Ethambutol - description of the drug, instructions for use, reviews

Pharmacodynamics

It has a pronounced bacteriostatic effect against Mycobacterium tuberculosis, as well as some atypical mycobacteria (M.avium, M.kansasii, M.xenopi). The drug inhibits the proliferation of mycobacteria resistant to streptomycin, isoniazid, PAS, ethionamide, kanamycin and others

anti-tuberculosis drugs. The mechanism of action of ethambutol after its penetration into the mycobacterium is associated with inhibition of RNA and protein synthesis, the ability to interact with ions of divalent biometals (copper, magnesium), disruption of the structure of ribosomes and inhibition of the intensity of lipid metabolism. About 1% of patients have primary resistance to the drug. With monotherapy for tuberculosis, tolerance develops quickly.

Pharmacokinetics

When administered orally, 75-80% of the drug is absorbed from the digestive tract. Simultaneous food intake enhances and accelerates the absorption process. The maximum concentration of ethambutol in the blood is reached after approximately 2 hours and is 4-5 mcg/ml when the drug is administered at a dose of 25 mg/kg and 8-9 mcg/ml when the drug is administered at a dose of 50 mg/kg. Binding to blood plasma proteins depends on the dose taken and is 10-40%. The half-life (T½) is 3.3-3.5 hours.

A feature of the pharmacokinetics of ethambutol is that it selectively accumulates in erythrocytes (the concentration is 2 times higher than in blood plasma). Ethambutol penetrates into the cerebrospinal fluid, through the placenta and into breast milk.

The drug is excreted primarily unchanged in the urine. Approximately 10-20% of ethambutol is excreted in feces in the form of inactive metabolites (aldehydes, dicarboxylic acids). Prescribing ethambutol for impaired renal function can lead to its accumulation in the body.

Side effects

Cardiovascular system: pericarditis, myocarditis, arterial hypotension, tachycardia.
Blood system and lymphatic system: leukopenia, neutropenia, thrombocytopenia, eosinophilia, lymphadenopathy.

Nervous system: headache, dizziness, confusion, disorientation, hallucinations, convulsions, disorientation, depression, peripheral neuritis, paresthesia in the extremities, numbness, paresis.

Visual organs: retrobulbar inflammation of the optic nerve, optic neuropathy, unilateral or bilateral decrease in visual acuity, including irreversible blindness, impaired color vision (mainly green and red), development of central or peripheral scotoma, limitation of visual fields, retinal hemorrhage.

The occurrence of visual disturbances depends on the duration of treatment and previous or existing diseases of the visual organs.

Respiratory system, chest and mediastinal organs: pulmonary infiltrates with or without eosinophilia, pneumonitis.

Hepatobiliary system: impaired liver function, increased activity of liver transaminases, hepatitis, jaundice.

Digestive tract: metallic taste in the mouth, nausea, vomiting, dyspepsia, heartburn, abdominal pain, diarrhea, anorexia, pseudomembranous colitis (when used together with rifampicin and isoniazid).

Urinary system: increased creatinine levels, increased urea levels, interstitial nephritis.

Skin and subcutaneous tissue: rash, itching, hyperemia, dermatitis, tingling sensation.

Musculoskeletal system and connective tissue: arthralgia.

Metabolic disorders: decreased clearance of uric acid in the blood serum, the phenomenon of uric acid diathesis, exacerbation of gout.

Immune system: anaphylactic/anaphylactoid reactions, including anaphylactic shock, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), bronchospasm, vasculitis.

General disorders: increased body temperature, chills, general weakness, swelling.

Use of the drug Ethambutol

As part of combination therapy. Prescribed in a continuous mode - once a day at a dose of 25 mg/kg or in an intermittent mode - at a dose of 30-40 mg/kg 3 times a week. When the tuberculosis process is stabilized, a dose of 15 mg/kg/day is prescribed. As an alternative method, ethambutol is prescribed at a dose of 15 mg/kg/day throughout the entire treatment period. Taking ethambutol after meals improves its tolerability. The duration of treatment depends on the form of tuberculosis and the treatment regimen used and ranges from 6 to 12 months.

