Rifampicin + Isoniazid + Pyrazinamide + Ethambutol
Indications
Treatment of both pulmonary and extrapulmonary tuberculosis in the intensive initial phase of treatment.
Pharmacology
Rifampicin: It is a semisynthetic derivative of rifamycin, suppresses bacterial RNA synthesis by binding to the β-subunit of DNA-dependent RNA polymerase, thus inhibiting the attachment of the enzyme to DNA, blocking RNA transcription and elongation. It does not inhibit the counterpart mammalian enzyme.
Rifampicin has a bactericidal action and a potent sterilizing effect against both intracellular and extracellular tubercle bacilli. Cross-resistance has been shown only with other rifamycin derivatives.
Isoniazid: It kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acids, which are the major components of the bacterial cell wall of Mycobacterium tuberculosis.
Pyrazinamide: Pyrazinamide, an antituberculous drug, is the pyrazine analog of nicotinamide. The precise mechanism of action of pyrazinamide is not known. Its metabolite, pyrazinoic acid, which is less active in vitro may possibly be involved in the in vivo activity of pyrazinamide.
Ethambutol: Ethambutol diffuses slowly into actively growing Mycobacteria cells eg, tubercle bacilli. It inhibits the synthesis of 1 or more metabolites, thus causing impaired cell metabolism, arrest cell multiplication and induce cell death. No cross-resistance with other agents has been demonstrated.
Spectrum of Activity: Rifampicin, isoniazid, pyrazinamide, and ethambutol, at therapeutic levels, have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organism.
Rifampicin has a bactericidal action and a potent sterilizing effect against both intracellular and extracellular tubercle bacilli. Cross-resistance has been shown only with other rifamycin derivatives.
Isoniazid: It kills actively growing tubercle bacilli by inhibiting the biosynthesis of mycolic acids, which are the major components of the bacterial cell wall of Mycobacterium tuberculosis.
Pyrazinamide: Pyrazinamide, an antituberculous drug, is the pyrazine analog of nicotinamide. The precise mechanism of action of pyrazinamide is not known. Its metabolite, pyrazinoic acid, which is less active in vitro may possibly be involved in the in vivo activity of pyrazinamide.
Ethambutol: Ethambutol diffuses slowly into actively growing Mycobacteria cells eg, tubercle bacilli. It inhibits the synthesis of 1 or more metabolites, thus causing impaired cell metabolism, arrest cell multiplication and induce cell death. No cross-resistance with other agents has been demonstrated.
Spectrum of Activity: Rifampicin, isoniazid, pyrazinamide, and ethambutol, at therapeutic levels, have demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organism.
Dosage & Administration
Adults: 3 tablets/day for an average body weight of 50 kg.
Patients weighing-
Patients weighing-
- >70 kg: 5 tablets
- 55-70 kg: 4 tablets
- 38-54 kg: 3 tablets
- 30-37 kg: 2 tablets
Interaction
Rifampicin: Induces microsomal enzymes (accelerates clearance of methadone, oral anticoagulants, glucocorticoids, oestrogen, oral hypoglycaemic agents, digitoxin, antiarrhythmics, theophylline, anticonvulsants, azole antifungal, cyclosporin).
Isoniazid: Inhibits metabolism of antiepileptics, benzodiazepines, warfarin, theophylline. Increases metabolism of enflurane. Alcohol, ASA, Al-containing antacids, corticosteroids, ketoconazole, propranolol.
Pyrazinamide: Decreases efficacy of gout therapy agents.
Ethambutol: Neurotoxic agents.
Isoniazid: Inhibits metabolism of antiepileptics, benzodiazepines, warfarin, theophylline. Increases metabolism of enflurane. Alcohol, ASA, Al-containing antacids, corticosteroids, ketoconazole, propranolol.
Pyrazinamide: Decreases efficacy of gout therapy agents.
Ethambutol: Neurotoxic agents.
Contraindications
Hypersensitivity to rifampicin, isoniazid, pyrazinamide or ethambutol.
Isoniazid: Previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid eg, fever, chills and arthritis; acute liver disease of any etiology, a history of previous hypersensitivity reaction to isoniazid including drug-induced hepatitis.
Isoniazid: Previous isoniazid-associated hepatic injury; severe adverse reactions to isoniazid eg, fever, chills and arthritis; acute liver disease of any etiology, a history of previous hypersensitivity reaction to isoniazid including drug-induced hepatitis.
Side Effects
Rifampicin: Reddish discolouration of body fluids, asymptomatic increase in liver enzymes, elevations of BUN & uric acid, hemolysis, hematuria, intestinal nephritis, renal insufficiency, Gl discomfort, CNS effects, hematological changes, skin rash, endocrine effects.
Isoniazid: Disturbances of liver function, hepatitis, Gl disturbances, peripheral neuropathy, dizziness, lightheadedness, hematological changes, allergic reactions.
Pyrazinamide: Transient rise in serum transaminases, hepatotoxicity, hepatomegaly, jaundice, hyperuricemia, intestinal nephritis, dysuria, Gl disturbances, hematological changes, allergic reactions.
Ethambutol: Confusion, disorientation, headache, visual disturbances, jaundice, transient liver dysfunction, Gl disturbances, hematological changes, allergic effects, acute gout (rare).
Isoniazid: Disturbances of liver function, hepatitis, Gl disturbances, peripheral neuropathy, dizziness, lightheadedness, hematological changes, allergic reactions.
Pyrazinamide: Transient rise in serum transaminases, hepatotoxicity, hepatomegaly, jaundice, hyperuricemia, intestinal nephritis, dysuria, Gl disturbances, hematological changes, allergic reactions.
Ethambutol: Confusion, disorientation, headache, visual disturbances, jaundice, transient liver dysfunction, Gl disturbances, hematological changes, allergic effects, acute gout (rare).
Pregnancy & Lactation
Rifampicin: Since rifampicin has been reported to cross the placental barrier and appear in cord blood and in maternal milk, neonates and newborns of rifampicin-treated mothers should be carefully observed for any evidence of untoward effects.
Ethambutol: While administration of ethambutol to pregnant human patients has produced no detectable effect upon the fetus, the possible teratogenic potential in women capable of bearing children would be weighed carefully against the benefits of therapy. There are published reports of 5 women who received ethambutol during pregnancy without apparent adverse effect upon the fetus.
Ethambutol: While administration of ethambutol to pregnant human patients has produced no detectable effect upon the fetus, the possible teratogenic potential in women capable of bearing children would be weighed carefully against the benefits of therapy. There are published reports of 5 women who received ethambutol during pregnancy without apparent adverse effect upon the fetus.
Precautions & Warnings
Impaired renal or liver function, DM, chronic alcoholism, undernourishment, history of gout, patients with convulsive disorders, acute porphyria. Elderly. Pregnancy & lactation. Perform periodic blood counts & liver function tests. Avoid use with soft contact lenses.
Children <8 year or patients who are not able to communicate visual disturbances. Check visual ability before starting treatment & monitor during treatment.
Children <8 year or patients who are not able to communicate visual disturbances. Check visual ability before starting treatment & monitor during treatment.
Use in Special Populations
Use in children: Ethambutol is not recommended for use in children <13 years since safe conditions for use have not been established.
Therapeutic Class
Combined anti- Tubercular Preparations
Storage Conditions
Store at temperatures not exceeding 30°C.
