ATNI-VIRAL DRUGS

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ATNI-VIRAL DRUGS

  1. 1. Know the history of virus!IVANOVSKY– 1892BEIJERINCK-1898LANDSTEINER &POPPER – 1909RUSKA – 1934LUCMONTAGNIER –1981
  2. 2. • They are obligate intracellular parasites.• Lack cell wall & membrane, metabolism.• Directs host cells to synthesize new virusparticles.• Clinical symptoms appears late in course ofdiseases at a time where most viruses havereplicated. (contrast to bacteria).• Responsible for 60% of human diseases.• Has genome(DNA/RNA), enzymes, capsid, envelope (lipidlayer).ULTIMATE MICROBES - VIRUS
  3. 3. ABOUT PATHOGENESIS…2.Release ofviral genes &enzymes.3.Replicationof viralcomponents.4.Assemblyinto completeviral particles.5.Release ofviral particles.1.Attachmentto host cell.
  4. 4. VIEW OF VIRUS & DISEASES.COMMON VIRUSES ITS DISEASES1. HEPATITIS A,E & B,C. HEPATITIS & CIRRHOSIS.2. RHINO VIRUS COMMON COLD3. VARICELLA ZOSTER CHICKEN POX4. HUMAN IMMUNO DEFICIENCY AIDS5. INFLUENZA (A) INFLUENZA (BIRD FLU)6. RUBELLA & PARAMYXO MEASLES & MUMPS7. HERPES SIMPLEX HERPES SIMPLEX8. RESPIRATORY SYNCYTIAL RESPIRATORY INFECTION9. LYSSA & POLIO RABIES & POLIO10. ANDES & HANTAAN PULMONARY & RENAL SYNDROME11. HUMAN HERPES 1 & 2 ORAL & GENITAL INFECTIONS12. SUDAN & RESTON HEMORRHAGIC FEVER13. RHADINO KAPOSI SARCOMA.
  5. 5. PROPERTIES OF ANTIVIRAL DRUGS:-Key characteristics of antiviral drugs:*Able to enter the cells infected with virus.*Interfere with viral nucleic acid synthesisand/or regulation.*Some agents interfere with ability of virusto bind to cells.*Some agent stimulate body’s immune system.Viruses killed by current antiviral therapy:• cytomegalovirus (CMV)• herpes simplex virus (HSV)• human immunodeficiency virus (HIV)• influenza A (the “flu”)• respiratory syncytial virus (RSV).
  6. 6. RECALL THE CLASSIFICATION!!.ANTI – HERPESVIRUSANTI –INFLUENZAVIRUSNON SELECTIVEANTI VIRALS*Idoxuridine*Acyclovir*Valacyclovir*Famciclovir*Ganciclovir*Foscarnet*Amantadine*Rimantadine*Oseltamivir*Zanamivir*Ribavirin*Lamivudine*Adefovir dipivoxil*Interferon.
  7. 7. Continued… ANTI-RETRO VIRALS• STAVUDINE• ABACAVIR• LAMIVUDINE• ZIDOVUDINE• DIDANOSINENucleoside reversetranscriptaseinhibitors.• NEVIRAPINE• EFAVIRENZ• DELAVIRDINENon nucleosidereverse transcriptaseinhibitors. • NELFINAVIR• INDINAVIR• RITONAVIR• SAQUINAVIR• LOPINAVIRProtease inhibitors.
  8. 8. ANTI-HERPES -ACYCLOVIR Deoxiguanosine analogue. Inhibits DNA synthesis and viralreplication. Active only against herpes groupof viruses. Acyclovir is taken up by virusinfected cells.PK: Attains good CSF concentration. Penetrates cornea well. Plasma t ½:- 2-3 hours. Excreted unchanged in urine.