Interaction with other drugs

With simultaneous use of the drug Ethambutol:
with anti-tuberculosis drugs - increased effects of anti-tuberculosis drugs.

To treat tuberculosis in complex therapy with ethambutol, you can use isoniazid, para-aminosalicylic acid (PAS), streptomycin, cycloserine, pyrazinamide; with isoniazid with simultaneous use of cyclosporine A - increased degradation of cyclosporine A with the risk of transplant rejection; with digitoxin – decreased effectiveness of the latter; with ciprofloxacin, aminoglycosides, asparaginase, carbamazepine, lithium preparations, imipenem, methotrexate, quinine - the effects are enhanced and the neurotoxicity of the above drugs increases; with aluminum preparations and other antacids - deterioration of ethambutol absorption; with disulfiram – increased concentration of ethambutol and increased toxicity; with ethionamide - simultaneous use of ethambutol with ethionamide is not recommended due to pharmacological antagonism (it is better to alternate the drugs every other day); with pyrazinamide – a synergistic effect on the excretion of uric acid; with ethyl alcohol – the negative effect of ethambutol on the organs of vision increases, so during treatment you should avoid drinking alcohol. Ethambutol alters the metabolism of some trace elements, mainly zinc. Features of application. The drug should only be prescribed in combination with other anti-tuberculosis drugs. Before and during treatment, a systematic examination of the fundus, intraocular pressure, refraction, visual fields, visual acuity and color perception (especially differentiation of red and green, blue and green) is necessary.

In patients with impaired renal function, ophthalmological monitoring should be carried out daily.

Ophthalmological control is carried out for each eye separately and for both eyes together, since changes in visual acuity can be monoteral or bilateral. It is necessary to inform the doctor about any changes in vision function. If visual impairment occurs, to prevent optic nerve atrophy, you must immediately stop using Ethambutol. Vision changes are usually reversible, disappearing after stopping treatment within a few weeks, or in some cases within a few months. In exceptional cases, vision changes are irreversible due to optic nerve atrophy. For visual impairment, use hydroxycobalamin or cyanocobalamin.

Ethambutol should be prescribed with caution to patients with gout or hyperuricemia. In patients with renal failure, the dose of Ethambutol should be reduced as the drug accumulates in the body. Treatment with ethambutol may increase the concentration of urate in the blood, which is associated with a weakening of the excretion of uric acid by the kidneys. It is recommended to periodically monitor peripheral blood parameters, liver and kidney functions. At the beginning of treatment, the cough may increase and the amount of sputum may increase. To reduce these symptoms, prescribe B vitamins and expectorants. In patients who have previously taken drugs with a tuberculostatic effect, bacterial resistance to ethambutol develops more often. Long-term or repeated use of ethambutol may lead to the development of secondary infections. If you suspect an infection, you should consult a doctor. If symptoms of tuberculosis do not disappear within 2-3 weeks or if the condition worsens, it is recommended to consult a doctor. It is necessary to complete the full course of treatment with the drug, regardless of whether symptoms of the disease are present or absent, to prevent relapse or the development of resistance. Ethyl alcohol enhances the toxic effect of ethambutol on the organs of vision, so you should avoid drinking alcohol during treatment. If side effects occur, it is necessary to adjust the dose in the direction of reducing it; if this step is not possible, switch to intermittent use of the drug (every other day or 2 times a week).

