What Are the Most Common Aminophylline Side Effects?

Aminophylline is a double salt of theophylline and ethylenediamine, and its pharmacological action mainly comes from theophylline, and ethylenediamine enhances its water solubility. Insoluble in methanol, ethanol and ether. This product has a direct relaxation effect on the smooth muscles of the respiratory tract. Its mechanism of action is relatively complicated. It was thought that the inhibition of phosphodiesterase increased the intracellular cAMP content.

Aminophylline is a double salt of theophylline and ethylenediamine, and its pharmacological action mainly comes from theophylline, and ethylenediamine enhances its water solubility. Insoluble in methanol, ethanol and ether. This product has a direct relaxation effect on the smooth muscles of the respiratory tract. Its mechanism of action is relatively complicated. It was thought that the inhibition of phosphodiesterase increased the intracellular cAMP content.

Chinese name

Aminophylline

Foreign name

Aminophylline

Alias

Amfeline, Ethylamine

Water soluble

Strong

Method

Neutralization titration

Introduction to aminophylline compounds

Amino Tea Base Book Information

Chinese name: aminophylline

Chinese alias: (theophylline) 2. ethylenediamine; 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione-1,2-ethylenediamine salt; theophylline Amine; Ondol; Theophylline ethylene diamine; Theophylline tablets; Aminophylline sustained-release tablets; Ethylenediamine theophylline; Aminofilin

English name: Aminophylline

English alias: lasodex; aminodur; carena; tefamin; theomin; Aminodur

CAS number: 317-34-0

Molecular formula: C ₁₆ H ₂₄ N ₁₀ O ₄

Molecular weight: 420.42600

Exact mass: 420.19800

PSA: 197.40000

Aminophylline physicochemical properties

Appearance and properties: white to slightly yellow powder or granular

Melting point: 269-270 ° C

Boiling point: 454.1ºC at 760mmHg

Water solubility: soluble in water

Stability: Stable under normal temperature and pressure. Will absorb carbon dioxide in the air. Acid solution is unstable

Storage conditions: -20ºC

Aminophylline Safety Information

Packing level: III

Hazard category: 6.1 (b)

Customs Code: 2939590000

Dangerous Goods Transport Code: UN 2811 6.1 / PG 3

WGK Germany: 3

Danger category code: R22; R34; R42 / 43

Safety instructions: S45-S36 / 37 / 39-S26-S23

RTECS number: XH5600000

Dangerous goods mark: C ^[1]

Aminophylline production method

This product is a double salt of theophylline and ethylenediamine. Put theophylline into the mixer, stir and cool, spray the mixed solution of freshly distilled ethylenediamine and distilled water with compressed air, spray it, and continue stirring for 10 minutes to obtain aminophylline ^[1] .

Use of aminophylline

Aminophylline Aminophylline drugs have the strongest relaxing effect on bronchial smooth muscle, which can make bronchi dilate, increase vital capacity, and have a longer-lasting effect, especially on bronchi with spasticity. In addition, aminophylline also expands coronary arteries. Increase myocardial blood supply and strengthen cardiac contractility. It is mostly used in equine emphysema and asthma in dogs due to heart congestion (heart wheezing) caused by heart failure ^[1] .

Aminophylline Pharmacopoeia Standard

Aminophylline source (name), content (potency)

This product is 1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione-1,2-ethylenediamine salt dihydrate. Calculated as anhydrous, theophylline (C ₇ H ₈ N ₄ O ₂ ) should be 84.0% to 87.4%; ethylene diamine (C ₂ H ₈ N ₂ ) should be 13.5% to 15.0%.

Ammonia tea alkaline

This product is white to slightly yellow granules or powder, easy to agglomerate; slightly smelly ammonia, bitter taste; absorb carbon dioxide in the air, and decompose into theophylline; the aqueous solution is alkaline reaction.

This product is soluble in water, slightly soluble in ethanol, and almost insoluble in ether.

