antivirals and anti fungals

8/7/2019 antivirals and anti fungals

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AntiAnti--fungal and Antifungal and Anti--viralsvirals

ANTIANTI--VIRALSVIRALS

AntiherpesvirusAntiherpesvirus Acyclovir and ValacyclovirAcyclovir and Valacyclovir Gancyclivir and ValgancyclovirGancyclivir and Valgancyclovir

Famciclovir and PenciclovirFamciclovir and Penciclovir FoscarnetFoscarnet IdxuridineIdxuridine

AntiAnti--influenzainfluenza Amantadine and RimantadineAmantadine and Rimantadine OseltamivirOseltamivir

Anti HIVAnti HIV NRTINRTI ZidovudineZidovudine StayudineStayudine


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Didanosine Lamivudine Zalcitabine

NNRTI Nevirapine Efavirenz Delavirdine

Protease Inhibitors Saquinovir Ritonavir Nelfinavir

IndinavirOthers: Immune globulin Interferon


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POLYENE ANTIBIOTICSPOLYENE ANTIBIOTICSAMPHOTERICIN BAMPHOTERICIN B

MOA:MOA: Binds to fungal cell membraneBinds to fungal cell membrane ergosterolergosterol creating porescreating poresleading toleading to increased cell permeability and loss ofincreased cell permeability and loss ofcellular constituents;cellular constituents;

Cholesterol, present in host cell membrane closely resembleCholesterol, present in host cell membrane closely resemble ergosterolergosterol,,thethe polyenespolyenes bind to it as well, though with less affinity, thus thebind to it as well, though with less affinity, thus the

selectivity of action ofselectivity of action of polyenespolyenes is lowis low

PK:PoorlyPK:Poorly absorbed in the GIT, primarily IV useabsorbed in the GIT, primarily IV use>90% protein bound, long plasma life>90% protein bound, long plasma life

PoorPoor meningealmeningeal penetration with or without inflammationpenetration with or without inflammationPrimary route of elimination: hepatic metabolismPrimary route of elimination: hepatic metabolism

AE:AE: The toxicity of AMB is highThe toxicity of AMB is high


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Acute reactions: infusion related toxicity: chills, fever, dyspnea, rarelyAcute reactions: infusion related toxicity: chills, fever, dyspnea, rarelyhemodynamic collapse/hypotension; probably due to release ofhemodynamic collapse/hypotension; probably due to release ofproinflammatory cytokinase and does not appear due to histamineproinflammatory cytokinase and does not appear due to histaminerelease.release.

Long term toxicity: Nephrotoxicity is the most common and mostLong term toxicity: Nephrotoxicity is the most common and mostserious long term toxicityserious long term toxicity due to decreased glomerular and tubulardue to decreased glomerular and tubularblood flow through its vasoconstrictive effects; occurs fairly uniformlyblood flow through its vasoconstrictive effects; occurs fairly uniformlyand is dose related; manifestations: kaliuresis and hypokalemia, fall inand is dose related; manifestations: kaliuresis and hypokalemia, fall inserum bicarbonate (may proceed to renal tubular acidosis); decreasedserum bicarbonate (may proceed to renal tubular acidosis); decreasedin renal erythropoietin and anemia, rising BUN and creatinine.in renal erythropoietin and anemia, rising BUN and creatinine.

Anemia: due to bone marrow depression; reversibleAnemia: due to bone marrow depression; reversible

CNS toxicity: occurs only on intrathecal injectionCNS toxicity: occurs only on intrathecal injection


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New AMB formulations:New AMB formulations:

AMB lipid complex (ABLC): contains 35% AMB incorporated in ribbon likeAMB lipid complex (ABLC): contains 35% AMB incorporated in ribbon likeparticles f dimyristoyl phospholipidsparticles f dimyristoyl phospholipids

AMB colloidal dispersion (ABCD): disc shaped particles containing 50%AMB colloidal dispersion (ABCD): disc shaped particles containing 50%each of AMB and cholesterol sulfate are prepared as aqueous dispersioneach of AMB and cholesterol sulfate are prepared as aqueous dispersion

Lipsomal AMB (small unilamellar vesicles; SUV): consist of 10% AMBLipsomal AMB (small unilamellar vesicles; SUV): consist of 10% AMBincorporated in uniform sized unilamellar liposomes made up of lecithinincorporated in uniform sized unilamellar liposomes made up of lecithinand other phospholipids.and other phospholipids.

Special features:Special features: produce milder acute reactions (specially liposomal formulation) on IVproduce milder acute reactions (specially liposomal formulation) on IV

infusioninfusion can be used in patients not tolerating infusion of conventional AMBcan be used in patients not tolerating infusion of conventional AMB much lower nephrotoxicitymuch lower nephrotoxicity cause minimal anemiacause minimal anemia Liposomal preparations delivers AMB specially to reticuloendothelial cells inLiposomal preparations delivers AMB specially to reticuloendothelial cells in

the liver and spleenthe liver and spleen


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However, some preparations, specially ABLC and ABCD produce lower AMBHowever, some preparations, specially ABLC and ABCD produce lower AMBlevels and NONE of the lipid preparation has shown superior efficacy comparedlevels and NONE of the lipid preparation has shown superior efficacy comparedto conventional AMB in prospective trials. They are very expensive.to conventional AMB in prospective trials. They are very expensive.

