CHEMOTERAPY OF TUBERCULOSIS

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

2. FURTHER READING • GOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS - 11th Ed Anggelia P, MD; Pharmacology and theraupetic dept

3. 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. Anggelia P, MD; Pharmacology and theraupetic dept

4. DIAGNOSE • Definite case of tuberculosis. 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. Anggelia P, MD; Pharmacology and theraupetic dept

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

6. 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. Anggelia P, MD; Pharmacology and theraupetic dept

7. 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, 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 Anggelia P, MD; Pharmacology and theraupetic dept

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

9. Anggelia P, MD; Pharmacology and theraupetic dept

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

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

12. RIFAMPISIN • Complex macrocyclic antibiotics produced by Amycolatopsismediterranei. • Rifampin is bactericidal for both intracellular and extracellular microorganisms. • Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis. Anggelia P, MD; Pharmacology and theraupetic dept

13. RIFAMPISIN • Lipid soluable • Following absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile_enterohepatic ensues. • Metabolic rx (phase II)__active bacterial activity • Well distributed throught the body • C max 2-4 h after administer. • T ½ 1,5-5 h, shortened first 14 days of treatment. • 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. Anggelia P, MD; Pharmacology and theraupetic dept

14. RIFAMPISINReduced of the following [drug] Anggelia P, MD; Pharmacology and theraupetic dept

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

16. 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, tears, saliva, sweat, semen and sputum), and that contact lenses and clothing may be irreversibly stained. Anggelia P, MD; Pharmacology and theraupetic dept

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

18. ISONIAZID • Readily absorbed PO or parenterally. • C max 1-2 hours (oral dose) • Diffuse readily into all body fluid, significant in pleural, 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. Anggelia P, MD; Pharmacology and theraupetic dept

19. ISONIAZID Dose 5 mg/kg (4–6 mg/kg) daily, maximum 300 mg 10 mg/kg (8–12 mg/kg) three times weekly, maximum 900 mg. Contraindications Known hypersensitivity. Active, 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, benzodiazepines metabolized by oxidation (such as triazolam), acetaminophen, valproate, serotonergic antidepressants, disulfiram, warfarin and theophylline Anggelia P, MD; Pharmacology and theraupetic dept

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

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

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

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

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

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

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

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

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

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

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

31. 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. If must be used 15 mg/kg, two/three times per week, max 1 gr/dose. • Adjusted etambutol (15 mg/kg) and pyrazynamid (25 mg/kg) 3 times a week. Anggelia P, MD; Pharmacology and theraupetic dept

32. Dosisuntukpaduan OAT KDT untukKategori 1 Anggelia P, MD; Pharmacology and theraupetic dept

33. Dosispaduan OAT-KombipakuntukKategori 1 Anggelia P, MD; Pharmacology and theraupetic dept

34. Dosisuntukpaduan OAT KDT Kategori 2 Anggelia P, MD; Pharmacology and theraupetic dept

35. Dosispaduan OAT KombipakuntukKategori 2 Anggelia P, MD; Pharmacology and theraupetic dept

36. Dosis KDT untuksisipan Anggelia P, MD; Pharmacology and theraupetic dept

37. Dosis OAT kombipakuntuksisipan Anggelia P, MD; Pharmacology and theraupetic dept

38. Anggelia P, MD; Pharmacology and theraupeticdept

39. Dosis OAT Kombipak-fase-awal/intensifpadaanak Anggelia P, MD; Pharmacology and theraupetic dept

40. Dosis OAT Kombipak-fase-lanjutanpadaanak Anggelia P, MD; Pharmacology and theraupetic dept

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

42. THAX 4 UR ATTENTION Anggelia P, MD; Pharmacology and theraupetic dept