Aminophylline identification

(1) Take about 0.2g of this product, add 10ml of water to dissolve, continue stirring, drop 1ml of dilute hydrochloric acid to precipitate theophylline, and filter; filter the residue after washing with a small amount of water, and dry at 105 ° C for 1 hour, its infrared light absorption spectrum It should be consistent with the control spectrum ("Infrared Spectra of Drugs" 272).

(2) Take about 30mg of this product, add 1ml of water to dissolve it, add 2 ~ 3 drops of 1% copper sulfate solution, shake, the solution will initially show purple; continue to drop the copper sulfate solution, gradually change to blue-violet, and finally become dark blue.

(3) In the chromatogram recorded under the content determination item, the retention time of the main peak of the test solution should be consistent with the retention time of the main peak of the reference solution ^[2] .

Aminophylline check

Clarity and color of the solution

Take 0.50g of this product, add 10ml of fresh boiling cold water, dissolve slightly, the solution should be clear and colorless, if color is developed, check according to law (Appendix A of the second edition of the Pharmacopoeia of 2010 Edition, method A), and yellow green The standard colorimetric solution must not be deeper.

relative substance

Take 0.20g of this product, add 2ml of water, dissolve it with slight heat, let cool, dilute to 10ml with methanol, shake well, as a test solution, take 1ml precisely, dilute to 200ml with methanol, and shake as the control solution. According to the thin layer chromatography (2010 edition Pharmacopoeia Part II Appendix VB) test, draw 10 l each of the two solutions, and point them on the same silica gel GF254 thin-layer plate, with n-butanol-acetone-trichloromethane-concentrated ammonia solution ( 40: 30: 30: 10) as the developing agent, unfolded, dried, and placed under an ultraviolet light (254nm) for inspection. If the test solution shows obvious spots of impurities, it must not be deeper than the main spots of the control solution.

Moisture

Take this product and measure it according to the Moisture Determination Method (Appendix M, First Method A, Part Two of the Pharmacopoeia, 2010 Edition). The moisture content must not exceed 8.0%; if it is anhydrous aminophylline, the moisture content must not exceed 1.5%.

Residue on ignition

Not more than 0.1% (Appendix N of Part Two of the 2010 Pharmacopoeia) ^[2] .

Determination of aminophylline

Ethylenediamine

Take about 0.25g of this product, accurately weigh, add 25ml of water to dissolve, add 8 drops of sodium alizarin sulfonate indicator solution, titrate with sulfuric acid titration solution (0.05mol / L) until the solution becomes yellow. Each 1ml of sulfuric acid titration solution (0.05mol / L) is equivalent to 3.005mg of C ₂ H ₈ N ₂ .

Anophylline

It was determined by high performance liquid chromatography (Appendix D, Part Two of the Pharmacopoeia, 2010 Edition).

1 Chromatographic conditions and system suitability tests

Octadecylsilane-bonded silica gel was used as a filler; a methanol-0.12% sodium pentanesulfonate solution (20:80) (pH adjusted to 2.9 ± 0.1 with glacial acetic acid) was used as the mobile phase; the detection wavelength was 254 nm. Take the appropriate amount of theophylline reference substance and theobromine reference substance, add methanol-water (1: 4) to dissolve and dilute to make a solution containing 0.064mg per 1ml, take 10l into the liquid chromatograph, the theoretical number of plates according to tea The alkali peak calculation is not less than 2000, and the resolution between theophylline peak and theobromine peak should be greater than 3.0.

2 Assay

Take an appropriate amount of this product, accurately weigh it, add methanol-water (1: 4) to dissolve and quantitatively dilute to make a solution containing about 0.08 mg of theophylline per 1 ml. Take a precise amount of 10 l, inject it into a liquid chromatograph, and record the chromatogram. ; Take another theophylline reference substance and measure in the same way. Calculate the peak area according to the external standard method to get ^[2] .

Aminophylline category

Smooth muscle relaxants, diuretics.

Aminophylline storage

Shaded and sealed.

Aminophylline

(1) Aminophylline tablets (2) Aminophylline injection (3) Aminophylline sustained-release tablets

Aminophylline version

The 2010 Edition of the Pharmacopoeia of the People's Republic of China ^[2]

Aminophylline drug determination

Method name: Determination of Aminophylline-Ethylenediamine and Anophylline-Neutralization Titration

Scope of application: This method uses titration to determine the content of ethylenediamine and theophylline in aminophylline.

