Theophylline

Pharmacological properties

theophylline is a bronchodilator, antispasmodic. the mechanism of bronchodilator action is due to theophyllines ability to block adenosine receptors, non-selectively inhibit the PDE enzyme and thereby increase the concentration of cyclic 3 ′, 5′-amph (cAMP) in tissues, inhibit the transport of calcium ions through “slow” channels of cell membranes and reduce its exit from intracellular depot. theophylline inhibits the release of inflammatory mediators from mast cells, increases mucociliary clearance, stimulates diaphragm contraction and improves respiratory and intercostal muscle function.

It exhibits a pronounced bronchodilator effect due to direct relaxation of the smooth muscles of the bronchi. The severity of the bronchospasmolytic effect depends on the concentration of theophylline in blood plasma.

It normalizes respiratory function, helps to saturate the blood with oxygen and reduce the concentration of carbon dioxide; stimulates the respiratory center. Enhances ventilation in hypokalemia.

Inhibits platelet aggregation (inhibits platelet and prostaglandin E activation factor₂), increases the resistance of erythrocytes to deformation (improves the rheological properties of blood), reduces thrombosis and normalizes microcirculation.

It has a stimulating effect on the central nervous system and heart activity, increases the strength and heart rate, increases coronary blood flow and myocardial oxygen demand. Reduces the tone of blood vessels (mainly the vessels of the brain, skin and kidneys). Reduces pulmonary vascular resistance, lowers pressure in the pulmonary circulation. Increases renal blood flow, has a moderate diuretic effect. Extends extrahepatic biliary tract.

Therapeutic effects develop 5-15 minutes after injection.

Pharmacokinetics The bioavailability of the drug is 80-100%. Communication with blood plasma proteins is about 60%. Penetrates through the placental barrier and into breast milk. It is metabolized in the liver (90%) with the participation of several cytochrome P450 enzymes (the most important CYP 1A2). The main metabolites of the drug are 1,3-dimethyl uric acid and 3-methylxanthine. Metabolites are excreted by the kidneys. About 7–13% of the administered dose is excreted unchanged (in children - 50%). In newborns, a significant part is excreted in the form of caffeine (due to the immaturity of the pathways of its further metabolism). T_½ in non-smoking patients - 6-12 hours; in smokers - significantly shorter - 4–5 hours, in children - 1–5 hours, in newborns and premature babies - 10–45 hours. In patients with cirrhosis, patients with renal failure and patients with alcoholism T_½ lengthens. The total clearance is reduced in patients with fever, patients with severe respiratory, liver and heart failure, with viral infections in patients over the age of 55 years.

Indications

Bronchial obstructive syndrome in BA, bronchitis, pulmonary emphysema, disorders of the respiratory center (nocturnal paroxysmal apnea), "pulmonary heart".

Application

The drug is administered iv. select a dose individually, given the possibility of different rates of excretion.

If the patient takes theophylline preparations by mouth, the dose of theophylline for parenteral administration should be reduced.

With the introduction of the drug, the patient is in a supine position; the doctor controls blood pressure, heart rate, respiratory rate and the general condition of the patient.

Solution to be prepared immediately before use: for iv injection, a single dose of the drug should be diluted in 10–20 ml of 0.9% sodium chloride solution; for iv drip, a single dose of the drug must first be diluted in 100-150 ml of 0.9% sodium chloride solution.

Intravenously injected slowly (for at least 5 minutes), iv drip at a rate of 30-50 drops per minute.

With the introduction of the drug, the dose is calculated in milligrams of theophylline, given that 1 ml of the drug contains 20 mg of theophylline.

For adults, iv daily in a daily dose of 10 mg / kg body weight (on average 600-800 mg of theophylline), distributed over 3 injections. With cachexia and in individuals with initial underweight, the daily dose should be reduced to 400–500 mg, while during the first administration, not more than 200–250 mg should be administered.

When there is an acceleration of the heartbeat, dizziness, nausea, the rate of administration is reduced or switched to a drip of the drug.

Children over the age of 14 iv / drip at a dose of 2-3 mg / kg body weight. The maximum daily dose for children over the age of 14 is 3 mg / kg body weight.

The maximum daily doses that can be used without monitoring theophylline concentration in blood plasma: children 3–9 years old - 24 mg / kg body weight, 9-12 years old - 20 mg / kg body weight, 12-16 years old - 18 mg / kg body weight body, patients over 16 years old - 13 mg / kg body weight (or 900 mg).

