ANTIVIRAL DRUGS Viruses They are obligate intracellular parasites.

They are made up of a nucliec acid core enclosed in a protien coat called capsid which consists of identical subunits called capsomeres.They lack cell wall and cell membrane and do not carry out metabolic processes on their own.So replication depends on the host cell machinery. Types of viruses DNA viruses:They include Herpes simplex,Varicella zoster, Smallpox, Hepatitis B,Human CMV. RNA viruses:They include HIV,influenza,measles,rabies,rubella. Steps in viral replication: Most viruses survive only for a short time outside the host cells.After penetration viral replication occurs in the following steps: 1) adsorption and penetration into cell 2) uncoating of viral nucleic acid 3) synthesis of regulatory proteins 4) synthesis of RNA or DNA 5) synthesis of structural proteins 6) coating and maturation of virus particles 7) release from host cell DIFFICULTY IN VIRAL CHEMOTHERAPY: Firstly, the drug which is expected to destroy the viruses is likely to destroy the normal host cells also. Secondly, they easily undergo structural changes and develop drug resistance easily. And thirdly,most antiviral drugs are effective during the early stages of infection which is difficult to detect diagnose. So it very difficult to develop viral chemotherapy. Classification I.BASED ON TYPE OF VIRUS ON WHICH THEY ACT: -Anti herpes virus -Anti retro virus -Anti influenza virus -Non selective anti viral drugs

II.BASED IN THEIR MODE OF ACTION -Compounds interfering with nucleic acid synthesis idoxuridine,acyclovir,zidovudine -Inhibitors of attachment and penetration amantadine -Inhibitors of reverse transcriptase lamivudine -Acting through immune mechanism interferons,gamma globulins, monoclonal antibodies ANTIHERPES DRUGS: They include Idoxuridine , Acyclovir(prototype) ,Valacyclovir, Famciclovir , Gancyclovir, Docosanol, Foscarnet, Cidofovir. IDOXURIDINE(5-iodo 2 deoxyuridine) It is a thymidine analogue and is the first pyramidine antimetabolite.Some other such pyrimidine antimetabolites are trifluridine,vidarabine etc. Mechanism of action: It acts by competing with thymidine in DNA synthesis Uses :It is effective against DNA viruses only.It is clinically used only for the topical treatment of herpes simplex keratitis(0.1%eye drops),herpes labialis Disadvantages:It interferes with the normal synthesis of DNA and hence is too toxic for systemic use.It has low virus selectivity.And it rapidly develops viral resistance. ACYCLOVIR Mech of action:It is an acyclic guanosine derivative and is phosphorylated by viral thymidine kinase enzyme,and Di-and tri-phosphorylated by host cellular kinases Inhibits viral DNA synthesis by: 1) competing with dGTP for viral DNA polymerase,followed by 2) chain termination. Uses:Mainly used in various infections like Genital herpes simplexHSV2(primary and recurrent lesions), Mucocutaneous herpes simplexHSV1(200mg,5times a day,5days),Herpes simplex encephalitis(iv,1020mg/kg,8hrly,10 days),Herpes simplex keratitis(5% eye ointment),Herpes zoster(800mg,5times a day,7days),Chicken pox(iv 15mg/kg for 7days). Pharmacokinetics:Given orally-bioavailability is only 20%

Major anti viral spectrum Herpes Simplex Virus 1 and 2 (HSV), Varicellazoster virus (VZV),Epstien barr virus(EBV). Side Effects:When used topically it produces stinging and burning sensation.When used orally it produces headache,nausea.When given iv it may produce rashes, sweating ,fall in blood pressure in some cases.Dose dependant decrease in glomerular filtration rate is common and is especially toxic for those with kidney disorders.Reversible neurological manifestations like hallucinations,tremors are common on high doses Mechanism of Resistance:it develops resistance either by alteration in viral thymidine kinase,or by alteration in viral DNA polymerase,or by deficiency of thymidine kinase .It may develop cross-resistance with valacyclovir, famciclovir, and ganciclovir.Alternatively foscarnet or cidofovir can be used VALACICLOVIR: It is an ester prodrug of acyclovir with improved bioavailability.It is completely converted to acyclovir while passage through git and liver.So plasma level following the oral administration of valacyclovir is equal to that after iv infusion of acyclovir. Mechanism of action is same as that of acyclovir Uses: It is used mainly in recurrent genital herpes infections(2g bd), herpes zoster infections(1g tds), herpes labialis(0.5-1g bd). Prophylactically,valacyclovir at 2g BD on the day of dental procedure and 1g BD the day after suppresses the recurrence of HSV infections Side Effects: nausea, diarrhea, and headache are common. FAMCICLOVIR: It is a prodrug of penciclovir which is a guanosine analog.it is rapidly absorbed on oral administration.and the mechanism of action is same as that of acyclovir. Uses:used in various infections like HSV-1, HSV-2, VZV, EBV, and hepatitis B Side Effects: nausea, diarrhea, headache are common Dosage:125-500mg can be used based on severity for herpes labialis,genital herpes,herpes zoster etc. GANCYCLOVIR: It is an analogue of acyclovir and requires tri-phosphorylation for activation similar to acyclovir.Monophosphorylation is catalyzed by phosphotransferase enzyme in CMV and by thymidine kinase in HSV cells. Mechanism of action is same as acyclovir

