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Mechanism of action

Phosphodiesterase inhibitor, a purine derivative. Increases cAMP accumulation in tissues, blocks adenosine (purine) receptors; reduces the entry of Calcium ions through the channels of cell membranes, reduces the contractile activity of smooth muscles. It relaxes the muscles of the bronchi, blood vessels (mainly the vessels of the brain, skin and kidneys); has a peripheral vasodilating effect, increases renal blood flow, has a moderate diuretic effect. Stabilizes the mast cell membrane, inhibits the release of mediators of allergic reactions. Increases mucociliary clearance, stimulates contraction of the diaphragm, improves the function of the respiratory and intercostal muscles, stimulates the respiratory center. Normalizing the respiratory function, helps to saturate the blood with oxygen and reduce the concentration of carbon dioxide; stimulates the respiratory centers. Strengthens ventilation of the lungs in the conditions of a hypokalemia.

It has a stimulating effect on the activity of the heart, increases the strength of heart contractions and heart rate, increases coronary blood flow and the need of myocardium for oxygen. Reduces the tone of blood vessels (mainly vessels of the brain, skin and kidneys). Reduces pulmonary vascular resistance, lowers blood pressure in the pulmonary circulation.

Increases renal blood flow, has a moderate diuretic effect. Expands extrahepatic biliary tract. It inhibits platelet aggregation (inhibits platelet activating factor and PgE2α), increases erythrocyte resistance to deformation (improves the rheological properties of blood), reduces thrombosis and normalizes microcirculation.

Pharmacokinetics

When ingested, theophylline is rapidly and completely absorbed from the gastrointestinal tract. The presence of food in the stomach can affect the rate (but not the degree) of theophylline absorption, as well as its clearance. When using the dosage form of the usual duration of action of Cmax in plasma is achieved in 1-2 hours

After i / m injection, absorption is slow and incomplete.

Plasma protein binding is approximately 40%; in newborns, as well as in adults with diseases, the binding is reduced.

Theophylline is metabolized in the liver with the participation of several cytochrome P450 isoenzymes, the most important of which is CYP1A2. In the process of metabolism 1,3-dimethyl uric acid, 1-methyl uric acid and 3 methylxanthine are formed. These metabolites are excreted in the urine. Unchanged in adults is 10%. In newborns, a significant part is excreted in the form of caffeine (due to the immaturity of the pathways of its further metabolism), unchanged - 50%.

Significant individual differences in the rate of hepatic metabolism of theophylline are the reason for the pronounced variability of clearance values, plasma concentrations, and half-life.The hepatic metabolism is influenced by such factors as age, addiction to tobacco smoking, diet, diseases, simultaneously conducted drug therapy.

T1 / 2 of theophylline in non-smoking patients with bronchial asthma with practically no pathological changes from other organs and systems is 6-12 hours, in children - 1-5 hours, in smokers - 4-5 hours, in newborns and premature babies - 10- 45 h.

Theophylline T1 / 2 is increased in the elderly and in patients with heart failure or liver disease.

Clearance decreases with heart failure, abnormal liver function, chronic alcoholism, pulmonary edema, and COPD.

Indications and usage

Broncho-obstructive syndrome of various genesis: bronchial asthma (a drug of choice for physical stress asthma and as an additional agent for other forms of bronchial asthma), COPD (chronic obstructive bronchitis, pulmonary emphysema). Pulmonary hypertension, pulmonary heart, edematous syndrome of renal genesis (as part of combination therapy), sleep apnea.

Install individually. The initial dose is an average of 400 mg / day. With good tolerance, the dose can be increased by approximately 25% from the initial every 2-3 days until the optimum therapeutic effect is achieved.

The maximum dose that can be used without controlling the concentration of theophylline in the blood plasma: children aged 3-9 years - 24 mg / kg / day., 9-12 years old - 20 mg / kg / day., 12-16 years old - 18 mg / kg / day.; patients aged 16 years and older - 13 mg / kg / day. or 900 mg / day.

If, when used in the indicated doses, symptoms of toxic action appear or the need arises to further increase the dose (due to insufficient therapeutic effect), it is recommended to control the concentration of theophylline in the blood plasma. The optimal therapeutic concentration of theophylline - 10-20 mg / ml. At lower concentrations, the therapeutic effect is mild, at large concentrations, there is no significant increase in the therapeutic effect, while the risk of side effects increases significantly. The frequency of administration depends on the dosage form.

Adverse reactions

From the side of the central nervous system: dizziness, headache, insomnia, agitation, anxiety, irritability, tremor.