Higher doses for adults. In / in: single - 250 mg, daily - 500 mg.

Higher doses for children. In / in: single - 3 mg / kg body weight.

The duration of treatment depends on the severity of the course of the disease, sensitivity to the drug and ranges from several days to 2 weeks (but no more than 14 days).

Do not use in patients with severe renal and / or liver failure (see CONTRAINDICATIONS).

Contraindications

Hypersensitivity to the components of the drug, as well as other xanthine derivatives (caffeine, pentoxifylline, theobromine), acute heart failure, angina pectoris, acute myocardial infarction, decompensated chronic heart failure, paroxysmal tachycardia, extrasystole, severe arterial hypertension and hypotension, vascular disease, pulmonary edema, hemorrhagic stroke, retinal hemorrhage, a history of bleeding, a history of gastric and duodenal ulcer (stage o ostreniya), gastroesophageal reflux disease, epilepsy, convulsive increased readiness, uncontrolled hypothyroidism, hyperthyroidism, hyperthyroidism, severe liver and / or kidney failure, porphyria, sepsis, applying in children simultaneously with ephedrine.

Side effects

From the central and peripheral nervous system: excitement, anxiety, anxiety, sleep disturbances, insomnia (especially in children), headache, dizziness, tremors, irritability, convulsions, hallucinations, delusions, epileptiform seizures, confusion / loss of consciousness, presyncopal state.

From the cardiovascular system: palpitations, cardialgia, arrhythmias, tachycardia, extrasystole, decreased blood pressure, heart failure, increased frequency of angina attacks, collapse (with rapid administration), shock.

From the urinary system: increased urine output (due to increased glomerular filtration), in elderly patients - difficulty urinating (due to relaxation of the detrusor).

On the part of the immune system: allergic reactions, including rash, urticaria, pruritus, angioedema, exfoliative dermatitis, anaphylactic shock, bronchospasm.

From the gastrointestinal tract: stimulation of secretion of gastric juice, pain in the stomach, decreased appetite, diarrhea, intestinal atony, gastroesophageal reflux, heartburn, exacerbation of peptic ulcer, nausea, vomiting.

Metabolic disorders: metabolic acidosis, hypokalemia, hypercalcemia, hyperuricemia, hyperglycemia, impaired acid-base balance in the blood, rhabdomyolysis.

Local reactions: at the injection site (induration, hyperemia, soreness).

Others: fever, chills, facial flushing, sensation of heat, increased sweating, weakness, shortness of breath.

special instructions

Before administration, the solution must be heated to body temperature.

Use with caution in diseases of the cardiovascular system, liver, viral infection, prolonged hyperthermia, prostatic hypertrophy, severe hypoxia, diabetes mellitus, glaucoma, elderly people (over 60 years old).

Use with caution only in case of emergency in case of impaired renal function, in patients with a history of stomach ulcer and duodenal ulcer. Patients with a history of convulsive conditions should avoid using theophylline and resort to alternative treatment. Increased attention requires the use of the drug in patients with insomnia.

Smoking and drinking alcohol can lead to increased clearance of theophylline and, consequently, to a decrease in its therapeutic effect and the need for higher doses.

Fever, regardless of the cause, can reduce the rate of theophylline excretion.

Theophylline can change some laboratory parameters: increase the amount of fatty acids and the level of catecholamines in the urine.

Use during pregnancy and lactation. The drug is contraindicated during pregnancy. If necessary, the use of the drug should stop breast-feeding.

Children. The drug should not be used for administration in children under 3 years of age.

For children over the age of 3 years, the use of the drug is possible for health reasons, but not longer than 14 days.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Given that in sensitive patients, when using the drug, adverse reactions (dizziness, etc.) may occur, during the period of use of the drug should refrain from driving vehicles and performing other work requiring attention.

Interactions

During treatment, you should not drink alcoholic beverages, a large amount of food and drinks containing methylxanthine (coffee, tea, cocoa, chocolate, Coca-Cola), theophylline-related drugs (caffeine, theobromine, pentoxifylline), because these substances can enhance stimulant theophylline effect on central nervous system.

