notphosphorylate

acyclovir.11/17/2012 Dr.T.V.Rao MD 19


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Mechanism of Action of Acyclovir

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Anti-Viral drugsAntiviral spectrum :

Acyclovir: HSV-1, HSV-2, VZV, Shingles.

Ganciclovir / Cidofovir : CMV Famciclovir : Herpes genitalis and shingles

Foscarnet : HSV, VZV, CMV, HIV

Penciclovir : Herpes labialis Trifluridine : Herpetic keratoconjunctivitis

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Anti-Viral drugs

Pharmacokinetics of Acyclovir :

Oral bioavailability ~ 20-30%

Distribution in all body tissuesincluding CNS

Renal excretion: > 80%

Half lives: 2-5 hours

Administration: Topical, Oral , IV

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Anti-viral drugs

Adverse effects of Acyclovir /Ganciclovir

Nausea, vomiting and diarrhea Nephrotoxicity - crystalluria,

haematuria, renal insufficiency

Myelosuppression Neutropeniaand thrombocytopenia

Ganciclovir11/17/2012 Dr.T.V.Rao MD 23


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Anti-viral drugs

Therapeutic uses :Acyclovir is the drug of choice for:

HSV Genital infections

HSV encephalitis HSV infections in immunocompromised patient

Ganciclovir is the drug of choice for:

CMV retinitis in immunocompromised patient Prevention of CMV disease in transplant patients

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Anti-viral drugs

Cidofovir :

It is approved for the treatment ofCMVretinitis in immunocompromised patients

It is a nucleotide analog of cytosine nophosphorylation required.

It inhibits viral DNA synthesis

Available for IV, Intravitreal inj, topical Nephrotoxicity is a major disadvantage.

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Anti-viral drugs

PHARMACOLOGY OFVIDARABINEVidarabine is a nucleoside analog.

(adenosine)

Antiviral spectrum of Vidarabine :

HSV-1, HSV-2 and VZV.

Its use is limited to HSV keratitis only

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Anti-viral drugsVidarabine The drug is converted to its triphosphate

analog which inhibits viral DNA-

polymerase. Oral bioavailability ~ 2% Administration: Ophthalmic ointment Used in HSV keratoconjunctivitis in

immunocompromised patient. Anemia and SIADH are adverse

effects.

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Anti-viral drugs

PHARMACOLOGY OF TRIFLURIDINE

Trifluridine is a Pyrimidine nucleosideanalogs - inhibits viral DNA synthesis.

Antiviral spectrum Trifluridine :

HSV-1, HSV-2 and VZV.

Use is limited to Topical - Ocular HSVKeratitis

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Anti-viral drugs

PHARMACOLOGY OF FOSCARNET

Foscarnet is an inorganic

pyrophosphate analog It directly inhibits viral DNA and RNA

-polymerase and viral inverse

transcriptase (it does not requirephosphorylation for antiviral activity)

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Anti-viral drugs

Foscarnet

HSV-1, HSV-2, VZV, CMV and

HIV.


Distribution to all tissuesincluding CNS

Administration: IV11/17/2012 Dr.T.V.Rao MD 30


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Anti-viral drugs

Adverse effects of Foscarnet

Hypocalcemia and hypomagnesemia (dueto chelation of the drug with divalent

cations) are common. Neurotoxicity (headache, hallucinations,

seizures)

Nephrotoxicity (acute tubular nephrosis,interstitial nephritis)

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Anti-viral drugs

Therapeutic uses of Foscarnet

It is an alternative drug for

HSV infections (acyclovir resistant/ immunocompromised patient )

CMV retinitis (ganciclovir resistant/ immunocompromised patient )

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Anti-viral drugs

Respiratory viral infections

Influenza

Amantadine / Rimantadine Oseltamivir / Zanamavir

(Neuraminidase inhibitors)

RSV bronchiolitis

Ribavirin

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Anti-viral drugs

Amantadine and Rimantadine :Influenza

Prevention & Treatment of influenza A

Inhibition of viral uncoatingbyinhibiting the viral membrane proteinM2

Influenza A virus

Amantadine has anti-parkinsonian

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Anti-viral drugs

Pharmacokinetics of Amantadine


Amantadine cross extensivelyBBB whereas Rimantadine

does not cross extensively .Administration: Oral

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Anti-viral drugs

Neuraminidase inhibitors : Influenza

Oseltamivir / Zanamavir

Influenza contains an enzymeneuraminidasewhich is essential for thereplication of the virus.

Neuraminidase inhibitors prevent therelease of new virions and their spreadfrom cell to cell.

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Anti-viral drugs

Neuraminidase inhibitors : InfluenzaOseltamivir / Zanamavir

These are effective against both types of

influenza A and B. Do not interfere with immune response to

influenza A vaccine.

Can be used for both prophylaxis andacute treatment.

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Anti-viral drugs

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Anti-viral drugsNeuraminidase inhibitors :

Influenza

Oseltamivir / Zanamavir Oseltamivir is orally administered.

Zanamavir is given intranasal. Risk of bronchospasm with

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Anti-viral drugs

PHARMACOLOGY OF RIBAVIRIN

Ribavirin is a guanosine analog.

Inhibition of RNA polymerase

Antiviral spectrum : DNA and RNA

viruses are susceptible, includinginfluenza, parainfluenza viruses,RSV, Lassa virus

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Anti-viral drugsRibavirin :RSV

Distribution in all body tissues, except

CNSAdministration : Oral, IV, Inhalational

in RSV.

Anemia and jaundice are adverseeffects

Not advised in pregnancy.11/17/2012 Dr.T.V.Rao MD 41


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Anti-viral drugs

Therapeutic uses Ribavirin

Ribavirin is the drug of choice for:

RSV bronchiolitis and pneumonia in

hospitalized children (given by aerosol) Lassa fever

Ribavirin is an alternative drug for:

Influenza, parainfluenza, measles virusinfection in immunocompromised patients

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Anti-viral drugs

Hepatic Viral infections :

Interferons

Lamivudine cytosine analog HBV Entecavir guanosine analog HBV lamivudine resistance strains

Ribavirin Hepatitis C (withinterferons)

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Anti-viral drugs

InterferonsInterferons (IFNs) are natural proteins

produced by the cells of the immune

systems in response to challenges by foreignagents such as viruses, bacteria, parasitesand tumor cells.

Antiviral, immune modulating andanti-proliferative actions

Three classes of interferons , ,

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Anti-viral drugs

Interferons and interferons are produced by

all the cells in response to viralinfections interferons are produced only by T

lymphocyte and NK cells in response to

cytokinesimmune regulating effects has less anti-viral activity compared

to and interferons

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Anti-viral drugsMechanism of action of Interferons : Induction of the following enzymes:1) aprotein kinasewhich inhibits protein

synthesis2) anoligo-adenylate synthasewhich leads to

degradation of viral mRNA3) aphosphodiesterasewhich inhibit t-RNA

The action of these enzymes leads toaninhibition of translation

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Anti-viral drugs

Antiviral spectrum :Interferon

Includes HBV, HCV

and HPV. Anti-proliferative

actions may inhibitthe growth of certain

cancers - like Kaposisarcoma and hairycell leukemia.

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Anti-viral drugs

Pharmacokinetics :Interferons

Oral bioavailability:

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Antiviral Drugs Medical Students