Title 14. CHEMOTHERAPY OF TUBERCULOSIS AND LEPROSY.pdf ✅

PHARMD GURU Page 1 CHEMOTHERAPY OF TUBERCULOSIS Tuberculosis (TB) is a chronic infectious disease caused by M. tuberculosis. Mycobacterial infections require prolonged treatment. Since TB is a chronic infection, it consists of excessive fibrous tissue with central necrosis. So vascularity of the lesion is poor; hence, the penetration of the drug into the lesion is decreased. CLASSIFICATION: 1. First-line antitubercular drugs (standard drugs): Isoniazid (H), rifampin (R), pyrazinamide (Z), ethambutol (E), streptomycin (S) 2. Second-line antitubercular drugs (reserve drugs): para-Aminosalicylic acid (PAS), thiacetazone, cycloserine, ethionamide, kanamycin, capreomycin, amikacin, levofloxacin, moxifloxacin, ofloxacin, clarithromycin, rifabutin, rifapentine. Another form of classification is shown in Table 11.14. FIRST-LINE ANTITUBERCULOSIS DRUGS: They are cheap, more effective, routinely used and less toxic. ISONIAZID (ISONICOTINIC ACID HYDRAZIDE [INH]): Isoniazid is a highly effective and the most widely used antitubercular agent. It is orally effective, cheapest and has tuberculocidal activity. It is active against both CHEMOTHERAPY OF TUBERCULOSIS AND LEPROSY
PHARMD GURU Page 2 intracellular and extracellular bacilli. It is a first-line drug for the treatment of TB. It is also used for chemoprophylaxis of TB. MECHANISM OF ACTION: Isoniazid inhibits biosynthesis of mycolic acids, which are essential constituents of the mycobacterial cell wall. PHARMACOKINETICS: INH is readily absorbed from the gut, distributed well all over the body, tubercular cavities and body fluids like CSF, and also crosses placental barrier. It is metabolized by acetylation and the metabolites are excreted in urine. The rate of acetylation of INH is under genetic control resulting in either rapid or slow acetylators. USES: Isoniazid (INH) is a first-line drug for the treatment of TB. It is also used for chemoprophylaxis of tuberculosis. ADVERSE EFFECTS AND DRUG INTERACTIONS: 1. Hepatotoxicity: The risk of hepatic damage is more in chronic alcoholics, elderly patients and rapid acetylators. It is reversible on discontinuation of the drug. Patients receiving INH should be monitored for symptoms like anorexia, nausea, vomiting and jaundice. 2. Peripheral neuritis: It is a dose-related toxicity. Isoniazid is structurally similar to pyridoxine; hence, INH competitively interferes with utilization of pyridoxine. It also promotes the excretion of pyridoxine. Peripheral neuritis is more common in slow acetylators. Pyridoxine 10 mg/day is generally given along with INH to reduce the risk of peripheral neuritis in alcoholics, diabetic patients and HIV positive patients receiving antitubercular therapy. It is also used for the treatment (100 mg/day) of INH-induced peripheral neuritis.
PHARMD GURU Page 3 3. Other side effects are fever, skin rashes, arthralgia, anaemia, GI disturbances, psychosis and rarely convulsions. Isoniazid inhibits the metabolism of phenytoin, carbamazepine, warfarin, etc. → increases plasma levels of these drugs → may result in toxicity. RIFAMPIN (RIFAMPICIN): Rifampin is a derivative of rifamycin and is a first-line antitubercular drug. It rapidly kills intracellular and extracellular bacilli including spurters (those residing in caseous lesion). It is the only agent that can act on all types of bacillary subpopulations; hence, it is called sterilizing agent. MECHANISM OF ACTION: Rifampin binds to bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis. It has bactericidal effect against mycobacteria, N. meningitidis, H. influenzae, S. aureus, E. coli, Pseudomonas, etc. PHARMACOKINETICS: It is given orally and is rapidly absorbed from the GI tract but presence of food reduces its absorption; it is distributed widely throughout the body and gets metabolized in liver. The active deacetylated form is excreted in bile and undergoes enterohepatic recycling. The rest of the drug is excreted in urine. USES: 1. Tuberculosis: Rifampin is used along with INH and other antitubercular drugs for the treatment of TB. It is also used for chemoprophylaxis of tuberculosis. 2. Leprosy. 3. Prophylaxis of meningococcal and H. influenzae meningitis: Rifampin reaches high concentration in the nasopharynx and eradicates the carrier state in case of meningococcal and H. influenzae infections. It is given orally 600 mg every 12 hours for four doses in adults. In children, the dose of rifampin is 10 mg/kg every 12 hours for four doses. 4. Rifampin, in combination with β-lactam antibiotics, may be useful in staphylococcal infections, such as endocarditis and osteomyelitis. 5. Rifampin is used with doxycycline for the treatment of brucellosis.
PHARMD GURU Page 4 ADVERSE EFFECTS AND DRUG INTERACTIONS: 1. Hepatitis is the main adverse effect – the risk of hepatotoxicity is more in alcoholics and elderly patients. 2. Flu-like syndrome with fever, chills, headache, muscle and joint pain. 3. GI disturbances, such as nausea, vomiting and abdominal discomfort. 4. Skin rashes, itching and flushing. It stains various body fluids, such as urine, tears, saliva, sweat and sputum, orange red, which is harmless. Rifampin is a potent microsomal enzyme inducer, hence reduces the plasma levels of a number of drugs, such as oral contraceptives (resulting in contraceptive failure), oral anticoagulants, oral antidiabetic drugs, HIV PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs). It also induces its own metabolism. PYRAZINAMIDE: Pyrazinamide is a synthetic analogue of nicotinamide. It is active in acidic pH – effective against intracellular bacilli (has sterilizing activity). It has tuberculocidal activity. Like INH, pyrazinamide inhibits mycobacterial mycolic acid biosynthesis but by a different mechanism. It is given orally, absorbed well from the GI tract and distributed widely throughout the body including CSF. It is metabolized in liver and excreted in urine. The most important adverse effect of pyrazinamide is dose-dependent hepatotoxicity. It impairs the excretion of urates resulting in hyperuricaemia and may also precipitate acute attacks of gout in susceptible individuals. The other side effects are anorexia, nausea, vomiting, fever and skin rashes. ETHAMBUTOL: It is a first-line antitubercular drug. It inhibits arabinosyl transferases that are involved in mycobacterial cell wall synthesis. It is a bacteriostatic drug. It is used in combination with other antitubercular drugs to prevent emergence of resistance and for faster sputum conversion. There is no cross-resistance with other antitubercular drugs. Patients tolerate ethambutol well as it causes fewer adverse effects, and it is effective even in MAC infections.