Antivirals Updated

7/31/2019 Antivirals Updated

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ANTIVIRAL DRUGS

Meera Ababneh, Pharm.D, PhD


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General Characteristics of Viruses

Viruses lack both a cell wall and a cell membrane anddo not carry out any metabolic process

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Viruses contain a single type ofnucleic acid (DNA

or RNA) and a protein coat, sometimes enclosedby an envelope composed of lipids, proteins, andcarbohydrates.


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Viruses are obligatory intracellular parasites.They multiply by using the host cell's synthesizingmachinery to cause the synthesis of specializedelements that can transfer the viral nucleic acid toother cells.


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Antiviral Drugs

Viruses are entirely dependent on the host

for replication, and replicate in host cells,

therefore:

Antivirals must selectively inhibit viral but not

host enzymes/proteins

Antivirals inhibit viral replication but do not

actually destroy viruses, therefore: Host immune response is of extreme importance in

ultimate viral containment


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Herpes Viruses

Herpes Simplex I (HSVI) - herpes labialis(cold sores), herpes keratitis (eye infections)

HSVII - herpes genitalis (genital herpes)

Varicella Zoster virus (VZV) - chicken poxprimary infection, shingles

Cytomegalovirus (CMV) - retinitis

Epstein-Barr Virus (EBV) - mononucleosis

Herpes viruses encode their own DNApolymerase and thymidine kinase (salvageenzyme)


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Anti-viral drugs

Anti-herpes virus agents

Acyclovir / Valacyclovir

Famciclovir / Penciclovir

Ganciclovir / Cidofovir

Foscarnet

Trifluridine / Idoxuridine / Vidarabine


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Acyclovir and congeners

All are guanine nucleoside analogs.

Valacyclovir is a prodrug of Acyclovir withbetter bioavailability.

Famciclovir is hydrolyzed to Penciclovirand has greatest bioavailability.

Penciclovir is used only topically whereasFamciclovir can be administered orally.


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MOA:

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 areinhibited


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Antiviral 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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PK of Acyclovir

Oral bioavailability ~ 15%-20%

Distribution in all body tissues includingCNS

Renal excretion: > 80%

Half lives: 2.5-3 hours

Administration: Topical, Oral , IV


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Adverse Effects

Adverse effects of Acyclovir /Ganciclovir

Nausea, vomiting and diarrhea Nephrotoxicity - crystalluria,

haematuria, renal insufficiency (IV)

Myelosuppression Neutropenia andthrombocytopenia Ganciclovir


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Therapeutic uses :

Acyclovir is the drug of choice for:

HSV Genital infections

HSV encephalitis

HSV infections in immunocompromisedpatient

Ganciclovir is the drug of choice for: CMV retinitis in immunocompromised patient

Prevention of CMV disease in transplantpatients


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Cidofovir

Cidofovir :

It is approved for the treatment of CMVretinitis 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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Vidrabine

PHARMACOLOGY OF VIDARABINE

Vidarabine 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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Vidarabine

The drug is converted to its triphosphateanalog 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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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 HSV

Keratitis


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Foscarent

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

Oral bioavailability is poor Distribution to all tissues including CNS

Administration: IV


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Foscarent

Adverse effects

Hypo or hypercalcemia, hypo- orhyperphosphatemia, hypokalemia, and

hypomagnesemia Neurotoxicity (headache, hallucinations,

seizures)

Nephrotoxicity (acute tubular nephrosis,interstitial nephritis) Sodium preload may help


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Foscarent

Therapeutic uses

It is an alternative drug for

HSV infections (acyclovir resistant /immunocompromised patient )

CMV retinitis (ganciclovir resistant /

immunocompromised patient )


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Respiratory viral infections

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Influenza

Amantadine / Rimantadine

Oseltamivir / Zanamavir

(Neuraminidase inhibitors)RSV bronchiolitis

Ribavirin
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Amantadine andRimantadine

Influenza

Prevention & Treatment of influenza A

Inhibition of viral uncoating byinhibiting the viral membrane protein M2

Influenza A virus

Amantadine has anti-parkinsonian effects.


