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CHEMOTERAPY OF

TUBERCULOSIS
ANGGELIA PUSPASARI, MD
PHARMACOLOGY AND THERAPEUTIC DEPT.
FACULTY OF MEDICINE AND HEALTH SCIENCES
UNIVERSITY OF JAMBI, INDONESIA
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Anggelia P, MD; Pharmacology and
theraupetic dept

FURTHER READING
 GOODMAN & GILMAN'S THE

PHARMACOLOGICAL BASIS OF
THERAPEUTICS - 11th Ed

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Anggelia P, MD; Pharmacology and
theraupetic dept

INTRODUCTION
Mycobacteria grow slowly and may be dormant in the

host for long periods
Many antibacterial agents do not penetrate the cell
walls of mycobacteria, and a portion of mycobacteria
can reside inside macrophages, adding another
permeability barrier that effective agents must cross.
 Mycobacteria are agile in developing resistance to
single chemotherapeutic agents.
Effective therapy of mycobacterial infections
requires a prolonged course (months to years)
of multiple drugs.
Issues of patient compliance and drug toxicity
are important, as are drug interactions.
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Anggelia P, MD; Pharmacology and
theraupetic dept

DIAGNOSE Definite case of tuberculosis. MD. Pharmacology and theraupetic dept . A patient with Mycobacterium tuberculosis complex identified from a clinical specimen:  Culture or by a newer method such as molecular line probe assay  A pulmonary case with one or more initial sputum smear examinations positive for acid-fast bacilli (AFB) Cases of TB are also classified according to the  Anatomical site of disease  Bacteriological results (including drug resistance)  History of previous treatment  HIV status of the patient. 4 Anggelia P.

CHILD TB DIAGNOSE 5 Anggelia P. Pharmacology and theraupetic dept . MD.

Pharmacology and theraupetic dept . 6 Anggelia P.AIMS OF TREATMENT  To cure the patient and restore quality of life and productivity To prevent death from active TB or its late effects  To prevent relapse of TB To reduce transmission of TB to others To prevent the development and transmission of drug resistance. MD.

the optimal dosing frequency for new patients with pulmonary TB is daily throughout the course of therapy  2HRZE/6HE shoul be phased out.  TB patients returning after defaulting or relapsing from their first treatment course may receive the retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are unavailable 7 Anggelia P. MD. Pharmacology and theraupetic dept .WHO RECOMMENDATION OF REGIMENT  New patients with pulmonary TB/extra pulmonary should receive a regimen containing 6 months of rifampicin: 2HRZE/4HR_(Strong/High grade of evidence)  Daily or three times weekly intensive phase? Wherever feasible.

MD.FIRST LINE ANTITUBERCULOSIS DRUG 8 Anggelia P. Pharmacology and theraupetic dept .

Pharmacology and theraupetic dept . MD.9 Anggelia P.

THERAPY MONITORING Sign and symptoms? Bacterial smear/culture? MDR/XDR TB? 10 Anggelia P. Pharmacology and theraupetic dept . MD.

Pharmacology and theraupetic dept . MD.PHARMACOLOGY CHEMOTERAPY AGENT FOR MYCOBACTERIUM TUBERCULOSIS 11 Anggelia P.

RIFAMPISIN Complex macrocyclic antibiotics 12 produced by Amycolatopsis mediterranei. MD. Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria. Pharmacology and of chain formation (but not chain theraupetic dept . Rifampin is bactericidal for both intracellular and extracellular microorganisms. leading to suppression of initiation Anggelia P.

RIFAMPISIN Lipid soluable Following absorption from the gastrointestinal tract. MD. T ½ 1. rifampin is eliminated rapidly in the bile_enterohepatic ensues.5-5 h. Metabolic rx (phase II)__active bacterial activity Well distributed throught the body C max 2-4 h after administer. Pharmacology and theraupetic dept . 13 Anggelia P. 30 % excreted in urine and 60 % in feces Aminosalicylic acid may delay the absorption of rifampin and cause a failure to reach adequate plasma concentrations. shortened first 14 days of treatment.

Pharmacology and theraupetic dept . MD.RIFAMPISIN Reduced of the following [drug] 14 Anggelia P.

Contraindications Known hypersensitivity to rifamycins. Active. maximum 600 mg.RIFAMPISIN Rifampin and isoniazid are the most effective drugs available for the treatment of tuberculosis. Pharmacology and theraupetic dept . unstable hepatic disease (with jaundice) 15 Anggelia P. Preferably given 1 h before meal or 2 hours after meal. 10 mg/kg (8–12 mg/kg) daily or 3 times weekly. MD.

Pharmacology and theraupetic dept . sweat. 16 Anggelia P. tears. semen and sputum). and that contact lenses and clothing may be irreversibly stained.RIFAMPISIN Use in pregnancy Vitamin K should be administered at birth to the infant of a mother taking rifampicin because of the risk of postnatal haemorrhage Warned to patient! Patients should be warned that treatment may cause reddish coloration of all body secretions (urine. MD. saliva.

Inhibit the biosynthesis of mycolic acids (mycobacterium cell wall). but is for rapidly dividing microorganisms. mycobacterial catalaseperoxidase converts isoniazid into an active metabolite. Isoniazid penetrates cells with ease and is just as effective against bacilli growing within cells Isoniazid is a prodrug. Isoniazid also inhibits mycobacterial catalase-peroxidase (damage mycobacterium). MD. Pharmacology and theraupetic dept . 17 Anggelia P.ISONIAZID Isoniazid is bacteriostatic for "resting" bacilli.

ascitic fluid 75%-95% excreted in urine (most inactive metabolite) in 24 h T ½ 1-4 h (based on slow or fast acetylator) Pyridoxine 10-50 mg/day should be administered with isoniazid to minimize risk of periperal neuropathy and CNS toxicity. significant in pleural. C max 1-2 hours (oral dose) Diffuse readily into all body fluid. MD. 18 Anggelia P.ISONIAZID Readily absorbed PO or parenterally. Pharmacology and theraupetic dept .

