pharmachologic effect
Bronchodilator, methylxanthine derivative; inhibits phosphodiesterase, increases the accumulation of cyclic adenosine monophosphate (cAMP) in tissues, blocks adenosine (purine) receptors; reduces the flow of calcium ions through the channels of cell membranes, reduces the contractile activity of smooth muscles.
Relaxes the bronchial muscles, stimulates the respiratory center and improves alveolar ventilation, which ultimately leads to a reduction in the severity and frequency of apnea episodes.
It has a stimulating effect on the activity of the heart, increases the strength and frequency of heart contractions, increases coronary blood flow and myocardial oxygen demand. Reduces the tone of blood vessels (mainly those of the brain, skin and kidneys). It has a peripheral venodilating effect, reduces pulmonary vascular resistance, and lowers pressure in the pulmonary circulation. Increases renal blood flow and has a moderate diuretic effect. Expands extrahepatic bile ducts.
Stabilizes mast cell membranes, inhibits the release of mediators of allergic reactions.
Inhibits platelet aggregation (suppresses platelet activating factor and prostaglandin E2 alpha), increases the resistance of red blood cells to deformation (improves the rheological properties of blood), reduces thrombus formation and normalizes microcirculation.
It has a tocolytic effect, increases the acidity of gastric juice. When used in large doses, it has an epileptogenic effect.
Pharmacokinetics
Bioavailability and absorption kinetics depend on the dosage form of the drug. Bioavailability for liquid dosage forms is 90-100%. The time to reach the maximum concentration of the drug in plasma with intravenous administration of 0.3 g is 15 minutes, the maximum concentration of the drug in the blood is 7 mcg/ml. The volume of distribution is in the range of 0.3-0.7 l/kg (30-70% of “ideal” body weight), with an average of 0.45 l/kg. Communication with plasma proteins in adults - 60%, in newborns - 36%, in patients with liver cirrhosis - 36%. Penetrates into breast milk (10% of the dose taken), through the placental barrier (the concentration in the fetal blood serum is slightly higher than in the maternal serum).
Aminophylline exhibits bronchodilating properties in concentrations of 10-20 mcg/ml. Concentrations above 20 mg/ml are toxic. The stimulating effect on the respiratory center is realized at a lower content of the drug in the blood - 5-10 mcg/ml.
Metabolized at physiological pH values with the release of free theophylline, which is further metabolized in the liver with the participation of several cytochrome P450 isoenzymes. As a result, 1,3-dimethyluric acid (45-55%) is formed, which has pharmacological activity, but is 1-5 times inferior to theophylline. Caffeine is an active metabolite and is formed in small quantities, with the exception of premature newborns and children under 6 months, in whom, due to the extremely long half-life of caffeine, its significant accumulation in the body occurs (up to 30% of that for aminophylline).
In children over 3 years of age and in adults, the phenomenon of caffeine accumulation is absent.
The half-life in newborns and children under 6 months is more than 24 hours; in children older than 6 months. — 3.7 hours; in adults - 8.7 hours; for “smokers” (20-40 cigarettes per day) - 4-5 hours (after quitting smoking, pharmacokinetics normalize after 3-4 months); in adults with chronic obstructive pulmonary disease, pulmonary heart disease and pulmonary heart failure - over 24 hours. Excreted by the kidneys. In newborns, about 50% of theophylline is excreted unchanged in the urine versus 10% in adults, which is associated with insufficient activity of liver enzymes.
Eufillin solution for intravenous administration 24 mg/ml in ampoules 5 ml No. 10
Name
Eufillin solution din. 24 mgml per pack. 5 ml per pack No. 10
Release form
Solution
Description
clear, colorless or slightly yellowish liquid.
Compound
One ampoule (5 ml) contains - active ingredient: aminophylline for injection - 120 mg; excipient: water for injection.
INDICATIONS FOR USE
Broncho-obstructive syndrome in bronchial asthma and chronic obstructive pulmonary disease.