Pharmacological properties of the drug Ethambutol

A synthetic derivative of ethylenediamine - has a specific antibacterial effect against Mycobacterium tuberculosis and Mycobacterium bovis , as well as some atypical (opportunistic, non-tuberculous) species of mycobacteria. It does not show activity against other bacteria, as well as viruses and fungi. Acts bacteriostatically. It is active against mycobacteria resistant to other anti-tuberculosis drugs, therefore it is a second-line agent. Primary resistance of M. tuberculosis and M. bovis to ethambutol is observed very rarely, secondary resistance develops slowly. Can be used in combination with other anti-tuberculosis drugs. After oral administration, about 80% of ethambutol is absorbed. Eating food at the same time speeds up and enhances the absorption process. Serum concentrations after oral administration are proportional to the administered dose. The maximum concentration of ethambutol in the blood is reached after approximately 2 hours and is 4–5 mcg/ml for a dose of 25 mg/kg body weight and 8–9 mcg/ml for a dose of 50 mg/kg. The concentration of the drug in the blood serum decreases within 8 hours to 50% and within 24 hours - to 10%. Ethambutol accumulates in red blood cells; 2 hours after oral administration, the concentration of ethambutol in erythrocytes is approximately 2 times higher than its concentration in blood plasma. Plasma protein binding is highly concentration dependent and ranges from 10 to 40%. Ethambutol penetrates into the cerebrospinal fluid, through the placenta and into breast milk. The half-life is 3.3–3.5 hours. Ethambutol is excreted predominantly unchanged, mainly in the urine; complete elimination occurs after a few days. During the first 24 hours, about 60% of the administered dose is excreted in the urine. Approximately 10–20% is excreted in the feces in the form of inactive metabolites (aldehyde, dicarboxylic acid derivative). If the excretory function of the kidneys is impaired, ethambutol can accumulate in the body.

Overdose

Symptoms
Development of neurological disorders, damage to the optic nerve (blindness may occur), deterioration of visual acuity or increased manifestations of other adverse reactions, loss of appetite, nausea, vomiting, diarrhea, fever, headache, dizziness, confusion, hallucinations, polyneuritis, respiratory depression, asystole.

Treatment

There is no specific antidote, treatment is symptomatic. Due to the rapid absorption of the drug, immediately after administration it is necessary to induce vomiting or lavage the stomach, and also prescribe enterosorbents. Monitor and take measures to support the vital functions of the body, and, if necessary, carry out resuscitation measures. Forced diuresis, peritoneal dialysis or hemodialysis are indicated. For allergic reactions, the use of desensitizing agents is indicated. In threatening conditions, a blood transfusion is necessary to remove red blood cells where ethambutol accumulates.

Special instructions for the use of the drug Ethambutol

If visual impairment occurs, treatment with ethambutol should be stopped immediately to prevent optic nerve atrophy. In most cases, disorders are reversible if they are detected early enough. For visual impairment, the use of hydroxicobalamin or cyanocobalamin is indicated. Vision restoration usually occurs within a few weeks or months, in rare cases within a year or longer, in some cases the changes are irreversible. Optic neuritis and the degree of decrease in visual acuity depend on the dose and duration of use of ethambutol, however, there have been cases of visual impairment (even blindness) after taking ethambutol, even in low doses. Before starting treatment, it is necessary to conduct an ophthalmological examination, including determination of visual acuity, the ability to distinguish colors (especially differentiate between red and green, blue and green), testing visual fields, measuring intraocular pressure and examining the fundus. Throughout the entire period of treatment with ethambutol, the ophthalmologist should conduct a follow-up examination every 2–4 weeks. In patients with impaired renal function, ophthalmological monitoring should be carried out weekly. Before starting treatment, it is necessary to warn the patient about the possible deterioration of vision and the development of possible side effects (for example, difficulty reading newspapers, differentiating between red, green and blue colors), which he should report to the doctor. If such effects occur, therapy should be discontinued immediately. If visual impairment occurs, it is imperative to discontinue further treatment with ethambutol. To date, there have been no cases of negative effects on the fetus or the appearance of symptoms of intoxication in newborns whose mothers took ethambutol during pregnancy. In one case, however, it was suspected that ethambutol, which was prescribed in combination with isoniazid during pregnancy, caused the development of a neoplasm of the digestive tract. When prescribing ethambutol to patients with gout or hyperuricemia, extreme caution should be exercised. Before and during treatment with ethambutol, the functional state of the kidneys and liver should be monitored.

