ANTIVIRAL DRUGSANTIVIRAL DRUGS

Faraza JavedFaraza Javed

Mphil PharmacologyMphil Pharmacology

WHAT IS VIRUS?WHAT IS VIRUS?

An obligate intracellular microorganism which multiply in the nucleus or cytoplasm of host cell and use metabolic machinery of host cell is called virus.

The drugs used against the replication of virus in host cell is known as antiviral drugs.

CLASSIFICATION OF VIRUSCLASSIFICATION OF VIRUS

Viruses are not usually classified into conventional taxonomic groups but are usually grouped according to such properties as size, the type of nucleic acid they contain, the structure of the capsid and the number of protein subunits in it, host species, and immunological characteristics.

Two classification systems exist:Two classification systems exist:

The Hierarchical virus classification system

The Baltimore Classification System

The Hierarchical virus classification The Hierarchical virus classification systemsystem

In 1962 Lwoff, R. W. Horne, and P. Tournier advanced a comprehensive scheme for the classification of all viruses consisting of phylum - class - order - family - subfamily - genus - species - strain/type.

Four main characteristics are used: Nature of the nucleic acid: RNA or DNA Symmetry of the capsid

Presence or absence of an envelope Presence or absence of an envelope Dimensions of the virion and capsidDimensions of the virion and capsid

All Families have the suffix -viridae e.g. Caliciviridae, Picornaviridae, Reoviridae. Genera have the suffix -virus. Within the Picornaviridae there are 5 genera: enterovirus, cardiovirus, rhinovirus, apthovirus and hepatovirus.

The Baltimore ClassificationThe Baltimore Classification

The Baltimore system of virus classification provides a useful guide with regard to the various mechanisms of viral genome replication.

These various types of virus genomes can be broken down into seven fundamentally different groups, which obviously require different basic strategies for their replication. .

David Baltimore, who originated the scheme, has given his name to the so-called "Baltimore Classification" of virus genomes. The replication strategy of the virus depends on the nature of its genome. Viruses can be classified into seven (arbitrary) groups: :

I: Double-stranded DNAI: Double-stranded DNA

Some replicate in the nucleus e.g. adenoviruses using cellular proteins. Poxviruses replicate in the cytoplasm and make their own enzymes for nucleic acid replication. (Adenoviruses; Herpesviruses; Poxviruses, etc)

II: Single-stranded (+)sense DNAII: Single-stranded (+)sense DNA

Replication occurs in the nucleus

involving the formation of a (-)sense strand, which serves as a template for (+)strand RNA and DNA synthesis. e.g. (Parvoviruses).

III: Double-stranded RNAIII: Double-stranded RNA These viruses have segmented genomes.

Each genome segment is transcribed separately to produce monocistronic mRNAs. (Reoviruses, Birnaviruses).

IIV: Single-stranded (+)sense RNAV: Single-stranded (+)sense RNA

Naked RNA is infectious, no involvement of virion particle associated polymerase. e.g. (Picornaviruses, Togaviruses).

V: Single-stranded (-)sense RNAV: Single-stranded (-)sense RNA

Must have a virion particle RNA directed RNA polymerase. e.g. (Orthomyxoviruses, Rhabdoviruses etc).

VI: Single-stranded (+)sense RNA with DNA VI: Single-stranded (+)sense RNA with DNA intermediate in life-cycleintermediate in life-cycle (RT-RNA-virus)(RT-RNA-virus)

Genome is (+)sense but unique among viruses in that it is DIPLOID, and does not serve as mRNA, but as a template for reverse transcription. e.g. (Retroviruses)

VII: Double-stranded DNA with RNA VII: Double-stranded DNA with RNA intermediateintermediate (RT-DNA-virus)(RT-DNA-virus)

This group of viruses also relies on reverse

but unlike the Retroviruses, this occurs inside

the virus particle on maturation. On infection of a new cell, the first event to occur is repair of the gapped genome, followed by transcription. e.g. (Hepadnaviruses).

