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Robbii zidni ‘ilmaaRobbii zidni ‘ilmaawarzuqnii fahmaawarzuqnii fahmaaAamiin....Aamiin....

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CURRICULUM VITAECURRICULUM VITAE

Wiwik Kusumawati, Wiwik Kusumawati, MDMD, M, Master of Health aster of Health ScienceScience

Lecturer of Pharmacology (1996 to Lecturer of Pharmacology (1996 to nownow)) Lecturer of Medical Education (2004 to Lecturer of Medical Education (2004 to nownow)) Vice Dean for academic affair (2004 to 2007)Vice Dean for academic affair (2004 to 2007) Coordinator of Pharmacology Dept (1996 to Coordinator of Pharmacology Dept (1996 to

2002)2002) Coordinator of Medical Education Unit (2004 to Coordinator of Medical Education Unit (2004 to

2010)2010)

CURRICULUM VITAECURRICULUM VITAE PhD Cand. of Medical Education of PhD Cand. of Medical Education of Faculty of Faculty of

Medicine Gadjah Mada University, Yogyakarta Medicine Gadjah Mada University, Yogyakarta ((20072007 – – nownow))

Magister of Health Sciences from Faculty of Magister of Health Sciences from Faculty of Medicine of Gadjah Mada University, Medicine of Gadjah Mada University, Yogyakarta (1997 – 2000)Yogyakarta (1997 – 2000)

Medical Doctor from Faculty of Medicine of Medical Doctor from Faculty of Medicine of Airlangga University, Surabaya (1985 – 1991)Airlangga University, Surabaya (1985 – 1991)

General Practitioner (PTT doctor) at Ende, General Practitioner (PTT doctor) at Ende, Flores, NTT (1992Flores, NTT (1992 – – 1995)1995)

ANTITUBERCULOSIS ANTITUBERCULOSIS DRUGSDRUGSByBy

Wiwik KusumawatiWiwik Kusumawati

INTRODUCTIONINTRODUCTION

Tuberculosis InfectionTuberculosis Infection

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INTRODUCTIONINTRODUCTION

Pulmonary tuberculosisPulmonary tuberculosis 7.5 to10.2 million new cases of tbc (WHO) 7.5 to10.2 million new cases of tbc (WHO) 2.5 to 3.5 million tuberculosis death2.5 to 3.5 million tuberculosis death Develop and developing countriesDevelop and developing countries Immunodeficiency virus (HIV) infectionImmunodeficiency virus (HIV) infection Up 80 % tbc px are HIV positiveUp 80 % tbc px are HIV positive 3.5 million, dual infection3.5 million, dual infection Reactivation – dormant infectionReactivation – dormant infection

INTRODUCTIONINTRODUCTION

Tbc infection in Indonesia?Tbc infection in Indonesia? PopulationPopulation Status of immunityStatus of immunity Status of economy Status of economy - nutrition - nutrition

CASE CASE

A A 554 years old man 4 years old man bring to the hospital with bring to the hospital with cough more than 3 weeks, cough more than 3 weeks, fever,fever, and and decreasing of appetitedecreasing of appetite after taking history and after taking history and conducting clinical examination, the doctor do conducting clinical examination, the doctor do laboratory test (sputum test). Laboratory result laboratory test (sputum test). Laboratory result revealed mycobactterium tbc positive and the revealed mycobactterium tbc positive and the doctor prescribe antituberculosis drugs.doctor prescribe antituberculosis drugs.

