AntiviralAgents

Virusesareobligateintracellularparasites;
theirreplicationdependsprimarilyon
syntheticprocessesofthehostcells.
Antiviralagentsmusteitherblockviralentry
into orexit fromthecellorbeactiveinside
thehostcell.
Antiviralagentsaremostactive,whenviruses
arereplicating.
Theearlierthattreatmentisgiven,betterthe
result.
 Difficultiesintreatment
1. Substantialmultiplicationhasalready
occurred,beforesymptomsoccur.
2. Intracellular usehostmetabolicprocesses
Highlyselectivetoxicityishardertoachieve.
3.Resistancetothedrug
 DNAVIRUSES
Adenoviruses (URT&eyeinfection)
Hepadnaviruses (hepatitis B)
Herpesviruses
HerpesSimplexVirustype1 causesoralherpes,
ocularherpes,viralencephalitis,herpeskeratitis
HerpesSimplexVirustype2 genitalherpes
Varicella ZosterViruschickenpox,zosterorshingles
Cytomegalovirus infectiousmononucleosis
EpsteinBarrvirus inf.mono,Bcelllymphoma
Papillomavirus warts
Poxvirus smallpox
 RNAVIRUSES
Picornaviruses Polioviruscausingpolio&
hepatovirus causinghepatitisA
Orthomyxovirus influenzaA,B,C
influenza,H1B1causesswineflu
Paramyxoviruses rubellaviruscausing
mumps,RSVcausingLRTI,
Rhabdoviruses causingrabies
Arbovirus ,rotavirus,retrovirus,arenavirus,
coronavirus
 Viralreplication
Viralattachment&entry
Penetration
Uncoating
Earlyproteinsynthesis
Nucleicacidsynthesis
Lateproteinsynthesis&processing
Packaging&assembly
Viralrelease
 ViralReplication
Recognise hostsurfaceproteins&get
attached
Virusus penetratesthehostcellmembraneby
endocytosis
Envelopemergeswiththehostcellmembrane
Capsid alongwithgenomeenterstheinterior
ofcell
Capsid removedwithinthecell,tofreethe
genomecontainingDNA
 Viralgenomeentersthecellnucleus&itsDNAis
transcribedintoviralmRNAbythehostcells
RNApolymerase.
Hostcellsribosomes thenutilise theviral
mRNAforthesynthesisofviralproteinsand
enzymes.
Duringthisprocess,regulatoryproteinsare
synthesised first,whichinitiatethetranscription
ofearlygenesresponsibleforviralDNA
replicationbyviralDNApolymerase.
 AfterDNAreplicationlategenesare
transcribed&translatedtoproducestructural
proteins requiredforassemblyofnewvirions.
Viralcomponentsarethenassembled toform
amaturevirusparticle.
Releaseofprogenyvirustakesplacethrough
buddingofhostcell.
 C/FOFANTIVIRALDRUGS