Clinical use:Clinical use: DOC for nearly all lifeDOC for nearly all life--threatening mycotic infectionsthreatening mycotic infections Broad spectrum of activity: yeasts, Candida sp., CryptococcusBroad spectrum of activity: yeasts, Candida sp., Cryptococcus

neoformans, endemic mycoses, Aspergillus fumigatusneoformans, endemic mycoses, Aspergillus fumigatus

NYSTATINNYSTATIN

MOA is similar to that of amphotericin BMOA is similar to that of amphotericin B Too toxic for systemic use; topical: virtually no adverse effectsToo toxic for systemic use; topical: virtually no adverse effects Use limited to topical treatment of superficial or local candidal infectionsUse limited to topical treatment of superficial or local candidal infections

oropharyngeal, vaginal intertriginous areas.oropharyngeal, vaginal intertriginous areas.


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THE AZOLESTHE AZOLES

MOA:bind to and inhibit cytochrome p450 enzymeMOA:bind to and inhibit cytochrome p450 enzyme

lanosterol 14lanosterol 14--demethlase responsible for demethylation ofdemethlase responsible for demethylation oflanosterol to ergosterol thus leading to decreasedlanosterol to ergosterol thus leading to decreasedergosterol synthesisergosterol synthesis..

Greater affinity for fungal cytochrome p450 toxicity profile and drugGreater affinity for fungal cytochrome p450 toxicity profile and druginteractions: imidazoles have lesser degree of specificity thus higherinteractions: imidazoles have lesser degree of specificity thus higherincidence of drug interactions and side effects; the lower toxicity ofincidence of drug interactions and side effects; the lower toxicity of

triazoles compares to imidazoles has correlated with their lower affinitytriazoles compares to imidazoles has correlated with their lower affinityfor mammalian CYP450 and lesser propensity to inhibit mammalianfor mammalian CYP450 and lesser propensity to inhibit mammaliansterol synthesissterol synthesis

BroadBroad--spectrum activity: Cryptococcus, Candida, endemic mycoses,spectrum activity: Cryptococcus, Candida, endemic mycoses,dermatophytes. Generally nondermatophytes. Generally non--toxic.toxic.


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KETOCONAZOLEKETOCONAZOLE

Good oral absorption but requires an acidic gastric environmentGood oral absorption but requires an acidic gastric environment High plasma protein bindingHigh plasma protein binding Extensive metabolized by the liver and excreted in bileExtensive metabolized by the liver and excreted in bile Penetration to CSF is negligiblePenetration to CSF is negligible

Greater propensity to inhibit mammalians cp450; less selectivity for fungal p450 than newerGreater propensity to inhibit mammalians cp450; less selectivity for fungal p450 than newerazolesazoles --> more side effects and significant drug interactions> more side effects and significant drug interactions

Drug interactions:Drug interactions: H2 blockers. PPI and antacids decrease oral absorptionH2 blockers. PPI and antacids decrease oral absorption Rifampicin, Phenobarbital carbamazepine and phenytoin induce ketoconazole metabolism andRifampicin, Phenobarbital carbamazepine and phenytoin induce ketoconazole metabolism and

decrease efficacydecrease efficacy KTZ inhibits cyp450 specially CYP3A4KTZ inhibits cyp450 specially CYP3A4 --> inc blood levels of drugs including warfarin,> inc blood levels of drugs including warfarin,

sulfonylureas, phenytoin, cyclosporine, diazepam, indinavirsulfonylureas, phenytoin, cyclosporine, diazepam, indinavir Dangerous interaction with terfenadine, astemizole, cisaprideDangerous interaction with terfenadine, astemizole, cisapride --> Torsades de pointes> Torsades de pointes

Useful in the treatment of cutaneous and mucous membrane dermatophytes and yeastUseful in the treatment of cutaneous and mucous membrane dermatophytes and yeastinfections; systemic mycoses but does not exceed efficacy of AMBinfections; systemic mycoses but does not exceed efficacy of AMBAE: high doses cause significant reduction in testosterone synthesis and displacement ofAE: high doses cause significant reduction in testosterone synthesis and displacement of

testosterone from protein binding sites and blocks adrenal response to corticotrophintestosterone from protein binding sites and blocks adrenal response to corticotrophin -->>gynecomastia, decreased sperm counts, libido; menstrual irregularities may occur due togynecomastia, decreased sperm counts, libido; menstrual irregularities may occur due tosuppression of estradiol synthesis.suppression of estradiol synthesis.


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FLUCONAZOLEFLUCONAZOLE

Does not require an acidic environment for oral absorption. High oral bioavailability.Does not require an acidic environment for oral absorption. High oral bioavailability. Long plasma halfLong plasma half--lifelife Penetrates widely into most tissues including normal and inflamed meningesPenetrates widely into most tissues including normal and inflamed meninges

Excreted unchanged in urineExcreted unchanged in urine

AE: few side effectsAE: few side effects

Has the least effect of all azoles on hepatic microsomal enzymes; higher selectivityHas the least effect of all azoles on hepatic microsomal enzymes; higher selectivityfor fungal cytochrome P450for fungal cytochrome P450 --> drug interaction is less common> drug interaction is less common

Does not inhibit steroid synthesis and anti androgenic and other endocrine sideDoes not inhibit steroid synthesis and anti androgenic and other endocrine sideeffects have not occurredeffects have not occurred