Pulmonary Pulmonary TTuberculosisuberculosis

Prompt diagnosis and effective treatmentPrompt diagnosis and effective treatment General symptomsGeneral symptoms

Weight loss, malaise, feversWeight loss, malaise, fevers

Respiratory symptomsRespiratory symptoms Cough, sputum and haemoptysisCough, sputum and haemoptysis

Resistance of M. Resistance of M. tuberculosis tuberculosis Spontaneous mutationSpontaneous mutation Improperly prescribed therapyImproperly prescribed therapy Erratic drug ingestionErratic drug ingestion Inadequate dosageInadequate dosage Incomplete therapyIncomplete therapy Lack of compliance by pxLack of compliance by px

Resistance of M. Resistance of M. tuberculosis tuberculosis MDR : INH and RifampicinMDR : INH and Rifampicin XDR : + Fluoroquinolone + 1 injection XDR : + Fluoroquinolone + 1 injection

drugdrug Primary Primary Secondary Secondary

Distribution of Primary MDRDistribution of Primary MDR

Distribution of Secondary Distribution of Secondary MDRMDR

MAJOR PROBLEM?MAJOR PROBLEM?

Compliance ?Compliance ?

DOT’SDOT’S

DIRECTLY OBSERVE THERAPYDIRECTLY OBSERVE THERAPY Five component of DOTSFive component of DOTS

CLASSCLASS ROUTEROUTE MAJOR INDICATIONMAJOR INDICATION

IsoniazidIsoniazid POPO Primary Primary

RifampinRifampin IV, POIV, PO Primary Primary

StreptomycinStreptomycin IMIM Primary Primary

EthambutolEthambutol POPO Primary Primary

PyrazinamidePyrazinamide POPO Primary CNS or Primary CNS or secondary secondary

CapreomycinCapreomycin IMIM Secondary or atypicalSecondary or atypical

KanamycinKanamycin IMIM Secondary Secondary

CycloserineCycloserine POPO Secondary Secondary

EthionamideEthionamide POPO Secondary or atypical Secondary or atypical

Aminosalicylic acidAminosalicylic acid POPO Secondary Secondary

ClofazimineClofazimine POPO Atypical in HIV pxAtypical in HIV px

RifabutinRifabutin POPO Atypical in HIV pxAtypical in HIV px

DRUGSDRUGS

INH & RifampinINH & Rifampin Tuberculocidal for both extracellular intracellular Tuberculocidal for both extracellular intracellular

organismorganism Streptomycin Streptomycin

Tuberculocidal for extracellular organism onlyTuberculocidal for extracellular organism only Pyrazinamide Pyrazinamide

Tuberculocidal for intracellular organismTuberculocidal for intracellular organism Ethambutol, p-aminosalicylic acid & Ethambutol, p-aminosalicylic acid &

ethionamideethionamide Tuberculostatic Tuberculostatic

DRUGS (INH)DRUGS (INH)

Bactericidal – cell wall synthesisBactericidal – cell wall synthesis Combination Combination

Active infectionActive infection Secondary chemoprophylaxis Secondary chemoprophylaxis should be given with should be given with

2 or more effective drugs2 or more effective drugs

Should never be used as a single to treat Should never be used as a single to treat active tbcactive tbc

Single agent (monotherapy)Single agent (monotherapy) Primary chemoprophylaxisPrimary chemoprophylaxis

DRUGS (INH)DRUGS (INH) PO: well and rapidly absorbedPO: well and rapidly absorbed Peak concentration 1 to 2 hoursPeak concentration 1 to 2 hours The distribution is extensiveThe distribution is extensive 3 to 5 mg/kg/day – 20 mg/kg/day 3 to 5 mg/kg/day – 20 mg/kg/day Metabolism by acetylation and hydroxylation Metabolism by acetylation and hydroxylation

Slow acetylators (Scandinavia, North Africa) – Slow acetylators (Scandinavia, North Africa) – adverse effectsadverse effects

Rapid acetylators (Japan, Escimo) – Rapid acetylators (Japan, Escimo) – intermittent intermittent regimenregimen

No influence both the effect of therapy and side No influence both the effect of therapy and side effect if INH given everyday effect if INH given everyday

DRUGS (INH)DRUGS (INH)