DNAPOLYMERASEINHIBITORS
PURINEANALOGUES
ACYCLOVIRVALACYCLOVIR
GANCICLOVIRVALGANCICLOVIR
FAMCICLOVIRPENCICLOVIR
CIDOFOVIRADEFOVIR
ENTECAVIRVIDARABINE
PYRIMIDINEANALOGUES
IDOXURIDINE,TRIFLURIDINE,TELBIVUDINE
NONNUCLEOSIDES FOSCARNET
 mRNASYNTHESISINHIBITORS
RIBAVIRIN,FOMIVIRSEN
INHIBITORSOFVIRALPENETRATION&UNCOATING
AMANTADINE,RIMANTADINE,DOCOSANOL
NEURAMINIDASEINHIBITORS
ZANAMIVIR,OSELTAMIVIR,PERAMIVIR
IMMUNOMODULATORS
INTERFERONS,PALIVIZUMAB,IMIQUIMOD
ANTIRETROVIRALDRUGS
DrugsforHerpesSimplexVirus(HSV)&
VaricellaZosterinfection
Acyclovir
Valacyclovir
Famciclovir
AcyclovirisonlyoneavailableforI/Vuse.
Valacyclovir &Famcyclovir Superiorfor
Herpeszoster
Notindicatedinvaricella
 Acyclovir
HSV1,HSV2,VZV
INDICATIONS
Skininfections Initial&recurrentlabial&genital
herpes(asacream),mosteffectivelywhennew
lesionsareforming.ForSkin&m.m.infections as
tabletsororalsuspensions.
Ocularkeratitis asointment
Prophylaxis&Treatmentinimmunocompromised
Oral,tab,suspension,
Encephalitis,disseminateddisease
 Acyclovir
VZviruses
Chickenpox
immunocompromised (i.v.),
immunocompetent withpneumonitis ,hepatitis
Shingles
inimmunocompetent ,tab/suspensionwithin48
hrsofappearanceofrash
Inimmunocompromised i.v.
Oral&topical5timesaday.
 Mechanism:
Threephosphorylation stepsforactivation.
Firstconvertedtothemonophosphate derivative
bythevirusspecified thymidine kinase;
selectiveactivation
Thentothedi andtriphosphate compoundsby
hosts cellularenzymes.
Acyclovirtriphosphate inhibitsviralDNAsynthesis
bytwomechanisms:
Inhibitionof viralDNApolymerase,withbinding
totheDNAtemplateasanirreversiblecomplex;
IncorporationintotheviralDNAchain
termination
 ADRs
Gen.welltolerated
N/D,Headache
I/V Extravasation localinflammation
Reversiblerenaldysfunction
Neurologictoxicity
 Valacyclovir
Prodrug ofacyclovir
Oralbioav.54%,given8hrly
Use
genitalherpes
Orolabialherpes
S/Es N/V,rash,dizziness,liverenzyme
elevation,anemia,neutropenia ,confusion,
hallucinations,seizures.
 Cytomegalovirus
Inadvancedimmunosuppression
Reactivationoflatentinfection
Endorgandisease Retinitis,Colitis,
esophagitis,CNSds .&pneumonitis
AIDS&organtransplantation
GANCICYCLOVIR
VALGANCICLOVIR
FOSCARNET
CIDOFOVIR
 GANCICLOVIR
SIMILARTOACYCLOVIRINITSMODEOF
ACTIONBUTMUCHMORETOXIC.
I/VORORALLY,ELIMINATEDINURINE,
UNCHANGED.
HALFLIFE 4HRS.
I.V.USEISLIMITEDTO LIFEORSIGHT
THREATENINGCMVINFECTIONINIMMUNO
COMPROMISEDPTS.
 GANCICLOVIR
ORAL FORMAINTENANCEOFSUPPRESSIVE
TREATMENTOFRETINITISINPTSWITHAIDS.
TOPREVENTCMVDISEASEINPATIENTSWHO
AREIMMUNOCOMPROMISED&
FOLLOWINGORGANTRANSPLANTATION.
ADRs NEUTROPENIA,THROMBOCYTOPENIA,
FEVER,RASH,GISYMPTOMS,CONFUSION&
SEIZURE.
 FOSCARNET

I.V.FORRETINITISDUETOCMVINPATIENTS
WITHHIVINFECTION(WHENGANC.C/I)
ACYCLOVIRRESISTANTHSVINFECTION
S/Es RENALTOXICITY,N/V,NEUROLOGICAL
REACTIONS,MARROWSUPPRESSION
 FOMIVIRSEN
ANOLIGONUCLEOTIDE
ANTICMVAGENT
BINDSTOmRNAINHIBITSTHESYNTHESISOF
IMMEDIATEEARLYPROTEINSNEEDEDFORVIRAL
REPLICATION
RESISTANCELEASTCOMMON
SELECTIVEACCUMULATIONINRETINA&VITREOUS
HUMOUR
INJECTEDINTRAVITREALLYFORCMVRETINITISINAIDS
PATIENTS
S/Es IRITIS,VITREITIS,INCREASEDINTRAOCULAR
PRESSURE
 TRIFLURIDINE
PYRIMIDINE NUCLEOSIDE.AGAINST HSV1,HSV2,
VACCINIA ,ANDSOMEADENOVIRUSES.
INCORPORATIONOFTRIFLURIDINE TRIPHOSPHATE
INTOBOTHVIRALANDCELLULARDNAPREVENTSITS
SYSTEMICUSE.
THERAPYFORKERATOCONJUNCTIVITISANDFOR
RECURRENTEPITHELIALKERATITIS DUETOHSV1
ANDHSV2.
TOPICALAPPLICATION,ALONEORINCOMBINATION
WITHINTERFON ALFA,HASBEENUSED
SUCCESSFULLYINTREATMENTOFACYCLOVIR
RESISTANTHSVINFECTIONS.
 IDOXURIDINE