Uses: it is the first drug of choice in CMV* infections.it is also used in other infections like HSV, VZV,and EBV. Side Effect: Myelosuppression is the most important side effect. DOCOSANOL: N-docosanol inhibits HSV replication mainly by interfering with early intracellular events.It is a highly lipophilic compound and targets those viruses with lipid containing envelopes like HSV.As it does not act via thymidine kinase/dna polymerase it is active against acyclovir resistant HSV strains.10% DOCOSANOL applied topically is effective FOSCARNET: It is an inorganic pyrophosphate and acts by inhibiting viral DNA polymerase, RNA polymerase, and HIV reverse transcriptase.It does not have to be phosphorylated. Uses:used mainly against HSV, VZV, CMV, EBV, HHV-6, HBV, and HIV infections Resistance due to mutations in DNA polymerase gene is common. Side Effects: hypocalcaemia or hypercalcaemia and hypophosphotaemia,and is highly toxic causing damage to kidneys. It has low virus selectivity. Dosage:40mg/kg 8hrly,iv. CIDOFOVIR: It is a cytosine analogue.Its phosphorylation is not dependent on viral enzymes.It is phosphorylated by host thymidine kinase and so,active against ACV resistant strains mainly HSV. It is an important anticytomegalovirus drug. Uses: various infections like CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, adenovirus, and human papillomavirus can be treated using cidofovir Side Effects: nephrotoxicity (prevented by administration of probenecid) Dosage:Facial HSV infection.:topical 1% cidofovir,CMV retinitis-iv 5mg/kg,7days. ANTIRETROVIRAL DRUGS These are the drugs which are active against retroviruses like HIV.It consists of four groups of drugs like: 1) Nucleoside Reverse Transcriptase Inhibitors (NRTIs) 2) Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) 3) Protease inhibitors 4) Fusion inhibitors

These drugs are useful in prolonging and improving the quality of life of HIV infected patients and postponing the complications of AIDS. Nucleoside Reverse Transcriptase Inhibitors: They include Zidovudine (AZT),Didanosine,Lamivudine,Stavudine etc.The first anti retroviral drug to be developed was zidovudine. Mechanism of action of NRTI s: They mimic the other nucleosides and are incorporated into DNA strand and thus prevent the addition of natural nucleosides into DNA strand and halts the production of new virion particles. ZIDOVUDINE(AZT) It is a thymidine analogue, and a prototype NRTI.It is phosphorylated to zidovudine triphophate in the host cell and selectively inhibits viral reverse trancriptase thus inhibiting the conversion of Single stranded viral RNA into Double stranded viral DNA. It is available in IV and oral formulations. Clinical Uses: It is active against HIV-1, HIV-2.Mainly used for treatment of HIV, decreases rate of progression and prolongs survival of the patient.It is also used for post exposure prophylaxis of HIV.It can be given as Monotherapymainly to prevent mother to newborn transmission of HIV(300 mg BD oral) or as Combination therapy.Combination therapy is preferred now due less chances of developing resistance. With zidovudine,the immune status of the patient is improved and opportunistic infections become less common. Side Effects :Myelosuppression, including anemia and neutropenia develop in a dose related manner,and GI intolerance, headaches, and insomnia may develop at the start of therapy but diminish later. Drug interactions:Paracetomol increases AZT toxicity by competing with glucuronidation, and azole antifungal drugs also inhibit AZT metabolism. Mechanism of Resistance:Resistance develops mainly due to mutations in the reverse transcriptase gene.It develops more frequent after prolong therapy in persons with HIV Available as RETROVIR,ZIDOVIR. DIDANOSINE- It is a synthetic deoxy-adenosine analog(a purine nucleoside analogue).after its conversion into didanosine triphosphate inhibits HIV reverse transcriptase similar to zidovudine. Dosage:200mg bd.Available as DINEX.

