ANTI VIRAL DRUGS

CONTENTS 1. Viruses, what are they, who are they? 2. Virus Classification 3. Drug Development 4. Antiviral Drugs 5. Conclusions and Overview 6. Refrences

STAGES OF REPLICATION (DNA virus) Attachment Penetration Uncoating Transfer of DNA to cell nucleus INTRODUCTION Viruses have no cell wall and made up of nucleic acid components Viruses containing envelope antigenic in nature Viruses are obligate intracellular parasite They do not have a metabolic machinery of their own uses host enzymes Certain viruses multiply in the cytoplasm but others do in the nucleus Most multiplication take place before diagnosis is made

DEFINITION Many antiviral drugs are Purine or Pyrimidine analogs. Many antiviral drugs are Prodrugs. They must be phosphorylated by viral or cellular enzymes in order to become active. Anti-viral agents inhibits active replication so the viral growth resumes after drug removal.

CLASSIFICATION OF ANTI VIRAL DRUGS ANTI HERPES VIRUS Acyclovir Farciclovir Ganciclovir Foscarnet Retro viral Drugs Specific retroviral drugs Reverse transcriptase inhibitors

Nucleosides (NRTIs) Non-nucleosides (NNRTIs) Protease inhibitors Anti Retro Virus Nucleoside reverse transcriptase inhibitors Zidovudine (AZT) Didanosine Lamivudine Non-nucleoside reverse transcriptase inhibitors

Nevirapine

PROTEASE INHIBITORS Ritonavir

ANTI INFLUENZA VIRUS Amantadine NON-SELECTIVE ANTIVIRAL DRUGS

Ribavirin Lamivudine Interferon a

ANTI HERPES VIRUS Acyclovir / Valacyclovir Famciclovir / Penciclovir Ganciclovir / Cidofovir Foscarnet Trifluridine / Vidarabine ACYCLOVIR & CONGENERS Valacyclovir is a prodrug of Acyclovir with better bioavailability. Famciclovir is hydrolyzed to Penciclovir and has greatest bioavailability. Penciclovir is used only topically whereas Famciclovir can be administered orally. These drugs are predominately acyclic analogues of Guanosine

Derived from thimadine kinase(TK)enzymes. It is slowly and incompletely absorbed by Oral dosing. Much better levels are achieved by I.V. Or by useof prodrug Valaciclover

PHARMACOLOGY OF ACYCLOVIR: MECHANISM OF ACTION OF ACYCLOVIR All drugs are phosphorylated by a viral thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs. The analog inhibits viral DNA-polymerase Only actively replicating viruses are inhibited ROUTES OF ADMINISTRATION OF ACYCLOVIR TOPICAL (ZOVIRAX) Used in Herpes Labialis. DOSAGE- 5% cream qid for 4days. CONTRA INDICATIONS-Hypersensitivity.

SIDE EFFECT- pain& burning. ORAL ROUTE INDICATIONChicken pox (esp. in immunosuppressed). DOSAGE- 200-400mg 5 times a day. SIDE EFFECTSToxicity INTRAVENOUS INDICATIONSHerpes Simplex infection Genital tract infection. Eye infection. SIDE EFFECTSIncrease in urea & creatinine.

PHARMACOLOGY OF ACYCLOVIR AND CONGENERS Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs. PHARMACOKINETICS OF ACYCLOVIR Oral bioavailability ~ 20-30% Distribution in all body tissues including CNS Renal excretion: > 80% Half lives: 2-5 hours Administration: Topical, Oral , IV Adverse effects of Acyclovir Nausea, vomiting and diarrhea Nephrotoxicity - haematuria, renal insufficiency Renal dysfunction CNS Disturbance- Hallucination Rashes & Headache Gastrointestinal Toxicity

Neurotoxicity. 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 GANCICLOVIR It is an Analogue of Acyclovir. It is more active than Acyclovir against CMV. It has a same activity as Acyclovir against HSV-1&2. It is intravenous medication for CytomegaloVirus infection inHIV disease.

ROUTES OF DRUG ADMINISTRATION By Intravenous. By Oral route. ADVERSE EFFECTS Bone Marrow suppression Thrombocytopenia Neutropenia. Nephrotoxicity. PHARMACOLOGY OF VIDARABINE Vidarabine is a nucleoside analog. (adenosine) HSV-1, HSV-2 and VZV. Its use is limited to HSV keratitis only VIDARIBINE The drug is converted to its triphosphate analog which inhibits viral DNApolymerase. Oral bioavailability ~ 2%

Administration: Ophthalmic ointment Used in HSV keratoconjunctivitis in immunocompromised patient. Anemia and SIADH are adverse effects. TRIFLURIDINE PHARMACOLOGY OF TRIFLURIDINE Trifluridine is a Pyrimidine nucleoside analogs - inhibits viral DNA synthesis. HSV-1, HSV-2 and VZV. Use is limited to Topical - Ocular HSV Keratitis FOSCARNET PHARMACOLOGY OF FOSCARNET Foscarnet is an inorganic pyrophosphate analog It directly inhibits viral DNA and RNA -polymerase and viral inverse transcriptase (it does not require phosphorylation for antiviral activity) INDICATIONS & ROUTES OF ADMINISTRATION Foscarnet HSV-1, HSV-2, VZV, CMV and HIV.

