Pharmacological properties
Pharmacodynamics. Euphyllin is a bronchodilator, antispasmodic agent of the methylxanthine group (purine derivative).
The mechanism of bronchodilator action is due to the ability of theophylline to block adenosine receptors, non-selectively inhibit the PDE enzyme and thereby increase the concentration of cyclic 3 ', 5'-AMP (cAMP) in the tissues, inhibit the transport of calcium ions through slow channels of cell membranes and reduce its release from intracellular depots. Theophylline inhibits the release of inflammatory mediators from mast cells, increases mucociliary clearance, stimulates diaphragm contraction and improves the function of respiratory and intercostal muscles.
It has a pronounced bronchodilator effect, due to direct relaxation of bronchial smooth muscles. The severity of the bronchospasmolytic effect depends on the concentration of theophylline in the blood plasma.
Normalizes respiratory function, promotes oxygen saturation of the blood and a decrease in carbon dioxide concentration; stimulates the respiratory center. Enhances lung ventilation in conditions of hypokalemia.
Inhibits platelet aggregation (inhibits platelet activating factor and prostaglandin E2), increases the resistance of erythrocytes to deformation (improves the rheological properties of blood), reduces thrombus formation, and normalizes microcirculation.
It has a stimulating effect on the central nervous system and heart activity, increases the force and frequency of heart contractions, increases coronary blood flow and myocardial oxygen demand. It reduces the tone of blood vessels (mainly vessels of the brain, skin and kidneys). It reduces pulmonary vascular resistance, reduces pressure in the small circle of blood circulation. It increases renal blood flow, has a moderate diuretic effect. It dilates the extrahepatic bile ducts.
Therapeutic effects develop 5-15 minutes after intravenous injection.
Pharmacokinetics. Bioavailability - 80-100%. Binding to blood plasma proteins - 40-60%; in newborns, as well as in adults with liver diseases, protein binding is reduced.
Penetrates through the blood-brain barrier and placental barrier, into cerebrospinal fluid, saliva, sputum and other body secretions, is determined in breast milk. Metabolized in the liver (90%) with the participation of several cytochrome P450 isoenzymes (the most important is CYP 1A2). The main metabolites are 1,3-dimethyluric acid (has pharmacological activity, inferior to theophylline by 2-5 times) and 3-methylxanthine. Caffeine is an active metabolite and is formed in small quantities, with the exception of premature newborns and children under 6 months of age, in whom its significant accumulation in the body occurs (due to a long T ½). In children over 6 years of age and adults, the phenomenon of caffeine accumulation is absent.
It is excreted by the kidneys in the form of metabolites and unchanged (in adults - 7-13% of the administered dose, in children - 50%).
Due to significant individual differences in the rate of hepatic metabolism of theophylline, its clearance, plasma concentration, and T ½ are characterized by pronounced variability. The rate of theophylline metabolism in the liver depends on age, smoking habits, diet, concomitant diseases, and concomitant drug therapy.
T ½ in adult patients with bronchial asthma with practically no pathological changes in other organs and systems and non-smokers - 6-12 hours, in smokers - 4-5 hours. T ½ is prolonged in patients with alcoholism, heart failure, pulmonary heart failure, "pulmonary" heart, with impaired liver and kidney function, pulmonary edema, chronic obstructive bronchitis, in elderly patients. Total clearance is reduced in children under 1 year of age, patients with fever, severe respiratory failure, liver and heart failure, with viral infections, in patients over 55 years of age.
The optimal therapeutic concentrations of theophylline in blood plasma are: to achieve a bronchodilator effect - 10-20 μg/ml, for an exciting effect on the respiratory center - 5-10 μg/ml. At lower concentrations, the therapeutic effect is weakly expressed, at high concentrations - there is no significant increase in the therapeutic effect, while the risk of side effects increases significantly.
Indication
Bronchoobstructive syndrome in BA, bronchitis, pulmonary emphysema, disorders of the respiratory center (paroxysmal nocturnal apnea), "pulmonary heart".
Application
The dose of the drug is selected individually, taking into account the possibility of different rates of administration. If the patient is taking theophylline preparations orally, the dose of theophylline for parenteral administration is reduced.
When administering the drug, the patient is in a supine position; the doctor monitors blood pressure, heart rate, respiratory rate, and the patient's general condition.