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Ethambutol[edit | edit code]

Chemical properties[edit | edit code]

Ethambutol is soluble in water and stable in heat. The structural formula of the drug is as follows:

Structural formula of ethambutol

Antimicrobial activity[edit | edit code]

Ethambutol acts only on mycobacteria, inhibiting their growth. Almost all strains of Mycobacterium tuberculosis and Mycobacterium kansasii, as well as some strains of Mycobacterium avium-intracellulare are sensitive to it (Pablos-Mdndezetal., 1998). The sensitivity of other mycobacteria varies. Ethambutol is active against most strains of Mycobacterium tuberculosis resistant to isoniazid and streptomycin. In vitro resistance to ethambutol develops very slowly.

When added to a culture in the logarithmic growth phase, the drug quickly penetrates into the mycobacterial cell. However, a noticeable bacteriostatic effect occurs only after 24 hours. Ethambutol blocks arabinosyltransferases involved in the synthesis of the mycobacterial cell wall (Takayama et al., 1979). In vivo, during monotherapy with ethambugol, resistance develops to it due to single amino acid substitutions in the product of the ethambugol gene (Belangeret al., 1996).

Ethambutol tablets p/o 400 mg No. 10x5

Name

Ethambutol tablet p/o 400 mg in container pack No. 10x5

Description

White film-coated tablets with a biconvex surface.

Release form

film-coated tablets

Dosage

400mg

Pharmacological properties

Pharmacodynamics

Anti-tuberculosis drug, acts bacteriostatically; penetrates into actively growing mycobacterial cells, inhibiting RNA synthesis, disrupts cellular metabolism, causes cessation of reproduction and death of bacteria. It acts on both extracellular and intracellular forms of bacteria (intracellular concentrations are 2 times higher). Active only against rapidly dividing mycobacteria Mycobacterium tuberculosis (minimum inhibitory concentration (MIC) 1–2 μg/ml), Mycobacterium kansanii (MIC 16 μg/ml), Mycobacterium avium (MIC 31.2 μg/ml), Mycobacterium xenopi, inhibits their growth and reproduction, including strains resistant to streptomycin, isoniazid, para-aminosalicylic acid (PAS), ethionamide, and kanamycin. With monotherapy, mycobacterial resistance develops quite quickly. About 1% of pathogens have primary resistance to ethambutol.

Pharmacokinetics

Absorption – high; bioavailability – 75–80%. After oral administration of a dose of 25 mg, the maximum concentration (Cmax – 1–5 mcg/ml is achieved after 2–4 hours. Plasma protein binding – 20–30%. Fat-rich foods slow down the absorption of ethambutol and reduce its maximum concentration in the blood. Penetrates well into tissues and organs, as well as into biological fluids, with the exception of ascitic and pleural fluid (into the cerebrospinal fluid only with meningitis). The highest concentrations are created in the kidneys, lungs, saliva, urine. Penetrates into breast milk. Does not pass through the intact blood-brain barrier. Partially metabolized in the liver (15%) with the formation of inactive metabolites. Half-life (T1/2) - 3-4 hours, in case of impaired renal function - 8 hours. Excreted by the kidneys - 80-90% (50% - unchanged, 15% – in the form of inactive metabolites) and with feces – 10–20% (unchanged). Excreted during hemodialysis and peritoneal dialysis.

Indications for use

Primary and repeated treatment of tuberculosis, prevention in case of inactive tuberculosis or major tuberculin-positive reaction. Ethambutol should only be used in combination with other anti-tuberculosis drugs to which the pathogens are susceptible.

Directions for use and doses

Adults and children over 13 years of age Primary treatment: prescribe the drug at a dose of 15 mg/kg body weight 1 time per day. Repeated course of treatment: prescribe the drug at a dose of 25 mg/kg 1 time per day, then switch to taking the drug at a dose of 15 mg/kg 1 time per day. During the period when the patient uses the drug at a dose of 25 mg/kg body weight, a monthly examination by an ophthalmologist is recommended. In case of functional renal failure, the drug should be prescribed depending on the clearance rate. The maximum daily dose for children is 1 g. The duration of treatment depends on the form of tuberculosis and ranges from 6 months to 12 months. Taking ethambutol after meals improves its tolerability. Children Do not use in children under 13 years of age.

