Ethambutol

Ethambutol is an Antitubercular agent belonging to mycobacterial infection.

Ethambutol is used in the treatment of Tuberculosis. It is also used to treat Mycobacterium avium complex disease.

Ethambutol is absorbed from the gastrointestinal tract. Time to peak plasma concentration: Within 4 hours.

It get Distributed to most tissues, including kidneys, lungs, and erythrocytes and crosses the placenta and enters breastmilk. Plasma protein binding: 20-30%.It is partially metabolised in the liver into inactive aldehyde and dicarboxylic acid derivatives.

It get excreted mainly via urine (approx 50% as unchanged drug and 8-15% as metabolites); faeces (approx 20% as unchanged drug).

The Tmax of Ethambutol was achieved Within 2-4 hours .Cmax was about 20-50 mg/L

Ethambutol shows common side effects like Headache, dizziness, Diarrhea, sore throat, runny nose, sneezing, joint pain, etc.

Ethambutol is available in the form of tablets

Ethambutol is available in India, Germany, Canada, Italy, USA

Ethambutol diffuses into Mycobacterium cells. Once inside the cell, ethambutol inhibits the arabinosyltransferases (embA, embB, and emcee), preventing formation of the cell wall components arabinogalactan and lipoarabinomannan, and preventing cell division. Decreased concentrations of arabinogalactan in the cell wall reduces the number of binding sites for mycolic acid, leading to the accumulation of mycolic acid, trehalose monomycolate, and trehalose dimycolate.

Ethambutol is available in the form of Tablets.

Ethambutol is used in the treatment of Tuberculosis. It is also used to treat Mycobacterium avium complex disease.

Ethambutol, an antimycobacterial, is bacteriostatic against susceptible bacteria. It appears to inhibit synthesis of bacterial metabolites thereby, inhibiting cellular metabolism and multiplication.

Ethambutol is approved for use in the following clinical indications

Tuberculosis:

Treatment of pulmonary tuberculosis in combination with other antituberculosis agents.

Ethambutol is available in various strengths as 100 mg, 400 mg.

Ethambutol is available in the form of tablets.

• Dosage Adjustment in Kidney Patient

There are no dosage recommendations specific for pediatric patients; ethambutol is primarily renally excreted; monitor serum levels to determine adjustments; experience in adult patients suggests dosing adjustment necessary.

• Dosage Adjustment in Hepatic impairment Patient

There are no dosage adjustments provided in the manufacturer’s labeling; however, use with caution, may accumulate and additional liver damage may occur in patients with preexisting liver disease. Contraindicated in patients with acute liver disease or previous Ethambutol -associated hepatic injury.

For ALT or AST >3 times the ULN: discontinue or temporarily withhold treatment. Treatment with Ethambutol for latent tuberculosis infection should be deferred in patients with acute hepatic diseases.

· Dosage Adjustment for Pediatric Patients:-

Tuberculosis, active treatment (excluding meningitis): Note: Recommendations often change due to epidemiology (resistance) and emerging information; consult CDC and WHO for current recommendations, as appropriate. Always use as part of a multidrug regimen. Any regimens using less than once daily dosing should administer dosing as directly observed therapy (DOT). Treatment regimens for pulmonary tuberculosis consist of an initial 2-month intensive phase of a 4-drug regimen, followed by a continuation phase of an additional 4 to 7 months of isoniazid and rifampin. Ethambutol frequency and dosing differs depending on treatment regimen selected; consult current drug-sensitive TB guidelines for detailed information.

