Physicochemical Properties
The primary active substance of this group is theophylline. Its main pharmacological limitation is its extremely low water solubility, with a ratio of 1:180.
To overcome this barrier and enable liquid pharmaceutical formulations, aminophylline (widely known as euphyllin) was synthesized. It is a combination mixture consisting of 80% theophylline and 20% ethylenediamine. The sole role of ethylenediamine is to ensure high solubility of the active substance in aqueous media.
Molecular Mechanism of Action
The pharmacological effects of methylxanthines are mediated through two parallel intracellular mechanisms:
- Receptor blockade: They act as direct antagonists of adenosine A1 receptors located on the membranes of smooth muscle cells.
- Enzyme inhibition: They cause non-selective inhibition of phosphodiesterase (PDE), particularly types III and IV.
In bronchial smooth muscle, this process triggers a specific biochemical cascade. Inhibition of PDE type IV leads to intracellular accumulation of cyclic adenosine monophosphate (cAMP). Elevated cAMP levels reduce the intracellular concentration of calcium ions (Ca2+). Calcium deficiency decreases the activity of myosin light-chain kinase, disrupting the normal interaction between actin and myosin. The result is marked relaxation of smooth muscle and relief of bronchospasm. A similar mechanism causes relaxation of vascular smooth muscle.
Pharmacodynamics: Systemic Effects
The effects of theophylline are multifaceted and tissue-dependent:
- Respiratory system: Beyond relieving bronchospasm, it stimulates the respiratory center, enhances mucociliary clearance, and markedly improves the contractility of respiratory muscles (intercostal muscles and diaphragm).
- Cardiovascular system: Vasodilation and a reduction in pulmonary vascular resistance occur in blood vessels. However, in cardiac myocytes, PDE III inhibition leads to cAMP accumulation and an increase in calcium ion concentration. This causes tachycardia and increases myocardial contractility.
- Mast cells: Suppression of PDE type IV decreases intracellular calcium, inhibiting degranulation. This prevents the release of allergic and inflammatory mediators (anti-allergic effect).
- Additional effects: The agents possess mild diuretic and weak antiplatelet activity.
Pharmacokinetics and Extended-Release Formulations
When taken orally, theophylline is rapidly and completely absorbed, with a bioavailability exceeding 90%. Peak blood concentration for standard formulations is reached within 2 hours. It is metabolized in the liver into inactive metabolites. The average duration of action varies among patients but is typically around 6 hours.
To ensure a stable therapeutic effect and patient convenience, extended-release (retard) formulations (such as prolonged-action aminophylline, theopeck, and theodur) have been developed. They feature slow drug release: peak concentration is achieved only after 6 hours, and the total duration of action extends up to 12 hours. Rectal formulations (aminophylline suppositories) are also available and are administered twice daily.
Adverse Effects
Adverse reactions are classified by organ system and directly relate to the mechanism of action of methylxanthines:
- Central nervous system: Headache, sleep disturbances, tremor, and generalized anxiety. The cause lies in the blockade of adenosine receptors in the CNS.
- Cardiovascular system: Tachycardia and various arrhythmias. This is the result of combined effects: blockade of cardiac adenosine receptors and inhibition of PDE III.
- Gastrointestinal tract: Nausea, vomiting, and diarrhea may occur.