Oral bioavailability ~ 10-20% Distribution to all tissues including CNS Administration: IV ADVERSE EFFECTS OF FOSCARNET Hypocalcemia and hypomagnesemia (due to chelation of the drug with divalent cations) are common. Neurotoxicity (headache, hallucinations, seizures) Nephrotoxicity (acute tubular nephrosis, interstitial nephritis) THERAPEUTIC USES OF FOSCARNET Therapeutic uses of Foscarnet It is an alternative drug for HSV infections (acyclovir resistant / immunocompromised patient ) CMV retinitis (ganciclovir resistant / immunocompromised patient )

RETRO VIRUSES A family of RNA viruses containing a reverse transcriptase enzyme which allows the viruses' genetic information to become part of the genetic information of the host cell upon replication. Any member of a large family of RNA viruses that includes the lentiviruses and certain oncoviruses, given this name because they carry reverse transcriptase ANTI- RETROVIRUSES NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS. Zidovudine(AZT) Didanosine NONO- NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSNevirapine. ZIDOVUDINE (1987) The first drug to enter clinical practice in 1987. It is a Thymidine Analogue

MECHANISM OF ACTIONIt iself gets incorporated into the growing Viral DNA & termintes chain elongation. INDICATION In HIV infected patients in combination with atleast 2 other Anti-Retrovirus drugs. PHARMACOKINETICS Absorbed orally. Bioavailability- 65%. 15-20% of drug is excreted un urine. ADVERSE EFFECTS Anaemia Neutropenia. Nausea. Anorexia. Abdominal pain

 Hepatomegaly. Insomnia Myalgia. LATEST ANTI VIRAL DRUGS Epivir (lamivudine) Viramune (neviripine) ANTI INFLUENZA DRUGS Respiratory viral infections Influenza Amantadine / Rimantadine Oseltamivir / Zanamavir RSV bronchiolitis Ribavirin AMANTADINE & RIMANTADINE Amantadine and Rimantadine : Influenza

Prevention & Treatment of influenza A Inhibition of viral uncoating by inhibiting the viral membrane protein M2 Influenza A virus Amantadine has anti-parkinsonian effects. PHARMACOKINECTICS OF AMANTADINE Oral bioavailability ~ 50-90% Amantadine cross extensively BBB whereas Rimantadine does not cross extensively . Administration: Oral NON SELECTIVE ANTI VIRAL DRUGS Ribavirin. Lamivudine. Interferon -a RIBAVIRIN PHARMACOLOGY OF RIBAVIRIN

Ribavirin is a guanosine analog.

 Inhibition of RNA polymerase Antiviral spectrum : DNA and RNA viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus RIBAVIRIN :RSV Distribution in all body tissues, except CNS Administration : Oral, IV, Inhalational in RSV. Anemia and jaundice are adverse effects Not advised in pregnancy. THERAPEUTIC USES OF 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 virus infection in immunocompromised patients HEPATIC VIRAL INFECTIONS Interferons

 Lamivudine cytosine analog HBV Entecavir guanosine analog HBV lamivudine resistance strains Ribavirin Hepatitis C (with interferons) INTERFERONS Interferons Interferons (IFNs) are low molecular natural glycoproteins cytokines produced by host cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. Antiviral, immune modulating and anti-proliferative actions

Three classes of interferons , ,

INDICATIONS Therapeutic uses Interferons Chronic hepatitis B and C (complete disappearance 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 INTERFERONS and interferons are produced by all the cells in response to viral infections interferons are produced only by T lymphocyte and response to cytokines immune regulating effects has less anti-viral activity compared to and interferons Anti VIRAL spectrum:Interferon a Antiviral spectrum : Interferon Includes HBV, HCV and HPV. Anti-proliferative actions may inhibit the growth of certain cancers - like hairy cell leukemia. PHARMACOKINETICS :Interferons Oral bioavailability: < 1% Administered Intralesionally, S.C, and I.V Distribution in all body tissues, except CNS and eye.

Half lives: 1-4 hours ADVERSE EFFECTS OF INTERFERONS Acute flu-like symptoms (fever, fatigue,dizziness,visual & taste disturbance headache) Bone marrow suppression (granulocytopenia, thrombocytopenia) Neurotoxicity (confusion, seizures, convulsions) Cardiotoxicity - arrhythmia Impairment of fertility Hypotension, liver dysfunction.

REFERENCES
Goodman and Glickman K.D. Tripathi Devidson Burkets

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