Ethambutol
Introduction
Ethambutol is a bacteriostatic antimycobacterial agent primarily used in the treatment of tuberculosis. It is often administered in combination with other antitubercular drugs to prevent the development of drug resistance. Ethambutol was first synthesized in 1961 and has since become a critical component in the multi-drug therapy for tuberculosis.
Chemical Properties
Ethambutol is chemically known as (2S,2'S)-2,2'-(ethane-1,2-diyldiimino)bis-butan-1-ol. Its molecular formula is C10H24N2O2, and it has a molecular weight of 204.31 g/mol. The compound is a white crystalline powder that is soluble in water and slightly soluble in ethanol. The structural formula of ethambutol includes two chiral centers, making it a chiral molecule with four stereoisomers. The clinically used form is the dextro-isomer, which is more effective and less toxic than its levo counterpart.
Mechanism of Action
Ethambutol works by inhibiting the synthesis of mycobacterial cell walls. Specifically, it targets the enzyme arabinosyl transferase, which is involved in the polymerization of arabinogalactan, an essential component of the mycobacterial cell wall. By inhibiting this enzyme, ethambutol disrupts the cell wall structure, leading to increased permeability and eventual cell death. This mechanism is particularly effective against actively dividing mycobacteria.
Pharmacokinetics
Ethambutol is well-absorbed from the gastrointestinal tract, with peak plasma concentrations occurring within 2-4 hours after oral administration. The drug is widely distributed throughout the body, including the lungs, kidneys, and cerebrospinal fluid. Ethambutol is primarily excreted unchanged in the urine, with a half-life of approximately 3-4 hours in individuals with normal renal function. In patients with renal impairment, the half-life can be significantly prolonged, necessitating dosage adjustments.
Clinical Uses
Ethambutol is mainly used in the treatment of tuberculosis, both pulmonary and extrapulmonary forms. It is a part of the standard first-line treatment regimen, which also includes isoniazid, rifampicin, and pyrazinamide. Ethambutol is particularly valuable in preventing the development of resistance to other antitubercular drugs. It is also used in the treatment of Mycobacterium avium complex (MAC) infections, often in combination with other antimycobacterial agents.
Dosage and Administration
The recommended dose of ethambutol for adults is 15-25 mg/kg per day, administered orally. For children, the dose is typically 15 mg/kg per day. Ethambutol is usually taken once daily, but in some cases, it may be administered intermittently (e.g., three times a week) under directly observed therapy (DOT) to ensure compliance. Dosage adjustments are necessary for patients with renal impairment to avoid toxicity.
Side Effects
Common side effects of ethambutol include gastrointestinal disturbances such as nausea, vomiting, and abdominal pain. More serious adverse effects include optic neuritis, which can lead to visual impairment or blindness if not detected early. Patients on ethambutol should undergo regular ophthalmologic examinations to monitor for signs of optic neuritis. Other potential side effects include peripheral neuropathy, hypersensitivity reactions, and hepatotoxicity.
Drug Interactions
Ethambutol has relatively few drug interactions compared to other antitubercular agents. However, it may interact with antacids containing aluminum hydroxide, which can reduce its absorption. It is advisable to administer ethambutol at least two hours before or after taking such antacids. Ethambutol does not significantly induce or inhibit cytochrome P450 enzymes, making it less likely to interact with other drugs metabolized by this pathway.
Resistance
Resistance to ethambutol can develop through mutations in the embB gene, which encodes the arabinosyl transferase enzyme. These mutations can lead to reduced binding affinity of ethambutol to the enzyme, rendering the drug less effective. The development of resistance is more likely when ethambutol is used as monotherapy, which is why it is always administered in combination with other antitubercular drugs.
Monitoring and Safety
Patients on ethambutol therapy should be monitored for visual acuity and color discrimination to detect early signs of optic neuritis. Baseline and periodic liver function tests are also recommended to monitor for hepatotoxicity. Renal function should be assessed before initiating therapy and periodically thereafter, especially in patients with pre-existing renal impairment.
Conclusion
Ethambutol is a crucial drug in the treatment of tuberculosis and other mycobacterial infections. Its ability to inhibit cell wall synthesis makes it an effective bacteriostatic agent, particularly when used in combination with other antitubercular drugs. While generally well-tolerated, careful monitoring for side effects such as optic neuritis and hepatotoxicity is essential to ensure patient safety.