Euphyllin [Aminophylline]

Euphyllin - a bronchodilator, PDE inhibitor. It is theophylline ethylene diamine salt (which facilitates solubility and increases absorption). It has a bronchodilator effect, apparently due to a direct relaxing effect on the smooth muscles of the respiratory tract and blood vessels of the lungs. It is believed that this action is caused by the selective inhibition of the activity of specific PDEs, which leads to an increase in the intracellular concentration of cAMP. The results of experimental studies in vitro show that the main role seems to be played by isoenzymes of types III and IV. Suppression of the activity of these isoenzymes may also cause some side effects of aminophylline (theophylline), including vomiting, hypotension and tachycardia. Blocks adenosine (purine) receptors, which may be one of the factors of action on the bronchi.

Reduces airway hyperreactivity associated with the late phase of the reaction caused by inhalation of allergens through an unknown mechanism that does not relate to the inhibition of PDE or to the blockade of adenosine action. There are reports that aminophylline increases the number and activity of T-suppressors in peripheral blood.
It increases mucociliary clearance, stimulates contraction of the diaphragm, improves the function of the respiratory and intercostal muscles, stimulates the respiratory center, increases its sensitivity to carbon dioxide and improves alveolar ventilation, which ultimately leads to a decrease in the severity and frequency of episodes of apnea. Normalizing the respiratory function, helps to saturate the blood with oxygen and reduce the concentration of carbon dioxide. Strengthens ventilation of the lungs in the conditions of a hypokalemia.

It has a stimulating effect on heart activity, increases strength and heart rate, increases coronary blood flow and increases myocardial oxygen demand. Reduces the tone of blood vessels (mainly vessels of the brain, skin and kidneys). It has a peripheral venodilating effect, reduces pulmonary vascular resistance, lowers the pressure in the pulmonary circulation. Increases renal blood flow, has a moderate diuretic effect. Expands extrahepatic biliary tract. Stabilizes the membranes of mast cells, inhibits the release of mediators of allergic reactions. It inhibits platelet aggregation (inhibits platelet activating factor and PgE2α), increases erythrocyte resistance to deformation (improves blood rheology), reduces blood clot formation and normalizes microcirculation. It has a tocolytic effect, increases the acidity of gastric juice. In high doses, it has an epileptogenic effect.

Pharmacokinetics
In the body, aminophylline is metabolized at physiological pH values ​​with the release of free theophylline. Bronchodilating properties appear at plasma concentrations of theophylline 10–20 mcg / ml. Concentration over 20 mg / ml is toxic. The stimulating effect on the respiratory center is realized at a lower concentration - 5-10 μg / ml.
Binding of theophylline to plasma proteins is approximately 40%; in newborns, as well as in adults with diseases, the binding is reduced. Plasma protein binding is about 60% in adults, 36% in newborns, and 36% in patients with liver cirrhosis. Gets through a placental barrier (concentration in blood serum of a fruit is slightly higher, than in serum of mother). It is excreted in breast milk.

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 asthma with virtually no pathological changes from other organs and systems is 6-12 hours, in smokers - 4-5 hours, in children - 1-5 hours, in newborns and premature babies - 10- 45 hours
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, chronic obstructive pulmonary disease.
Ethylenediamine does not affect theophylline pharmacokinetics.