Question 11

Describe the mechanism of action, dose, pharmacokinetics and pharmacodynamics of aminophylline.

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College Answer

This question required a detailed description of the many mechanisms of action of aminophylline. This included PDE inhibition and the down stream pathway and its adenosine antagonist and antiinflammatory actions. Important pharmacokinetic concepts included hepatic metabolism with saturable kinetics and thus a narrow therapeutic window/index requiring need for drug monitoring and the risk of metabolic interactions with accelerated or reduced metabolism from inducers or inhibitors of the main enzyme (CYP1A2). Detailed pharacodynamic consequences on the respiratory and cardiovascular


Name Aminophylline
Class Adenosine receptor antagonist
Chemistry Methylxanthine
Routes of administration IV or oral
Absorption Well absorbed after oral administration, about 90% bioavailability
Solubility pKa = 5.0, good water solubility (much better than theophylline, which is why this is the IV alternative to it)
Distribution VOD=0.3-0.7L/kg, 60% protein-bound
Target receptor Adenosine A1 and A2 receptors, which inhibit neurotransmitter releease by regulating presynaptic potassium and calcium traffic. Also phospodiesterase type III and IV
Metabolism A pro-drug - really just an ethylenediamine salt of theophylline, and so it immediately dissociates into theophylline, which is the main pharmacologically active agent.
Elimination Minimal free drug is eliminated in the urine
Time course of action Half-lie of aminophylline itself is minuscule, whereas the half-life of theophylline is 8 hours.
Mechanism of action Multiple effects:
- Adenosine receptor inhibiition leads to the ihibition of leukotriene release by mast cells
- A1 and A2 receptior inhibition also has the undesirable cardiovascular effects by increasing the release of catecholamines
- Phosphodiesterase inhibition leads to increased cAMP and cGMP, leading to the relaxation of smooth muscles in bronchi and pulmonary vessels, but also to diuresis and cardiovascular stimulation
- increases the action and recruitment of histone deacetylases to the site of active inflammation
- Increased calcium uptake through the adenosine-mediated calcium channels in the diaphragm leads to increased contraction and reversal of diaphragm fatigue
Clinical effects Bronchodilation, pulmonary arterial vasodilation, increased diaphragmatic contractility, tachycardia, increased cardiac output, arrhythmias, diuresis, increased gastric acid secretion, and rhabdomyolysis and seizures in overdose
Single best reference for further information Stirt & Sullivan, 1981


Stirt, Joseph A., and Stuart F. Sullivan. "Aminophylline." Anesthesia & Analgesia 60.8 (1981): 587-602.

Tong, Theodore G. "Aminophylline—review of clinical use." Drug Intelligence & Clinical Pharmacy 7.4 (1973): 156-167.