Xanthines Dipyridamole

Initially, it was beheved that the abiUty of xanthines phosphodiesterase (PDF) led to bronchodilation (Fig. 2). One significant flaw in this proposal is that the concentration of theophylline needed to significantly inhibit PDE in vitro is higher than the therapeutically useful semm values (72). It is possible that concentration of theophylline in airways smooth muscle occurs, but there is no support for this idea from tissue distribution studies. Furthermore, other potent PDE inhibitors such as dipyridamole [58-32-2] are not bronchodilators (73). EinaHy, although clinical studies have shown that neither po nor continuous iv theophylline has a direct effect on circulating cycHc AMP levels (74,75), one study has shown that iv theophylline significant potentiates the increase in cycHc AMP levels induced by isoproterenol (74). 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

Adverse effects with dipyridamole thallium testing are minimal, the main adverse effects being chest pain (with or without ischemic changes on the ECG), headache, dizziness, and nausea. Adverse effects are related to the increased adenosine activity and can be ameliorated by xanthine compounds because they are direct competitive antagonists of adenosine. Caffeine products must be avoided for about 24 hours prior to the test. Adenosine is associated with a higher incidence of adverse effects (80% versus 50%), but these are very transient, and some studies have shown that patients prefer it over dipyridamole. Both agents are relatively contraindicated in patients with a history of bronchospasm. 

It appears that xanthine derivatives such as caffeine and theophylline might antagonise some of the haemodynamic effects of dipyridamole because they act as competitive antagonists of adenosine (an endogenous vasodilator involved in the action of dipyridamole). Due to these opposing effects, parenteral aminophylline has been used to treat adverse events associated with intravenous dipyridamole, - and it is recommended that aminophylline should be made available before beginning dipyridamole echocardiography. ... 

Patients should therefore abstain from caffeine (tea, coffee, chocolate, cocoa, cola, caffeine-containing analgesics etc.) - and other xanthine derivatives such as theophylline for 24 hours before dipyridamole testing, and if during the test the haemodynamic response is low (e.g. no increase in heart rate) the presence of caffeine should be suspected. ... 

Other calorimetric studies [22] on human blood platelets were performed in order to clarify the mechanism of action of xanthine derivatives in relation to adenosine receptor. In addition, there were investigations on the effect of adenosine and adenosine agonists on platelet metabolism. The results showed that the two xanthine derivatives tested, enprofylline and theophylline, at therapeutic concentrations, did not modify the heat production induced by adenosine. Both adenosine and one adenosine agonist, NECA (5-N-ethyl carboxamide adenosine) increased platelet metabolism. The other adenosine agonist tested, PIA (L-N -phenylisopropyl-adenosine) induced a reduction of heat production. The adenosine uptake inhibitor, dipyridamol, was without effect. Thus, by microcalorimetry, useful information could be obtained concerning the complex mechanisms behind the effects on human cell metabolism of adenosine and adenosine agonists. The same applies to substances used in the treatment of asthma, xanthine derivatives they are thought to act by inhibition of adenosine receptors. 

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