  9. 9. USES OF ACYCLOVIRGENITAL HERPES SIMPLEXTYPE 2PRIMARY DISEASE(TOPICAL & ORAL) -RECURRENT DISEASE(I.V.) -6 TIMES/DAY X 10 DAYS400mg/TDS X 10 DAYS5mg/kg(1 hr.) rep. 8hrly x 10DMUCOCUTANEOUS HERPESSIMPLEX- TYPE 1LOCALISED TO LIPS & GUMS.ORAL/I.V. ACYCLOVIR15mg/kg/day x 7 DAYSHERPES SIMPLEXENCEPHALITIS-TYPE 1EARLY TREATMENT ISEFFECTIVE.(I.V.)20mg/kg/8hr. X 10 daysHERPES SIMPLEX KERATITIS –TYPE 1EFFECTIVE IN SUPERFICIALDENDRITIC CORNEAL ULCER –EYE OINTMENT5 TIMES DAILY X 3 DAYSHERPES ZOSTER HIGHER DOSES REQUIRED.I.V./ORAL10 mg/kg/8hr. X 7 DAYS800 mg (5times daily)CHICKEN POX REDUCES FEVER,ERUPTION.HASTENS HEALING &PREVENTVISCERAL COMPLICATIONS.15 mg/kg/day x 7 DAYS400mg / q.i.d x 7 DAYS
  10. 10. ADVERSE EFFECTS:TOPICAL: Stinging & burning sensation after each application.ORAL: Headache, nausea, malaise, some CNS effects.Intravenous: Rashes, sweating, emesis, fall in B.P. Dose dependent decrease in G.F.R – important toxicity. Reversible neurological manifestations- tremors, hallucinations,lethargy, convulsion, coma.(higher doses).
  11. 11. IDOXURIDINE:• 5iodo 2deoxyuridine.• Thymidine analogue.• Effective against DNA viruses.• Treatment of H.Simplexkeratitis, labial & genitalherpes.• Not used now.VALACICLOVIR:• Ester prodrug of Aciclovir.• Converted to aciclovir byesterases• Effective in herpes zostertreatment.• Plasma t ½: 3 hrs.• Genital herpes simplex:1 gmbdx10d• Orolabial herpes: 2gm bd x 1day.
  12. 12. FAMCICLOVIR:-Ester prodrug ofguanine nucleosideanalogue.Metabolised toactive penciclovir.Active DNApolymerase inhibitor.Used as analternative to acyclovirin genital herpes &herpes zoster.Side effects: nausea,headache loosemotions, itching,rashes & mentalconfusions.GANCICLOVIR:-Analogue ofaciclovir.Active against allherpes viruses.GivenI.V., penetrates CSF.Excreted in urineT1/2: 2 to 4 hrs.Used in CMVretinitis.(10mg/kg/day).Sideeffects:rash, fever, vomitting, bone marrowdepression, neuropsychiatricdisturbances.FOSCARNET:-Pyrophosphatederivative.Inhibits viral DNApolymerase & reversetranscriptase.Active againstH.Simplex, CMV, HIV.Given I.V., t 1/2:- 4to 8 hours.Used in CMVretinitis, other CMVinfections in AIDS ptSide effects:anemia, phlebitis, tremor, convulsions,damages kidney.
  13. 13. ANTI-INFLUENZA VIRUS DRUGS –AMANTADINE:Inhibits replication(viral uncoating) of influenza A virus.MOA: blocks viral membrane protein M2 which functions aschannel for H2 ion.(this channel is required for fusion of viral membrane with cellmembrane)PK:Well absorbed orally, penetrates CNS, eliminated in urine.Plasma t ½ : 16 hrs.RESISTANCE:Due to mutation in the M2 matrix protein.ADVERSE EFFECTS:Insomnia, dizziness, ataxia, nausea, anorexia, ankle edema.It is embryo toxic.Rimantadine t ½ is 30 hrs.(long acting).
  14. 14. USES OF AMANTADINE: Prophylaxis of influenza A2.Treatment of influenza A2.(5 daystreatment).In parkinsonism: Acts on NMDAtype of glutamate receptors, bypromoting pre-synaptic synthesis &release of DA in brain.Dose:100mg B.D(lasts 12 hrs.)SIDE EFFECTS:Livedo reticularis(due to releaseof CA resulting in vasoconstriction)Ankle edema.