Azole of choice in the treatment and secondary prophylaxis of cryptococcalAzole of choice in the treatment and secondary prophylaxis of cryptococcalmeningitis (acceptable alternative to amphotericin B for mild cryptococcalmeningitis (acceptable alternative to amphotericin B for mild cryptococcalmeningitis but superior to it in long term prevention of relapsing meningitis);meningitis but superior to it in long term prevention of relapsing meningitis);

Systemic and mucosal candidiasis; coccidioidal meningitis and hiptosplasmosis; (noSystemic and mucosal candidiasis; coccidioidal meningitis and hiptosplasmosis; (noactivity against Aspergillus)activity against Aspergillus)


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ITRACONAZOLEITRACONAZOLE

Lipophilic, requires low gastric pH for absorption specially the tablet form;Lipophilic, requires low gastric pH for absorption specially the tablet form;solution is taken in fasted state; tablet and solution forms are notsolution is taken in fasted state; tablet and solution forms are notinterchangeable, solution preferred; solution achieves a higher peakinterchangeable, solution preferred; solution achieves a higher peakconcentrationconcentration

Variable bioavailabilityVariable bioavailability Highly protein bound, large VdHighly protein bound, large Vd Interacts with hepatic microsomal enzymes though less than ketoconazoleInteracts with hepatic microsomal enzymes though less than ketoconazole Effectivity limited by reduced bioavailabilityEffectivity limited by reduced bioavailability Poor CSF penetrationPoor CSF penetration Has activity against Aspergillus; preferred over KTZ for most systemicHas activity against Aspergillus; preferred over KTZ for most systemic

mycoses that are not associated with meningitismycoses that are not associated with meningitis

Broader spectrum of activity than KTZ or fluconazole; superior toBroader spectrum of activity than KTZ or fluconazole; superior tofluconazole for Histoplasmosis, Blastomycosis, Sporotrychosis andfluconazole for Histoplasmosis, Blastomycosis, Sporotrychosis andOnychomycosisOnychomycosis

Well tolerated in low doses 400 mg/day gastricWell tolerated in low doses 400 mg/day gastricintolerance is significant, dizziness, pruritus, headache and hypokalemiaintolerance is significant, dizziness, pruritus, headache and hypokalemia

Drug interaction profile similar to KTZDrug interaction profile similar to KTZ


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FLUCYTOSINEFLUCYTOSINE

Fluorinated analogue of cytosineFluorinated analogue of cytosineMOA: 5MOA: 5--FC taken up by fungal cells by cytosine premease then intracellularlyFC taken up by fungal cells by cytosine premease then intracellularly

is converted to 5is converted to 5--FU by cytosine deaminase then to 5FU by cytosine deaminase then to 5--fluorodeoxyuridylicfluorodeoxyuridylicacid which is an inhibitor of thymidylate synthesis which is an importantacid which is an inhibitor of thymidylate synthesis which is an important

component of DNA;component of DNA; Fungal selectivity of 5Fungal selectivity of 5--FC depends on the fact that mammalian cellsFC depends on the fact that mammalian cells(except some marrow cells) are unable to convert drug to active(except some marrow cells) are unable to convert drug to activemetabolites;metabolites;

PK: well absorbed; poorly protein bound; penetrates well into body fluids includingPK: well absorbed; poorly protein bound; penetrates well into body fluids includingCSF; excreted in urineCSF; excreted in urine

AE: toxicity results to metabolism to toxic antineoplastic compound fluoruracilAE: toxicity results to metabolism to toxic antineoplastic compound fluoruracil bone marrow toxicitybone marrow toxicity

Clinical use: limited antifungal activity; not used as monotherapy due toClinical use: limited antifungal activity; not used as monotherapy due todevelopment of resistance;development of resistance;

Useful as part of combination treatment with amphotericin B for cryptococcalUseful as part of combination treatment with amphotericin B for cryptococcalmeningitis and with itraconazole for chromoblastomycosismeningitis and with itraconazole for chromoblastomycosis


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CharacteristiCharacteristi

cscs

AMBAMB 55--FCFC KTZKTZ FLUFLU ITR ITR

AntifungalAntifungal

spectrumspectrum

BroadBroad NarrowNarrow BroadBroad BroadBroad BroadBroad

Water solubleWater soluble NoNo YesYes YesYes YesYes YesYes

AbsorbedAbsorbed

orallyorally

NoNo YesYes YesYes YesYes YesYes

AdministeredAdministered

IVIV

YesYes YesYes NoNo YesYes NoNo

Resistance (inResistance (in

vivo)vivo)

NoNo YesYes NoNo NoNo NoNo

NephrotoxicityNephrotoxicity YesYes NoNo NoNo NoNo NoNo

AnemiaAnemia YesYes MildMild NoNo NoNo NoNo

LeukopeniaLeukopenia NoNo YesYes NoNo NoNo NoNo

GI upsetGI upset YesYes YesYes MildMild MildMild ModerateModerate

OverallOveralltoxicitytoxicity

HighHigh MediumMedium LowLow LowestLowest LowestLowest


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GRISEOFULVINGRISEOFULVIN

MOA: binds to microtubules responsible for mitotic spindleMOA: binds to microtubules responsible for mitotic spindle

formation leading to defective cell wall development; bindsformation leading to defective cell wall development; bindsto newly formed keratin protecting the skin from newto newly formed keratin protecting the skin from newformationformation