Once daily or 5-times-weekly (DOT):

• Infants, Children, and Adolescents <15 years, weighing <40 kg: Oral: 20 mg/kg/dose once daily or 5-times-weekly DOT, suggested range: 15 to 25 mg/kg/dose

• Children and Adolescents <15 years weighing ≥40 kg or Adolescents ≥15 years: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established): Oral: Weight-band dosing for whole tablets:

• 40 to 55 kg: 800 mg (14.5 to 20 mg/kg/dose) once daily or 5-times-weekly (DOT)

• 56 to 75 kg: 1,200 mg (16 to 21.4 mg/kg/dose) once daily or 5-times-weekly (DOT)

• 76 to 90 kg: 1,600 mg (17.8 to 21.1 mg/kg/dose) once daily or 5-times-weekly (DOT)

• Three-times-weekly DOT: Note: Although suggested dosing based on experience with twice-weekly regimen; experts suggest 3-times-weekly regimens are more effective than twice weekly DOT regimens; ethambutol-containing 3-times-weekly DOT may be used as part of an intensive phase; consult guidelines for specific information

• Infants, Children, and Adolescents, weighing <40 kg: Oral: 50 mg/kg/dose 3-times-weekly
• Children and Adolescents weighing ≥40 kg: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established); Oral: Weight-band dosing for whole tablets:

• 40 to 55 kg: 1,200 mg (21.8 to 30 mg/kg/dose) 3-times-weekly

• 56 to 75 kg: 2,000 mg (26.7 to 35.7 mg/kg/dose) 3-times-weekly

• 76 to 90 kg: 2,400 mg (26.7 to 31.6 mg/kg/dose) 3-times-weekly

• Twice weekly DOT: Note: Regimen not generally recommended; do not use in HIV patients or those with smear-positive and/or cavitary disease. This therapy should only be used following completion of a 2-week intensive phase once daily (or 5-times-weekly) regimen. Missed doses result in the equivalent of once-weekly dosing which has been shown to be inferior and is associated with treatment failure, relapse, and development of drug resistance.

• Infants, Children, and Adolescents <15 years, weighing <40 kg: Oral: 50 mg/kg/dose twice weekly

• Children and Adolescents <15 years weighing ≥40 kg or Adolescents ≥15 years: Note: Doses should be based on lean body weight for patients within a normal weight range for their height (optimal dosing for obese patients has not been established); Oral: Weight-band dosing for whole tablets:

• 40 to 55 kg: 2,000 mg (36.4 to 50 mg/kg/dose) twice weekly
• 56 to 75 kg: 2,800 mg (37.3 to 50 mg/kg/dose) twice weekly

• 76 to 90 kg: 4,000 mg (44.4 to 52.6 mg/kg/dose) twice weekly

Mycobacterium avium complex (MAC) in HIV-exposed/-infected:

Treatment:

Infants and Children: Oral: 15 to 25 mg/kg/dose once daily; maximum dose: 2,500 mg/dose; in combination with clarithromycin (or azithromycin); for severe disease add rifabutin

Adolescents: Oral: 15 mg/kg/dose once daily in combination with clarithromycin (or azithromycin)

Chronic suppressive therapy : Infants and Children: Oral: 15 to 25 mg/kg/dose once daily; maximum dose: 2,500 mg/dose with clarithromycin (or azithromycin) with or without rifabutin

• Nontuberculous mycobacterial infection (eg, m. kansasii): Limited data available: Infants, Children, and Adolescents: 15 to 25 mg/kg/dose once daily; maximum dose: 2,500 mg/dose

Do not take with food; avoid tyramine- and/or histamine-containing foods. Increase dietary intake of folate, niacin, magnesium

Hypersensitivity to ethambutol or any component of the formulation; optic neuritis (risk vs benefit decision); use in young children, unconscious patients, or any other patient who may be unable to discern and report visual changes.

Concerns related to adverse effects:

• Hepatic toxicity: Has been reported, possibly due to concurrent therapy.

• Optic neuritis: May cause optic neuritis (unilateral or bilateral), resulting in decreased visual acuity or other vision changes. Discontinue promptly in patients with changes in vision, color blindness, or visual defects (effects normally reversible, but reversal may require up to a year). Irreversible blindness has been reported.

Disease-related concerns:

• Ocular disease: Evaluation of visual acuity changes may be more difficult in patients with cataracts, optic neuritis, diabetic retinopathy, and inflammatory conditions of the eye; consideration should be given to whether or not visual changes are related to disease progression or effects of therapy.

• Renal impairment: Use with caution in patients with renal impairment; dosage modification recommended.

