Duralyn-CR Mechanism of Action

Pharmacology: Theophylline directly relaxes the smooth muscle of the bronchial airway and pulmonary blood vessels, thus acting mainly as a bronchodilator and smooth muscle relaxant. It has also been demonstrated that aminophylline has a potent effect on diaphragmatic contractility in normal persons and may then be capable of reducing fatigability and thereby improve contractility in patients with chronic obstructive airway disease. Theophylline is also a central respiratory stimulant.
For many years, the proposed main mechanism of action of the xanthines was inhibition of phosphodiesterase, which results in an increase in cyclic adenosine monophosphate (cAMP). However, this effect is negligible at therapeutic concentrations. Other effects that appear to occur at therapeutic concentrations and may collectively play a role in the mechanism of xanthines including inhibition of extracellular adenosine (which causes bronchoconstriction), stimulation of endogenous catecholamines, antagonism of prostaglandins, PGE₂ and PGF₂, direct effect on mobilization of intracellular calcium resulting in smooth muscle relaxation and β-adrenergic agonist activity on the airways.
Pharmacokinetics: Absorption: Theophylline is completely absorbed after oral administration. After administration of 400 mg Duralyn-CR, mean peak plasma concentrations of about 4.65 mcg/mL were reached at a mean of 3.83 hrs. The area under the plasma curve (AUC) is 56.64 mcg·hr/mL.
Distribution: Average volume of distribution is 0.45 L/kg (range 0.3-0.7 L/kg). Theophylline does not distribute into fatty tissue, but readily crosses the placenta and is excreted into breast milk. Approximately 40% are bound to plasma proteins.
Metabolism and Excretion: Xanthines are biotransformed in the liver (85-90%) to 1,3-dimethyluric acid, 3 methylxanthine and 1-methyluric acid. Excretion is by the kidneys; <15% of the drug is excreted unchanged. The half-life of theophylline is influenced by a number of known variables. It may be prolonged in chronic alcoholics, particularly those with liver disease (cirrhosis or alcoholic liver disease), in patients with congestive heart failure, and in patients taking certain other drugs. In cigarette smokers (1-2 packs/day), the mean half-life is much shorter than in non-smokers. The increase in clearance associated with smoking is presumably due to stimulation of the hepatic metabolic pathway by components of cigarette smoke.