Side effect Side effect Peripheral neuropathy – 10 mg/day of Peripheral neuropathy – 10 mg/day of

pyridoxine pyridoxine Induced hepatic injuryInduced hepatic injury

DRUGS (Rifampicine)DRUGS (Rifampicine)

A first-line bactericidal anti-tuberculosisA first-line bactericidal anti-tuberculosis Inhibits RNA-polymeraseInhibits RNA-polymerase Combination with pyrazinamide : “persisters” Combination with pyrazinamide : “persisters” PO, IVPO, IV PO : well and completely absorbtion (empty PO : well and completely absorbtion (empty

stomach)stomach) Peak concentration 2 to 4 hoursPeak concentration 2 to 4 hours Combination with INH not influence absorbtionCombination with INH not influence absorbtion

DRUGS (Rifampicine)DRUGS (Rifampicine)

Distribution is extensive, protein Distribution is extensive, protein (albumin) binding 80%(albumin) binding 80%

Red-brown colouration of body fluidRed-brown colouration of body fluid Metabolism deacetylation – active Metabolism deacetylation – active

metabolitemetabolite Excretion : biliary and renal (30%)Excretion : biliary and renal (30%) Resistant rifampicine – rifabutine Resistant rifampicine – rifabutine

DRUGS (Rifampicine)DRUGS (Rifampicine)

Dose 450 – 600 mg/day (adult); 10 – 20 mg/kg Dose 450 – 600 mg/day (adult); 10 – 20 mg/kg BW/day (children)BW/day (children)

Side effectSide effect Rash, fever, nausea, vomitingRash, fever, nausea, vomiting Flu like syndromeFlu like syndrome Hepatotoxic – hepatitis Hepatotoxic – hepatitis

DRUGS (Rifampicine)DRUGS (Rifampicine)

Enzyme hepatic inducer (increase metabolism Enzyme hepatic inducer (increase metabolism of oral contraception, corticosteroid, of oral contraception, corticosteroid, hypoglycemic agent, vitamine D)hypoglycemic agent, vitamine D)

PAS inhibits absorbtion of rifampicinePAS inhibits absorbtion of rifampicine Rifampicine + INH (slow acetlators) Rifampicine + INH (slow acetlators)

DRUGS (Pyrazinamide)DRUGS (Pyrazinamide)

Bactericidal to mycobacteria multiplying Bactericidal to mycobacteria multiplying intracellularly at low pH levelintracellularly at low pH level

The first 2 months of a treatment regimenThe first 2 months of a treatment regimen Reduce later relaps ratesReduce later relaps rates A shorter duration of therapyA shorter duration of therapy PO : well absorbedPO : well absorbed Penetrates well in CSFPenetrates well in CSF Nausea, flushing, arthralgia, Nausea, flushing, arthralgia, hepatotoxic hepatotoxic

reactionsreactions

STREPTOMYCINSTREPTOMYCIN

An aminoglycosideAn aminoglycoside Extracellular bacteria Extracellular bacteria Single drug – no effective Single drug – no effective Must be given by injection (IM)Must be given by injection (IM) Widely distributions – doesn’t cross well Widely distributions – doesn’t cross well

into CSFinto CSF 30 % protein binding 30 % protein binding 90 % drugs excreted via urine 90 % drugs excreted via urine

STREPTOMYCINSTREPTOMYCIN

Dose Dose 20 mg/kg BW – maximally 1 gram/day20 mg/kg BW – maximally 1 gram/day Side effectSide effect Neurotoxic and nephrotoxicNeurotoxic and nephrotoxic 8 cranial nerve damage, vestibular 8 cranial nerve damage, vestibular

toxicity, rashtoxicity, rash Caution Caution Pregnancy, elderly, renal disease, etcPregnancy, elderly, renal disease, etc

ETHAMBUTOLETHAMBUTOL

An essentially bacteriostaticAn essentially bacteriostatic Inhibits mycobacterial cell wall synthesisInhibits mycobacterial cell wall synthesis PO : well absorbed (75% to 80 %)PO : well absorbed (75% to 80 %) Doesn’t cross BBBDoesn’t cross BBB Excretion : unchanged in the urineExcretion : unchanged in the urine