Ethambutol may cause liver problems, and using it with substantial quantities of ethanol may increase that risk.

Ethambutol is present in breast milk.

The manufacturer suggests use during breastfeeding only if benefits to the mother outweigh the possible risk to the infant. Breastfeeding is not a contraindication during therapy for drug-susceptible tuberculosis in patients deemed noninfectious who are treated with first-line agents (ie, ethambutol). Exposure to ethambutol via breast milk should not be considered effective treatment for the breastfed infant. Breastfed infants should be monitored for jaundice . Patients with multidrug-resistant tuberculosis and a sputum smear-positive test should avoid breastfeeding when possible

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. There are reports of ophthalmic abnormalities occurring in infants born to women on antituberculous therapy that included Ethambutol . Ethambutol should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

Ethambutol has been shown to be teratogenic in pregnant mice and rabbits when given in high doses. When pregnant mice or rabbits were treated with high doses of ethambutol hydrochloride, fetal mortality was slightly but not significantly (P>0.05) increased. Female rats treated with ethambutol hydrochloride displayed slight but insignificant (P>0.05) decreases in fertility and litter size.

• Common Adverse effects

Optic neuritis, visual disturbances (e.g. colour blindness and irreversible blindness). Blood and lymphatic system disorders: Thrombocytopenia, eosinophilia, leucopenia, neutropenia.

• Less Common Adverse effects:

Nausea, vomiting, abdominal pain, gastrointestinal upset, Confusion, disorientation, hallucinations.

• Rare Adverse effects

Dermatitis, erythema multiforme, pruritus.

Antagonises the effect of uricosuric agents (e.g., probenecid, sulfinpyrazone). May reduce the contraceptive effect of oestrogens. May inactivate oral typhoid vaccine. May increase the serum concentration of ciclosporin. May enhance the hepatotoxic effect of rifampicin.

The common side effects of Ethambutol include the following

Optic neuritis, visual disturbances (e.g. color blindness and irreversible blindness). Blood and lymphatic system disorders: Thrombocytopenia, eosinophilia, leucopenia, neutropenia.

Patients experiencing a chronic overdose of ethambutol may present with disturbances in color vision and reduced visual acuity as symptoms of optic neuropathy. In these cases, ethambutol should be stopped. Data regarding acute overdose of ethambutol are not readily available. Patients experiencing an acute overdose of ethambutol may be experience an increased risk and severity of adverse effects such as pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucinations. Patients should be treated with symptomatic and supportive measures.

Pharmacodynamic

Ethambutol is indicated in combination with other anti-tuberculosis drugs in the treatment of pulmonary tuberculosis. It has a long duration of action as it is administered daily, and a moderate therapeutic window.Patients should be counselled regarding the risk of optic neuritis and hepatic toxicity.

Pharmacokinetics

● Absorption: Oral ethambutol is approximately 75-80% orally bioavailable. A 25 mg/kg oral dose of ethambutol reaches a C_max of 2-5 µg/mL, with a T_max of 2-4 hours. In a separate study, the AUC_0-8 varied from 6.3 ± 5.5 h*mg/L to 10.8 ± 7.6 h*mg/L depending on CYP1A2 genetic polymorphisms.

● Distribution: Patients coinfected with tuberculosis and HIV have an estimated ethambutol volume of distribution of 76.2 L.

● Metabolism: Ethambutol is mainly oxidized by an aldehyde dehydrogenase to an aldehyde metabolite, followed by conversion to the dicarboxylic acid 2,2'-(ethylinediimino)di-butyric acid.

● Excretion: Ethambutol is 50% eliminated in the urine as the unmetabolized parent compound and 8-15% as inactive metabolites. 20-22% of a dose is eliminated unchanged in the feces.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1364710/
• https://reference.medscape.com/drug/colestid-Ethambutol -342452
• https://go.drugbank.com/drugs/DB00375
• https://www.sciencedirect.com/topics/medicine-and-dentistry/Ethambutol
• https://europepmc.org/article/med/6988203