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L/O/G/O

L/O/G/O

FarmakologiObatAntituberculosis
FarmakologiObatAnti

FajarWahyuPribadi
Worldwideepidemiology,stopTB
strategy&otherfacts(1
strategy&otherfacts(13)
8.6millioncases(22%ofHBCs PursuehighqualityDOTS
qualityDOTS HIV/TBcoinfections:2134
accountfor80%ofcases) expansion&enhancement/health more
940,000deaths(34% systemsstrengthening likelytobecomesickwithTB
HIV+) AddressHIV/TB/MDRTB/
AddressHIV/TB/MDR 11.2millionsmearpositiveTB
58%ofglobalcasesin needsofpoor&vulnerablepops. casesdetected&treated
SouthEastAsia& Engageallcareproviders ~22millionlivessavedthrough
WesternPacificregions Empowerpts./communities DOTS&StopTBstrategy
13%HIV/TBcasesworldwide throughpartnership TBdeathrates45%(1990
2012)
Highestproportion Enableandpromoteresearch
Affordable1stlinedrugs:$20$40
inAfricanregion forfullcourse(4)

StopTBstrategy TB2nd onlyto


Epidemiology
HIV/AIDSassingle
(2012) (20112015) infectiouskiller

DOTS,DirectlyObservedTreatment,ShortCourseHBC,highburdencountries:Afghanistan,Bangladesh,Brazil,Cambodia,China,D
burdencountries:Afghanistan,Bangladesh,Brazil,Cambodia,China,DemocraticRepublicof
Congo,Ethiopia,Indonesia,Kenya,Mozambique,Myanmar,
India,Nigeria,Pakistan,Philippines,RussianFederation,SouthAfrica,Thailand,Tanzania,Uganda,Vietnam,ZimbabweMDR,
India,Nigeria,Pakistan,Philippines,RussianFederation,SouthAfrica,Thailand,Tanzania,Uganda,Vietnam,ZimbabweMDR,multidrug resistantpts,
patientspops,populations
1. WorldHealthOrganization.GlobalTuberculosisReport2013http://www.who.int/tb/publications/global_report/gtbr13_main_text.pdf
http://www.who.int/tb/publications/global_report/gtbr13_main_text.pdf.
2. WorldHealthOrganization.TheStopTBStrategy. http://www.who.int/tb/strategy/stop_tb_strategy/en/
3. WorldHealthOrganization.TuberculosisfactsheetNo.1042014 http://www.who.int/mediacentre/factsheets/fs104/en/
4. KanekoT,CooperC,Mdluli K.ChallengesandopportunitiesindevelopingnoveldrugsforTB.Futuremedicinalchemistry.20113(11):1373400.
K.ChallengesandopportunitiesindevelopingnoveldrugsforTB.Futuremedicinalchemistry.20113(11):1373
10
Symptoms
Sitesof
extrapulmonary
tuberculosis
DOTS

24
24
DOTS
DOTS,toensurecureby
providingmedicine&
confirmingitstaken
INTENSIVEPHASE pt
swallowsdruginpresenceof
healthworker
CONTINUATIONPHASE
CONTINUATIONPHASE 1
wkmedicinein multiblister
combipack(1st dosein
presenceofhealthworker)
Nextweekmedicineonly
afterreturnofemptyblister
25
Advantages
Highcurerate

Drugresistance

ADRcanbemonitored

26
PHASESOFCHEMOTHERAPY

INITIATIONPHASE CONTINUATION
PHASE
23months
45drugs 46months
Rapidlykills 23drugs
bacilli Eliminates
remainingbacilli
Preventsrelapse

27
Firstlinedrugs: killactivebacteria,
importantintheearlystagesofinfection
importantintheearlystagesofinfection.

Second linedrugs: hinder bacterial


growth.
Strengthentreatmentinthecaseof
resistantbacteria.
Lessefficientandgenerallymoretoxicthan
Lessefficientandgenerallymoretoxicthan
firstlinedrugs.
AlternativegroupingofAntitubercular
AlternativegroupingofAnti
drugs
GROUP1 First lineoralantiTBdrugs Isoniazid,Rifampin,Pyrazinami
de,Ethambutol