Ineffective topicallyIneffective topically Poor oral absorption but improved with microcrystallinePoor oral absorption but improved with microcrystalline

processing or when taken with fatty mealsprocessing or when taken with fatty meals Well toleratedWell tolerated Oral fungistatic agent used in the systemic treatment of dermatophytosis; reserved forOral fungistatic agent used in the systemic treatment of dermatophytosis; reserved for

cases with nail, hair or large body surface environmentcases with nail, hair or large body surface environment


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TERBINAFINETERBINAFINE

Synthetic allylamine available for topical and systemicSynthetic allylamine available for topical and systemic(oral) use in the treatment of dermatophyte skin and nail(oral) use in the treatment of dermatophyte skin and nailinfectionsinfections

MOA: reversible nonMOA: reversible non--competitive inhibition of squalenecompetitive inhibition of squalenemonooygenase (squalene epoxidase) which convertsmonooygenase (squalene epoxidase) which convertssqualene to lanosterolsqualene to lanosterol --> ergosterol;> ergosterol;

Keratophilic and fungicidal, accumulation of squalene within the fungalKeratophilic and fungicidal, accumulation of squalene within the fungalcells appears to be responsible for its fungicidal activitycells appears to be responsible for its fungicidal activity

Well tolerated; mammalian enzyme inhibited only by 1000 fold higherWell tolerated; mammalian enzyme inhibited only by 1000 fold higherconcentrations of terbinafineconcentrations of terbinafine

Does not inhibit cytochrome p450Does not inhibit cytochrome p450


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VIRUSESVIRUSES

Obligate intracellular parasitesObligate intracellular parasites

To reproduce, viruses must enter the host cell, take over the host cellsTo reproduce, viruses must enter the host cell, take over the host cellsmechanism for nucleic acid and protein synthesis and direct the hostmechanism for nucleic acid and protein synthesis and direct the hostcell to make new viral replication particlescell to make new viral replication particles

Chemotherapy interferes with any or all steps in the viral replicationChemotherapy interferes with any or all steps in the viral replicationcyclecycle

But because viral replication and host cell processes are linked, theBut because viral replication and host cell processes are linked, themain problem in the chemotherapy of viruses is finding a drug that ismain problem in the chemotherapy of viruses is finding a drug that isselectively toxic to the virusselectively toxic to the virus

Viruses with specificViruses with specific txtx:: hyperviruseshyperviruses HSV1, HSV2, VZV, CMV; RSV;HSV1, HSV2, VZV, CMV; RSV;Hepatitis B and C, HIVHepatitis B and C, HIV


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ANTIHERPESVIRUS AGENTSANTIHERPESVIRUS AGENTS

Acyclovir andAcyclovir and ValacyclovirValacyclovirMOA: acyclovir is converted t metabolites via 3MOA: acyclovir is converted t metabolites via 3 phosphorylationphosphorylation steps:steps: AcyclovirAcyclovir acycloviracyclovir acyclovir acyclovir diPdiP acyclovir trip (active metabolite)acyclovir trip (active metabolite)

Herpes virus specificHerpes virus specific thymidinethymidine kinasekinase

AcyclovirAcyclovir

AcyclovirAcyclovir monophosphatemonophosphate

CellularCellular KinaseKinase

Inhibits herpes virus DNA polymerase competitivelyInhibits herpes virus DNA polymerase competitivelyAcyclovirAcyclovirTriphosphateTriphosphate

Gets incorporated in viral DNA and stop lengthening of DNAGets incorporated in viral DNA and stop lengthening of DNAstrand. The terminated DNA inhibits DNA polymerase irreversibly.strand. The terminated DNA inhibits DNA polymerase irreversibly.


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Acyclovir triphosphate is a competitive inhibitor for the incorporation ofAcyclovir triphosphate is a competitive inhibitor for the incorporation of

dGTP into viral DNA thus inhibiting DNA synthesisdGTP into viral DNA thus inhibiting DNA synthesis

Acyclovir that is incorporated acts as a chain terminator because it lacks 3OHAcyclovir that is incorporated acts as a chain terminator because it lacks 3OHgroup necessary for elongation because it requires viral kinase for the initialgroup necessary for elongation because it requires viral kinase for the initial

phosphorylation, acyclovir is selectively activated and accumulates only inphosphorylation, acyclovir is selectively activated and accumulates only in

infected cells; greater inhibitory effect on viral DNA synthesis, low toxicityinfected cells; greater inhibitory effect on viral DNA synthesis, low toxicity

for host cells.for host cells.

PK:PK: Valacyclovir rapidly and completely converted to acyclovir by intestinal andValacyclovir rapidly and completely converted to acyclovir by intestinal and

hepatic first pass metabolismhepatic first pass metabolism

Only 20% of oral acyclovir higher is absorbedOnly 20% of oral acyclovir higher is absorbed

Bioavailability of acyclovir higher after oral ValacyclovirBioavailability of acyclovir higher after oral Valacyclovir

Low plasma protein bindingLow plasma protein binding Widely distributed attaining CSF concentrations that is 50% of plasmaWidely distributed attaining CSF concentrations that is 50% of plasma

Excreted unchanged in urine by glomerular filtration and tubular secretionExcreted unchanged in urine by glomerular filtration and tubular secretion


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Clinical Uses:Clinical Uses: Active against herpes group of virus. HSV I most sensitive followed byActive against herpes group of virus. HSV I most sensitive followed byHSV II>VZV=; CMV not affectedHSV II>VZV=; CMV not affected