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Amantidine

PK:

Oral bioavailability ~ 50-90%

Amantadine is excreted unchanged in theurine

Rimantadine undergoes extensive

metabolism before urinary excretion.

Administration: Oral


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Neuraminidase inhibitors :Influenza


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

Neuraminidase inhibitors prevent therelease of new virions and their spread

from cell to cell.

Oseltamivir is orally administered.

Zanamavir is given intranasal.


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These are effective against both types ofinfluenza A and B.

Do not interfere with immune response to

influenza A vaccine. Can be used for both prophylaxis and

acute treatment.


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Oseltamivir / ZanamavirAdverse effects:

Oseltamivir: nausea, vomiting, abdominalpain.

Zanamavir: cough, bronchospasm,reversible decrease in pulmonary function,

and transient nasal and throat discomfort.


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RIBAVIRIN

Ribavirin is a guanosine analog.

Inhibition of RNA polymerase

Antiviral spectrum : DNA and RNAviruses are susceptible, includinginfluenza, parainfluenza viruses, RSV,Lassa virus


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Ribavirin

Distribution in all body tissues, except CNS

Administration : Oral, IV, Inhalational inRSV.

Anemia and jaundice are adverse effects

Not advised in pregnancy.


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Ribavirin

Therapeutic uses

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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Hepatic Viral infections

Interferons

Lamivudine cytosine analog HBV

Entecavir guanosine analog HBVlamivudine resistance strains

Ribavirin Hepatitis C (with interferons)

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Interferons

(IFNs) are natural proteins producedby the cells of the immune systemsin response to challenges by foreignagents such as viruses, bacteria,

parasites and tumor cells.Antiviral, immune modulating and

anti-proliferative actions

Three classes of interferons , ,


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Interferons

and interferons are produced byall the cells in response to viralinfections

interferons are produced only by Tlymphocyte and NK cells in response tocytokinesimmune regulating effects

has less anti-viral activity comparedto and interferons


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MOA: Interferons

Induction of the following enzymes:

1) a protein kinase which inhibits protein

synthesis2) an oligo-adenylate synthase which

leads to degradation of viral mRNA

3) a phosphodiesterase which inhibit t-RNA

The action of these enzymes leads toaninhibition of translation


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Interferons

Antiviral spectrum:

Includes HBV, HCV and HPV.

Anti-proliferative actions may inhibit thegrowth of certain cancers - like Kaposisarcoma and hairy cell leukemia.


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Interferons

PK:

Oral bioavailability: < 1%

Administered Intralesionally, S.C, and I.V Distribution in all body tissues, except CNS

and eye.

Half lives: 1-4 hours


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Interferns

Adverse effects

Acute flu-like syndrome (fever,

headache) Bone marrow suppression

(granulocytopenia, thrombocytopenia)

Neurotoxicity (confusion, seizures) Cardiotoxicity - arrhythmia

Impairment of fertility


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Interferons

Therapeutic uses

Chronic hepatitis B and C (completedisappearance is seen in 30%).

HZV infection in cancer patients (to prevent

the dissemination of the infection) CMV infections in renal transplant patients

Hairy cell leukemia (in combination with

zidovudine) AIDS related Kaposis sarcoma

D ( ) f Alternative


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Virus Diseases

Drug(s) of

choice

Alternative

drugs

FLU

A Influenza Amantadine

Rimantadine

RSVPneumonia,

bronchiolitis

Ribavirin

(aerosol)HSV Genital herpes Acyclovir Foscarnet

Keratitis

ConjunctivitisTrifluridine Idoxuridine

Vidarabine

Encephalitis Acyclovir

Neonatal HSV

infectionAcyclovir Vidarabine

Herpes infections in

immuno-

compromised host

Acyclovir Foscarnet


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VZVIn normal host No therapy

In immunocompro-mised host, or during

pregnancy

Acyclovir Foscarnet

CMV Retinitis Ganciclovir Foscarnet

HIVAIDS

HIV antibody

positive with CD4count < 500/mm3

Zidovudine

protease

inhibitors

Didanosine,

Stavudine

HBV Hepatitis B, C Interferons

Documents

Antivirals Updated