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CURRICULUM VITAE
Wiwik Kusumawati, MD, Master of Health Science Lecturer of Pharmacology (1996 to now) Lecturer of Medical Education (2004 to now) Vice Dean for academic affair (2004 to 2007) Coordinator of Pharmacology Dept (1996 to 2002) Coordinator of Medical Education Unit (2004 to 2010)

CURRICULUM VITAE
PhD Cand. of Medical Education of Faculty of Medicine Gadjah Mada University, Yogyakarta (2007 now) Magister of Health Sciences from Faculty of Medicine of Gadjah Mada University, Yogyakarta (1997 2000) Medical Doctor from Faculty of Medicine of Airlangga University, Surabaya (1985 1991) General Practitioner (PTT doctor) at Ende, Flores, NTT (1992 1995)

ANTITUBERCULOSIS DRUGS
By Wiwik Kusumawati

INTRODUCTION

Tuberculosis Infection

INTRODUCTION
Pulmonary tuberculosis 7.5 to10.2 million new cases of tbc (WHO) 2.5 to 3.5 million tuberculosis death Develop and developing countries Immunodeficiency virus (HIV) infection Up 80 % tbc px are HIV positive 3.5 million, dual infection Reactivation dormant infection

INTRODUCTION
Tbc infection in Indonesia? Population Status of immunity Status of economy - nutrition

CASE
A 54 years old man bring to the hospital with cough more than 3 weeks, fever, and decreasing of appetite after taking history and conducting clinical examination, the doctor do laboratory test (sputum test). Laboratory result revealed mycobactterium tbc positive and the doctor prescribe antituberculosis drugs.

Pulmonary Tuberculosis
Prompt diagnosis and effective treatment General symptoms
Weight loss, malaise, fevers

Respiratory symptoms
Cough, sputum and haemoptysis

Resistance of M. tuberculosis
Spontaneous mutation Improperly prescribed therapy Erratic drug ingestion Inadequate dosage Incomplete therapy Lack of compliance by px

Resistance of M. tuberculosis
MDR : INH and Rifampicin XDR : + Fluoroquinolone + 1 injection drug Primary Secondary

Distribution of Primary MDR

Distribution of Secondary MDR

MAJOR PROBLEM?
Compliance ?

DOTS
DIRECTLY OBSERVE THERAPY Five component of DOTS

CLASS
Isoniazid
Rifampin Streptomycin Ethambutol Pyrazinamide Capreomycin Kanamycin Cycloserine Ethionamide

ROUTE
PO
IV, PO IM PO PO IM IM PO PO

MAJOR INDICATION
Primary
Primary Primary Primary Primary CNS or secondary Secondary or atypical Secondary Secondary Secondary or atypical

Aminosalicylic acid
Clofazimine

PO
PO

Secondary
Atypical in HIV px

Rifabutin

PO

Atypical in HIV px

DRUGS
INH & Rifampin
Tuberculocidal for both extracellular intracellular organism

Streptomycin
Tuberculocidal for extracellular organism only

Pyrazinamide
Tuberculocidal for intracellular organism

Ethambutol, p-aminosalicylic acid & ethionamide

Tuberculostatic

DRUGS (INH)
Bactericidal cell wall synthesis Combination
Active infection Secondary chemoprophylaxis should be given with 2 or more effective drugs

Should never be used as a single to treat active tbc Single agent (monotherapy)
Primary chemoprophylaxis

DRUGS (INH)
PO: well and rapidly absorbed Peak concentration 1 to 2 hours The distribution is extensive 3 to 5 mg/kg/day 20 mg/kg/day Metabolism by acetylation and hydroxylation
Slow acetylators (Scandinavia, North Africa) adverse effects Rapid acetylators (Japan, Escimo) intermittent regimen No influence both the effect of therapy and side effect if INH given everyday

DRUGS (INH)
Side effect Peripheral neuropathy 10 mg/day of pyridoxine Induced hepatic injury

DRUGS (Rifampicine)
A first-line bactericidal anti-tuberculosis Inhibits RNA-polymerase Combination with pyrazinamide : persisters PO, IV PO : well and completely absorbtion (empty stomach) Peak concentration 2 to 4 hours Combination with INH not influence absorbtion

DRUGS (Rifampicine)
Distribution is extensive, protein (albumin) binding 80% Red-brown colouration of body fluid Metabolism deacetylation active metabolite Excretion : biliary and renal (30%) Resistant rifampicine rifabutine

DRUGS (Rifampicine)
Dose 450 600 mg/day (adult); 10 20 mg/kg BW/day (children) Side effect Rash, fever, nausea, vomiting Flu like syndrome Hepatotoxic hepatitis

DRUGS (Rifampicine)
Enzyme hepatic inducer (increase metabolism of oral contraception, corticosteroid, hypoglycemic agent, vitamine D) PAS inhibits absorbtion of rifampicine Rifampicine + INH (slow acetlators)

DRUGS (Pyrazinamide)
Bactericidal to mycobacteria multiplying intracellularly at low pH level The first 2 months of a treatment regimen Reduce later relaps rates A shorter duration of therapy PO : well absorbed Penetrates well in CSF Nausea, flushing, arthralgia, hepatotoxic reactions

STREPTOMYCIN
An aminoglycoside Extracellular bacteria Single drug no effective Must be given by injection (IM) Widely distributions doesnt cross well into CSF 30 % protein binding 90 % drugs excreted via urine

STREPTOMYCIN
Dose 20 mg/kg BW maximally 1 gram/day Side effect Neurotoxic and nephrotoxic 8 cranial nerve damage, vestibular toxicity, rash Caution Pregnancy, elderly, renal disease, etc

ETHAMBUTOL
An essentially bacteriostatic Inhibits mycobacterial cell wall synthesis PO : well absorbed (75% to 80 %) Doesnt cross BBB Excretion : unchanged in the urine

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

INITIAL TREATMENT
At least 3 drugs INH, Rifampicin, Pyrazinamide For at least 8 weeks sensitivity established

CONTINUATION TREATMENT
Rifampicin and INH Further 4 months 2HRZ/4HR 6 months 2EHR/7HR 9 month Rifampicin not included : 18 months

MONITORING
Monitoring adverse effect and efficacy of drugs Monitoring up to 1 year after a regimen completely

CASE
A 44 years old woman suffering from tbc infection and also A type of hepatitis infection. Health care provider give this patient rifampicine, INH, pyrazinamide as antituberculosis drugs for 2 months in intensive phase

SPECIFIC CONDITION
Treatment during pregnancy
INH, Ethambutol, Rifampicin (safely) INH, Pyrazinamide, Rifampicin (poorly tolerated) Ethionamide is contra indication Streptomycin is best avoided Rifampicin (normal dose) Other drugs (reduced dose) Pyrazinamide precipitate gout Streptomycin if essential Ethambutol is best avoided in renal failure (GFR 50 ml/min or 3 L/h)

Treatment in renal disease

SPECIFIC CONDITION
Treatment in liver disease
INH, rifampicin, ethionamide and pyrazinamide can all be hapatotoxic Ethambutol, Streptomycin, INH Regular liver function monitoring

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

Refferences
Averys Drug Treatment 4th edition (Trevor & Nicholas) : 1047 1054 Clinical Pharmacology, Basic Principles in Therapeutics (Melmon and Morellis) : 711 712

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