AEAE: generally well tolerated; IV may cause reversible renal dysfunction: generally well tolerated; IV may cause reversible renal dysfunction Secondary to crystalline nephropathy: neurologic toxicitySecondary to crystalline nephropathy: neurologic toxicity

Famciclovir and PenciclovirFamciclovir and Penciclovir

Famciclovir is converted to Penciclovir by first pass metabolismFamciclovir is converted to Penciclovir by first pass metabolismMOA: similar to acyclovir: it is monophosphorylated by viral thymidine kinase thenMOA: similar to acyclovir: it is monophosphorylated by viral thymidine kinase then

converted to triphosphate form by a cellular kinase: Penciclovir triphosphateconverted to triphosphate form by a cellular kinase: Penciclovir triphosphateacts as competitive of viral DNA polymerase:acts as competitive of viral DNA polymerase:

However does not cause chain terminationHowever does not cause chain termination

Lower affinity for viral kinase than acyclovir triphosphate but within increased ndLower affinity for viral kinase than acyclovir triphosphate but within increased ndprolonged intracellular concentrationsprolonged intracellular concentrations Bioavailability of Penciclovir higher after oral FamciclovirBioavailability of Penciclovir higher after oral Famciclovir Generally well toleratedGenerally well tolerated Penciclovir is effected against HSV I, HSV II, VZV and EBVPenciclovir is effected against HSV I, HSV II, VZV and EBV


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Ganciclovir and ValganciclovirGanciclovir and ValganciclovirMOA: same as acyclovir and causes chain termination.MOA: same as acyclovir and causes chain termination. 100x more concentrated in infected cells that normal host cells: preferentially100x more concentrated in infected cells that normal host cells: preferentially

incorporated into DNA by viral polymerase however, mammalian bone marrowincorporated into DNA by viral polymerase however, mammalian bone marrowcells are sensitive to growth inhibition by ganciclovircells are sensitive to growth inhibition by ganciclovir

Ganciclovir is poorly absorbed orally: Valganciclovir well absorbed from GIT andGanciclovir is poorly absorbed orally: Valganciclovir well absorbed from GIT andis rapidly metabolized to gancicloviris rapidly metabolized to ganciclovir

Excreted uncharged by kidneysExcreted uncharged by kidneys Treatment of CMV infectionTreatment of CMV infectionAE: Myelosuppression is most common and serious side effectAE: Myelosuppression is most common and serious side effect

IdoxuridineIdoxuridine Iodinated derivative of deoxyuridine that acts as a thymidine analogue thatIodinated derivative of deoxyuridine that acts as a thymidine analogue that

completes with thymidine: gets incorporated in DNA so that faulty DNA is formedcompletes with thymidine: gets incorporated in DNA so that faulty DNA is formedthus inhibiting both viral and cellular DNA synthesisthus inhibiting both viral and cellular DNA synthesis

Virus selectivity is low; significant host toxicityVirus selectivity is low; significant host toxicity--not used in treatment of systemicnot used in treatment of systemicviral infectionsviral infections

Clinical use limited to herpes simplex infection of eyelid conjunctiva and corneaClinical use limited to herpes simplex infection of eyelid conjunctiva and cornea


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FoscarnetFoscarnet Noncompetitive inhibitor of viral DNA polymerase and reverse transcriptaseNoncompetitive inhibitor of viral DNA polymerase and reverse transcriptase

by reversibly binding with pyrophosphate binding sites of viral enzyme;by reversibly binding with pyrophosphate binding sites of viral enzyme;straight chain phosphate unrelated to any nucleic acid precursorstraight chain phosphate unrelated to any nucleic acid precursor

Does not require activation by phosphorylationDoes not require activation by phosphorylation

Indicated for treatment of CMV retinitis acyclovir resistant HSV II and VZVIndicated for treatment of CMV retinitis acyclovir resistant HSV II and VZVin AIDS patientin AIDS patient

AEAE: renal toxicity, anemia, tremors and convulsions, hypoglycemia: renal toxicity, anemia, tremors and convulsions, hypoglycemia


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ANTIANTI--INFLUENZA AGENTSINFLUENZA AGENTS

Amantadine and RimantadineAmantadine and Rimantadine

MOA:MOA: inhibits uncoating of viral RNA by inhibition of viral M protein that acts asinhibits uncoating of viral RNA by inhibition of viral M protein that acts asH channelH channel

Both have good oral absorptionBoth have good oral absorption

Amantadine the replication of the 3 antigenic subtypes of influenza A (HINI,Amantadine the replication of the 3 antigenic subtypes of influenza A (HINI,H2N2, H3N2) BUT NOT influenza BH2N2, H3N2) BUT NOT influenza B

AE:AE: mild GI and neurologic complaintsmild GI and neurologic complaints

Uses:Uses:

Prophylaxis of influenza A2 during an epidemic of seasonal, especially in highProphylaxis of influenza A2 during an epidemic of seasonal, especially in highrisk patientsrisk patients

Treatment of influenza A2 illnessTreatment of influenza A2 illness ParkinsonismParkinsonism

RimantadineRimantadine-- more potent, long acting and better tolerated congener ofmore potent, long acting and better tolerated congener ofamantidineamantidine