  15. 15. OSELTAMIVIR-TAMIFLU Sialic acid analogues, inhibitsviral neuraminidase enzyme. Has broad spectrum activityagainst influenza A & B. In liver hydrolysed to activeform oseltemavir carboxylate. Active orally . t ½ 6-10 hrs. ,eliminated in urine. Side effects –nausea, headache,diarrhoea, cough, g.i. irritation,insomnia. Resistance occurs by mutationof neuraminidase.ZANAMIVIR-RELENZA Sialic acid analogue, inhibitsviral neuraminidase enzyme. Against influenza A &B, avian influenza. Administered intra-nasally(inhaled). T ½ 2-5 hrs. , eliminated inurine. Side effects – inducebronchospasm, headache, dizziness, nausea, rashes. Avoided in asthma & COPDpatients.
  16. 16. NON-SELECTIVE ANTI-VIRALS:RIBAVIRIN:Synthetic guanosine analogue has broad spectrumanti-viral activity, including DNA & RNA virus.Used in treating infant & childrens with RSVinfection.Also effective in influenza(A & B), measles, herpesinfection & acute hepatitis.{combined with interferonused in chronic hepatitis C infection}.PK:Oral bioavailability is approximately 50%.Absorption is increased when drug is taken withfatty meal.Nebulized ribavirin is used in RSV broncholitis inchildren.Adverse effects:Dose dependent anemia, elevatedbilirubin, hemolysis.Aerosol causes irritation of mucosa & bronchospasm.Contraindicated in pregnancy.(teratogenic effects)
  17. 17. DOSE:200mg qid (children 10mg/kg/day)RIBAVIRINRIBAVIRINTRI-PHOSPJATEINHIBITGUANOSINETRI-PHOSPHATEFORMATIONPREVENTSVIRAL mRNAcappingBLOCKS RNADEPENDENTRNAPOLYMERASE
  18. 18. ADEFOVIR DIPIVOXIL:Nucleotide analogue, activeagainst hepatitis B virus & otherDNA viruses.Oral availability isapproximately 60%.Plasma t ½ is 7 hrs. , excretedin urine.Dose 10mg/day.ADVERSE EFFECTS:Sore throat, headache, weakness, abdominal pain, flusyndrome, nephrotoxicity(inhigh doses) .ADEFOVIRMONO-PHOSPHATEADEFOVIRDI-PHOSPHATEINCORPORATEINTO VIRALDNATERMINATIONOF FURTHERDNASYNTHESISPREVENTSVIRALREPLICATIONMECHANISM
  19. 19. INTERFERON:Low molecular weight glycoprotein.Only naturally occuring anti-viral.Inhibit many RNA & DNA viruses.Not active orally.Administered s.c. /i.v./i.mPlasma t ½ : 24 hrs.
  20. 20. CHRONICHEPATITISB & C (HBV-DNADISAPPEARSFROM PLASMA)AIDS RELATEDKAPOSI’SSARCOMA.RHINO VIRALCOLDHERPESSIMPLEX, HERPESZOSTER, CMVINFECTIONS INIMMUNOCOMPROMI-SED PATIENTSCONDYLOMAACUMINATACAUSED BYPAPILLOMAVIRUSMULTIPLEMYELOMA &CHRONICMYELOGENOUSLEUKAEMIAADVERSE EFFECTS:FLU-LIKE SYMPTOMS-fatigue, malaise, fever, dizziness, anorexia, aches.Neurotoxicity-tremor, numbness, sleepiness, neuropathy, rarelyconvulsions.Myelosuppression-neutropenia, thrombocytopenia.Thyroid dysfunction(hypo & hyper).Hypotension, alopecia, transient arrythmia, liverdysfunction.
  21. 21. :-First antiretro viral isZIDOVUDINE.DRUGS USEDINPOSTPONINGCOMPLICATIONOF AIDS or AIDSRELATEDCOMPLEX.1. NRTI’ s2. NNRTI ‘s3. PI’ s4. EntryInhibitors.5. IntegraseInhibitors.
  22. 22. NUCLEOSIDE/ NULEOTIDE REVERSETRANSCRIPTASE INHIBITORS- zidovudine..• Thymidine analogue.(azidothymidine)• Zidovudine inhibits viralreverse transcriptaseenzyme.• Also gets incorporated intogrowing viral DNA &terminates chain elongation.Effective only againstretroviruses.• PK:- oral bioavailability is65%. Metabolism by hepaticglucoronidation, plasmat 1/2: 1 hour.