INHIBITIONOFVIRALDNA POLYMERASE
BLOCKSDNASYNTHESIS.
NOEFFECTONRNAVIRUS.
ONLYTOPICALAPPLICATIONBECAUSEOFITS
GREATERSIDEEFFECTSINSYSTEMIC
APPLICATION.
TREATMENTOFOCULAR ORDERMAL
INFECTIONSDUETOHERPESVIRUS,
ESPECIALLYACUTEEPITHELIALKERATITIS DUE
TOHERPESVIRUS.
 VIDARABINE

ADENINE NUCLEOSIDEANALOGUE
AGAINSTHSV,VZV,CMV,HBVANDSOMERNA
VIRUSES.
PHOSPORYLATED INTRACELLULARBYHOSTENZYMES
TOFORM VIDARABINE TRIPHOSPHATE &INHIBITS
VIRALDNAPOLYMERASE
ACTSASDNA CHAINTERMINATOR
BUTINCORPORATEDINTOBOTHVIRALAND
CELLULARDNAEXCESSIVETOXICITY
 VIDARABINE
RAPIDLYMETABOLIZEDTOHYPOXANTHINE
ARABINOSIDE.
INSTABILITYANDTOXICITYLIMITEDITSCLINICAL
UTILITY.
ONLYTOPICALUSE INHSVKERATO CONJUCTIVITIS,
SUPERFICIALKERATITISINPTSNOTRESPONSIVETO
IDOXURIDINE.
S/E LACRIMATION,IRRITATION,PHOTOPHOBIA
 RIBAVIRIN
GUANOSINE ANALOG.
PHOSPHORYLATED INTRACELLULARLY BYHOSTCELL
ENZYMES.
MECHANISM:TOINHIBITTHEVIRALRNADEPENDENT
RNAPOLYMERASEOFCERTAINVIRUSES
RIBAVIRIN TRIPHOSPHATE INHIBITSTHEREPLICATIONOF
AWIDERANGEOFDNAANDRNAVIRUSES,INCLUDING
INFLUENZAAANDB, PARAINFLUENZA,RESPIRATORY
SYNCYTIAL VIRUS,PARAMYXOVIRUSES,HCV ,
ANDHIV1.
 RIBAVIRIN
Oralabsorptionisrapid,first passextensive,yet
oralbioav.65%
Alsogivenasaerosoltotreatinfluenza&
infectionsduetorespiratorysyncytial virus
i.v.toreducemortalityinlassa fever(arena)
Highlyeffectiveag.InfluenzaA&Bviruses.
Oralribavirin &s.c.interferonalpha2bis
synergisticallyeffectiveag.HepatitisC.
 ANTIHEPATITISAGENTS