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OseltamivirOseltamivir Analogue of neuramic acid which is a reversible antagonist of viral neuraminidaseAnalogue of neuramic acid which is a reversible antagonist of viral neuraminidase Prevention of release and spread or progeny virusPrevention of release and spread or progeny virus Rapidly absorbed and metabolizedRapidly absorbed and metabolized Eliminated by the kidneysEliminated by the kidneysAE: most frequent: nausea and vomiting; bronchitis, insomnia, vertigoAE: most frequent: nausea and vomiting; bronchitis, insomnia, vertigo Has activity against BOTH influenza A and influenza BHas activity against BOTH influenza A and influenza BClinical useClinical use Treatment of uncomplicated acute influenza in patients. 1 y/o; decrease duration ofTreatment of uncomplicated acute influenza in patients. 1 y/o; decrease duration of

illness by to 1.5 days when treatment is initiated within 48hours of onsetillness by to 1.5 days when treatment is initiated within 48hours of onsetsymptomssymptoms

Prophylaxis of influenza in individuals > 13 y/oProphylaxis of influenza in individuals > 13 y/o

ZANAMIVIRZANAMIVIR oral bioavailability 7 y/o


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RibavirinRibavirin Guanosine analogue that inhibits synthesis of viral mRNAGuanosine analogue that inhibits synthesis of viral mRNA Undergoes phosphorylation by host cell enzymesUndergoes phosphorylation by host cell enzymes Oral absorption is rapid and first pass metabolism is extensive;Oral absorption is rapid and first pass metabolism is extensive; Bioavailability increased when given with high fat meals; oral bioavailability isBioavailability increased when given with high fat meals; oral bioavailability is

50%50% Accumulates in the body and persists months after discontinuationAccumulates in the body and persists months after discontinuation When administered by aerosol, has minimal systemic absorptionWhen administered by aerosol, has minimal systemic absorption

Clinical Use:Clinical Use: Ribavirin aerosolRibavirin aerosol high risk infants and young children with severehigh risk infants and young children with severeRSV bronchiolitis or pneumonia; oral RibavirinRSV bronchiolitis or pneumonia; oral Ribavirin-- in combination with interferonin combination with interferonagainst hepatitis C; influenza A and Bagainst hepatitis C; influenza A and B

AE:AE: aerosolizedaerosolized-- local reaction; systemiclocal reaction; systemic hemolytic anemiahemolytic anemia Mutagenic, teratogenic, embryotoxic, contraindicated in pregnant women and theMutagenic, teratogenic, embryotoxic, contraindicated in pregnant women and the

male partners of pregnant womenmale partners of pregnant women


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ANTIANTI--HIVHIV

Viral ReplicationViral ReplicationViral entry:Viral entry: gp 120 in the surface of viral envelopegp 120 in the surface of viral envelope

attaches to CD4 surface glycoprotein of target cell thenattaches to CD4 surface glycoprotein of target cell thenundergoes conformational change that allows it to bindundergoes conformational change that allows it to bindwith chemokine receptors (CXCR for CD4with chemokine receptors (CXCR for CD4--T calls orT calls or

CCR5 for macrophages)CCR5 for macrophages)ViralViral reverse transcriptasereverse transcriptase synthesize DNA using viralsynthesize DNA using viral

RNA as template.RNA as template.

DNA integrates into host genome byDNA integrates into host genome by integrase;integrase; viralviraltranscription to viral proteins and progeny viral RNAtranscription to viral proteins and progeny viral RNAASSEMBLY maturation in which polyproteinsASSEMBLY maturation in which polyproteinsare cleaved by protease.are cleaved by protease.


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Drug Therapy of HIVInfectionDrug Therapy of HIVInfection The replicative cycle of HIV presents many opportunities for the targeting of antiThe replicative cycle of HIV presents many opportunities for the targeting of anti--viral agents.viral agents. The drugs in clinical uses are classified as NRTIs, NNRTIs, NTRTIs and PIThe drugs in clinical uses are classified as NRTIs, NNRTIs, NTRTIs and PI Single agents are seldom used to treat HIV infection. Multidrug therapy is used to counteract theSingle agents are seldom used to treat HIV infection. Multidrug therapy is used to counteract the

rapid mutation rate of HIV and to minimize drug toxicity. HAART (Highly Active Anti Retroviralrapid mutation rate of HIV and to minimize drug toxicity. HAART (Highly Active Anti RetroviralTherapy) uses combination of PI and RTI. In this system, drugs working by different mechanismTherapy) uses combination of PI and RTI. In this system, drugs working by different mechanismproduce a sequential blockade of steps required for viral reproduction.produce a sequential blockade of steps required for viral reproduction.

NUCLEOSIDEREVERSETRANSCRIPTASENUCLEOSIDEREVERSETRANSCRIPTASEINHIBITORSINHIBITORS

(NRTIs)(NRTIs) Undergoes phosphorylation to triphophates by the host kinase, compete withUndergoes phosphorylation to triphophates by the host kinase, compete with

nucleoside triphosphate for access to reverse transcriptasenucleoside triphosphate for access to reverse transcriptase Block HIV replication and therefore the infection of new cells but have little effectBlock HIV replication and therefore the infection of new cells but have little effect

on cells already infected with the viruson cells already infected with the virus Lack 3OH group thus their incorporation into DNA results in chain terminationLack 3OH group thus their incorporation into DNA results in chain termination Inhibits cellular and mitochondrial DNA, polymerase and kinase toxicityInhibits cellular and mitochondrial DNA, polymerase and kinase toxicity ALL NRTIs can produce a potentially fatal syndrome of lactic acidosis and severeALL NRTIs can produce a potentially fatal syndrome of lactic acidosis and severe

hepatomegaly with hepatic necrosis; women alcoholics, obesity, prolong nucleosidehepatomegaly with hepatic necrosis; women alcoholics, obesity, prolong nucleosideexposure are risk factors for liver disease increases risk for lactic acidosis.exposure are risk factors for liver disease increases risk for lactic acidosis.


