CHEMOTERAPY OF TUBERCULOSIS

ANGGELIA PUSPASARI, MD

PHARMACOLOGY AND THERAPEUTIC DEPT.FACULTY OF MEDICINE AND HEALTH SCIENCESUNIVERSITY OF JAMBI, INDONESIA

Anggelia P, MD; Pharmacology and theraupetic dept1CHEMOTERAPY OF TUBERCULOSISFURTHER READINGGOODMAN & GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS - 11th Ed

Anggelia P, MD; Pharmacology and theraupetic dept2INTRODUCTIONMycobacteria grow slowly and may be dormant in the host for long periodsMany 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 dept3DIAGNOSEDefinite 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 theAnatomical site of disease Bacteriological results (including drug resistance)History of previous treatmentHIV status of the patient.Anggelia P, MD; Pharmacology and theraupetic dept4CHILD TB DIAGNOSE

Anggelia P, MD; Pharmacology and theraupetic dept5AIMS OF TREATMENT To cure the patient and restore quality of life and productivityTo prevent death from active TB or its late effects To prevent relapse of TBTo reduce transmission of TB to othersTo prevent the development and transmission of drug resistance.Anggelia P, MD; Pharmacology and theraupetic dept6WHO RECOMMENDATION OF REGIMENTNew 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 therapy2HRZE/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 dept7FIRST LINE ANTITUBERCULOSIS DRUG

Anggelia P, MD; Pharmacology and theraupetic dept8

Anggelia P, MD; Pharmacology and theraupetic dept9THERAPY MONITORINGSign and symptoms?Bacterial smear/culture?MDR/XDR TB?Anggelia P, MD; Pharmacology and theraupetic dept10PHARMACOLOGY CHEMOTERAPY AGENT FOR MYCOBACTERIUM TUBERCULOSISAnggelia P, MD; Pharmacology and theraupetic dept11RIFAMPISINComplex macrocyclic antibiotics produced by Amycolatopsis mediterranei.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 dept12RIFAMPISINLipid soluableFollowing absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile_enterohepatic ensues.Metabolic rx (phase II)__active bacterial activityWell distributed throught the bodyC max 2-4 h after administer.T 1,5-5 h, shortened first 14 days of treatment.30 % excreted in urine and 60 % in fecesAminosalicylic acid may delay the absorption of rifampin and cause a failure to reach adequate plasma concentrations.

Anggelia P, MD; Pharmacology and theraupetic dept13RIFAMPISINReduced of the following [drug]

Anggelia P, MD; Pharmacology and theraupetic dept14RIFAMPISIN

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 (812 mg/kg) daily or 3 times weekly, maximum 600 mg.ContraindicationsKnown hypersensitivity to rifamycins.Active, unstable hepatic disease (with jaundice) Anggelia P, MD; Pharmacology and theraupetic dept15RIFAMPISIN

Use in pregnancyVitamin 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 dept16ISONIAZIDIsoniazid 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 mycolic acids (mycobacterium cell wall), Isoniazid also inhibits mycobacterial catalase-peroxidase (damage mycobacterium).Anggelia P, MD; Pharmacology and theraupetic dept17ISONIAZIDReadily absorbed PO or parenterally.C max 1-2 hours (oral dose)Diffuse readily into all body fluid, significant in pleural, ascitic fluid75%-95% excreted in urine (most inactive metabolite) in 24 hT 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 dept18ISONIAZIDDose5 mg/kg (46 mg/kg) daily, maximum 300 mg 10 mg/kg (812 mg/kg) three times weekly, maximum 900 mg.ContraindicationsKnown hypersensitivity.Active, unstable hepatic disease (with jaundice) Use in pregnancyNot known to be harmful in pregnancyDrug interactionReduction 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 dept19PYRAZINAMIDThe 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 dept20PYRAZINAMIDPyrazinamide 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 (2030 mg/kg) daily 35 mg/kg (3040 mg/kg) 3 times weekly.Anggelia P, MD; Pharmacology and theraupetic dept21PYRAZINAMIDContraindications Known hypersensitivity, Active, unstable hepatic disease (with jaundice), Porphyria.PrecautionsPatients with diabetes should be carefully monitored since blood glucose concentrations may become labile. Gout may be exacerbated. Clinical monitoring liver function testsIn patients with renal failure, pyrazinamide should be administered three times per week, rather than daily.Anggelia P, MD; Pharmacology and theraupetic dept22ETHAMBUTOLEthambutol inhibits arabinosyl transferases 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 24 hours and decay with a half-life of 34 hours. 75% of an ingested dose of ethambutol is excreted unchanged in the urineAnggelia P, MD; Pharmacology and theraupetic dept23ETHAMBUTOLEthambutol accumulates in patients with impaired renal function, and adjustment of dosage is necessary. Ethambutol is 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 (1520 mg/kg) daily 30 mg/kg (2535 mg/kg) 3 times weekly. Anggelia P, MD; Pharmacology and theraupetic dept24ETHAMBUTOLContraindicationsKnown hypersensitivity.Pre-existing optic neuritis from any causeUse in pregnancyEthambutol is not known to be harmful in pregnancy Anggelia P, MD; Pharmacology and theraupetic dept25STREPTOMYSINAdults: 15 mg/kg (1218 mg/kg) daily, or 2 or 3 times weekly; maximum daily dose is 1000 mg.ContraindicationsKnown hypersensitivity.Auditory nerve impairment.Myasthenia gravis.Pregnancy (auditory nerve impairment and nephrotoxicity in the fetus)Anggelia P, MD; Pharmacology and theraupetic dept26STREPTOMYSINaminoglycoside antibiotic derived from Streptomyces griseus that 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 bacillusStreptomycin is not absorbed from the gastrointestinal tract but intramuscular administration. T 2-3 hExcreted unchanged in urineAnggelia P, MD; Pharmacology and theraupetic dept27SIDE EFFECT 1 st line antituberculosis

Anggelia P, MD; Pharmacology and theraupetic dept28SIDE EFFECT 1 st line antituberculosis

Anggelia P, MD; Pharmacology and theraupetic dept29LIVER DISORDER REGIMENT

Anggelia P, MD; Pharmacology and theraupetic dept30RENAL FAILURE AND SEVERAL RENAL INSUFFICIENCYIsoniazid and rifampicin are eliminated by biliary excretion, so no change dosing necesseryAvoid 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 dept31HOME WORKPHARMACOLOGY SECOND LINE DRUG OF ANTITUBERCULOSIS, INCLUDE BEDAQUILINE (NEW WHO AND FDA APPROVAL 2011 FOR TREATMENT MDR TB)^_^Anggelia P, MD; Pharmacology and theraupetic dept32THAX 4 UR ATTENTIONAnggelia P, MD; Pharmacology and theraupetic dept33