INTERFERONES
RELEASEDBYHOSTCYTOKINES
COMPLEXANTIVIRAL,IMMUNOMODULATORY
ANTIPROLIFERATIVEACTIVITIES
,, accordingtoantigenic&physical
properties.
 INF synthesised primarilybyhuman
leukocytes
INF fromfibroblasts
INF whichisalymphokine ,isproducedbyT
lymphocytesasapartoftheimmuneresponse
toviralandnonviralantigens.
CommercialsynthesisofIFNsisdoneby
recombinantDNAtech.in bacterialcultures.
INF& exertpotentantiviraleffects
IFN hasantiviral&immunomodulatory
effects.
 BINDINGTOSPECIFICCELLMEMBRANE
RECEPTORS&AFFECTVIRALREPLICATIONAT
MULTIPLESTEPS
INHIBITIONOFVIRALPENETRATION,UNCOATING
INHIBITIONOFTRANSLATION
INHIBITIONOFTRANSCRIPTION,PROTEIN
PROCESSING,MATURATION&RELEASE
INCREASEDEXPRESSIONOFMHCantigen
ACTIVATIONOFMACROPHAGES&NATURALKILLER
CELLSALONGWITHMODULTIONOFCELLSURFACE
PROTEINSTOFASCILITATEIMMUNERECOGNITION
 ALLDNA&RNAVIRUSESARESENSITIVETO
IFNs
ENDOGENOUSIFNsARERESPONSIBLEFOR
MAKINGMOSTVIRALINFECTIONSSELF
LIMITING.
IFNSCANBEADMINISTEREDS.C.,I.M.,I.V.,OR
INTRALESIONALLY
DONOTCROSSBBB
ELIMINATEDTHROUGHPHAGOCYTOSIS ORBY
KIDNEY/LIVER.
 CLINICALUSES
IFN 2achronichepatitisBinfection,AIDS
relatedKaposissarcoma,chronichepatitisC,
hairycellleukemia&chronicmyelogenous
leukemia
IFN 2b (s.c.,i.m.)HepatitisC,malignant
melanoma,condyloma acuminata ,chronic
hepatitisB,chronichepatitisCandnon
hodgkins lymphoma
Asanadjunt intreatmentofviralinfections
includingAIDS.
 S/Es flulikesyndrome Headache,fever,
chills,myalgias ,malaise,transienthepatic
enzymeelevation.
Chronictherapy neurotoxicities ,
myelosuppression ,profoundfatigue,
wt.loss ,rash,cough,myalgia ,alopecia,
tinnitus,hepaticandthyroiddysfunction.
 Lamivudine
Cytosineanalogue
InhibitsHBVDNApolymerase
InhibitsHIVreversetranscriptasebycompeting
withdeoxycytidine triphosphate for
incorporationintoviralDNA
Resultinginchaintermination.
AgainstHIV1,synergisticwithavarietyof
antiretroviralnucleosideanalogs,including
zidovudine andstavudine.
TreatmentofchronichepatitisBinfection.
 oralbioavailability>80%
Notfooddependent
Themajorityoflamivudine iseliminated
unchangedintheurine.
Excellentsafetyprofile
Headache,nausea,dizziness,
CoinfectionwithHIV riskofpancreatitis.
 Antiinfluenzaagents

Amantadine &Rimantadine
Zanamivir &Oseltamivir
 Amantadine
Inhibitsuncoating ofviralRNAwithininfectedhost
cells
InhibitsreplicationofInfluenzaA
AprotonionchannelM2oftheviralmembraneisthe
target.
InhibitionofM2protein preventionofH+mediated
dissociationofribonucleoprotein coresegment(a
prerequisiteforviralreplication)
Wellabsorbedorally
Excretedunchangedinurineover23days
Halflife16hours
 Rimantadine
410timesmoreactivethanamantidine
Bettertolerated,longeracting,morepotent.
Dosereductionrequiredforbothin elderly
&inpatientswithrenalinsufficiency.
Forrimantadine inpatientswithmarked
hepaticinsufficiencyalso.
 S/Es generallywelltolerated
Nausea,Anorexia,insomnia,dizziness,
nightmares,lackofmentalconc.,
hallucinations,posturalhypotension,ankle
edema.
Uses prophylaxisofInfluenzaA2
TreatmentofinfluenzaA2
Parkinsonism
C/I Epilepsy&otherCNSds,gastriculcer,
pregnancy
 Zanamivir &Oseltamivir
Neuraminidaseinhibitors
Interferewiththereleaseofprogenyinfluenza
virusfrominfected newhostcells
(Neuraminidaseenzymerequiredforrelease)
Preventingthespreadofinfectionin
respiratorytract
Activityag.BothInfl.A &Infl.B
 Zanamivir isgiventhroughinhalation
515%oftotaldoseisabsorbed&excretedin
theurine.
S/Es Cough,brochospasm ,reversible
decreaseinpulmonaryfunction&transient
nasal&throatdiscomfort.
 Oseltamivir
isorallygiven
Aprodrug
Activatedbyhepaticesterases
Widelydistributedthroughoutthebody
Headache,fatigue&diarrhea.
AVIANINFLUENZA
 PERAMIVIR
FOREMERGENCYTREATMENTOF
HOSPITALISEDPATIENTSWITHH1N1
INFLUENZA
ORALBIOAV.POOR
USEDFORPATIENTSSHOWINGRESISTANCETO
OSELTAMIVIRORTOZANAMIVIRINHALATION
USEDASTHEONLYI/VOPTIONFOR
TREATINGSWINEFLU
CLEAREDPHASEIII
AntiRetroviral(AntiHIV)Agents
 reverse
double helix HIV integrase Incorporated
Viral transcriptase into host
RNA DNA
genome
transcription
translation
Final HIV protease
structural Polyproteins
proteins