CONTRAINDICATIONS
- hypersensitivity to ethylenediamine or allergy to theophyllines, caffeine and theobromine,
- simultaneous use with other xanthine-containing drugs. When therapeutic doses of aminophylline and/or theophylline are administered simultaneously, by more than one route of administration, or in more than one drug product, the risk of serious toxicity increases,
- children up to 6 months old,
- acute porphyria,
- acute period of myocardial infarction,
- paroxysmal tachycardia.
METHOD OF APPLICATION AND DOSES
The drug is intended for slow intravenous administration. The solution should be administered very slowly over 4-6 minutes, 5-10 ml of the drug (0.12-0.24 g), which is pre-diluted with a small volume (5-10 ml) of 5% dextrose or 0.9% solution sodium chloride for injection. Before administration, the solution must be warmed to body temperature. Eufillin is administered parenterally up to 3 times a day, for no more than 14 days. Higher doses of aminophylline for adults when administered intravenously: single - 0.25 g, daily - 0.5 g. Maintenance therapy can be provided by administering large volumes of infusion solutions, the rate of administration is adjusted so as to provide the required amount of the drug every hour. Typically, when administered by drip, 10-20 ml of the drug (0.24-0.48 g) is diluted in 100-150 ml of 0.9% sodium chloride solution and administered at a rate of 30-50 drops per minute. Theophylline therapeutic plasma concentrations are considered to range from 5 to 20 mcg/mL, and levels above 20 mcg/mL are most likely associated with toxicity. There is also individual patient variation in the dosage required to achieve plasma theophylline concentrations within the desired therapeutic range. During therapy, patients should be closely monitored for toxicity and, where possible, theophylline levels should also be monitored; doses should be based on ideal body weight; the drug is not recommended for children under 6 months of age due to significant fluctuations in the metabolism of theophylline in young children. Patients who have not received drugs containing theophylline A. A loading dose of aminophylline 6 mg/kg body weight can be administered intravenously slowly at a rate not exceeding 25 mg/min. B. Depending on the patient's condition, the maintenance dose for the next 12 hours can be calculated as follows:
- children aged 6 months to 9 years: 1.2 mg/kg/hour (decrease to 1 mg/kg/hour after 12 hours);
- children aged 9 to 16 years and young adult smokers: 1 mg/kg/hour (decrease to 0.8 mg/kg/hour after 12 hours);
- healthy non-smoking adults: 0.7 mg/kg/hour (decrease to 0.5 mg/kg/hour after 12 hours);
- elderly patients and those with cor pulmonale: 0.6 mg/kg/hour (decrease to 0.3 mg/kg/hour after 12 hours);
- patients with congestive heart failure or liver disease: 0.5 mg/kg/hour (decrease to 0.1-0.2 mg/kg/hour after 12 hours).
Patients already receiving theophylline The loading dose can be calculated on the basis that each 0.5 mg/kg theophylline administered as a loading dose may result in a 1 mcg/mL increase in serum theophylline concentration. Ideally, administration should be delayed until serum theophylline is determined. If this is not possible and if the clinical situation requires that the drug be administered, then administer 3.1 mg/kg aminophylline (equivalent to 2.5 mg/kg theophylline anhydrous) on the basis that this may result in increased serum theophylline concentrations approximately 5 mcg/ml when administered as a loading dose. In the future, the maintenance dose is recommended to be the same as described above.
PACKAGING AND CONDITIONS OF DISCHARGE FROM PHARMACIES
5 ml in ampoules in packaging No. 10, No. 5x2. By doctor's prescription.
Contraindications
Hypersensitivity to the drug (including other xanthine derivatives: caffeine, pentoxifylline, theobromine), severe arterial hypotension or hypertension, paroxysmal tachycardia, extrasystole, myocardial infarction with cardiac arrhythmias, epilepsy, increased convulsive readiness, hypertrophic obstructive cardiomyopathy , thyrotoxicosis, pulmonary edema, severe coronary insufficiency, liver and/or renal failure, hemorrhagic stroke, retinal hemorrhage, recent history of bleeding.