Cardiovascular: heartbeat, tachycardia (including the fetus when taken in the third trimester), arrhythmias, decreased blood pressure, cardialgia, increased frequency of strokes.

On the part of the digestive system: gastralgia, nausea, vomiting, gastroesophageal reflux, heartburn, exacerbation of peptic ulcer, diarrhea, with prolonged use - loss of appetite.

Allergic reactions: skin rash, itching, fever.

Other: pain in the chest, tachypnea, sensation of hot flashes to the face, albuminuria, hematuria, hypoglycemia, increased diuresis, increased sweating. Side effects decrease with decreasing dose.

Contraindications

Epilepsy, peptic ulcer of the stomach and duodenum in the acute phase, gastritis with increased acidity, recent hemorrhage from the gastrointestinal tract, severe arterial hyper- or hypotension, severe tachyarrhythmias, hemorrhagic stroke, hemorrhage into the retina of the eye, children (up to 3 years old, for prolonged periosis forms - up to 12 years), hypersensitivity to theophylline and to other xanthine derivatives (caffeine, Pentoxifylline, theobromine).

Pregnancy and breastfeeding

Theophylline penetrates the placental barrier, is excreted in breast milk.

In pregnancy, theophylline is used only if the intended benefit to the mother exceeds the possible risk to the fetus.

If necessary, use during lactation should take into account that theophylline is excreted in breast milk.

Special notes

Use with caution in severe coronary insufficiency (acute phase of myocardial infarction, angina), widespread vascular atherosclerosis, hypertrophic obstructive cardiomyopathy, ventricular extrasystole, chronic heart failure, increased seizure readiness, in case of heart failure, and had to have heart disease and had to have a simple case, in case of heart disease, and had to have a simple case, it is unacceptable, in case of heart disease, and had to have heart disease and had to have heart disease and had to have a heart disease, he had heart disease, he had heart disease, and he had heart disease, he had heart disease, and he had heart disease, he had heart disease, and he had heart disease, he had heart disease, and he had heart disease, he had heart disease, and he had heart disease, he had heart disease, he had heart disease, he had heart disease, he was ill, he had heart disease, he had a heart failure, he had heart disease, he had a heart failure, he had a heart disease in history), with uncontrolled hypothyroidism (the possibility of cumulation) or thyrotoxicosis, prolonged hyperthermia, gastroesophageal Mr. reflux, prostatic hypertrophy, during pregnancy, during lactation, in elderly patients, in children (especially for oral forms).

Use with caution rectal with diarrhea and diseases of the rectum.

The intensity of theophylline may decrease in smokers.

Theophylline is not used simultaneously with other xanthine derivatives.

In severe diseases of the cardiovascular system, liver, viral infections, as well as in elderly patients, the dose of theophylline should be reduced.

With simultaneous use with macrolide antibiotics, Allopurinol, cimetidine, oral contraceptives, isoprenaline, Lincomycin, theophylline clearance decreases.

With simultaneous use of beta-blockers, especially non-selective, can cause a narrowing of the bronchi, which reduces the bronchodilatory effect of theophylline. Perhaps a decrease in the effectiveness of beta-blockers.

With the simultaneous use of stimulants β2-adrenergic receptors, caffeine, Furosemide, theophylline effect increases.

With simultaneous use with aminoglutetimid may reduce the effectiveness of theophylline due to the increase in its elimination from the body.

With simultaneous use with Acyclovir, it is possible to increase the concentration of theophylline in the blood plasma and increase adverse reactions.

With simultaneous use with Verapamil, diltiazem, Nifedipine, felodipine, the concentration of theophylline in the blood plasma usually slightly or moderately changes in the absence of changes in the bronchodilator action.Cases of increasing theophylline concentration in plasma and enhancing its side effects in patients simultaneously receiving verapamil or nifedipine are described.

With the simultaneous use of disulfiram, theophylline concentration in the blood plasma increases and toxic reactions develop.

With the simultaneous use of lithium salts may reduce their effectiveness.

With simultaneous use with propranolol, theophylline clearance decreases.

With simultaneous use with phenytoin, plasma concentrations of theophylline and phenytoin decrease and their therapeutic efficacy decreases.

With simultaneous use with phenobarbital, rifampicin, isoniazid, Carbamazepine, sulfinpyrazone, the intensity of theophylline may decrease due to an increase in its clearance.

With simultaneous use with enoxacin or other fluoroquinolones, a significant increase in plasma theophylline concentration is possible.

B. List: In a dry, dark place at room temperature.