ETHAMBUTOLETHAMBUTOL

Dose 15 mg/kg BW/dayDose 15 mg/kg BW/day Side effectSide effect Retrobulbar neuritis (bilateral)Retrobulbar neuritis (bilateral) Rash, fever, Increasing blood uric acid, Rash, fever, Increasing blood uric acid,

etcetc

INITIAL TREATMENTINITIAL TREATMENT

At least 3 drugsAt least 3 drugs INH, Rifampicin, PyrazinamideINH, Rifampicin, Pyrazinamide For at least 8 weeks – sensitivity For at least 8 weeks – sensitivity

establishedestablished

CONTINUATION CONTINUATION TREATMENTTREATMENT

Rifampicin and INHRifampicin and INH Further 4 monthsFurther 4 months 2HRZ/4HR – 6 months2HRZ/4HR – 6 months 2EHR/7HR – 9 month2EHR/7HR – 9 month Rifampicin not included : 18 months Rifampicin not included : 18 months

MONITORINGMONITORING

Monitoring adverse effect and efficacy of Monitoring adverse effect and efficacy of drugsdrugs

Monitoring up to 1 year after a regimen Monitoring up to 1 year after a regimen completely completely

CASE CASE

A A 444 years old 4 years old woman suffering from tbc woman suffering from tbc infection and also A type of hepatitis infection. infection and also A type of hepatitis infection. Health care provider give this patient Health care provider give this patient rifampicine, INH, pyrazinamide as rifampicine, INH, pyrazinamide as antituberculosis drugs for 2 months in intensive antituberculosis drugs for 2 months in intensive phasephase

SPECIFIC CONDITIONSPECIFIC CONDITION Treatment during pregnancyTreatment during pregnancy

INH, Ethambutol, Rifampicin (safely)INH, Ethambutol, Rifampicin (safely) INH, INH, PyrazinamidePyrazinamide, Rifampicin (poorly tolerated), Rifampicin (poorly tolerated) Ethionamide is contra indicationEthionamide is contra indication Streptomycin is best avoidedStreptomycin is best avoided

Treatment in renal diseaseTreatment in renal disease Rifampicin (normal dose)Rifampicin (normal dose) Other drugs (reduced dose)Other drugs (reduced dose) Pyrazinamide – precipitate gout Pyrazinamide – precipitate gout Streptomycin – if essentialStreptomycin – if essential Ethambutol is best avoided in renal failure (GFR 50 Ethambutol is best avoided in renal failure (GFR 50

ml/min or 3 L/h)ml/min or 3 L/h)

SPECIFIC CONDITIONSPECIFIC CONDITION Treatment in liver diseaseTreatment in liver disease

INH, rifampicin, ethionamide and pyrazinamide can INH, rifampicin, ethionamide and pyrazinamide can all be hapatotoxicall be hapatotoxic

Ethambutol, Streptomycin, INH Ethambutol, Streptomycin, INH Regular liver function monitoringRegular liver function monitoring

Treatment in childrenTreatment in children Standard initial regimen Standard initial regimen INH, rifampicin and pyrazinamideINH, rifampicin and pyrazinamide if 2 drugs regimen if 2 drugs regimen (INH and rifampicin) (INH and rifampicin) : 9 months: 9 months Ethambutol is best avoidedEthambutol is best avoided

RefferencesRefferences

Avery’s Drug Treatment 4Avery’s Drug Treatment 4thth edition edition (Trevor & Nicholas) : 1047 – 1054(Trevor & Nicholas) : 1047 – 1054

Clinical Pharmacology, Basic Principles Clinical Pharmacology, Basic Principles in Therapeutics (Melmon and Morelli’s) : in Therapeutics (Melmon and Morelli’s) : 711 – 712 711 – 712

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