Side effects:Dose related toxicity includes peripheral neuropathy, and pancreatitis.Nausea,diarrhea,adominal pain are other side effects. STAVUDINE- thymidine analog acts similar to zidovudine.Zidovudine antagonizes the effect of stavudine by utilizing the same thymidine kinase enzyme. Anti HIV efficacy is is similar to AZT and is mostly used in combination regimen Side effects:causes pancreatitis, peripheral neuropathy,lipodystrophy-serious toxicity which have restricted its use. Dosage:40 mg bd.Available as STAVIR LAMIVUDINE: It is a cytosine analog phosphorylated intracellularly and inhibits HIV reverse transcriptase as well as hepatitis B virus DNA polymerase. Uses:Used against HIV(150mg bd) and chronic hep-B(100 mg bd) Side effects:Include fatigue,head ache,nausea,anorexia,abdominal pain. Other NRTIs:Zalcitabine- cytosine analog; causes peripheral neuropathy* Abacavir- guanosine analog; more effective than the other agents; fatal hypersensitivity reactions can occur. Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs) Nevirapine Efavirenz Delavirdine They are given as combinations regimens for treatment Mechanism of Action.:They are nucleoside unrelated drugs.They bind to site on viral reverse transcriptase, different from NRTIs and results in blockade of RNA without the need for intracellular phosphorylation. More potent against HIV-1. NEVIRAPINE- Prevents transmission of HIV from mother to newborn when given at onset of labor and to the neonate at delivery. Dosage:Given at a dosage of 200mg/day oral.It is well absorbed orally.Available as NEVIVIR,NEVIPAN side effects:Nausea,head ache etc.It is potentially hepatotoxic. EFAVIRENZ-Its oral absorbtion is incomplete.It is teratogenic , therefore can not be given during pregnancy. Dosage:600mg/day orally.On empty stomach.It is available as EFAVIR.

Side effects:head ache,nausea,insomniaand various neuro psychiatric manifestations Protease Inhibitors: Indinavir Ritonavir Saquinavir Nelfinavir Amprenavir The aspartic protease enzyme encoded by HIV is involved in: 1)production of structural proteins and enzymes (including reverse transcriptase)of the virus 2)The large viral polyproteins are broken into various functional components by this enzyme. 3)This enzyme also acts ata late step in HIV replication,i.e maturation of new virus particles These agents inhibit protease and prevent the spread of infection.These agents cause a syndrome of altered body fat distribution, insulin resistance, and hyperlipidemia leading to lipodystrophy(abdominal obesity,buffalo hump with wasting of limbs and face)which necessitate hypolipidaemic drugs INDINAVIR: Mechanism of action.: Specific inhibitors of the HIV-1 protease enzyme Mechanism of resistance:Medited by expression of multiple and variable protease amino acid substitions Dosage:800mg (tds) given with meals.Available as INDIVIR Side Effects:Hyperbilirubinemia, nephrolithiasis so excess water has to be consumed to avoid this. Contraindications:Should not be given with antifungal azoles RITONAVIR:More potent drug compared to indinavir. Dosage:600mg(bd) taken with food. Side effects:Drug interactions,nausea,lipid abnormalities are common side effects Nelfinavir: Mechanism of action.: They are specific inhibitors of the HIV-1 protease enzyme Mechanism of resistance.:It is mediated by expression of multiple and variable protease amino acid substitution Side Effects: Diarrhoea and flatulence

Nelfinavir dosage:750 mg TDS SANQUINAVIR:A synthetic peptide-like substrate analog which inhibits HIV-1 proteasetwo types of formulations available are hardgel capsulrs,and soft gel capsules. Dosage:1200mg tds Amprenavir:Acts similar to other drugs but can cause Stevens-Johnson syndrome Previously,monotherapy of these drugs were used but were not so effective.So combination therapy with NRTIs, and PIs are found to be effective.At present triple therapy is more effective with the use of PI in combination with the use of 2NRTIS or protease inhibitors with one NRTI and one NNRTI. FUSION INHIBITORS: ENFUVIRTIDE:-It is a recently developed HIV derived synthetic peptide.It inhibits the entry of HIV into CD4 cells by binding to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational changes required for fusion of the viral and cellular membranes.By blocking fusion (entry into cell), FUZEON prevents HIV from infecting CD4 cells.It is not active against HIV2.There is no crossresistance with other classes of antiretro viral drugs. HAART(HIGHLY ACTIVE ANTI RETRO VIRAL THERAPY) Upto 99% of virions are killed rapidly but a small number survive with in resting CD4 lymphocytesgive rise to relapse when treatment is discontinued.most common antiretro viral drug combinations used are 2NRTI+1NNRTI(zidovudine (500mg)+lamivudine(150 mg)+efavirenz) 2NRTI+1PI(zidovudine(500mg)+lamivudine(150mg)+indinavir(600mg)) 3NRTI(lesscommonly used zidovudine+lamivudine+abacavir) Pregnancy:Peri natal prophylaxis 300mg Zidovudine BD from 2nd trimester till post natal period,with treatment of neonate till 6 weeks age. ANTIINFLUENZA DRUGS Amantadine Rimantadine Oseltamivir