GROUP 2 Injectable antiTBdrugs Streptomycin, Kanamycin,


Amikacin,Capreomycin

GROUP3 Fluoroquinolones Ofloxacin,Levofloxacin,Moxiflo


xacin,Ciprofloxacin
GROUP 4 SecondlineoralantiTBdrugs
TBdrugs Ethionamide
,Prothionamide,Cycloserine,Te
rizidone,PAS

GROUP5 Drugswithunclearefficacy Thiacetazone, Clarithromycin,


Clofazimine,Linezolid,Amoxicill
in/clavulanate,Imipenem/cilas
tatin
FIRSTLINEDRUGS
FIRSTLINEDRUGS
PHARMACOKINETICS
INHisreadilyabsorbedfromGIT.

INHreadilydiffusesinallbodyfluids.

Peakplasmaconcentrationof35g/mlwithin12hrs.
Peakplasmaconcentrationof3

Halflifeisabout13hrs.

DOSAGE : 5mg/kg/dayoncedaily.
Upto10mg/kg/daycanbeusedifmalabsorption isnotan
Upto10mg/kg/daycanbeusedif
issue.
Highdose upto 15mg/kg/daytwiceaweek.
15mg/kg/daytwiceaweek.
Pharmacokinetics
Absorption: well absorbed
Distribution: widely into body tissues and fluids including liver, lung,
and CSF
Relative diffusion from blood into CSF: adequate with or without
inflammation
CSF: blood level ratio: inflamed meninges: 100%
Protein binding: 50%
Metabolism: hepatic
Halflife elimination: 910 hr
Time to peak, serum concentration: within 2 hr
Excretion: urine (4% as unchanged drug)
Pregnancy & Lactation
Pregnancy Category: C
Lactation: enters breast milk
Pharmacokinetics
Absorption
Bioavailability: ~80%
Peak Plasma Time: 24 hr
Distribution
Widely throughout body; concentrated in kidneys, lungs, saliva, and red
blood cells
CSF: blood level ratio: 0% (normal meninges); 25% (inflamed meninges)
Protein binding: 2030%
Metabolism
Hepatic (20%) to inactive metabolite
Elimination
Halflife elimination: 2.53.6 hr; 715
15 hr (endstage
(end renal disease)
Excretion: ~50% urine; ~50% feces as unchanged drug.
Pharmacokinetics
Absorption: IM: well absorbed;
absorbed not absorbed from gut
Distribution: To extracellular fluid including serum,
abscesses, ascitic, pericardial, pleural, synovial,
lymphatic, & peritoneal fluids;
fluids crosses placenta; small
amounts enter breast milk
Protein Bound: 34%
Halflife elimination: newborns:
newborns 410 hr; adults: 24.7
hr, prolonged with renal impairment
Peak Plasma Time: within 1 hr
Excretion: urine (90% as unchanged drug); feces,
saliva, sweat, & tears (<1%%)
EthambutolcausingRed
causingRedGreenColour
Blindness
Blindness
AMIKACIN
Mechanism of Action
Irreversibly binds to 30S subunit of bacterial ribosomes; blocks
recognition step in protein synthesis;
synthesis causes growth inhibition.
For gramnegative bacterial coverage of infections resistant to
gentamicin and tobramycin
Pharmacokinetics
Absorption: IM: May be delayed in bedridden patient
Vd: 0.250.4 L/kg, primarily into extracellular fluid (highly
hydrophilic); penetrates bloodbrain
blood barrier when meninges
inflamed; crosses placenta.
Excretion: urine (9498%)
HalfLife: 23 hr
Peak Plasma Time: IM: 45120 120 min
Protein Binding: 011%
Dosing
15 mg/kg/day divided IV/IM q812hr
q8
Renal Impairment/Elderly
CrCl >90 mL/min & <60 years old: q8hr
CrCl 6090
90 mL/min OR >60 years old: q12hr
CrCl 2560
60 mL/min: q24hr
CrCl 1025
25 mL/min: q48hr
CrCl <10 mL/min: q72hr
q72hr
Interactions
Interactions