  23. 23. USES:- In HIV infected persons only in combination with other 2 anti retro virals.o Reduces neurological manifestations and kaposi’s sarcoma.o good choice of post exposure prophylaxis & in pregnancy transmissions.ADVERSE EFFECTS:oAnaemia & neutropaenia are important side effects.oNausea anorexia, headache, insomnia, myalgia, abdominal pain.INTERACTIONS:-oParacetamol increases AZT toxicityoStavudine & zidovudine exhibit mutual antagonism.
  24. 24. DIDANOSINE STAVUDINE LAMIVUDINE1. Purine nucleoside analogue. Thymidine analogue. Deoxycytidine anlogue2.DDL----> DDATP---->Incorporation into viral DNAInhibit HIV revers transcriptase---->terminates proviral DNA.Acts same as that of AZT. Terminates synthesis of thepro- viral DNA chain. Inhibitsreverse transcriptase & hep.BDNA polymerase.3. Due to its acid lability,absorption is best at fastingstate.Well absorbed orally & rapidlymetabolised.Oral bio availability is high.4. Plasma T ½ :- 1 to 1.5 hrs.Crosses blood brain barrier.Plasma T ½ :- 1.5 hrs.Penetrates blood brain barrier.Plasma T ½ :- 6 to 8 hrs.5. Used only in combinationregimens. 2nd drug to treatHIV-1 infection.Used in combinationregimens. Not combined withAZT,due to mutual antagonismUsed with other HIV drugs.Frequently used for chronichepatitis B infection.6.Diarrhoea, abdominal pain,nausea, peripheralneuropathy, pancreatitis.Peripheral neuropathy,lipodystrophy, rarelypancreatitis.Headache, fatigue, nausea,anorexia, abdominal pain.7. DOSE- 200 mg BD for > 60kg b wt.taken 2 hr before mealDOSE- 40 mg Bd for > 60 kg bwt.For HIV- 150 mg BDFor chronic hepB- 100mg OD
  25. 25. ADVERSE EFFECTSϪ Guanosine analogue.Ϫ Converted to carbovirtriphosphate & then acts.Ϫ Oral bioavailability is 80%. Eliminated by kidney.Ϫ Plasma t ½ is 1 to 1.5 hrs.Intracellular t ½ is > 12hrs.Ϫ Hypersensitivityreactions likerashes, fever, flu-likesymptoms are side effects.Ϫ Exhibit little crossresistance with other NRTIϪ DOSE: 300mg BD.
  26. 26. NON NUCLEOSIDE REVERSE TRANSCRIPTASEINHIBITORS – NEVIRAPINE & EFAVIRENZ.• They are nucleoside unrelated compounds. They directly inhibitHIV-1 Reverse transcriptase.• Viral resistance occurs by point mutations.• They induce CYP 3A4, 2D6 enzymes & enhance their own metabolism• Are indicated in combination regimens for HIV.NEVIRAPINE EFAVIRENZWELL ABSORBED ORALLYMETABOLISED IN LIVERPENETRATES CNS.INCOMPLETE ORAL ABSORPTIONMETABOLISED IN LIVERPENETRATES CNS.PLASMA T ½ IS – 30 Hrs.DOSE – 200 mg /day.PLASMA T ½ IS – 48 Hrs.DOSE – 600 mg OD on empty stomach.Side effects- rashes, nausea, headache, feverraise in liver enzymes.Side effects – rashes, headache, dizziness,insomnia, neuropsychiatric symptoms.
  27. 27. PROTEASE INHIBITORS:The structural proteins & enzymes production of the virusinvolves an aspartic protease enzyme encoded by HIV.This protease enzyme acts at a late step(maturation of new virusparticles).RNA genome acquires core protein & genome.The protease inhibitors bind to protease molecule, interfere withits cleaving function.Effective in both newly & chronically infected cells.Salivary protein “secretory leucocyte protease inhibitor” has someanti-HIV activity.(HIV doesn’t spread through saliva).ADVERSE EFFECTS:G.i. intolerance, headache, dizziness, facial & limb tingling,numbness, rashes.Lipodystrophy.(abdominal obesity, buffalo hump, wasting of limbs& face.Dyslipidaemia.(raised triglycerides & cholesterol)Indinavir crystalises in urine- risk of urinary calculi.