Principle of the method: Ethylenediamine: Take an appropriate amount of this product, add water to dissolve, add sodium alizarin sulfonate indicator solution, titrate with sulfuric acid titration solution (0.05mol / L) until the solution becomes yellow, and read the amount of sulfuric acid titration solution , Calculation, that is.

Anhydroophylline: Take the above titrated solution, add silver nitrate titration solution (0.1mol / L), shake, quickly titrate with sodium hydroxide titration solution (0.1mol / L), read out the sodium hydroxide titration solution Use, calculate, and get.

Reagent: 1. Water (new boiling to room temperature)

2. Sodium hydroxide titration solution (0.1mol / L)

3. Sulfuric acid titration solution (0.05mol / L)

4. Silver nitrate titration solution (0.1mol / L)

5.Alizarin sulfonate indicator solution

preparation

Sodium hydroxide titration solution (0.1mol / L)

Preparation: Take 56mL of clear saturated sodium hydroxide solution, add fresh boiling cold water to make 1000mL.

Calibration: Take about 6.0g of standard potassium hydrogen phthalate dried to constant weight at 105 , accurately weigh, add 50mL of freshly boiled cold water, shake it to make it dissolve as much as possible; add 2 drops of phenolphthalein indicator solution, use When this solution is titrated, when the end point is reached, potassium hydrogen phthalate should be completely dissolved and titrated until the solution becomes pink. Each 1mL of sodium hydroxide titration solution (1mol / L) is equivalent to 204.2mg of potassium hydrogen phthalate. Calculate the concentration of this solution based on the consumption of this solution and the amount of potassium hydrogen phthalate taken.

Storage: Put it in a polyethylene plastic bottle and keep it in a sealed container. There are 2 holes in the plug. One glass tube is inserted into the hole. One tube is connected to the soda lime tube. One tube is used to suck out the liquid.

3.3 Sulfuric acid titration solution (0.05mol / L)

Preparation: Take 3mL of sulfuric acid, slowly inject an appropriate amount of water, cool to room temperature, add water to dilute to 1000mL, and shake well.

Calibration: Take about 0.15g of constant anhydrous standard sodium carbonate dried at 270-300 , accurately weigh, add 50mL of water to dissolve, add 10 drops of methyl red-bromocresol green indicator liquid, titrate with this liquid to When the solution changes from green to purplish red, boil for 2 minutes, cool to room temperature, and continue titration until the solution turns green to dark purple. Each 1mL of sulfuric acid titration solution (0.05mol / L) is equivalent to 5.30mg of anhydrous sodium carbonate. Calculate the concentration of the solution according to the consumption of the solution and the amount of anhydrous sodium carbonate taken, that is, obtained.

2. Silver nitrate titration solution (0.1mol / L)

Preparation: Take 17.5g of silver nitrate, add an appropriate amount of water to dissolve it into 1000mL, and shake well.

Calibration: Take about 0.2g of standard sodium chloride dried to constant weight at 110 , accurately weigh, add 50mL of water to dissolve, add 5mL of cyclodextrin solution (1 50), 0.1g of calcium carbonate and fluorescent yellow indicator Eight drops were titrated with this solution until the turbid liquid changed from yellow-green to reddish. Each 1mL of silver nitrate titration solution (0.1mol / L) is equivalent to 5.844mg of sodium chloride. Calculate the concentration of the solution based on the consumption of the solution and the amount of sodium chloride taken, that is.

3.Alizarin sulfonate indicator solution

Take 0.1 g of sodium alizarin sulfonate and add 100 mL of water to dissolve.

Aminophylline tablets

Operation steps: Diethylamine: accurately weigh 0.25g of test sample, add 25mL of water to dissolve, add 8 drops of sodium alizarin sulfonate indicator solution, titrate the solution with sulfuric acid titration solution (0.05mol / L), and read sulfuric acid The amount of titrant used, calculated, 1mL sulfuric acid titrant (0.05 mol / L) is equivalent to 3.005mg of diethylamine (C ₂ H ₈ N ₂ ).