Contraindicated
amphotericin b deoxycholate
cidofovir
neomycin
Serious Use Alternative
Atracurium
BCG vaccine live
Bumetanide
cyclosporine
ethacrynic acid
Furosemide
ADR
110%
Neurotoxicity
Nephrotoxicity (if trough >10 mg/L)
Ototoxicity
<1%: Hypotension, Headache, Drug fever, Rash,
Nausea, Vomiting, Eosinophilia, Tremor, Arthralgia
Contraindications
Documented hypersensitivity
Cautions
Renal impairment
Risk of neurotoxicity, ototoxicity,
ototoxicity nephrotoxicity risk
of ototoxicity increase with concurrent loop diuretics
diuretics
Pregnancy & Lactation
Pregnancy Category: D
Lactation: excretion in milk unknown/not
recommendedIV Preparation
Dilute 500 mg to 100 or 200 mL sterile diluent
(usu NS or D5W)
IV/IM Administration
IM: give undiluted to upper outer quadrant of
buttocks
IV: infuse over 3060
60 min in adults and children and
12 hr in infants
KANAMYCIN
Mechanism of Action
Bactericidal and believed to inhibit protein synthesis
by binding to 30 S ribosomal subunit.
Pharmacokinetics
Metabolism: unknown
Excretion: urine
Dosing&Uses
IV Administration: 57.5
7.5 mg/kg/dose divided q812hr;
q8 not
to exceed 15 mg/kg/day divided q612hr;
q6 administer slowly
IM Administration: 57.5
7.5 mg/kg/dose divided q812hr;
q8 not
to exceed 15 mg/kg/day IM divided q12hr at equally divided
intervals;
Renal Impairment
CrCl 5080 mL/min: give 6090% of usual dose or give q8
12hr
CrCl 1050 mL/min: give 3070% of usual dose or give
q12hr
CrCl <10 mL/min: give 2030%
30% of usual dose or give q24
q24
48hr
ADR
Agranulocytosis, Anorexia, Diarrhea, Dyspnea, Elevated BUN,
Enterocolitis, Headache, Incr salivation, Muscle cramps, Nausea,
Nephrotoxicity, Neurotoxicity, Ototoxicity,
Ototoxicity Pruritus.
Contraindications
Documented hypersensitivity
Cautions
Auditory toxicity more common with kanamycin than with
streptomycin and capreomycin;
monthly audiometry is recommended while patients are being
treated with this drug;
renal toxicity occurs at a frequency similar to that of capreomycin;
regular monitoring of serum creatinine recommended
Renal impairment
Myasthenia gravis
Nephrotoxic agents
Pregnancy&Lactation
Pregnancy Category: D
Lactation: usually compatible
ADMINISTRATION
IV Preparation
For adults, IV infusions are prepared by adding 500 mg
of kanamycin to 100200 mL of usual IV infusion
fluid such as NS or D5W or by adding 1 g of the drug
to 200400 mL of diluent
IV/IM Administration
Administer by deep IM injection, or IV infusion
May administer by intraperitoneal instillation,
irrigation, or inhalation
Infuse over 3060 min
Pharmacokinetics:
Absorption: completely absorbed following oral administration
Bioavailability approximately 100%.
Volume of distribution 93.5 L.
Protein binding :Approximately 30% bound to proteins.
Metabolism: Hepatic . Metabolized to the active metabolite
sulfoxide,, and several inactive metabolites.
The sulfoxide metabolite has been demonstrated to have
antimicrobial activity against Mycobacterium tuberculosis.
Route of elimination: Less than 1% of the oral dose is excreted as
ethionamide in urine.
Half life2 to 3 hours
Dose:
Tuberculosis:
1520 mg/kg/day PO Max: 1000 mg/day
Renal Impairment
CrCl <10 mL/min:
/min: decrease dose 50%
Administration
Part of multidrug
drug regimen; not firstline
first treatment
Take with food
Monitor:
baseline & periodic LFTs, TFTs, glucose

Interactions
Significant MonitorClosely
cycloserine
isoniazid
magnesiumoxide/anhydrouscitricacid
magnesiumoxide/anhydrouscitricacid
Pharmacokinetics
Rapidly absorbed orally but food delays absorption,
BA: C 6080%, L 100%, G 96%
PPB: C 2035%, L 15%, G 20%
Vd: C 34%, L8%,
Half life: C 35hrs, L8hrs, G 8hrs