CLASSIFICATIONCLASSIFICATION

Anti HIV drugsAnti HIV drugs Nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase

inhibitors Protease inhibitors Entry inhibitors Integrase inhibitors

Other viral drugs Other viral drugs Viral DNA polymerase inhibitors Inhibitor of viral uncoating and viral assembly Neuraminidase inhibitors immunomodulators

Nucleoside Reverse trancriptase Nucleoside Reverse trancriptase inhibitorsinhibitors

This include group of drugs which are nucleoside analogue e.g. analogue of thymidine, adenosine,cytosine,guanosine. All are phosphorylated by host cell enzymes to give the 5-triphosphate. This compete with host nucleosides which are essential substrate for the formation of proviral DNA by viral reversetrancriptase. So, incorporation of analogues of nucleosides into growing viral

DNA chain thus terminating the chain. Zidovudine and stavudine(analogue of

thymidine) Didanosine(analogue of deoxyadenosinea) Lamvidine(analogue of cytosine) Abacavir(analogue of guanosine)

Non nucleoside reversetranscriptase Non nucleoside reversetranscriptase inhibitorsinhibitors

These are chemically diverse compounds that are not nucleosideanalogue but blocks reverse transcriptase by binding near the catalytic site and denature it. Drug examples are

Efavirenz nevirapine

Protease inhibitorsProtease inhibitors

Protease is an enzyme present in HIV virus that converts the polyprotiens into various structural and functionalprotins by cleavage at the appropriate positions. The drug target this enzyme and viral replication stops.

Squinavir Nelfinavir Indinavir ritonavir

Entry inhibitorsEntry inhibitors It inhibits entry of virus into the host cell by

inhibiting the conformational change in glycoproteins of virus that is necessary for attachment to the receptors on host cell.

Enfurvirtide

Integrase inhibitorsIntegrase inhibitors Inhibits the integration of viral DNA into the

host cell DNA Raltegravir

Viral DNA polymerase inhibitorsViral DNA polymerase inhibitors

Viral DNA polymerase inhibitors prevent the replication by blocking DNA polymerase either by nucleoside or non-nucleoside analogue.

Nucleoside analogueNucleoside analogue

aciclovir, cidofovir, famciclovir, ganciclovir, idoxuridine, penciclovir, ribavarin, valaciclovir, valganciclovir

Non nucleoside analogueNon nucleoside analogue

foscarnet

Inhibitor of viral uncoating and viral Inhibitor of viral uncoating and viral assemblyassembly

A viral membrane protien M2 functions as an H+ ion channel in two steps of replication

When fusion of viral membrane and endosome membrane

Assembly and release of virion

Inhibition of this protein inhibits viral uncoating and assembly.

Amantadine and rimantadine

Neuraminidase inhibitorsNeuraminidase inhibitors

Neuraminidase is an enzyme present in virus that helps in budding of new virus from infected cell. Neuraminidase inhibitors inhibits this enzyme.

Oseltamivir Zanamivir

Biologics and immunomodulatorsBiologics and immunomodulators

Immunomodulators enhance the host defence. Pooled immunoglobulin contains antibodies against various viruses which are directed against virus envelop and can neutralize some viruses and prevent their attachment to host cells.

e.g. interferon-α, pegylated interferon-α, inosine pranobex, palivizumab.

RibavirinRibavirin

•It is effective against a broad spectrum of DNA and RNA viruses for example severe RSV infection in children.• It is used in combination with interfero-a-2b to eliminate chronic hepatitis C infection.

Mechanism of actionMechanism of action

• MOA of ribavirin is studied on influenza virus.• The drug is first converted to ribivirin- triphosphate (5 phosphate derivative), which exerts its antiviral action By inhibiting the guanosine-triphosphate formation Preventing viral mRNA capping Blocking RNA-dependent RNA polymerase

PharmacokineticsPharmacokinetics• Ribavirin is effective orally and intravenously• Absotion is increased if drug is taken with fatty meal• Aerosol is used in certain respiratory viral infections e.g in the treatmen of RSV infection.• The drug is retained in all tissues except brain• Drug and its metabolite are eliminated in the urine.

Adverse effectsAdverse effects

• When given orally and intravenously: Dose dependent transient anemia Elevated bilirubin• When given through aerosol it is safer but can Deteriorate the respiratory function of infants. Therefore monitoring is essential.• Teratogenic effects so contraindicated in pregnancy

Interferon:Interferon: Naturally occurring inducible glycoprotein Interfere with ability of viruses to infect cells Synthetically prepared by Recombinant DNA

technology Three types Exist ▪ Alpha ▪ Beta ▪ Gamma Interferon alpha-2b has been approver for the treatment

of Hepatitis B & C, Condylomata acuminata and Cancer Interferon Beta has some effectiveness in treatment of