Theophylline effect can be enhanced with the simultaneous use of allopurinol, acyclovir, carbimazole, zafirlukast, cimetidine, nizatidine, disulfiram, phenylbutazone, fluvoxamine, fluconazole, fluoroquinolones, furosemide, imipenem, isoprenaline, islamonazone azonazone azonazone azonazone azonazone azonazone azonazone macrolides, amiodarone, mexiletine, methotrexate, paracetamol, pentoxifylline, oral contraceptives, probenecid, propafenone, propranolol, ranitidine, tacrine, thiabendazole, ticlopidine, vi oxazine or flu vaccine. In patients taking one or more of the above drugs in parallel with theophylline, the plasma concentration of theophylline should be monitored and the dose reduced if necessary.

A combination of theophylline and fluvoxamine should be avoided. If it is impossible to avoid this combination, patients should take half the dose of theophylline and carefully monitor the plasma concentration of the latter.

With the simultaneous administration of ciprofloxacin, the dose of theophylline must be reduced by at least 60%, and with the simultaneous administration of enoxacin, by 30%.

Theophylline effect may decrease while taking antiepileptic drugs (e.g. phenytoin, carbamazepine, primidone), barbiturates (especially phenobarbital and pentobarbital), aminoglutethimide, magnesium hydroxide, morazizin, rifampicin, ritonavir or sulfinpyrazone. Theophylline effect may also be lower in smokers. In patients who take one or more of the above drugs at the same time as theophylline, the concentration of theophylline in the blood serum should be monitored and the dose adjusted.

The simultaneous use of theophylline with herbal preparations containing St. Johns wort (Hypericum perforatum) should be avoided.

Ephedrine enhances theophylline action.

Theophylline may enhance the effect of β-receptor agonists, diuretics, and reserpine. Theophylline may decrease the effectiveness of adenosine, lithium carbonate, and β-receptor antagonists.

The parallel use of theophylline and β-receptor antagonists should be avoided, since theophylline may lose its effectiveness.

With extreme caution, combinations of theophylline and benzodiazepine, halotane and lomustine should be used. Halothane anesthesia can cause serious heart rhythm disturbances in patients taking theophylline.

The simultaneous use of theophylline with ketamine can reduce the seizure threshold, with doxapram - cause stimulation of the central nervous system.

During treatment with theophylline, hypokalemia can occur, especially with combined treatment with β-receptor agonists, thiazide diuretics, furosemide, corticoids, as well as with hypoxemia; therefore, it is recommended to periodically check the level of potassium in the blood plasma.

Incompatibility. Do not use in the same syringe with other injectable drugs, with the exception of 0.9% sodium chloride solution, due to pharmaceutical incompatibility. The drug can not be used with solutions of glucose, fructose and levulose.

It is necessary to take into account the pH of the solutions used simultaneously with aminophylline - pharmaceutical preparations are incompatible with the solutions of acids.

Overdose

With rapid administration, convulsions, arrhythmias, severe hypotension, angina pectoris are possible.

At a concentration of theophylline in blood plasma of 20 mg / ml (110 μmol / L), nausea, vomiting (repeated vomiting, sometimes with blood, can lead to dehydration), diarrhea, agitation, tremor, hypertension, hyperventilation, supraventricular and ventricular arrhythmias, arterial hypotension, convulsions, metabolic disorders (hypokalemia, hypercalcemia, hypophosphatemia, hyperuricemia, hyperglycemia, metabolic acidosis, respiratory alkalosis). Other toxic manifestations include dementia, toxic psychosis, symptoms of acute pancreatitis, rhabdomyolysis with renal failure.

Treatment depends on the severity of symptoms and includes drug withdrawal, hemodynamic correction, stimulation of theophylline elimination from the body (forced diuresis, hemosorption, plasmosorption, hemodialysis, peritoneal dialysis), the appointment of symptomatic agents, oxygen therapy, mechanical ventilation. Diazepam should be used to relieve seizures. The use of barbiturates is impractical. With ventricular arrhythmias, the use of antiarrhythmic drugs with anticonvulsant effects such as lidocaine should be avoided because of the risk of exacerbation of seizures.

For efficiency and safety, the plasma concentration of the drug should be maintained within 10-15 mg / kg, in the absence of the ability to determine the concentration of theophylline in the blood, its daily dose should not exceed 10 mg / kg.

Storage conditions

In the original packaging at a temperature not exceeding 25 ° C. do not freeze.