NRTIs
NNRTIs

Drugs PIs
 SurfaceproteinsgP120,linkedtoa
transmembrane stalk(gP41)
Antigenic&fascilitate viralattachmenttoCD4
cellsofTlymphocytes
CoregenomecontainsRNAalongwith3genes
:gag,pol,env
Gag&pol codeforformationofreverse
transcriptase,integrase &proteaseenzymes
Env genescodefortheformationofenvelope
proteinsgP120&gP41.
 Integratedintohostgenomebyviralenzyme
integrase
ProvirusDNAtranscribedintonewgenomicRNA
&mRNA
mRNAtranslatedintoviralproteinsbyhost
ribosomes
Assemblyofvirion
Maturationinwhichviralproteaseenzyme
cleavesthepolypeptideintofunctionalstructural
proteins&viralenzymes.
Budding&Releasetoinfectothercells
 Primetarget HelperTlympocytes ,which
haveCD4expressedontheirsurface.
gP120bindstoCD4&toChemokine co
receptors(CXCR4),(CCR5formacrophages)
Gp 41causesfusion ofviralenvelopewith
plasmamembraneofTcells.
Afterfusion,virusenters thetargetcells.
Uncoating
Viralreversetranscriptasesynthesises DNA
fromviralRNA.
 C/FOFANTIHIVDRUGS

NucleosideReverseTranscriptase
Inhibitors(NRTIs)
Zidovudine
Stavudine
Lamivudine
Abacavir
Zalcitabine
Emtricitabine
Didanosine
 NonnucleosideReversetranscriptase
inhibitors(NNRTIs)
Efavirenz
Nevirapine
Delavirdine
Etravirine
NucleotideReversetranscriptaseinhibitors
Tenofovir
 ProteaseInhibitors(PIs)
Saquinavir
Indinavir
Nelfinavir
Amprenavir
Fosamprenavir
Ritonavir
Lopinavir
 Entry/fusionInhibitors
Enfuvirtide

CCR5Inhibitors
Maraviroc

Integrase Inhibitors
Raltegravir
NucleosideReverseTranscriptaseInhibitors
 MechanismofAction
Competitiveinhibition ofHIV1reverse
transcriptase;
Incorporatedinto thegrowingviralDNA
chaincausetermination
Drugsrequiresintracytoplasmic activation
phosphorylation triphosphate form
MosthaveactivityagainstHIV2 aswellas
HIV1.
 Zidovudine
Azidothymidine AZT
Deoxythymidine analog
antiHIV1andHIV2
Wellabsorbedfromthegutanddistributedto
mostbodytissuesandfluids,includingthe
cerebrospinalfluid.
Eliminatedprimarilybyrenalexcretion
followingglucuronidation intheliver.
 Decreasestherateofclinicaldiseaseprogression
andprolongssurvival.
Reducestherateofvertical(mothertonewborn)
transmission ofHIV.
Beginb/w1434weeks
Inneonate,birthto6weeksofage.
Alsousedforpostexposureprophylaxisforhealth
careworkers.
Adverseeffect: myelosuppressionanemiaor
neutropenia; gastrointestinalintolerance,
headache,insomnia,myopathy
 Lessfrequent thrombocytopenia,
hyperpigmentation ofnails