Anhydrophylline: Take the above titrated solution, add 20 mL of silver nitrate titration solution (0.1 mol / L), shake, and quickly titrate with sodium hydroxide titration solution (0.1 mol / L) until the solution becomes red, read hydrogen The amount of sodium oxide titration solution used, calculated, each 1mL of sodium hydroxide titration solution (0.1 mol / L) is equivalent to 18.02mg of anhydrous theophylline.

Note 1: "Precision weighing" means that the weighed weight should be accurate to one thousandth of the weight. Precision requirements.

Note 2: "Determination of moisture" uses the drying method, taking 2 to 5 g of the test sample, and spreading it in a flat weighing bottle that is dry to constant weight, the thickness is not more than 5 mm, and the loose test sample is not more than 10 mm. Open the bottle cap and dry it at 100 105 for 5 hours. Place the cap on the dryer, cool it for 30 minutes, and weigh it precisely. Then dry it at the above temperature for 1 hour, cool it, and weigh it twice. The difference in weighing does not exceed 5 mg. Calculate the moisture content (%) in the test product based on the lost weight ^[3] .

Aminophylline drug description

Aminophylline classification

Respiratory Drugs> Asthma Drugs> Theophylline Drugs

Ammonia tea alkaline

White or light yellow granules or powders; easy to agglomerate; slightly smelly ammonia, bitter taste. It is soluble in water, slightly soluble in ethanol, and almost insoluble in ether.

Aminophylline dosage form

1. Tablets: 0.05g, 0.1g, 0.2g each;

2. Injection: 0.25g (10ml);

3. Controlled release tablet: 100mg;

4. Compound long-acting aminophylline tablets: the white outer layer contains 100 mg of theophylline, the chlorpheniramine 2 mg, the phenobarbital 15 mg, and the aluminum hydroxide 15 mg; the brown inner layer contains 100 mg of theophylline and theophylline;

5. Aminophylline sustained-release sustained-release sustained-release tablets: 100mg;

6. Chuanjing tablets: containing theophylline, caffeine, phenobarbital, ephedrine hydrochloride, Polygalax extract;

7. Compound Theophylline Tablets: Each tablet contains 25 mg of theophylline, 10 mg of ephedrine hydrochloride, 100 mg of phenacetin, 10 mg of phenobarbital, 100 mg of aminopyrine, 15 mg of caffeine, 25 mg of cocaine, and 2 mg of belladonna extract ;

8. Glycine theophylline theophylline tablets: 330mg each, containing 165mg theophylline;

9. Theophylline tablets: regular release tablets: 0.1g, sustained release tablets: 0.1g;

10. Zhichuan suppository: for adults, each containing 0.4g of aminophylline, 0.025g of promethazine hydrochloride, 0.045g of benzocaine; for children, each content is halved ^[4] .

Aminophylline pharmacological action

It is a double salt of theophylline and diethylamine. The base pharmacological effect mainly comes from theophylline. Ethylenediamine enhances its water solubility. Relaxation of bronchial smooth muscles can also relax a variety of smooth muscles of the intestine, biliary tract, etc., and it can also relieve hyperemia and edema of bronchial mucosa. Increase cardiac output, dilate output and enter renal arterioles, increase glomerular filtration rate and renal blood flow, and inhibit distal renal tubules from reabsorbing sodium and chloride ions. increase the contractility of isolated skeletal muscle; in the case of chronic obstructive pulmonary disease, improve muscle contractility. Theophylline increases hypoventilation during hypoxia is thought to be because it increases contraction of the diaphragm, and its effect in this respect exceeds that of the respiratory center.

Aminophylline pharmacokinetics

This product can be quickly absorbed orally, rectally or parenterally. In the body aminophylline releases theophylline, which has a protein binding rate of 60%. The distribution volume (Vd) is about 0.5 L / kg. The half-life is 3-9 hours. Intravenous injection of 6 mg / kg aminophylline within half an hour, its blood concentration can reach 10 mg / L, and its biotransformation rate in the body varies among individuals. This product was taken orally on an empty stomach and reached its peak plasma concentration within 2 hours. Most of this product is excreted in the form of metabolites through the kidney, and 10% is excreted in its original form.