Carefully
Severe coronary insufficiency (acute phase of myocardial infarction, angina pectoris), widespread vascular atherosclerosis, hypertrophic obstructive cardiomyopathy, frequent ventricular extrasystole, increased convulsive readiness, liver and/or renal failure, peptic ulcer of the stomach and duodenum (history), bleeding from gastrointestinal tract in a recent history, uncontrolled hypothyroidism (possibility of cumulation) or thyrotoxicosis, prolonged hyperthermia, gastroesophageal reflux, prostatic hypertrophy, children under 14 years of age, old age (over 55 years).
Prescribe with caution simultaneously with anticoagulants, with other theophylline and purine derivatives.
Use during pregnancy and breastfeeding
If necessary, prescribing the drug during pregnancy should be compared
expected benefit to the mother and potential risk to the fetus.
If it is necessary to use the drug during lactation, breastfeeding should be discontinued.
Newborns whose mothers received aminophylline during pregnancy (especially the third trimester) require medical supervision to monitor possible symptoms of methylxanthine intoxication.
special instructions
Use caution when consuming large amounts of caffeine-containing foods or drinks during treatment.
Elderly patients are recommended to reduce the dose of the drug due to its slow elimination from the body.
Smoking patients are advised to increase the dose due to the accelerated elimination of the drug from the body.
Before use, the drug solution must be warmed to body temperature.
Impact on the ability to drive vehicles and machinery.
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
Directions for use and doses
Adults are injected into a vein slowly (over 4-6 minutes) with 5-10 ml of a solution with a concentration of 24 mg/ml (0.12-0.24 g), which is pre-diluted in 10-20 ml of isotonic sodium chloride solution. If palpitations, dizziness, or nausea occur, the rate of administration is slowed down or switched to drip administration, for which 10-20 ml of a solution with a concentration of 24 mg/ml (0.24-0.48 g) is diluted in 100-150 ml of isotonic sodium chloride solution; administered at a rate of 30-50 drops per minute. Eufillin is administered parenterally up to 3 times a day, for no more than 14 days.
Higher doses of aminophylline for adults into a vein: single - 0.25 g, daily - 0.5 g.
Children under 14 years of age are advised to use the drug with caution due to possible side effects.
However, if necessary, children are administered aminophylline intravenously at a single dose of 2-3 mg/kg, preferably by drip.
Higher doses for children intravenously: single - 3 mg/kg, daily - up to 3 months of age. -0.03-0.06 g,
from 4 to 12 months. - 0.06-0.09 g,
from 2 to 3 years - 0.09-0.12 g,
from 4 to 7 years - 0.12-0.24 g,
from 8 to 18 years - 0.25-0.5 g.
Eufillin instructions for use
The single and daily dose of the drug is selected depending on the form of release, the disease and the age of the patient.
Adult patients are recommended to take 15 milligrams per kg of body weight 1 to 3 times a day. The pediatric dosage is 7-10 mg per kilogram of body weight 4 times a day. The course of treatment with tablets can vary from 3 days to several months.
When administered intravenously, the average daily dose ranges from 400 to 800 milligrams.
While taking the drug, it is necessary to monitor blood pressure, blood glucose and heart rate daily.
Side effect
From the nervous system:
dizziness, headache, insomnia, agitation, anxiety, irritability, tremor, convulsions.
From the cardiovascular system
: palpitations, tachycardia (including in the fetus when taken by a pregnant woman in the third trimester), arrhythmias, decreased blood pressure, cardialgia, increased frequency of angina attacks.
From the digestive system:
gastralgia, nausea, vomiting, gastroesophageal reflux, heartburn, exacerbation of peptic ulcer, diarrhea, with long-term use - loss of appetite.
Allergic reactions
: skin rash, skin itching, fever, exfoliative dermatitis.
Other:
chest pain, tachypnea, feeling of “hot flashes” in the face, albuminuria, hematuria, hypoglycemia, increased diuresis, increased sweating.
Side effects decrease with decreasing dosage of the drug.
Local reactions:
compaction, hyperemia, pain at the injection site.