Pharmacology and theraupetic dept . Active.ISONIAZID Dose 5 mg/kg (4–6 mg/kg) daily. unstable hepatic disease (with jaundice) Use in pregnancy Not known to be harmful in pregnancy Drug interaction Reduction in plasma levels of phenytoin and diazepam Isoniazid may increase the toxicity of carbamazepine. disulfiram. Contraindications Known hypersensitivity. warfarin and theophylline 19 Anggelia P. MD. maximum 300 mg 10 mg/kg (8–12 mg/kg) three times weekly. valproate. benzodiazepines metabolized by oxidation (such as triazolam). serotonergic antidepressants. maximum 900 mg. acetaminophen.

PYRAZINAMID The target of pyrazinamide appears to be the mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis. MD. It is highly effective during the first 2 months of treatment while acute inflammatory changes persist. particularly in the relatively acidic intracellular environment of macrophages and in areas of acute inflammation. Pharmacology and theraupetic dept . tuberculosis but has potent sterilizing activity. Only weakly bactericidal against M. 20 Anggelia P.

Adults dose (usually for the first 2 or 3 months of TB treatment): 25 mg/kg (20–30 mg/kg) daily Anggelia P. The drug is excreted primarily by renal glomerular filtration. Pyrazinamide is administered orally. 35 mg/kg . MD. T 1/2 9 to 10 hours in patients with normal renal function. Pharmacology and theraupetic dept (30–40 mg/kg) 3 times weekly.PYRAZINAMID Pyrazinamide is well absorbed from the 21 gastrointestinal tract and widely distributed throughout the body.

22 Anggelia P. Pharmacology and theraupetic dept . Precautions Patients with diabetes should be carefully monitored since blood glucose concentrations may become labile. rather than daily.PYRAZINAMID Contraindications Known hypersensitivity. Clinical monitoring liver function tests In patients with renal failure. MD. Active. Gout may be exacerbated. Porphyria. unstable hepatic disease (with jaundice). pyrazinamide should be administered three times per week.

75% to 80% of an orally administered dose of ethambutol is absorbed from the gastrointestinal tract.ETHAMBUTOL Ethambutol inhibits arabinosyl transferases involved in cell wall biosynthesis. Plasma concentrations peak in 2–4 hours and decay with a half-life of 3–4 hours. Pharmacology and theraupetic dept . 75% of an ingested dose of ethambutol is excreted unchanged in the urine 23 Anggelia P. MD.

Adults: 15 mg/kg (15–20 mg/kg) daily 30 mg/kg (25–35 mg/kg) 3 times weekly. 24 Anggelia P. MD. Pharmacology and theraupetic dept . resulting in decreased visual acuity and loss of ability to differentiate red from green.ETHAMBUTOL Ethambutol accumulates in patients with impaired renal function. Ethambutol is administered orally. and adjustment of dosage is necessary. Ethambutol is not recommended for children under 5 years of age. The most important side effect is optic neuritis. in part because of concern about the ability to test their visual acuity.

ETHAMBUTOL Contraindications Known hypersensitivity. Pharmacology and theraupetic dept . Pre-existing optic neuritis from any cause Use in pregnancy Ethambutol is not known to be harmful in pregnancy 25 Anggelia P. MD.

Pregnancy (auditory nerve impairment and nephrotoxicity in the fetus) 26 Anggelia P. maximum daily dose is 1000 mg. Contraindications Known hypersensitivity. Pharmacology and theraupetic dept . or 2 or 3 times weekly. Auditory nerve impairment.STREPTOMYSIN Adults: 15 mg/kg (12–18 mg/kg) daily. MD. Myasthenia gravis.

Pharmacology and Excreted unchanged in urine theraupetic dept . MD. activity of streptomycin in vivo is to suppress. T ½ 2-3 h Anggelia P.STREPTOMYSIN aminoglycoside antibiotic derived from 27 Streptomyces griseus that is used in the treatment of TB and sensitive Gramnegative infections. the tubercle bacillus Streptomycin is not absorbed from the gastrointestinal tract but intramuscular administration. not to eradicate.

MD. Pharmacology and theraupetic dept .SIDE EFFECT 1 st line antituberculosis 28 Anggelia P.

SIDE EFFECT 1 st line antituberculosis 29 Anggelia P. MD. Pharmacology and theraupetic dept .

Pharmacology and theraupetic dept . MD.LIVER DISORDER REGIMENT 30 Anggelia P.

If must be used 15 mg/kg. Adjusted etambutol (15 mg/kg) and pyrazynamid (25 mg/kg) 3 times a week. 31 Anggelia P.RENAL FAILURE AND SEVERAL RENAL INSUFFICIENCY Isoniazid and rifampicin are eliminated by biliary excretion. so no change dosing necessery Avoid to used streptomycin in renal failure patient. Pharmacology and theraupetic dept . max 1 gr/dose. MD. two/three times per week.

INCLUDE BEDAQUILINE (NEW WHO AND FDA APPROVAL 2011 FOR TREATMENT MDR TB)…^_^ 32 Anggelia P. Pharmacology and theraupetic dept .HOME WORK PHARMACOLOGY SECOND LINE DRUG OF ANTITUBERCULOSIS. MD.

THAX 4 UR ATTENTION 33 Anggelia P. MD. Pharmacology and theraupetic dept .