High tissue penetration: lungs, sputum, muscle, prostate but low


in CSF

Excreted primarily in urine, urinary and biliary concentrations are


1050
50 times more than plasma
Dosage
Ciprofloxacin 750mg BD,PO
Levofloxacin 500mg OD.PO
Moxifloxacin 400mg OD. PO

Interactions
All fluoroquinolones interact with aluminum or magnesium
containing antacids and products containing calcium, iron, or
zinc. Concomitant use invariably results in marked reduction of
oral absorption of the antimicrobial and decreased the
bioavailability of these drugs by up to 98% when given within
2 hours of antibiotic administration.
administration
Fluoroquinolones are administered with food, peak
concentration times are usually slightly delayed, and
maximum plasma concentrations (Cmax) are decreased
816%.
Reductions in renal and total systemic clearance caused
by probenecid are 24% for levofloxacin,[50% for
ciprofloxacin, and 42% for gatifloxacin.
Significantly interact with theophyllineciprofloxacin
decreased theophylline clearance by 2530%, and
increased theophylline plasma concentrations by up to
308%.
Cycloserine
Cycloserine
Dosinganduses
Active Tuberculosis
Initial: 250 mg PO BID
Maintenance: 500 mg 11 g/day in 2 divided doses for 18
18
24 months; not to exceed 1 g/day

Renal Impairment
CrCl 5080 mL/min:
/min: Give q1216hr
q12
CrCl 1049 mL/min:
/min: Give q2436hr
q24
CrCl <10 mL/min: Contraindicated

Administration
Part of multidrug
drug regimen; not firstline
first treatment
Pharmacokinetics
Distribution: CSF concentration equal to that in
plasma
Metabolism: liver
Excretion: urine

INTERACTIONS
Significant Monitor Closely
ethionamide
isoniazid
magnesium oxide/anhydrous citric acid
PAS
PAS
Para amino salicylic acid
Pharmacokinetics
Absorption
T max is about 6 h
Distribution
About 50% to 60% is protein bound.
Elimination
80% is excreted in the urine with at least 50% excreted in
acetylated form.
The t 1/2 of free aminosalicylic acid is 26.4 min.
Dose: 4g 3 times daily, children < 15yrs: 200300mg/kg
200
daily in 24 divided doses.
TypicalsecondlineDOTStherapies:drug
lineDOTStherapies:drug
classes(drugs)&someAEs(4)
Proteinsynthesisinhibition:bindstoRNApol. Proteinsynthesisinhibition:inhibitionof
30ssubunit translocation
SevereAEs:tinnitus,hearingloss,kidney AEsincludenephrotoxicity,8thcranialauditory
toxicity,allergytodrug(12) vestibularnervetoxicity(15)
Aminoglycosides Polypeptides,
,(kanamycin) (capreomycin)
DNAsynthesisinhibition:DNA gyrase Cellwallbiosynthesis:inhibitionof InhA
AEsincludediarrhea,nausea,&FDAblackbox Humanpotentialtoxicity&AEs:inhibitsthyroid
warningforincreasedriskoftendonitis(13) synthesis,drugdruginteractions(16)

Fluoroquinolones, Thioamides,
(ciprofloxacin) (ethionamide)
Cellwallbiosynthesis:alanineracemase &D Thymidylatesynthesisinhibition&interferencewith
AlaDAlaligase ironacquisition
AEsincludedizziness,seizure,somnolence(14) AEsincludeGIintolerance,hypersensitivityreactions
(17)
PAminosalicylic
Dcycloserine
AEs,adverseeventscanoccurinsomepatientsascollateralorsideeffectsof
acid
anintervention
4.KanekoT,CooperC,MdluliK.Challengesandopportunitiesindeveloping DOTS,DirectlyObservedTreatment,ShortCourseGI,gastrointestinal
noveldrugsforTB.Futuremedicinalchemistry.20113(11):1373400. 15.Capreomycin:Wikipedia http://en.wikipedia.org/wiki/Capreomycin
12.Kanamycin:Wikipedia http://en.wikipedia.org/wiki/Kanamycin. 16.Ethionamide:Wikipedia. http://en.wikipedia.org/wiki/Ethionamide.
13.Ciprofloxacin.Wikipedia: http://en.wikipedia.org/wiki/Ciprofloxacin. 17.pAminosalicylicacid. http://reference.medscape.com/drug/paser
14.Dcycloserine (seromycin):Medscape aminosalicylicacid999678#4.
http://reference.medscape.com/drug/seromycincycloserine342660#4.
DrugsensitiveTBinimmune
sensitiveTBinimmunecompetent
patients:Initialempiricaltreatment(4,6)
Isoniazid,rifampin,pyrazinamide,andeither ethambutol or
Isoniazid,rifampin,pyrazinamide,andeither
streptomycin
FourdrugcombinationforinitialtreatmentofDSTB
drugcombinationforinitialtreatmentofDSTB

