Physicochemical properties of the drugs
The base active substance of the group is theophylline. Its main pharmacological drawback is extremely low water solubility, with a ratio of 1:180.
To overcome this barrier and enable the creation of liquid dosage forms, aminophylline (widely known aseuphylline) was synthesized. Essentially, it is a combined mixture consisting of 80% theophylline and 20% ethylenediamine. The role of ethylenediamine is solely to ensure high solubility of the active substance in an aqueous medium.
Molecular mechanism of action
The pharmacological effects of methylxanthines are mediated through two parallel mechanisms at the cellular level:
- Receptor blockade: the drugs act as direct antagonists of adenosine A1 receptors located on the membranes of smooth muscle cells.
- Enzyme inhibition: there is non-selective inhibition of the enzyme phosphodiesterase (PDE), particularly its types III and IV.
In bronchial smooth muscle, this process triggers a distinct biochemical cascade. Inhibition of PDE type IV leads to the intracellular accumulation of cyclic adenosine monophosphate (cAMP). An increase in cAMP levels triggers a decrease in the concentration of calcium ions (Ca2+) inside the cell. Calcium deficiency reduces the activity of myosin light-chain kinase, thereby disrupting the normal interaction between actin and myosin. The result is pronounced smooth muscle relaxation and relief of bronchospasm. A similar mechanism provides smooth muscle relaxation in blood vessels.
Pharmacodynamics: complex effects on the body
The effects of theophylline are multifaceted and depend on the tissue type:
- Respiratory system: in addition to relieving bronchial spasm, the drug stimulates the respiratory center, enhances mucociliary clearance, and noticeably improves the contractility of respiratory muscles (intercostal muscles and diaphragm).
- Cardiovascular system: vasodilation and a decrease in pulmonary vascular resistance are observed in blood vessels. However, in the heart (cardiomyocytes), inhibition of PDE type III leads to cAMP accumulation and an increase in calcium ion concentration. This causes tachycardia and increases the force of heart contractions.
- Mast cells: suppression of PDE type IV decreases intracellular calcium levels, which inhibits degranulation. As a result, the release of allergy and inflammatory mediators is prevented (antiallergic effect).
- Additional effects: the drugs possess weak diuretic and mild antiplatelet activity.
Pharmacokinetics and sustained-release formulations
Upon oral administration, theophylline is absorbed rapidly and completely — its bioavailability exceeds 90%. Maximum blood concentration is reached within 2 hours for standard formulations. The drug is metabolized in the liver, forming inactive metabolites. The average duration of action varies among patients, but is typically about 6 hours.
Retard formulations (sustained-action drugs) such as euphylline retard N, euphylong, teopex, and theodur have been developed to ensure a stable therapeutic effect and patient convenience. They feature slow active substance release: the maximum concentration is reached only after 6 hours, and the overall duration of action increases up to 12 hours. Physicians also have rectal formulations at their disposal — aminophylline suppositories, which are used twice daily.
Side effects
Adverse reactions are classified by organ systems and are directly related to the mechanism of action of methylxanthines:
- Central nervous system: headache, sleep disturbances, tremor, and general anxiety. The cause lies in the blockade of adenosine receptors in CNS structures.
- Cardiovascular system: development of tachycardia and various arrhythmias. This is the result of a combined effect — blockade of cardiac adenosine receptors and inhibition of PDE type III.
- Gastrointestinal tract: nausea, vomiting, and diarrhea may occur.
Briefly: answers to topical questions
What metabolites are formed during the biotransformation of theophylline in the liver and what is their activity?
During the biotransformation of theophylline in the liver, inactive metabolites are formed. The specific names of the resulting substances are not provided in the text, but it is emphasized that they lack pharmacological activity. The rate of hepatic metabolism of theophylline depends on the activity of microsomal enzymes:
- Inducers (phenobarbital, rifampicin, phenytoin) — accelerate the metabolism of theophylline, weakening its therapeutic effect.
- Inhibitors (verapamil, cimetidine, ciprofloxacin) — slow down biotransformation, leading to drug accumulation and a high risk of toxic effects.
To avoid confusing the effect on calcium: in the bronchi, methylxanthines cause calcium to 'leave' (relaxation), while in the heart, they cause it to 'enter' (tachycardia and increased contractility).
Class and exam questions
Why is aminophylline not used as an inhaler like salbutamol?
Unlike beta-2 agonists, methylxanthines are not intended for inhalation administration. They are administered orally, intravenously, or rectally.
Why is ethylenediamine added to euphylline?
Pure theophylline is extremely poorly soluble in water (1:180 ratio). The addition of 20% ethylenediamine solves this problem by ensuring good solubility of the substance for creating liquid dosage forms.
How do methylxanthines exert their anti-allergic effect?
They inhibit phosphodiesterase type IV in mast cells. This leads to cAMP accumulation, a decrease in intracellular calcium, and, consequently, inhibition of degranulation and the release of allergy mediators.
What else to study on this topic
- Differences in the functions of phosphodiesterase isoenzymes (PDE III and PDE IV)
- Biochemical cascade of myosin light-chain kinase
- Mechanisms of arrhythmia development in methylxanthine overdose
- Effect of theophylline on mucociliary clearance and respiratory muscles
- Comparative pharmacokinetics of standard and sustained-release theophylline formulations
Master the entire topic in the «Pharmacology» course
This is a summary. The course covers everything tested in classes and exams.
- Complete study guide on 'Methylxanthines' and 5,304 more pages of the subject
- Assignments and quizzes after every topic — just like in a colloquium
- AI tutor answers questions on the topic anytime
- 116 video lessons on the subject
Other topics in the section 'Drugs acting on respiratory system functions'
Free video lessons: pharmacologyShort lessons with study notes — no registration required.
Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.