Use during pregnancy and lactation

The drug is contraindicated during pregnancy or breastfeeding.

Precautionary measures

The drug should be prescribed only in combination with other anti-tuberculosis drugs. Before starting and during treatment with ethambutol, ophthalmological monitoring should be carried out: examination of the fundus, intraocular pressure, refraction, visual fields, visual acuity and light perception (especially differentiation of red and green, blue and green colors). It is necessary to inform the patient about the obligation to inform the doctor about any changes in eye function. In patients with impaired renal function, ophthalmological monitoring should be carried out daily. Ophthalmological control is carried out for each eye separately and for both eyes together, since changes in visual acuity can be unilateral or bilateral. If changes in the function of the visual organs occur, treatment with ethambutol should be discontinued to prevent optic nerve atrophy. Vision changes are usually reversible after stopping treatment and disappear after a few weeks, in some cases after a few months. In exceptional cases, vision changes are irreversible due to optic nerve atrophy. For visual impairment, use hydroxocobalamin or cyanocobalamin. Vision is restored within a few weeks or even months. The use of ethambutol requires constant monitoring of peripheral blood parameters, the functional state of the liver and kidneys. Treatment with ethambutol may increase the concentration of urate in the blood, which is associated with a weakening of the excretion of uric acid by the kidneys. Use with caution in patients with elevated levels of uric acid in the blood. If side effects occur, it is necessary to adjust the dose in the direction of reducing it, and if this step is not possible, switch to intermittent use of the drug (every other day or 2 times a week). At the beginning of treatment, the cough may increase and the amount of sputum may increase. To reduce these symptoms, B vitamins and expectorants are prescribed. In patients with renal failure, the dose of ethambutol should be reduced because the drug accumulates in the body. In patients who have previously taken drugs with tuberculostatic effects, bacterial resistance to ethambutol develops more often. Long-term or repeated use of ethambutol may lead to the development of secondary infections. If you suspect an infection, you should consult a doctor. If symptoms of tuberculosis do not disappear within 2-3 weeks or if the condition worsens, it is recommended to consult a doctor. It is necessary to complete the full course of treatment, regardless of whether symptoms are present or absent, to prevent relapse or the development of resistance. Ethyl alcohol enhances the toxic effect of ethambutol on the organs of vision, so you should avoid drinking alcohol during treatment.

Interaction with other drugs

When used simultaneously with other drugs, it is possible:

• with anti-tuberculosis drugs – enhancing the effects of anti-tuberculosis drugs. To treat tuberculosis in complex therapy with ethambutol, you can use isoniazid, para-aminosalicylic acid (PAS), streptomycin, cycloserine, pyrazinamide;
• with ciprofloxacin, aminoglycosides, asparaginase, carbamazepine, lithium preparations, imipenem, methotrexate, quinine - when combined with ethambutol, the effects are enhanced and the neurotoxicity of the above drugs increases;
• with digitoxin – decreased effectiveness of the latter;
• with disulfiram – increased concentration of ethambutol and increased toxicity;
• with pyrazinamide – synergistic effect on the excretion of uric acid
• with isoniazid with simultaneous use of cyclosporine A - increased degradation of cyclosporine A with the risk of transplant rejection;
• with ethionamide - simultaneous use of ethambutol with ethionamide is not recommended due to pharmacological antagonism (the drugs are best prescribed every other day);
• with aluminum preparations and other antacids - deterioration of ethambutol absorption.

Ethambutol alters the metabolism of some trace elements, mainly zinc.

Contraindications

Hypersensitivity to the components of the drug, optic neuritis, cataracts; diabetic retinopathy; inflammatory eye diseases; gout; severe renal failure; situations when it is impossible to check the state of vision (serious condition, mental disorders).