The solution is prepared immediately before use - for intravenous jet administration, a single dose of the drug is pre-diluted in 10-20 ml of 0.9% sodium chloride solution; for intravenous drip administration, a single dose of the drug is pre-diluted in 100-150 ml of 0.9% sodium chloride solution.
Intravenous injection is administered slowly (for at least 5 minutes), intravenous drip - at a rate of 30-50 drops / min.
Adults are injected intravenously in a daily dose of 10 mg/kg of body weight (on average - 600-800 mg), divided into three injections. In case of cachexia and in people with an initial low body weight, the daily dose is reduced to 400-500 mg, while during the first injection no more than 200-250 mg is administered. If palpitations, dizziness or nausea occur, the injection rate is reduced or the injection is switched to intravenous drip.
Children over 14 years of age: intravenously drip at a dose of 2-3 mg/kg of body weight. The maximum daily dose for children over 14 years of age is 3 mg/kg.
Maximum daily doses that can be used without monitoring theophylline plasma concentrations: children aged 3-9 years - 24 mg/kg, 9-12 years - 20 mg/kg, 12-16 years - 18 mg/kg, patients over 16 years - 13 mg/kg (or 900 mg).
Higher doses for adults. Intravenous: single dose - 250 mg, daily dose - 500 mg.
Higher doses for children. IV: single dose - 3 mg/kg.
The duration of treatment depends on the severity and course of the disease, sensitivity to the drug and ranges from several days to 2 weeks (but not more than 14 days).
Contraindication
Increased individual sensitivity to the components of the drug, including other xanthine derivatives (caffeine, pentoxifylline, theobromine), pulmonary edema, severe arterial hyper- and hypotension, widespread atherosclerosis of vessels, acute heart failure, myocardial infarction, decompensated chronic heart failure, angina pectoris, tachyarrhythmia, epilepsy, increased convulsive readiness, severe hepatic and/or renal failure, uncontrolled hypothyroidism, hyperthyroidism, thyrotoxicosis, sepsis, history of bleeding, hemorrhagic stroke, retinal hemorrhage, pregnancy and breastfeeding.
Side effects
From the side of the central nervous system and peripheral nervous system: agitation, anxiety, sleep disturbances, headache, dizziness, tremor, irritability, convulsions, hallucinations, epileptiform seizures.
From the cardiovascular system: palpitations, tachyarrhythmia, tachycardia, extrasystole, decreased blood pressure, acute left ventricular heart failure, increased frequency of angina attacks, collapse (with rapid i.v. administration).
On the part of the urinary system: increased diuresis (due to increased glomerular filtration); in elderly patients - difficulty urinating (as a result of detrusor relaxation).
Allergic reactions: skin rash, itching; in rare cases, Quincke's edema is possible.
On the part of the digestive system: diarrhea, intestinal atony.
Local reactions: reactions at the injection site (induration, hyperemia, soreness).
Other: subfebrile temperature, skin hyperemia.
Special instructions
The drug should be used with caution in patients with prolonged hyperthermia, prostatic hypertrophy, and in elderly patients.
The drug should be used with caution in patients over 60 years of age with gastroesophageal reflux, gastric and duodenal ulcers (history), prostate adenoma, severe hypoxia, hypertension, severe liver and/or kidney dysfunction, diabetes mellitus, glaucoma.
Theophylline concentrations in the blood increase in patients with chronic hepatitis and cirrhosis of the liver, hypothyroidism, and viral infections. The increase in theophylline concentration is due to a decrease in the activity of the hepatic enzyme P450. In such situations, it is recommended to cancel (replace) these drugs or prescribe theophylline in a lower daily dose.
For better patients, it is recommended to increase the dose due to the accelerated elimination of the drug from the body.
Fever, regardless of its cause, can reduce the rate of excretion of Euphyllin-N 200. The course of treatment with the drug should not exceed 14 days; with a longer course of treatment, the risk and benefit for the patient must be compared.
Before parenteral administration, the solution must be warmed to body temperature.
The effects of the drug can be significantly enhanced when used simultaneously with products high in caffeine or theobromine (coffee, tea, chocolate, etc.).
The ability to influence the reaction rate when driving vehicles or working with other mechanisms. During the period of treatment, it is necessary to refrain from engaging in potentially dangerous activities that require increased attention and quick reactions.