Interactions increasedserumlevelsof
Probenecid,Phenytoin,Fluconazole,valproic
acid,lamivudine.
 Zalcitabine (ddC)
Cytosineanalogue
AntiHIV1
Zalcitabine +Zidovudine +oneproteaseinhibitor
Suitableforpatientsintoleranttoorresistantto
ziduvidine .
Longintracellularhalflifeof10hrs.
Dosedependentperipheralneuropathy.
Contraindicationtousewithotherdrugsthat
maycauseneuropathy.
Stomatitis &esophagealulceration
 Stavudine(d4T)
Thymidine analog(d4T),notusedwithAZTbecause
AZTmayreducethephosphorylation ofd4T.
AntiHIV1andHIV2
Highoralbioavailability (86%)thatisnotfood
dependent.
Plasmaproteinbinding isnegligible,mean
cerebrospinalfluidconcentrations are55%ofthose
ofplasma.
Excretionisbyactivetubularsecretion and
glomerular filtration.
 USEDFORTHETHERAPYOFHIVINFECTIONSASA
PARTOFMULTIDRUGREGIMEN&ALSOFORPOST
EXPOSUREPROPHYLAXIS
ADVERSEEFFECTS:
DOSELIMITINGTOXICITYISADOSERELATED
PERIPHERALSENSORYNEUROPATHY.
PANCREATITIS,ARTHRALGIAS ,ELEVATIONIN
SERUMAMINOTRANSFERASES.
 Didanosine (ddI)
SYNTHETICANALOGOFDEOXYADENOSINE
PLASMAPROTEINBINDINGISLOW(<5%),
CEREBROSPINALFLUIDCONCENTRATIONSARE20%
OFSERUMCONCENTRATIONS.
ELIMINATEDBYGLOMERULAR FILTRATIONAND
TUBULARSECRETION.
ADMINISTEREDINCOMBINATIONDUETO
RESISTANCE
SHOULDBETAKENONANEMPTYSTOMACH.
FQSANDTETRACYCLINS SHOULDBEGIVENATLEAST
2HRSBEFOREORAFTERDDI TOAVOIDDECREASED
ANTIBIOTICCONC.DUETOCHELATION .
 ADVERSEEFFECTS:
DOSEDEPENDENTPANCREATITIS
PAINFULPERIPHERALDISTALNEUROPATHY
DIARRHOEA
HEPATITIS
ESOPHAGEALULCERATION
CARDIOMYOPATHY
CENTRALNERVOUSSYSTEMTOXICITY(HEADACHE,
IRRITABILITY,INSOMNIA)
 Nonnucleosidereversetranscriptase
inhibitors
Includingdelavirdine,nevirapine,efavirenz.
Binddirectlytoasiteontheviralreverse
transcriptasethatisneartobutdistinctfromthe
bindingsiteoftheNRTIs.
Neithercompetewithnucleosidetriphosphates nor
requirephosphorylation tobeactive.
Thebindingtotheenzymesactivesiteresultsin
blockadeofRNA andDNAdependentDNA
polymeraseactivities.
 SpecificactivityagainstHIV1.
Crossresistance amongthisclassofagents.
Therapidemergenceofresistance prohibitsmono
therapy withanyoftheNNRTIs.
NocrossresistancebetweentheNNRTIsandthe
NRTIsortheproteaseinhibitors.
Oralbioavailabilityishigh.
MetabolizedbytheCYP3AP450isoform,excreted
intheurine.
Adverseeffects: skinrash,elevationinliver
enzymes
 NEVIRAPINE

Asacombinationofmultidrugantiretroviral
therapy.
200mg/dayoraliseffectiveinpreventing
verticaltransmission(givenatthetimeof
labour);singledoseof2mg/kgoraldosetobe
giventotheneonatewithin3daysafterbirth.
Halflife2530hrs.
 EFAVIRENZ
Usedaspostoperativeprophylaxis.
600mgorallyOD.
S/EsinvolveCNS:dizziness,nightmares,
insomnia,headache&euphoria
OtherS/Es skinrash,nausea,vomiting,
elevatedliverenzymesandserumcholesterol
levels.
teratogenic
 DELAVIRDINE
UsedfortreatmentofHIV1infectionasapartof
combinationtherapy.
Dose400mgTDS
Ifdidanosine orantacidsaretobeused,its
dosingtobewithheldby1hrastheydecreaseits
oralbioavailability.
Metabolised byandinhibitsCYP3A4&thus
increasestheplasmaconc.ofseveralprotease
inhibitorssuchasamprenavir ,indinavir ,
lopinavir,ritonavir,saquinavir.
Dosereductionoftheserequired.
 NtRTIs
Tenofovir
Availableastenofovir disproxil fumarate
Prodrug,firsthydrolysed inlivertotenofovir
Whichissubsequentlyphosphorylated toan
activetenofovir diphosphate (thatistheactive
form)
inhibitsHIVreversetranscriptaseenzyme
Causesterminationofchainelongationafter
gettingincorporatedintoviralDNA
Analogueofadenosine5monophosphate
 UsedalongwithotherantiHIVdrugsinthe
treatmentofHIVinadoseof300mgonce
dailyaftermeals.
Oralbioavailabilitywithmeals40%
Usuallywelltolerated
Nausea,Vomiting,diarrhoea and
osteomalacia
Hepatomegaly,pancreatitis,lacticacidosis
Increasestheplasmalevelsofdidanosine
leadingtotoxicity.
 Proteaseinhibitors
ritonavir ,nelfinavir ,saquinavir ,indinavir and
amprenavir