Aminophylline indications

1. Bronchial asthma and asthma-like bronchitis, combined with beta receptor agonist can improve the efficacy. In the persistent state of asthma, aminophylline and adrenocortical hormone are often used for treatment.

2. Treat asthma with acute heart failure and heart failure (cardiogenic asthma).

3. Bile colic.

4. Treat sick sinus node syndrome and sinoatrial block.

Aminophylline contraindications

Acute myocardial infarction Patients with acute myocardial infarction accompanied by a significant reduction in blood pressure are contraindicated.

Aminophylline precautions

1. Overdose treatment, the central excitatory effect can cause a few patients with irritability, insomnia and so on.

2. Excessive doses can cause delirium and convulsions.

3. Available sedatives.

4. Do not expose it to air to avoid yellowing and failure ^[4] .

Aminophylline dosage

1. Adults usually take it orally, 0.1 0.2g once, 0.3 0.6g per day; Extreme amount: 0.5g once, 1g per day. Intramuscular injection, 0.25 to 0.5 g at a time, 2% procaine hydrochloride should be added. Intravenous injection, 0.25 to 0.5 g at a time, 0.5 to 1 g a day, every 25 to 100 mg is diluted with 5% glucose injection to 20 to 40 ml, and the injection time should not be shorter than 10 minutes. Intravenous infusion, 0.25 to 0.5 g at a time, 0.5 to 1 g a day, diluted slowly with 5 to 10% glucose solution. Administration by injection, 0.5g once a day, 1g a day. Rectal administration, usually before bedtime or after defecation, once 0.25 ~ 0.5g, once or twice a day.

2. Children usually take it orally, taking 4 to 6 mg / kg of body weight in two to three times a day. Intravenous injection, once at a weight of 2 to 4 mg / kg, diluted with 5-25% glucose injection, and slowly injected.

Aminophylline adverse reactions

(1) Common adverse reactions are: nausea, upset stomach, vomiting, loss of appetite, headache, irritability, and irritability.

(2) When this product is poisoned, it manifests as arrhythmia, rapid heart rate, muscle tremor or epilepsy. Due to irritation of the gastrointestinal tract, bloody vomit or tar-like stools are visible.

Oral administration may cause nausea and vomiting; intramuscular injection of local swelling and pain; intravenous drip with dizziness, palpitations, arrhythmia, decreased blood pressure, convulsions, and convulsions. A few people may have insomnia and dizziness. Excessive doses may cause convulsions, delirium or slang .

Cardiovascular system: Elevated theophylline concentration in the blood can cause cardiovascular adverse reactions, and those who have cardiovascular disease use this drug, the risk of cardiac toxicity will increase. Tachycardia is a common symptom of poisoning, and patients with dyspnea are prone to ventricular fibrillation. Serum concentrations in excess of 35 g / ml have been reported and half of the patients have life-threatening ventricular arrhythmias.

Respiratory system: Aminophylline can sometimes make bronchospasm worse.

Nervous system: 12 cases of partially reversible airway obstruction were treated with 500mg aminophylline at one time using double-blind cross method, 8 of which developed neuropathy, nausea, vomiting, dizziness and palpitations. Severe poisoning can also occur at ordinary doses, which is due to incomplete degradation of theophylline. In addition to trembling, dizziness, anxiety, agitation, insomnia, visual disturbances, and seizures, depression, insanity, and toxic psychosis can also occur.

Digestive system: Aminophylline is given intravenously or anally in adults. The most common adverse reactions are nausea and gastrointestinal irritation.

Allergic reactions: Some people have emphasized that the allergic reactions caused by aminophylline are caused by ethylenediamine, because it is a sensitizing substance and can cause life-threatening angioedema. Delayed allergic reactions have been reported.