Givendaily(69 monts),curerates~85%havebeenreportedif
),curerates~85%havebeenreportedif
treatmentisstrictlyfollowed
Worksreasonablywell,but1.7 1.8millionpeoplestillkilledeveryyear
RiseinMDRTB(TBisolatethatisresistanttobothisoniazidand
TBisolatethatisresistanttobothisoniazidand
rifampin )&XDR TB(MDR+resistanceto
MDR+resistanceto fluoroquinolone and1ofthe
3injectabledrugs[amikacin,kanamycin,
,kanamycin, capreomycin])
MDR,multidrugresistantXDR,extensivelydrugresistant
4.KanekoT,CooperC,MdluliK.ChallengesandopportunitiesindevelopingnoveldrugsforTB.
Futuremedicinalchemistry.20113(11):1373400.
6.MultidrugResistantTuberculosis(MDRTB)andExtensivelyDrugResistant(XDR)TB:AWeb
DrugResistant(XDR)TB:AWebBasedSeminarpresentedbytheDivisionofTuberculosis
EliminationCentersforDisease
ControlandPrevention(CDC)injointsponsorshipwith:FrancisJ.CurryNationalTuberculosisCenter,HeartlandNationalTub
ControlandPrevention(CDC)injointsponsorshipwith:FrancisJ.CurryNationalTuberculosisCenter,HeartlandNationalTuberculosisCenter,Southeastern
NationalTuberculosisCenter,
NewJerseyMedicalSchoolGlobalTuberculosisInstitute
http://www.cdc.gov/tb/publications/webcourseswebinars/mdrandxdrtb/mdrxdr_webinar_final.ppt
http://www.cdc.gov/tb/publications/webcourseswebinars/mdrandxdrtb/mdrxdr_webinar_final.ppt
DrugResistantTB:Definitions
ResistantTB:Definitions

Monoresistant: Resistancetoasingledrug
Polyresistant: Resistancetomorethanonedrug,but
notthecombinationof isoniazid
isoniazidand rifampicin
Multidrugresistant(MDR):
resistant(MDR): Resistancetoatleast
isoniazid and rifampicin
Extensivelydrugresistant(XDR):
resistant(XDR): MDRplusresistance
to fluoroquinolones andatleast1ofthe3
andatleast1ofthe3injectable
drugs(amikacin, kanamycin,
kanamycin capreomycin)
MULTIDRUGRESISTANT
TUBERCULOSIS(MDRTB)
Globally,5%ofTBcaseswereestimatedto
havehadMDR TBin2013
TBin2013
Medical&financialtollsofMDR/XDRTB
Medical&financialtollsofMDR
intheUSA