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AgentAgent DoseDose AdministrationAdministrationCommon Side EffectsCommon Side Effects CommentsComments

ZidovudineZidovudine 200 mg tid or 300 mg200 mg tid or 300 mg

bidbid

Food interferes withFood interferes with

absorptionabsorption

Bone marrow toxicityBone marrow toxicity

anemia, neutropenia,anemia, neutropenia,nausea, insomnianausea, insomnia

Avoid concurrentAvoid concurrent

myelosuppressivemyelosuppressivedrugsdrugsRibavirin inhibitsRibavirin inhibitsactivity of ZDV;activity of ZDV;ZDV inhibits stavudineZDV inhibits stavudineactivity Doseactivity Doseadjustment needed inadjustment needed inrenal impairmentrenal impairment

StavudineStavudine 3030--40 mg bid40 mg bid Peripheral neuropathy;Peripheral neuropathy;lactic acidosis mostlactic acidosis most

common withcommon withstavudinestavudine

Avoid concurrent useAvoid concurrent useof ZDVof ZDV

DidanosineDidanosine 150150--200 mg bid200 mg bid 30 min before or 2 hrs30 min before or 2 hrsafter meals; foodafter meals; foodinterferes withinterferes withabsorptionabsorption

Main unwantedMain unwantedeffects: dose relatedeffects: dose related

pain and sensory losspain and sensory lossin the feet Dose relatedin the feet Dose related

pancreatitispancreatitis

Contains antacid NotContains antacid Notcombined withcombined withZalcitabineZalcitabine

LamivudineLamivudine 150 mg bid or 300 mg150 mg bid or 300 mgqdqd

Best tolerated NRTIBest tolerated NRTI Avoid use withAvoid use withZalcitabineZalcitabine inhibitinhibiteach other; Activeeach other; Activeagainst HBVagainst HBV

ZalcitabineZalcitabine 0.75 mg tid0.75 mg tid Avoid use with antacidAvoid use with antacidor foodor food

Peripheral NeuropathyPeripheral Neuropathy Avoid neuropathicAvoid neuropathicdrugsdrugs

AbacivirAbacivir Rash, hypersensitivityRash, hypersensitivityReactionReaction

Do not rechallengeDo not rechallengeafterafterHypersensitivityHypersensitivityReactionReaction


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Nucleotide Reverse Transcriptase InhibitorNucleotide Reverse Transcriptase InhibitorTenofovirTenofovir Converted by cellular enzymes to triphosphate which completes with dATP forConverted by cellular enzymes to triphosphate which completes with dATP for

access to reverse transcriptase and causes chain termination following itsaccess to reverse transcriptase and causes chain termination following itsincorporationincorporation

Generally well toleratedGenerally well tolerated Produces less mitochondrial toxicity than NRTIsProduces less mitochondrial toxicity than NRTIs

NONNON--NUCLEOSIDE REVERSENUCLEOSIDE REVERSETRANSCRIPTASE INHIBITORS (NNRTIS)TRANSCRIPTASE INHIBITORS (NNRTIS)

Inhibits viral reverse transcriptase by binding to adjacent to its active site inducingInhibits viral reverse transcriptase by binding to adjacent to its active site inducingconformational changes that causes enzyme inactivationconformational changes that causes enzyme inactivation

DO NOT require phosphorylation for activationDO NOT require phosphorylation for activation Undergoes significant metabolism by and induction of cytochrome p450 enzymesUndergoes significant metabolism by and induction of cytochrome p450 enzymes

adverse effects and multiple drug interactionsadverse effects and multiple drug interactions


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AgentsAgents DoseDose AdministrationAdministration Common SideCommon SideEffectsEffects

CommentsComments

EfavirenzEfavirenz 600mg qid600mg qid Not to be taken byNot to be taken byfatty mealsfatty meals

Dizziness,Dizziness,insomnia, rash,insomnia, rash,increaseincreasetransaminasetransaminase

Embryotoxic,Embryotoxic,teratogenocteratogenoc

NevirapineNevirapine 200 mg bid200 mg bid Oral bio A 90% notOral bio A 90% notfood dependentfood dependent

Hepatic toxicity,Hepatic toxicity,skin reactions (SJS,skin reactions (SJS,TEN,TEN,hypersensitivity)hypersensitivity)headacheheadache

DelaviridineDelaviridine Low gastric acidityLow gastric aciditydecrease absorptiondecrease absorption

Most common; rashMost common; rashwith pruritiswith pruritis


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PROTEASE INHIBITORSPROTEASE INHIBITORS

Protease required for production of mature infectiveProtease required for production of mature infectivevirus, cleaves polyproteins into structural and activevirus, cleaves polyproteins into structural and active

enzymesenzymesCan produce nausea, vomiting, diarrhea andCan produce nausea, vomiting, diarrhea and

paresthesias; hyperglycemia and insulin resistance:paresthesias; hyperglycemia and insulin resistance:hypercholesterolemia and hypertriglyceridemia; fathypercholesterolemia and hypertriglyceridemia; fat

distribution is common.distribution is common.