  28. 28. BUFFALO HUMP
  29. 29. INDINAVIR 800mg TDS• To be taken on empty stomach(g.i. intolerance common).• Excess fluids intake – avoid nephrolithiasis.NELFINAVIR 750mg TDS• Taken with meals.• Side effects include diarrhoea, flatulence.RITONAVIR 600mg BD• Potent protease inhibitor.• Nausea, diarrhoea, fatigue, lipid abnormalities.• Lopinavir – available in combination with RTV.improve bioavailabilitySAQUINAVIR 1200mg TDS• Hard gel & soft gel capsules available.•Side effects include photosensitivity.
  30. 30. ANTI-RETRO VIRAL THERAPY:All cases of symptomatic HIV disease –treatment necessary.Asymptomatic HIV disease with CD4count<200/µl – treatment necessary.Highly active antiretroviral therapyinvolves combination of 3 or more drugs asindicated.(HAART)ZIDOVUDINE+LAMIVUDINE+NEVIRAPINEZIDOVUDINE+LAMIVUDINE+LOPINAVIR/RTVZIDOVUDINE+LAMIVUDINE+NEVIRAPINELAMIVUDINE+STAVUDINE+EFAVIRENZLAMIVUDINE+STAVUDINE+NEVIRAPINELAMIVUDINE+ABACAVIT+NEVIRAPINELAMIVUDINE+ZIDOVUDINE+INDINAVIRLAMIVUDINE+STAVUDINE+RITONAVIRLAMIVUDINE+ABACAVIR+NELFINAVIRZIDOVUDINE+LAMIVUDINE+ABACAVIRBASIC(2 DRUG)REGIMENLOWRISKZIDOVUDINE 300mg+LAMIVUDINE 150mgBD X4WKSEXPANDED(3 DRUG)REGIMENHIGHRISKZIDOVUDINE300mg+LAMIVUDINE150mgBDX 4WKS+INDINAVIR 800mg TDS
  31. 31. Viral Infections IN OBSTETRICS…..AGENTS CAUSING VIRAL INFECTIONS IN PREGNANCY:-Rubella, cyto megala virus, herpes simplex, varicellazoster, influenza, mumps, HIV, hepatitis and entero viruses.Incidence of malformations :- THE FETAL DEFECTS:- Cataracts, deafness, CNS defects & Heart defects.Most common fetal viral infection :- cytomegala virus(3rd – 9th week, highly teratogenic)PARVO VIRUS B- 19 :- erythema infectiosum ( 5th disease of childhood). Leads to nonimmune fetal hydrops. ( 2nd or 3rd trimester).ANTIVIRALS UNSAFE DURING PREGNANCY:- Acyclovir, ganciclovir, Foscarnet, Amantadine, Vidarabine, Interferon-a.ANTI RETRO VIRALS UNSAFE DURING PREGNANCY:-Didanosine, Abacavir, Indinavir, Ritonavir, Efavirenz.1st TRIMESTER 2nd TRIMESTER 3rd TRIMESTER50% 20% 7%
  32. 32. PHARMACO ECONOMICSACYCLOVIR ACIHERPIN 200mg Rs.60DIDANOSINE VIROGINE Cap. Rs.42RITONAVIR RITOMAX Tab. Rs.28FAMCICLOVIR FAMTREX 250mg Rs.40GANCICLOVIR GANGUARD 250mg Rs.122INDINAVIR VIREDIN 400mg Rs.25INTERFERON SHANFERON 1 vial Rs.810RIBAVIRIN VIRAZIDE Tab. Rs.56NELFINAVIR NELVIR Tab. Rs.24NEVIRAPINE NEVIMUNE 200mg Rs.14DRUG NAME TRADE NAME DOSE COST
  33. 33. FUTURE BEGINSWITH...US !

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