Use during pregnancy or breastfeeding. The drug is contraindicated during pregnancy. If it is necessary to use the drug during lactation, breastfeeding should be discontinued.
Children. The drug is not used for intravenous administration to children under 3 years of age.
For children over 3 years of age, the drug can be used for vital indications, but not more than 14 days.
Interactions
Ephedrine, β-adrenostimulants, caffeine and furosemide enhance the effect of Euphyllin-N 200.
The drug increases the likelihood of developing side effects of glucocorticoids, mineralocorticoids (hypernatremia), and drugs for general anesthesia (the risk of ventricular arrhythmias and seizures increases).
In combination with phenobarbital, phenytoin, rifampicin, isoniazid, carbamazepine or sulfinpyrazone, there is a decrease in the effectiveness of euphyllin, which may require an increase in the dose of the drug.
The clearance of the drug is reduced when used in combination with macrolide antibiotics, lincomycin, allopurinol, cimetidine, isoprenaline, and β-adrenergic blockers, which may require a dose reduction.
Antidiarrheal drugs, intestinal sorbents weaken, and oral estrogen-containing contraceptives, H 2 histamine blockers, slow calcium channel blockers, mexiletine enhance the effect (bind with the cytochrome P450 enzyme system and change the metabolism of euphylline).
When used in combination with enoxacin and other fluoroquinolones, ethanol in low doses, disulfiram, recombinant alpha-interferon, methotrexate, propafenone, thiabendazole, ticlopidine, verapamil, and during influenza vaccination, the intensity of the action of Euphyllin may increase, which may require a reduction in its dose.
When levofloxacin and theophylline are used simultaneously, theophylline levels in the blood should be monitored and the dose adjusted accordingly.
The drug inhibits the therapeutic effects of lithium carbonate and β-adrenergic blockers. The use of β-adrenergic blockers prevents the bronchodilating effect of euphyllin and can cause bronchospasm.
Euphyllin potentiates the effect of diuretics by increasing glomerular filtration and reducing tubular reabsorption.
With caution, Euphyllin is prescribed simultaneously with anticoagulants, with other theophylline or purine derivatives. It is not recommended to use Euphyllin with CNS stimulants (increases neurotoxicity). When used with non-selective monoamine reuptake inhibitors, inhibition of psychomotor reactions is possible.
Incompatibility. Do not use in the same syringe with other injectable drugs, except for physiological sodium chloride solution, due to pharmaceutical incompatibility. The drug cannot be used with glucose solutions, glucose, fructose and levulose solutions.
The pH of solutions used together with euphylline should be taken into account: the pharmaceutical preparation is incompatible with acid solutions.
Overdose
In case of overdose, which occurs when the concentration of theophylline in the blood plasma exceeds 20 mg/kg, facial flushing, insomnia, motor agitation, anxiety, photophobia, anorexia, diarrhea, nausea, vomiting, epigastric pain, gastrointestinal bleeding, tachycardia, ventricular arrhythmias, tremor, generalized convulsions, hyperventilation, a sharp decrease in blood pressure are noted. In severe poisoning, epileptoid seizures may develop (especially in children, without the occurrence of any precursors), hypoxia, metabolic acidosis, hyperglycemia, hypokalemia, skeletal muscle necrosis, confusion, renal failure with myoglobinuria. Severe complications and signs of intoxication resulting from chronic overdose are more common in elderly patients (over 60 years of age) with plasma theophylline concentrations exceeding 30 mg/kg. Coma may develop at plasma concentrations above 40 mg/kg.
Treatment: depends on the severity of symptoms and includes discontinuation of the drug, correction of hemodynamics, stimulation of theophylline excretion from the body (forced diuresis, hemosorption, plasmasorption, hemodialysis, peritoneal dialysis), use of symptomatic agents, oxygen therapy, mechanical ventilation. Diazepam is used intravenously to stop seizures. The use of barbiturates is inappropriate.
For effectiveness and safety, the concentration of the drug in the blood serum should be maintained within 10-15 mg/kg; due to the inability to determine the concentration of theophylline in the blood, its daily dose should not exceed 10 mg/kg.
Storage conditions
In a place protected from light at a temperature of 15-25 °C.
