Aminophylline

Mechanism of action and pharmacologic effects

Aminophylline has a complex effect on the body, involving the respiratory and excretory systems.

• Effect on bronchi: The main clinical effect of the drug is the relaxation of bronchial smooth muscle. This bronchodilator action determines its use in bronchial asthma.
• Effect on kidneys: The drug causes blockade of $A_1$-adenosine receptors in the renal tubules. This leads to impaired reabsorption of sodium and chloride ions, as well as a slight increase in potassium excretion.
• Hemodynamic effects: Aminophylline increases renal blood flow and enhances glomerular filtration.

Note: Despite its proven diuretic effect, in modern practice the drug is used primarily as a bronchodilator.

Pharmacokinetics and chronopharmacology

Absorption and distribution: Upon oral administration, the active substance (theophylline) is absorbed rapidly and completely, with bioavailability exceeding 90%. The maximum concentration ($C_{max}$) for conventional formulations is reached after 2 hours. The duration of action varies among patients, but averages about 6 hours.

Chronopharmacokinetics: According to studies by Reinberg and Smolensky, the pharmacokinetics of theophylline depend on the time of day. The highest peak plasma and saliva concentrations are achieved when the drug is taken in the morning at 7:00.

Metabolism: Occurs in the liver with the formation of inactive metabolites via two pathways:

1. Microsomal oxidation: Takes place in the endoplasmic reticulum with the participation of cytochrome P-450. Theophylline undergoes dealkylation. The key isoenzyme for the drug is CYP1A2.
2. Non-microsomal oxidation: Occurs in the hepatocyte cytosol with the participation of the enzyme xanthine oxidase (hydroxylation of purine compounds).

Drug interactions

Aminophylline has a narrow therapeutic window, so changes in liver enzyme activity critically affect its safety.

Metabolic inhibition (risk of toxicity): Drugs can reduce cytochrome P-450 enzyme activity, slowing down the metabolism of theophylline and increasing its blood concentration to toxic levels.

• Potent CYP1A2 inhibitor: Ciprofloxacin (antibacterial drug). Its co-administration leads to a sharp increase in the toxicity of theophylline.
• Other inhibitors: Macrolides (erythromycin, clarithromycin), cimetidine, verapamil.

Metabolic induction (decreased efficacy): Inducers accelerate the metabolism of xanthines, leading to a weakened therapeutic effect.

• Drug inducers: Phenobarbital (Phenobarbitalum), phenytoin, rifampicin, omeprazole.
• Exogenous and dietary factors: The CYP1A2 isoenzyme is highly dependent on environmental factors. Its activity is increased by components of tobacco smoke, charred foods (benzopyrenes, methylcholanthrenes), and cruciferous vegetables (broccoli, brussels sprouts).

Use during lactation

Theophylline is able to cross the blood-milk barrier. Its concentration in breast milk is ~70% of plasma levels.

The transfer of substances into milk depends on physicochemical factors: lipophilicity, plasma protein binding, and acid-base status (weak bases accumulate in milk due to the 'ion trapping' phenomenon). Even microdoses of foreign substances in milk can provoke allergic reactions in the infant, requiring caution when prescribing the drug to nursing mothers.

Formulations and prescription rules

According to the prescription reference book, the drug is available in the following forms:

• Tablets 0.15 g;
• Suppositories 0.15 g;
• Solution in ampoules: 2.4% — 5–10 ml; 24% — 1 ml.

Dosing regimen:

• Orally: 1 tablet 3 times a day after meals. The maximum single dose is 0.5 g; the maximum daily dose is 1.5 g.
• Intravenously: 10 ml of a 2.4% solution must be diluted in 10 ml of 0.9% sodium chloride solution (NaCl). The drug should be administered slowly (over 4–6 minutes).

Briefly: answers to topical questions

Class and exam questions

What else to study on this topic

• Chronopharmacokinetics: influence of circadian rhythms on Cmax and AUC
• CYP1A2 isoenzyme: substrates, inducers, and inhibitors
• Differences between microsomal and non-microsomal oxidation in the liver
• Role of A1 adenosine receptors in renal physiology
• Physicochemical factors of drug excretion into breast milk

Other topics in the «Drugs and Prescriptions» section

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