Overdose (drug intoxication)
Symptoms: loss of appetite, gastralgia, diarrhea, nausea, vomiting (including blood), gastrointestinal bleeding, tachypnea, flushing of the facial skin, tachycardia, ventricular arrhythmias, insomnia, motor agitation, anxiety, photophobia, tremor, convulsions . In severe poisoning, epileptoid seizures may develop (especially in children without any warning signs), hypoxia, metabolic acidosis, hyperglycemia, hypokalemia, decreased blood pressure, skeletal muscle necrosis, confusion, renal failure with myoglobinuria.
Treatment: drug withdrawal, forced diuresis, hemosorption, plasma sorption, hemodialysis, symptomatic therapy. If convulsions occur, maintain airway patency and administer oxygen therapy. To relieve seizures - intravenous diazepam, 0.1-0.3 mg/kg (but not more than 10 mg). For severe nausea and vomiting, use metoclopramide or ondansetron (intravenously).
Instructions for use EUPHYLLINE solution
Aminophylline has a narrow therapeutic index. Theophylline toxicity is most likely to occur at serum concentrations greater than 20 mcg/mL and becomes increasingly severe at higher serum concentrations.
Doses greater than 3 g may be serious in adults (40 mg/kg in a child). The lethal dose may be as low as 4.5 g in adults (60 mg/kg in children), but is usually higher.
Death in adults may occur when aminophylline is administered IV in large doses in patients with renal, hepatic or cardiovascular impairment, or if the injection is given quickly.
Symptoms:
tachycardia, in the absence of hypoxia, fever, or during coadministration of sympathomimetic drugs, may be a sign of theophylline toxicity.
Gastrointestinal symptoms:
anorexia, nausea, vomiting, diarrhea, vomiting blood.
Neurological symptoms:
restlessness, insomnia, irritability, headache, agitation, hallucinations, extreme thirst, slight fever, dilated pupils and tinnitus. Seizures can occur even without previous symptoms of toxicity and often lead to death. Coma can develop in very severe cases.
Cardiovascular symptoms:
palpitations, arrhythmias, arterial hypotension, supraventricular and ventricular arrhythmias.
Metabolic symptoms:
hypokalemia can develop quickly and can be serious. Hyperglycemia, albuminuria, hyperthermia, hypomagnesemia, hypophosphatemia, hypercalcemia, respiratory alkalosis, metabolic acidosis, and rhabdomyolysis may also occur.
Treatment:
Treatment of overdose is supportive and symptomatic.
Serum theophylline and potassium levels should be checked. Repeated oral administration of activated charcoal helps eliminate theophylline from the body, even after intravenous administration. Aggressive antiemetic therapy may be required to allow oral administration of activated charcoal.
Convulsions can be stopped by intravenous administration of diazepam 0.1-0.3 mg/kg to 10 mg/kg. Restoring fluid and electrolyte balance is essential. Hypokalemia should be corrected by IV infusion of potassium chloride. Sedation with diazepam may be required in agitated patients.
Propranolol can be administered IV to reverse tachycardia, hypokalemia and hyperglycemia, provided the patient does not suffer from asthma.
In general, theophylline is metabolized quickly and hemodialysis is not warranted. In patients with congestive heart failure or liver disease, hemodialysis may increase the clearance of theophylline by 2-fold.
Hemosorption should be considered if:
- intestinal obstruction prevents the administration of several doses of activated carbon:
- plasma theophylline concentrations >80 mg/l (acute) or >60 mg/l (chronic). In the elderly, hemosorption should be considered at theophylline concentrations >40 mg/L. Clinical signs, rather than theophylline concentration, are the best guide for treatment.
Interaction with other drugs
Ephedrine and caffeine enhance the effect of the drug.
Pharmaceutically incompatible with acid solutions.
Increases the likelihood of developing side effects of glucocorticosteroids, mineralocorticosteroids (hypernatremia), drugs for general anesthesia (increases the risk of ventricular arrhythmias), drugs that excite the central nervous system (increases neurotoxicity).
Antidiarrheal drugs and enterosorbents reduce the absorption of aminophylline.
Rifampicin, phenobarbital, phenytoin, isoniazid, carbamazepine, sulfinpyrazone,
aminoglutethimide, oral estrogen-containing contraceptives and moracizine, being inducers of microsomal oxidation, increase the clearance of aminophylline, which may require an increase in its dose.
