Antitubercular Drugs

1. . Antitubercular Drugs

2. Tuberculosis • Mycobacterium tuberculosis is the bacteria that cause tuberculosis (TB). It is an aerobic bacillus, which means that it is rod shaped microorganisms (bacillus) that requires a lot of oxygen for it to grow and flourish (aerobic). • This bacteria needs highly oxygenated area body and most commonly affect lungs, growing ends of bones, and the brain (cerebral cortex), with the kidney, liver, and genitourinary tract.

3. Sources of Tuberculosis • Tuberculosis are transmitted from one the three sources: • Human being • Cows (bovine) • Birds (avian)

4. Anti-tubercular drug agents • The agents used to treat infections caused by all forms of mycobacterium are called ant tubercular agents, and these agents fall in to two categories: 1. Primarily (first line) 2. Secondary (second line) • The anti-microbial activity, efficacy, and potential adverse effect of the various agents determine which class they belong to.

5. First line drugs • Isoniazid • Rifampin • Pyrazinamide • Ethambutol • Streptomycin

6. Second line drugs • Thiacetazone • Paraaminosalicyclic acid • Ethionamide • Cycloserine • Kanamycin • Amikacin • Capreomycin • Ciprofloxacin

7. Drug effects • They are used as the initial treatment for patients with uncomplicated pulmonary TB and for most children and adults with extra pulmonary TB. • The ant tubercular drug effects have not been fully tested in pregnant women, but the combination of isoniazid and ethambutol has been used to treat pregnant women with clinically apparent TB without Teratogenic complications. • They are effectively used for the treatment of mycobacterium tuberculosis.

8. Mechanism of action • The mechanisms of action of various antitubercular drugs vary depending on the agent. These drugs act on M. tuberculosis in one of the three ways: • Inhibit protein synthesis e.g streptomycin, kanamycin, rifampin, and capreomycin. • Inhibit cell wall synthesis e.g cycloserine, isoniazid, and ethionamide. • Other mechanisms e.g isoniazid: hydrolyzes isonicotinic acid, ethionamide directly inhibits mycolic acid synthesis.

9. Therapeutic uses • The ant tubercular drugs are primarily used for the prophylaxis or treatment of the TB. The effectiveness of these agents depends on the type of infection, adequate dosing, sufficient duration of treatment, drug compliance, and the selection of effective drug combination.

10. Continue • Para-aminosalicylate used in the treatment of pulmonary and extra pulmonary mycobacterium tuberculosis infections. • Capreomycin used for the treatment of pulmonary TB caused by M.tuberculosis. • Cycloserine used for treatment of active pulmonary and extra pulmonary TB • Isoniazid used alone or in combination with other ant tubercular agents in the treatment and prevention of clinical TB.

11. Continue • Rifampin used in conjunction with other ant tubercular agents in the treatment of clinical TB. • Streptomycin used in combination with other ant tubercular agents in treatment of clinical TB and other mycobacterium diseases. • Kanamycin used in combination with other ant tubercular agents in the treatment of clinical TB. It is not intended for long term use.

12. Side-effects • Hepatotoxicity • Ototoxicity • Gi tract disturbances • Nephrotoxicty • Neutropenia • Discolored urine • Rash • Blood dyscrasia

13. Drug profiles • The ant tubercular drugs can only be obtained by prescription. • Indicated for the treatment of mycobacterium tuberculosis • They are available different dosage forms e.g orally, intravenously, intramuscularly.

14. Ethambutol (E) • It is a primary bacteriostatic agent used in the treatment of TB that is believed to work by diffusing into the mycobacteria and suppressing RNA synthesis. • Ethambutol is included with isoniazid, streptomycin, and rifampin in many TB combination drug therapies.

15. Continue • It is mechanism of action is not fully understood, but it inhibits arabinogalactan synthesis and interfere mycolic acid incorporation. • Caution is required in patients with renal disease because ethambutol it is excreted in urine by glomerular filtration and tubular secretion.

16. Continue • Loss of visual acuity/colour vision, field defects due to optic neuritis is the most important dose and duration of therapy dependent toxicity. • Because young children may be unable to report early visual impairment, it shouldn’t be used below 6 years of age. • It is a pregnancy category D agent

17. Continue • Contraindicated in patients with hypersensitivity to it and children less than 13 years old. • Available oral forms as a 100mg tablet and 400mg film coated tablet. • Adult dosage is 15mg/kg as a single dose.

18. Pyrazinamide (Z) • It is an antitubercular drug that can be either bacteriostatic or bactericidal, depending on it is concentration at the site of infection and the particular susceptibility of the mycobacteria. • It is frequently used in combination with other antitubercular drugs for the treatment of TB. It is mechanism of action is unknown, but it is believed to work by inhibiting lipid and nucleic acid synthesis in the mycobacteria.

19. Continue • Chemically similar to INH, pyrazinamide was developed parallel to it in 1952. • It is mechanism of action is inhibition of mycolic acid synthesis • It is a pregnancy category C agent • It is available 500mg tablet & 500mg/ml syrup • Hepatotoxicity is the most important dose related adverse effect

20. Continue • Daily doses is now limited to 25 – 30mg/kg which produces only a low incidence of Hepatotoxicity • Hyperuricaemia is common and is due to inhibition of uric acid secretion in kidney: gout can occur. • Adult dosage is 15 – 30mg/kg/day

21. Isoniazid-INH • Isoniazid is the antitubercular drug parexcelence and essential component of all antitubercular regimens. • It is primarily tuberculocidal. • It is equally active in acidic and alkaline environment. • It is one of the cheapest antitubercular drugs. • The most plausible mechanism of action of INH is inhibition of a synthesis of mycolic acid.

22. Continue • Isoniazid is completely absorbed orally and penetrates all body tissues, tubercular cavities, placenta, meninges. • It is extensively metabolized in the liver. • It is available 300mg tabs, 100mg tabs, and 100mg/5ml syrup.

23. Drug-Drug Interactions • Aluminum hydroxide inhibits absorption of isoniazid. • INH inhibits phenytoin, Carbamazepine, diazepam and Warfarin metabolism. • PAS inhibits INH metabolism and prolongs it is half life.

24. Rifampin • Rifampin is a semi-synthetic derivative of rifamycin B obtained from streptomyces mediterranei. • It is bactericidal m. tuberculosis and many other gram negative, positive bacteria's. • Rifampin inhibits DNA dependent RNA synthesis. • It is well absorbed orally and widely distributed in the body.

25. Uses • Leprosy • Prophylaxis of meningococcal and influenza meningitis and carrier state. • Second and third choice of MRSA • Combination of doxycyline and rifampin is the first line therapy of brucellosis.

26. Drug-Drug Interactions • Rifampin is a microsomal enzyme inducer increase several cytochrome enzymes. • Theophylline, Fluconazole, contraceptive pills, digoxin and steroids. • Side effect: the major side effect is Hepatitis, generally occur.

27. Treatment of Tuberculosis • Treatment for TB uses antibiotics to kill the bacteria. • The two antibiotics most commonly used drugs are rifampin and isoniazid. • The recommended treatment is 6 months.