Gag and Gag-Pol translate Polyproteins,

gene Immature budding particles
protease

Final structural proteins,

Mature virion core
 Proteaseisresponsibleforcleavingprecursor
moleculestoproducefinalstructuralproteins
ofmaturevirion core.
Bypreventingcleavage,PIsresultinthe
productionofimmature,noninfectiousviral
particles.
 CombinationtherapywithPIsandother
antiretroviraldrugssignificantlyimprovesthe
efficacybyblockingHIVreplicationatdifferent
stagesinintracellularlifecycle.
Crossresistancebetweenindinavir and
ritonavir canoccur.
 S/Es
Asyndromeofredistribution&accumulationof
bodyfatthatresultsincentralobesity,dorso
cervicalfatenlargement&acushingoid
apperance isseenwithPIs.
Increaseintriglyceride,LDLlevelsalongwith
glucoseintolerance&insulinresistance
Increaseinspontaneousbleedinginpatientswith
hemophiliaA&B.
Druginteractionsduetoenzymeinduction&
inhibition.
 Druginteractions

Competitiveinhibitorsofdrugsmetabolised by
CYP3A4family
Lifethreateningtoxicitieswith
Cisapride (arrythmias),
ergotalkaloids(vasospasm)
Statins (rhabdomyolysis)
Midazolam (resp.depression)
Enzymeinducersmaydecreaseplasmalevelsof
PIs.
 FusionInhibitors
ENFUVERTIDE
Blocksentryintocell
Bindstogp41subunitofviralenvelope
glycoprotein
Preventsconformationalchangesrequiredfor
fusionofviral&cellularmembranes.
Metabolismbyhydrolysis
WithoutinvolvementofCYP450
Eliminationhalflife38hrs
 S/Es
Mostcommons/eis localinjectionsite
reactions
H/S
Eosinophilia &pneumonialikemanifestations.
 Chemokine receptor5antagonists
Maraviroc
BindstoCCR5receptorsonCD4cell
membrane&preventstheentryofthevirus
intothehostcell
Usedalongwithotherantiretrovirals ,inhighly
resistantadultpatients
Mains/ehepatotoxicity
Otherscough,rash,fever,muscular pain,GIT
distress
 Integrase inhibitors(Raltegravir)
Inhibitstheviralenzymeintegrase ,therebypreventing
theinsertionofHIVgeneticmaterialinto
chromosomesofhostcells&haltingtheviral
replicationprocess
Notmetabolised byCytochrome P450system
Druginteractionsarenotclinicallysignificant
Rifampicin decreasesraltegravir levels
Antacidsandironbindtointegrase ,hencedosing
shouldbeseparatedby2hrs.
Usualoraldose200mgBDorally
S/Es nausea,diarrhea,fever,headache,myopathy.
 HAART
HighlyActiveAntiretroviralTherapy
CombinationofNRTIs&Proteaseinhibitors,workingwith
differentmechanisms,combineddrugsproducea
sequentialblockadeofviralreproductionattwodifferent
steps.HIVcannotdevelopmutantssimultaneouslyto
differentdrugsworkingbytwodifferentmechanisms.
Popularcombinationchoices
2NRTIs+1NNRTIorOne/twoproteaseinhibitorsi.e.
NRTIs(2)+PI(1)or
NRTIs(2)+NNRTI(1)or
NRTIs(2)+PI(1)+Ritonavir(PI)
 Preffered drugregimensare
Zidovudine +Lamivudine +efavirenz
Zidovudine +Lamivudine +Lopinavir/ritonavir
Alternatives
NRTI(1)+NNRTI(1)+PI(1)OR
NRTI(1)+NNRTI(1)+PI(2)