From the Guidelines
Rifampicin, isoniazid, pyrazinamide, and ethambutol are the cornerstone of tuberculosis treatment, with a standard regimen consisting of all four drugs for the initial 2 months, followed by rifampicin and isoniazid for 4 months, as recommended by the American Thoracic Society/ Centers for Disease Control and Prevention/Infectious Diseases Society of America 1.
Mechanism of Action
- Rifampicin works by inhibiting bacterial RNA polymerase, preventing RNA synthesis, and is bactericidal against both actively growing and dormant mycobacteria.
- Isoniazid is a prodrug activated by mycobacterial catalase-peroxidase, inhibiting mycolic acid synthesis in the bacterial cell wall, and is highly bactericidal against actively dividing bacteria.
- Pyrazinamide is also a prodrug converted to pyrazinoic acid in acidic environments, disrupting membrane transport and energy production in dormant or slowly replicating bacteria.
- Ethambutol inhibits arabinosyl transferase, preventing arabinogalactan synthesis in the mycobacterial cell wall.
Clinical Uses
- The standard first-line TB regimen includes all four drugs for the initial 2 months (intensive phase), followed by rifampicin and isoniazid for 4 months (continuation phase) 1.
- Treatment should be initiated as soon as possible, with a minimum of 6 months of treatment, and extended to 9 months if the 2-month culture is positive or if cavitation is present on the initial chest radiograph 1.
Adverse Effects
- Common adverse effects include hepatotoxicity (especially with rifampicin, isoniazid, and pyrazinamide), peripheral neuropathy with isoniazid (preventable with pyridoxine supplementation), optic neuritis with ethambutol, and orange discoloration of body fluids with rifampicin.
- Rifampicin also induces cytochrome P450 enzymes, causing numerous drug interactions.
- Regular monitoring of liver function, visual acuity, and adherence is essential during treatment to manage these potential adverse effects.
- In pregnant women, the initial treatment regimen should consist of INH, RIF, and EMB, with pyridoxine supplementation to prevent peripheral neuropathy, and breastfeeding should not be discouraged for women being treated with first-line agents 1.
From the FDA Drug Label
PRECAUTIONS General Rifampin for Injection should be used with caution in patients with a history of diabetes mellitus, as diabetes management may be more difficult. ADVERSE REACTIONS Gastrointestinal Heartburn, epigastric distress, anorexia, nausea, vomiting, jaundice, flatulence, cramps, and diarrhea have been noted in some patients. Table1: Drug Interactions with Rifampin that Affect Concomitant Drug Concentrationsa
The mechanism of action (MOA) of Rifampicin is by inhibiting DNA-dependent RNA polymerase in bacteria, which prevents the synthesis of messenger RNA (mRNA) and ultimately leads to the death of the bacterial cells. The clinical uses of Rifampicin include the treatment of tuberculosis, as well as other bacterial infections such as brucellosis, meningitis, and Legionnaires' disease. The adverse effects of Rifampicin include gastrointestinal reactions, hepatotoxicity, hematologic reactions, and hypersensitivity reactions. Rifampicin can also interact with other medications, such as antiretrovirals, antifungals, and oral hypoglycemic agents, which can lead to decreased efficacy or increased toxicity of these medications 2, 2, 2. Pyrazinamide works by inhibiting the growth of Mycobacterium tuberculosis, and its clinical uses include the treatment of tuberculosis. Isoniazid works by inhibiting the synthesis of mycolic acid, a component of the Mycobacterium tuberculosis cell wall, and its clinical uses include the treatment of tuberculosis. Ethambutol works by inhibiting the synthesis of arabinogalactan, a component of the Mycobacterium tuberculosis cell wall, and its clinical uses include the treatment of tuberculosis.
- Key points:
- Rifampicin, pyrazinamide, isoniazid, and ethambutol are all used to treat tuberculosis.
- Each medication has a unique mechanism of action and potential adverse effects.
- Interactions with other medications can occur, and patients should be closely monitored for signs of toxicity or decreased efficacy.
- The use of these medications should be guided by a healthcare professional, and patients should be educated on the proper use and potential risks associated with these medications.
From the Research
Mechanism of Action (MOA)
- Rifampicin: inhibits DNA-dependent RNA polymerase in bacteria, preventing RNA synthesis 3, 4
- Isoniazid: inhibits the synthesis of mycolic acid, a component of the mycobacterial cell wall 3, 4
- Pyrazinamide: inhibits the enzyme fatty acid synthase I, which is necessary for the synthesis of fatty acids in mycobacteria 3, 4
- Ethambutol: inhibits the enzyme arabinosyl transferase, which is involved in the synthesis of the mycobacterial cell wall 3, 4
Clinical Uses
- Rifampicin, isoniazid, pyrazinamide, and ethambutol are used in combination to treat tuberculosis (TB) 3, 5, 6
- The combination of these four drugs is effective against drug-susceptible and drug-resistant mycobacteria 3, 6
- Fixed-dose combination (FDC) formulations of these drugs are available and have been shown to be bioequivalent to separate formulations 4, 5
Adverse Effects
- Rifampicin: can cause hepatotoxicity, rash, and gastrointestinal symptoms 3, 7
- Isoniazid: can cause hepatotoxicity, peripheral neuropathy, and psychiatric symptoms 3, 7
- Pyrazinamide: can cause hepatotoxicity, arthralgias, and gastrointestinal symptoms 3, 7
- Ethambutol: can cause optic neuritis, gastrointestinal symptoms, and hepatotoxicity 3, 7
- The risk of adverse effects can be influenced by patient factors such as HIV infection, age, and sex, as well as treatment factors such as dosage and formulation 7
Pharmacokinetics
- The pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol can vary significantly between patients 7
- Factors that can influence pharmacokinetics include HIV infection, age, sex, and dosage 7
- Fixed-dose combination formulations can help to reduce variability in pharmacokinetics and improve treatment outcomes 4, 5