Multiple sclerosis

Mode of Action

Induction of host cell enzymes

Inhibit Viral RNA translation leading to

degradation of Viral mRNA & tRNA

The Exact mechanism is incompletely understood

Pharmacokinetics: Not active orally, but can be administered

Intralesionally ▪ Subcutaneously ▪Intravenously

Little active form is found in plasma

Metabolized in Liver

Cellular uptake and metabolism by Liver and

Kidney cause disappearance from plasma

Negligible Renal elimination

Adverse Effects: Flu-like symptoms (Fever, Chills, Myalgias,

Arthralgias, Gastrointestinal disturbances)

Fatigue

Mental Depression

Bone marrow suppression including

Granulocytopenia ,Neurotoxicity

Hypersensitivity reaction and Hepatic failure are rare

AcyclovirAcyclovir

It has greater specificity than Vidarabine against herpes viruses.

Use in the treatment of choice in HSV encephalitis and increase rate of survival.

It is given prophylactically to sero +ve patients before bone marrow & after heart transplants.

Mechanism of actionMechanism of action

Acyclovir, is a guanosine analog that lacks a true sugar moiety.

It is monophosphorylated in the cell by herpes virus encoded enzyme thymidine kinase.

Monophosphorylated analog is converted to di & triphosphate forms by the host cells.

Acyclovir triphosphate competes with deoxyguanosine triphosphate as a substrate for viral DNA polymerase & is itself incorporated into the viral DNA

cont.….cont.….

It cause premature DNA chain termination. Irreversible binding of acyclovir containing

template primer to viral DNA polymerase inactivate the enzyme.

The drug is less effective against the most enzyme.

PharmacokineticsPharmacokinetics

It is administered by intravenous, oral, tropical route.

It distributes well throughout the body including CSF.

It is partially metabolize to an inactive product. Excretion into the urine occurs both by

glomerular filtration & by tubular secretion.

It is accumulates in patients with renal failure. The valyl ester,valacyclovir has greater oral

bioavailability than acyclovir. This easter is rapidly hydrolyzed to acyclovir

& achieves levels of the later comparable to those from i.v acyclovir administration..

Adverse EffectsAdverse Effects

Adverse effects depends upon route of administration.

Local irritation may occur from topical application i.e. head,diarrhea,nausia,&vomiting may result after oral administration.

Transient renal dysfunction may occur at high doses or in dehydrated patient receiving the drug i.v.

High dose of Valacyclovir can cause gastrointestinal problems &thrombotic thrombocytopenia purpura in patients with AIDS..

ResistanceResistance Altered or deficient thymidine kinase &DNA

polymerases have been found in some resistant viral stains..

It is most commonly isolated from immunocompromised patients.

Cross resistance to other cyclovirs occurs.

EnfuviritideEnfuviritide

It is an HIV infusion inhibitor,the first of the novel class of antiretroviral drugs used in the combination therapy for the treatment of HIV-1 infection.

Mechanism of actionMechanism of action

It works by disrupting HIV-1 molecular machinery at the final stage of infusion with the target cell,preventing uninfected cells from being infected..

HIV binds to the host CD4+ cell via a viral transmembrane protein, then undergoes a conformational change that assists in the fusion of viral membrane to the host cell membrane. Enfuviritide binds to the viral transmembrane protein preventing the creation of an entry pore for the capsid of the virus, keeping it out of the cell.

Clinical useClinical use

The drug is generally given by subcutaneous injection in combination with others to treat HIV infection when resistance become a problem or when the patient is intolerant of other antiretrovirals.

PharmacokineticsPharmacokinetics

Enfuvirtide is a synthetic peptide and is thus not bioavailable orally. Following a twice-daily subcutaneous injection of 30 to 90 mg, its bioavailability is approximately 84.3%. Comparable absorption of the 90-mg dose has been reported in different injection sites of the abdomen, thigh, and arm. The volume of distribution is 5.5 liters, and the clearance rate is 1.4 liters/hour.

Adverse effectsAdverse effects

Flu-like symptoms

Central effects such as Headache Dizziness Alterations in mood Gastrointestinal effects Hypersensitivity reactions

Drug drug interactionsDrug drug interactions

Clinical studies involving enfuvirtide are limited. No clinically significant drug interaction was reported when this medication was used in combination with the other antiretroviral drugs. In cell culture media assays, enfuvirtide exhibited additive-to-synergistic effects when it was combined with individual members of various antiretroviral agents, such as zidovudine AZT, Retrovir drug, lamivudine.