When used simultaneously with macrolide antibiotics, lincomycin, allopurinol, cimetidine, isoprenaline, enoxacin, small doses of ethanol, disulfiram, fluoroquinolones, recombinant interferon alpha, methotrexate, mexiletine, propafenone, thiabendazole, ticlopidine, verapamil, and with influenza vaccination, the intensity of action of aminophylline may increase, which may require a reduction in its dose.
Enhances the effect of beta-adrenergic stimulants and diuretics (including by increasing glomerular filtration), reduces the effectiveness of lithium preparations and beta-blockers.
Compatible with antispasmodics, do not use in combination with other xanthine derivatives.
Prescribe with caution simultaneously with anticoagulants, with other theophylline or purine derivatives.
Eufillin (Euphillinim)
Aminophylline
M.v. 180.17
M.v. 60.10
Theophylline with 1,2-ethylenediamine
Aminophylline is a xanthine derivative.
Description: white or white with a yellowish tint crystalline powder with a faint ammonia odor. In air it absorbs carbon dioxide, and solubility decreases.
Solubility: soluble in water; aqueous solutions of the drug have an alkaline reaction.
Authenticity:
- The IR spectrum must match the spectrum of the standard.
- The UV spectrum in a solution of hydrochloric acid in the region of 250-300 nm has an absorption maximum of 273 nm.
- Murexide test (GPC). The reaction is based on the restorative properties of xanthine. The drug is dissolved in water, placed in a porcelain cup, diluted hydrochloric acid, a few drops of perhydrol are added, and evaporated to dryness in a boiling water bath. When moistened with 1-2 drops of ammonia solution, a purple-red color appears.
- Complexation reaction (CHR). The reaction is based on the presence of ethylene diamine, which is capable of forming a complex with copper (II) ion. A solution of copper (II) sulfate is added to an aqueous solution of aminophylline. A red-orange complex is formed.
- Isolation of theophylline base (GPC). Dilute hydrochloric acid is added to the solution. A white precipitate forms, which is filtered, washed with water and dried. The melting point of the resulting precipitate should be 269 – 274°C.
Purity:
- Sulfated ash.
- Heavy metals.
- Sulfates.
Quantitation:
- Acidimetry. Option for indirect neutralization. The method is based on the presence of ethylenediamine, which has basic properties.
A weighed portion of the drug (0.3) is dissolved in 25 ml of freshly boiled, cooled water, titrated with a 0.1 M solution of hydrochloric acid to an orange-pink color.
T – 0.1 M HCl
The indicator is methylene orange. (until orange-pink color)
f = ½
The ethylenediamine content in the drug should be 14.0 – 18.0%.
- Indirect neutralization method (quantitative detection of theophylline). The method is based on the presence in the theophylline molecule of a basic center capable of reacting with silver nitrate.
0.4 of the drug is placed in a wide-neck conical flask with a capacity of 250 ml and dried in an oven at 125 - 130° until the amines disappear (about 2.5 hours). The dried sample is dissolved in 100 ml of hot, freshly boiled water and boiled for 1 minute. Add 25 ml of 0.1 N silver nitrate solution to the cooled solution and titrate with 0.1 M sodium hydroxide solution until a red-violet color appears.
The liberated nitric acid is titrated with sodium hydroxide solution.
T – 0.1 NaOH
f = 1
The indicator is phenol red.
Until a violet-red color appears.
The theophylline content in the drug should be 80.0 – 85.0%.
Storage: List B, in a well-closed, filled to the top container, protected from light.
Application: antispasmodic (vasodilator, bronchodilator) agent.
Question: Why did the substance not completely dissolve?
Answer: Eufillin is a drug consisting of theophylline and ethylenediamine. Thanks to the presence of the latter, the substance dissolves better. In air it is able to absorb carbon dioxide due to the presence of ethylenediamine. At the same time, the solubility of the drug decreases. Probably incomplete dissolution of the drug is due to improper storage (not tightly closed containers).
Problem No. 8