Medicalcosts Financialcosts

5.UnitedStatesCentersforDiseaseControl.NewCDCdataforTBintheUS2013.AccessedMay2014
5.UnitedStatesCentersforDiseaseControl.NewCDCdataforTBintheUS2013.AccessedMay2014
http://www.cdc.gov/nchhstp/newsroom/2014/WorldTBDaygraphics.html .
ManagementofMDR
ManagementofMDR&XDRTB(5,1819)
HBCs(18)
~450,000patientsworldwidewithMDR
~450,000patientsworldwidewithMDRTB&XDRTB
WHOrecommends4antibioticstowhichTBis
sensitiveforaperiodof20months
Globally,<20%patientswithpulmonaryMDRTB/XDR
Globally,<20%patientswithpulmonaryMDR
TBarecurrentlyreceivingadequatetreatment
PediatricMDRTB/XDRTB:pooledtreatmentsuccess
TB:pooledtreatmentsuccess
SevereAEs instudieswas81.7%
Treatment
Successcompromisedby suboptimal
adherence,AEs,&hightreatmentcosts
duringlongcourseofMDR/XDRTB
treatment
Cure:Noevidenceoffailureafter
completionofrecommendednational
policy,&3consecutiveculturestaken30
daysapart,arenegativeaftertheintensive
phase
AEs,adverseeventsHBCs,highburdencountrieswithmultidrugresistant(MDR)TB:includeChina,India,RussianFederation,
drugresistant(MDR)TB:includeChina,India,RussianFederation, Pakistan,SouthAfricaWHO,
WorldHealthOrganizationXDR,extensivelydrugresistant
5.UnitedStatesCentersforDiseaseControl.NewCDCdataforTBintheUS2013.AccessedMay2014
http://www.cdc.gov/nchhstp/newsroom/2014/WorldTBDaygraphics.html
18.LangeC,AbubakarI, Alffenaar JW, Bothamley G, Caminero JA, Carvalho AC,etal.Managementofpatientswithmultidrugresistant/extensivelydrug
AC,etal.Managementofpatientswithmultidrug
resistanttuberculosisinEurope:aTBNETconsensusstatement.TheEuropeanrespiratoryjournal.2014(e
resistanttuberculosisinEurope:aTBNETconsensusstatement.TheEuropeanrespiratoryjournal.2014(epub).
19.TBAlliance.MDRTB/XDRTB[cited2014May]. http://www.tballiance.org/why/mdrxdr.php.
http://www.tballiance.org/why/mdr
ManagementofMDR/XDRTB
ForMDR
IntensivePhase(IP)of6drugs
IntensivePhase(IP)of6drugsshouldbegivenat
least6months.
ContinuationPhase,4drugs
ContinuationPhase,4drugsaregivenfor18
months.
ForXDR:
Atleastthreetofourdrugstowhichthestrainis
sensitiveneedtobeusedforeffectivetreatment
Surgeryoflung
120
Investigationalanti
InvestigationalantiTBagents(4,20)
Newantibiotics/vaccines
Inhibitionofcellwallbiosynthesis(CW)
alone/plusothertargets:
Ethylenediamines, lactams,
Ethylenediamine(SQ109):CW+
benzothiazinones , Lipouridine
otherunknowntargetsoneof4 Antibiotics(precinical/Ph i)
investigationalantibioticstargeting
CW
Inhibitionofmultipletargets
Nitroimidazolese.g.,OPC67683
Inhibitionofproteinsynthesis Nitroimidazoles(Ph II
III)
Oxazolidinonese.g.,sutezolidin
developmentforXDRTBlinezolidfor
MDRTB&XDRTB
InhibitionofDNA(DNA gyrase)orRNA Oxazolidinone s(Ph III)&
synthesis diarylquinolines (Ph IIIII)
Quinolonese.g.,gatifloxacin
Rifamycinse.g.,rifapentine Quinolones(Ph IIII)
InhibitionofATPsynthesis & Rifamycins (Ph II
Diarylquinolinese.g.,TMC207forDS III)
&MDRTB
Prime,prime/boost,&immunotherapeutic
14vaccinecandidatesintrials&>35in
vaccinationstrategies(5) discovery/pre
discovery/preclinicalphases

4.KanekoT,CooperC,MdluliK.ChallengesandopportunitiesindevelopingnoveldrugsforTB.Futuremedicinalchemistry.2
4.KanekoT,CooperC,MdluliK.ChallengesandopportunitiesindevelopingnoveldrugsforTB.Futuremedicinalchemistry.20113(11):1373400.
20. FrickM.TheTBvaccinespipeline2013http://www.tbvi.eu/fileadmin/user_upload/Documenten/News/TBVaccines_pipeline_report_TAG_1July2013.pdf
http://www.tbvi.eu/fileadmin/user_upload/Documenten/News/TBVaccines_pipeline_report_TAG_1July2013.pdf .

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