ANTI-VIRAL AGENTS

G Vijay Narasimha KumarAsst. Professor,

Dept. of. PharmacologySri Padmavathi School of

Pharmacy

Definition:• Antiviral drugs are a class of medication used

specifically for treating or controlling viral infections. Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antivirals do not destroy their target pathogen; instead they inhibit their development.

Classification of Antiviral Drugs• DNA polymerase inhibitors

Purine Analogues:

Acyclovir, Valacyclovir, Ganciclovir, Valganciclovir, Famciclovir, Penciclovir, Cidofovir, Adefovir, Entecavir, Vidarabine.

Pyrimidine analogues: Idoxuridine, Trifluridine, Telbivudine Non-nucleosides: Foscarnet

Contd….

• m-RNA synthesis inhibitors Ribavirin, Fomivirsen• Adamantase inhibitors: Amantidine, Rimantidine, Docosanol• Neuraminidase inhibitors: Oseltamivir, Zanamivir, Peramivir.• Immunomodulators: Interferons, Palivizumab, Imiquimod.

DRUG NAME ANALOGUE ACYCLOVIR Guanosine analogue

VALACYCLOVIR A L- valine ester of Acyclovir

GANCICLOVIR A hydroxymethylated analogue of Acyclovir.

VALGANCICLOVIR A valine ester of Ganciclovir

PENCICLOVIR Guanine nucleoside analogue

FAMCICLOVIR Diacetyl ester of penciclovir

VIDARABINE Adenine analogue

CIDOFOVIR Cytidine analogue

ADEFOVIR Adenosine monohoshate analogue

ENTECAVIR guanosine nucleoside analogue

IDOXURIDINE iodinated derivative of deoxyuridine

TRIFLURIDINE trifluoromethyl derivative of idoxuridine

TELBIVUDINE thymidine analogue

FOSCARNET an inorganic pyrophosphate derivative

DNA polymerase inhibitorsMechanism of action: The drug to exhibit it’s action, it should get convert to its active

metabolite via three phosphorylation steps.

In the presence of enzyme known as viral thymidine kinase, drug will convert into it’s monophosphate.

The monophosphate will further convert into diphosphate by an enzyme called Guanidylate kinase.

Finally, the diphosphate converts into triphosphate, which is an active metabolite.

The active metabolite inibits viral DNA polymerase

Thus, preventing the replication of DNA by terminating the elongation of the viral DNA

chain.

PHARMACOKINETICS:Absorption: Only about 20% of an oral dose of Acyclovir

is absorbed.

DISTRIBUTION: It is little plasma protein bound and is widely

distributed attaining CSF concentration that is 50% of plasma concentration.

It penetrates cornea well.

ELIMINATION: It is primarily excreted unchanged in urine,

both by glomerular filtration and tubular

secretion.

It’s plasma half life is 2-3 hours in healthy

persons and 20 hrs in patients with renal failure.

THERAPEUTIC USES Herpes simplex virus -1 (which causes herpes labialis,herpes esophagitis,herpes keratitis,herpes encephalitis and ocular herpes) Herpes simplex virus -2 (genital herpes) Varicella Zoster Virus (chicken pox and shingles) Epstein Barr Virus Cytomegalovirus

ADVERSE EFFECTS Topical: stinging and burning sensation after each

application. Oral: Headache, nausea, malaise and some CNS

effects are reported. Intravenous: Rashes, sweating, emesis, hypotension.

DRUG INTERACTIONS Cyclosporine and other nephrotoxic agents may increase the risk of renal toxicity. Probencid inhibits the renal excretion of Acyclovir.

FOSCARNET: It is an inorganic pyrophosphate derivative. It does not require phosphorylation for inhibitting viral DNA polymerase, but inhibits herpetic DNA polymerase activity by blocking the pyrophosphate binding site on the enzyme. The cleavage of the pyrophosphate moiety from the newly attached nucleotide is thus prevented which in turn inhibits viral chain elongation. It is 100 times more selective for Herpes DNA polymerase than for mammalian DNA polymerase.

PHARMACOKINETICS It has very poor bio-availability, hence administered intravenously. It accumulates in aqueous humour and bones. It is eliminated unchanged in urine.

THERAPEUTIC USES

Used in the treatment of Acyclovir resistant mucocutaneous HSV infections in AIDS patients and CMV retinitis in immunocomprimised patients.

ADVERSE EFFECTS Elevated serum creatinine levels. Electrolyte disturbances include:

– Hypocalcemia– Hypomagnesemia– Hypokalemia

Malaise, nausea, headache, vomiting, anaemia, leukopenia.

DRUG NAME ABSORPTION(bioavailability)

DISTRIBUTION(plasma protein binding)

METABOLISM EXCRETION

GANCICLOVIR 60% 1-2%t1/2 – 4.08 hrs Liver and also through kidney by glomerular filtration and active tubular secretion

Through urine

VALCICLOVIR 54.5% + 9.1% 13-18%t1/2– 2.5 – 3.3 hrs Intestinal and hepatic metabolism Through urineFAMCICLOVIR 77% 20-25%t1/2 – 10 hrs hepatic urineCEDOFOVIR 100% 6%t1/2 – 2.4-3.2 hrs _ _ADEFOVIR 59% < 4% t1/2 – 7.48 hrs kidney through glomerular filtration and active tubular secretion

urinePENCICLOVIR topical < 20%T1/2 – 2 hrs liver _ENTECAVIR 100% 13% t1/2 –15hrs liver _