Interacts with a large number of drugsInteracts with a large number of drugs by andby andinhibit cytochrome p450 enzymesinhibit cytochrome p450 enzymes


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AgentsAgents DoseDose AdministrationAdministration Common SideCommon SideEffectsEffects

CommentsComments

SaquinavirSaquinavir Within 2 hours of aWithin 2 hours of afull meal; food (highfull meal; food (highfat meal) incfat meal) incabsorptionabsorption

Nausea, diarrheaNausea, diarrhea Multiple nursingMultiple nursinginteractionsinteractionsLess potent inhibitorsLess potent inhibitorsof CYTP450of CYTP450

RitonavirRitonavir 600 mg bid600 mg bid With food first passWith food first passmetabolismmetabolism

Nausea, diarrhea,Nausea, diarrhea,paresthesias, hepatitisparesthesias, hepatitis

Most potent inhibitorMost potent inhibitorof CYP3A4of CYP3A4

IndinavirIndinavir 800mg tid800mg tid With water or other With water or otherliquids; a hr before orliquids; a hr before or2 hrs after meal2 hrs after meal

Nephrolithiasis LiverNephrolithiasis Liverfunctionfunctionabnormalitiesabnormalities

Drug interactionsDrug interactions

NelfinavirNelfinavir 750 mg tid or 1250750 mg tid or 1250mg bidmg bid

With foodWith food Diarrhea, nauseaDiarrhea, nausea Low incidence of Low incidence ofside effectsside effects


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FUSION INHIBITORFUSION INHIBITORENFUVITIDEENFUVITIDE Binds to qp41 subBinds to qp41 sub--unit of the glycoprotein preventing conformational changesunit of the glycoprotein preventing conformational changes

required for the viral cellular membranesrequired for the viral cellular membranes Administered subcutaneous; highly protein bund; metabolized by proteolyticAdministered subcutaneous; highly protein bund; metabolized by proteolytic

hydrolysishydrolysisAE: local reactionsAE: local reactions

ANTIANTI--HEPATITISHEPATITIS LamivudineLamivudine

ADEFOVIRADEFOVIR Analogue of adenosine monophosphate phosphorylated byAnalogue of adenosine monophosphate phosphorylated by

cellular kinases to active metabolites then competitivelycellular kinases to active metabolites then competitivelyinhibits HBV DNA polymerase and results in chaininhibits HBV DNA polymerase and results in chainterminationtermination


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IMMUNE GLOBULINIMMUNE GLOBULIN Inhibits viral penetration; opsonize viral particles, active complement,Inhibits viral penetration; opsonize viral particles, active complement,

stimulate cellstimulate cell-- mediated immunitymediated immunity Administered parenterallyAdministered parenterally

Protection lasts for 2Protection lasts for 2--3 weeks3 weeks

Specific immune globulin against CMV, HBV, rabies, RSV, VZVSpecific immune globulin against CMV, HBV, rabies, RSV, VZV

AE:AE: hypersensitivity reactions; infusion related reactionshypersensitivity reactions; infusion related reactions-- flushing,flushing,dizziness, BP changes; aseptic meningitis syndrome; can interfere withdizziness, BP changes; aseptic meningitis syndrome; can interfere withresponse to live virus vaccinesresponse to live virus vaccines

INTERFERONINTERFERON Inhibits viral penetrations, uncoating, mRNA synthesis, translation, assembly and releaseInhibits viral penetrations, uncoating, mRNA synthesis, translation, assembly and release

Interferon alpha and beta exert the most potent antiInterferon alpha and beta exert the most potent anti--viral effectsviral effects

Clinical Uses:Clinical Uses:

Interferon alpha 2aInterferon alpha 2a--chronic hep Cchronic hep C

Interferon alpha 2bInterferon alpha 2b-- chronic hep B and Cchronic hep B and C

AE:AE: fluflu--like symptoms; neurotoxicity, Myelosuppression, thyroid dysfunction, hypotension, transientlike symptoms; neurotoxicity, Myelosuppression, thyroid dysfunction, hypotension, transientarrhythmias, alopecia, liver dysfunctionarrhythmias, alopecia, liver dysfunction

Pegylated interferon alphaPegylated interferon alpha-- a linear or branched polyethylene glycol (PEG) miety is attached toa linear or branched polyethylene glycol (PEG) miety is attached tointerferon longer half life and slowed clearance; superior efficacy but more expensiveinterferon longer half life and slowed clearance; superior efficacy but more expensive

Peginterferon alphaPeginterferon alpha--2a and Peginterferon alpha2a and Peginterferon alpha--2b2b--used for chronic hepatitis Cused for chronic hepatitis C


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AntiAnti--ViralActions of Purine andPyrimidineAnalogsViralActions of Purine andPyrimidineAnalogs

Acyclovir

Famcyclovir

Ganciclovir

AcyclovirFamcyclovirGanciclovir

Acyclovir

Famcyclovir

GanciclovirAcyclovir

Famcyclovir

Ganciclovir

ViralKinase

Hostkinase

cell

ZidovudineIdoxiridine

VidarabineCytarabine

Nucelotideanalogues

Inhibition of

viral DNApolymerase

antivirals and anti fungals

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