Aminophylline drug interactions

1. Dilute hydrochloric acid can reduce its absorption in the small intestine.

2. Acidic drugs increase their excretion, while alkaline drugs decrease their excretion.

3. Cimetidine, erythromycin, clindamycin, lincomycin, and tetracycline can reduce the clearance of aminophylline in the liver, and make its t1 / 2 prolonged, so the blood concentration can be higher than normal. Easy to cause poisoning.

4. Phenytoin sodium accelerates metabolism and reduces blood drug concentration, and the dosage should be increased as appropriate.

5. When combined with propranolol, the bronchodilator effect of aminophylline may be inhibited.

6. Combined with lithium can accelerate the excretion of lithium by the kidney, so the efficacy of lithium decreases.

7. Intravenous infusion, avoid compatibility with vitamin C, corticotropin, norepinephrine, and tetracycline hydrochloride.

Drugs that enhance theophylline clearance are beneficial to amphorin, norepinephrine, barbiturates, and phenytoin ^[4] . It increases the clearance of lithium from the kidneys, resulting in a decrease in blood concentration; it is used in combination with prednisone to reduce the plasma concentration of both; within the normal range of digoxin blood concentration, it can induce arrhythmia. The use of theophylline can increase the concentration of caffeine to toxic levels. Pioneermycin or ethanol combined with it can produce alcohol withdrawal reaction. Low protein diets reduce its clearance, while high protein diets increase its clearance. Smokers have less adverse reactions to theophylline than others.

At present, mixtures containing theophylline, ephedrine and sedatives are still used as bronchodilators. Some studies have confirmed that theophylline combined with ephedrine can produce a synergistic toxic effect without a significant increase in efficacy. There have been reports evaluating the effects of theophylline (130mg), ephedrine (25mg) and hydroxyzine (Hydroxyzine) in the treatment of seasonal asthma. The combination of the three has fewer adverse reactions than theophylline or theophylline and ephedrine alone. It is nausea and nervousness. Some people compared the clinical efficacy of Tedral (containing theophylline 130mg, ephedrine 24mg and phenobarbital 8mg) and theophylline in treating 22 patients with bronchospasm. Lung function improvement was similar, but Tedral had fewer adverse reactions than theophylline. Therefore, it is believed that low-dose Tedral has a good effect in the treatment of asthma.

Aminophylline poisoning

Aminophylline is a complex of theophylline and ethylenediamine, in which theophylline accounts for 77% to 83%, is the main component for the treatment of asthma, and ethylenediamine is a common allergen. Can be taken orally, intramuscularly, intravenously or by drip after dilution.

Clinical manifestation

The toxic and side effects of aminophylline use are the same as theophylline. The accumulation of repeated use of aminophylline may cause excessive poisoning: nausea, vomiting, and even bloody vomit or tar-like stools, dizziness, insomnia, anxiety, and mental disorders , Paralysis or shock. The maximum tolerated amount per oral administration is 0.5 mg. Intravenous injection too fast (25mg / min) or high concentration (blood concentration> 25g / ml) can cause dizziness, palpitations, arrhythmias, sharp drop in blood pressure, convulsions, hives, pruritus, angioedema, or platelets may occur Reduction, allergic symptoms such as bleeding disorders.

diagnosis

The main points of diagnosis of aminophylline poisoning are:

There is a history of aminophylline application, the above manifestations.

treatment

The main points of treatment of aminophylline poisoning are:

The drug should be stopped in time and treated symptomatically. The indications of hemodialysis or hemoperfusion when aminophylline severe poisoning occurs are related to theophylline.

Hemodialysis and hemoperfusion can effectively remove theophylline from the body. In the case of theophylline poisoning, indications for the application of blood purification: blood concentration> 30-40 g / ml ^[5] .

Aminophylline expert review

Aminophylline is a drug with a long history of clinical application. The indications are properly selected and can receive good results. Because it can improve the contractility of the diaphragm, it is used to treat chronic obstructive pulmonary disease. Aminophylline has a good effect on hypoxemia and sleep disorders. It is used for awakening after general anesthesia to combat respiratory depression caused by morphine, and has a good effect. It can still regulate immune function, can inhibit transplant rejection, and can significantly prolong graft survival ^[4] .