DRUG NAME ABSORPTION DISTRIBUTION METABOLISM EXCRETIONVIDARABINE TOPICAL 24-38 % - -IDOXURIDINE OCCULAR - inactivated by enzymes deaminases -TRIFLURIDINE OPTHALMIC t1/2 – 12-18 mins - -TELBIVUDINE ORAL 3.3% t1/2 – 15 hrs kidney urineAMANTIDINE ORAL 67% kidney urineRIMANTIDINE ORAL 40% liver urineOSELTAMIVIR 75% 42%t1/2 – 1 -3 hrs liver urineZANAMIVIR 2% <10%T1/2 – 2.5-5.1 hrs not metabolised urinePALIVIZUMAB - t1/2 - 18-20 days Removed by opsonisation

-IMIQUIMOD well absorbed through skin as a cream

T1/2 -20hrs(topical dose)T1/2-2hrs(S.C dose) - -

NEURAMINIDASE INHIBITORS

• MECHANISAM OF ACTION: Viruses enters into host cell.

Multiplication of viral cells.

Viruses releases neuraminidase enzyme.

Which causes lysis of cell membrane and decrease the spread of infection to new cells.

OSELTAMIVIR:• It is a prodrug which converts to active form in

the liver.• PHARMACOKINETICS:• ABSORPTION:• It can be administered orally.

• METABOLISM: OSELTAMIVIR

hepatic esterases Oseltamivir carboxylate

EXCRETION:• It has bioavailability 80% .• Its plasma half life is 8 hrs.• Excretion via urine.

ZANAMIVIR:ABSORTION:It is taken as aerosol. METABOLISM: Metabolised by liver. EXCRETION: Its plasma half life is 3.5 hrs. Excretion through urine.

USES OF OSELTAMIVIR & ZANAMIVIR:• Used in the treatment of acute uncomplicated influenza A or influenza B infections.DOSE:• OSELTAMIVIR:75 mg BD orally for treatment.• 75 mg OD orally for prevention• ZANAMIVIR:10 mg BD inhalation for treatment.• 10 mg per day for prevention.

OSELTAMIVIRADVERSE EFFECTS:• Nausea,• Vomiting,• Vertigo,• Seizures,• Aggravation of diabetes

ZANAMIVIRADVERSE EFFECTS:• Bronchospasm,• Bronchosecretions,• Nasal discomfort

ADAMANTASE DERIVATIVES

AMANTADNE AND RIMANTIDINE:

• Both drugs are effective against influenza A virus and have negligible activity against influenza B virus and mumps virus.

MECHANISM OF ACTION: Both the drugs inhibit uncoating of influenza A viral RNA with in the infected host cells.

which inhibit the viral M2 protein present in the viral membrane. Which prevents H+ mediated dissociation of ribonuceloprotein core segment.

Prevents the viral replication.

PHARMACOKINETICS:ABSORPTION:

Both are absorbed rapidly from GIT.

Plasma half life in

AMANTIDINE:17 hrs in young adults

30 hrs in the elderly.

RIMANTIDINE:25 hrs in young adults

33 hrs in elderly.

METABOLISM:• Metabolism takes place in liver.EXCRETION:• AMANTIDINE mostly excreted unchanged in

the urine.• RIMANTIDINE is partly metabolised in liver.its

conjugated metabolites and some free drug is excreted in urine.

USES:• Both the drugs are administered orally for prevention and treatment of influenza A viral infections.• They reduce the duration of fever and the complaints by 1 to 2 days.• Amantadine prophylaxis reduce infection rates by 50% & illness rate by 60%.• Amantadine used in the therapy of parkinsons disease.

ADVERSE EFFECTS:• Nausea,• Anorexia,• Insomnia,• Dizziness,• Nightmares,• Lack of mental concentration,• Rarely hallucinatons,• Ankle edema

IMMUNOMODULATORS• Immunomodulators are the drugs which activate the immune mechanism to target the virus.INTERFERONS:MECHANISM OF ACTON:• Interferons are mainly produced during the viral infection.• Which interferes with the viral infection

• virus/bacteria/viralproteins/ exotoxins/endotoxins,viralRNA/DNA enters into human body.• Activates the toll like receptors• Which releases inflammatory mediators like NF-Kappa betta,IFR-12 • Which releases interferons

Interferon's acts against pathogens Inhibition of activate P53 activates the translation of gene immune cells viral mRNA

Viral proteins releases P 53 which MHC-I cause apoptosis MHC-II

PHARMACOKINETICS:ABSORBTION:It should be given subcutaneously, intramuscularly, intravenously.

DISTRIBUTION:Do not cross the blood brain barrier.

METABOLISM:Metabolised by liver

EXCRETION:Excretion through bile/kidney.

USES:

INTERFERON-ALFA -2a:• Chronic hepatitis-B infection,• AIDS related kaposi’s sarcoma,• Chronic hepatitis-C,• Hairy cell leukaemia and chronic myelogenous

leukaemia,DOSE:• 3mU,thre times weekly; S.C, OR I.M

INTERFERON-ALFA-2b:Hepatitis-C ,

Malignant melanoma;

Condylomata acuminata,

Chronic hepatitis-B,

Chronic hepatitis-C ,

Non-hodgkins lymphoma

DOSE:3mU,three times weekly; S.C, OR I.M

PEGYLATED INTERFERON:• Used to treat chronic hepatitis-B and C.• Pegylated interferon alfa-2a and 2b are given through SC.ADVERSE EFFECTS:• Fever,• Weakness,• Nausea,• Vomiting,• Headache,• Myalgia,• Flu like symptoms,

• Bone marrow depression,• Rashes,• Alopecia,• Cardiovascular, hepatic and thyroid dysfunction,• Insomnia,