AMANTADINE It is a tricyclic amine unrelated to any nucleic acid precursor. But inhibits the replication of influenza A virus at uncoating (an early step ) and viral assembly (a late step). Resistance develops by mutations causing amino acid substitutions in the M2 protein(target site) Side effects:Generally well tolerated but sometimes nausea,anorexia,insomnia,lack of mental concentration. Uses: prophylaxis of influenza A2, treatment of influenza illness( like reduction of fever ,cold ,cough),parkinsonism. Contraindicated in epilepsy,pregnancy,gastric ulcers Dosage:100mg BD RIMANTIDINE: More potent,long acting,and better tolerated than amantadine Dose ad clinical application similar to amantadine OSELTAMIVIR(TAMIFLU) It is a recently developed broad spetrum antiviral activity covering influenza A,influenza B,avian influenza(bird flu) Mechanism of action: It acts by inhibiting influenza virus neuraminidase enzyme during the release of virions from infected cells. Uses:prophylactic(dose-75mg od) , therapeutic(dose-75mg bd) treatment of influenza A,B,bird flu. Side effects:nausea,abd. Pain,diarrhoea, skin reactions. NON SELECTIVE ANTI VIRAL DRUGS: Ribavirin Interferon Alfa Pegylated Interferon Alfa RIBAVIRIN: It is a guanosine analog which has broad spectrum anti viral activity. It is phosphorylated intracellularly by host enzymes and thus inhibits replication of DNA and RNA viruses.Its mono and triphosphate derivatives generated intracellularly inhibit GTP and viral RNA synthesis

Uses:influenza A,B,herpes,acute hepatitis,respiratory syncytial virus broncholitis(nebulised ribavirin). Dosage:200 mg QID Side effects:anaemia,hemolysis,CNS and GI symptoms and is also teratogenic. INTERFERONS:Three types of human interferons are alpha,beta and gamma .They are produced by recombinant DNA technology .But only interferon alpha 2A and alpha2B have anti viral activity. INTERFERON ALPHA: They are low molecular weight endogenous proteins (cytokines) produced by host cells in response to viral infections and some other inducers. They bind to membrane receptors on cell surface and may also inhibit at multiple steps like viral penetration, uncoating, mRNA synthesis, and translation, and virion assembly and release.They are host specific that is those produced by another species have poor activity in man. Alpha-2A,2B,recently-pegylated interferons(expensive) Uses:chronic hep-A,B,Herpes,CMV,condyloma acuminata,Multiple myeloma,AIDS related Kaposi sarcoma,hairycell leukaemia Side effects:There are not effective orally .Subcutaneous and intra muscular injections are limited by substantial adverse effects.Flu like symptoms ,neurotoxicirty,myelosuppression(neutropenia,thrombocytopeninia),thyroid dysfunction,transient arrhythmias,alopecia,liver dysfunction. Trade names:ALFERON,VIRAFERON Dosage:3MU(vial injections) ANTI VIRAL DRUGS IN ORAL LESIONS: Herpetic gingivostomatitis(ACV-iv 5-10mg/kg 8 hrly for 5-10 days) Recurrent intraoral herpes simplex Herpes labialis Herpes zoster Eczema herpeticum(ACV 200-400mg oral 2-3 tims/day) In AIDS pts,recurrent herpetic lesions,HPV infections.oral hairy leukoplakia(topi:25%podophyllin resin+ACV qid CMV infections may cause aphthous like ulcers in oral cavity. FUTURE RESEARCHES:

Studies to identify genetic factors that modify immune response, latency, and metabolism of antiviral drugs are ongoing. Investigations with more sensitive techniques like PCR are done to identify the etiologic agents and newer anti viral drugs can be used for treatment.