Compound

One tablet contains: active ingredient – ​​ethambutol hydrochloride – 400 mg; excipients: calcium hydrogen phosphate dihydrate, lactose monohydrate, povidone, croscarmellose sodium, magnesium stearate, Opadry II (including polyvinyl alcohol, partially hydrolyzed; talc; macrogol 3350; titanium dioxide E 171).

Overdose

Symptoms: dizziness, headache, polyneuritis, optic neuritis (blindness may occur), deterioration of visual acuity, development of neurological disorders, confusion, hallucinations, lack of appetite, nausea, vomiting, diarrhea, fever, respiratory depression, asystole, fever. Treatment: there is no specific antidote; the drug should be discontinued, induce vomiting or gastric lavage, and prescribe enterosorbents. Intravenously administer Ringer's solution, sorbilact, rheosorbilact, and carry out forced diuresis. Prescribe B vitamins. Monitor and take measures to support the vital functions of the body, and, if necessary, carry out resuscitation measures. Forced diuresis, peritoneal dialysis or hemodialysis are indicated. In threatening conditions, exchange blood transfusion is indicated, since this also removes red blood cells in which ethambutol accumulates in significant quantities.

Side effect

From the cardiovascular system: pericarditis, myocarditis, arterial hypotension, tachycardia. From the blood and lymphatic system: leukopenia, neutropenia, thrombocytopenia, eosinophilia, lymphadenopathy, increased activity of serum transaminases. From the central and peripheral nervous system: headache, dizziness, confusion, disorientation, hallucinations, convulsions, disorientation, depression, peripheral neuritis - paresthesia in the extremities, numbness, paresis. From the organ of vision: retrobulbar inflammation of the optic nerve, optic neuropathy, unilateral or bilateral decrease in visual acuity, including irreversible blindness; impaired color vision (mainly green and red), development of central or peripheral scotoma, limitations of visual fields, retinal hemorrhage. The occurrence of visual disturbances depends on the duration of treatment and previous or existing diseases of the visual organs. From the respiratory system: infiltrates in the lungs with/or without eosinophilia, pneumonitis. From the digestive tract: lack of appetite, metallic taste in the mouth, nausea, vomiting, dyspepsia, heartburn, abdominal pain, diarrhea, anorexia. From the urinary system: increased creatinine levels, interstitial nephritis. From the skin and subcutaneous tissue: rash, itching, hyperemia, dermatitis, tingling sensation. From the musculoskeletal system: arthralgia, joint pain. From the side of metabolism, metabolism: decreased clearance of uric acid in the blood serum, the phenomenon of uric acid diathesis, exacerbation of gout, hyperuricemia. From the immune system: anaphylactic and anaphylactoid reactions, including anaphylactic shock, Stevens-Johnson syndrome, Lyell's syndrome (toxic epidermal necrolysis), bronchospasm, vasculitis. From the digestive system: increased activity of liver transaminases, hepatitis, jaundice, pseudomembranous colitis (when used together with rifampicin and isoniazid). General disorders: increased body temperature, chills, general weakness, swelling, tingling sensation.

Storage conditions

In a place protected from light and moisture, at a temperature not exceeding 25 ° C. Keep out of the reach of children.

Drug interactions Ethambutol

Aluminum hydroxide and similar antacids interfere with the absorption of ethambutol in the digestive tract, so they should not be taken simultaneously with ethambutol. Ethambutol and pyrazinamide act synergistically on the excretion of uric acid. Under the influence of ethambutol, the effectiveness of digitoxin may decrease. Combined treatment with ethambutol and isoniazid with simultaneous use of cyclosporine A leads to increased degradation of cyclosporine A with a risk of transplant rejection. With simultaneous treatment with disulfiram, it is possible to increase the concentration of ethambutol in the blood serum and increase toxicity. Ethyl alcohol enhances the toxic effect of ethambutol on the organ of vision, so during treatment you should avoid drinking alcohol.