The Fluoroquinolone Toxicity Research Foundation

 
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Subject: Re: Caffeine theophylline and Andenosine Receptors

Quinolones are associated with several clinically significant drug
interactions. Some of these agents are well-documented inhibitors of hepatic metabolism of theophylline, caffeine, and warfarin
http://pharminfo.com/pubs/msb/adenosine.html Adenosine is an endogenous purine nucleoside with potent atrioventricular
(AV) nodal blocking activity. The efficacy of adenosine for supraventricular arrhythmias was first described in 1933, but since it is a naturally occuring compound and thus cannot be patented, there was not much incentive to develop a product for the commercial market. However, in the last nine years or so adenosine has been intensively studied, and today it is widely used for terminating paroxysmal supraventricular tachycardia (PSVT) and as a diagnostic agent in narrow-QRS-complex or wide-complex tachycardia of uncertain cause. In the United States, adenosine (Adenocard Injection/Fujisawa) is approved only for terminating PSVT. Adenosine is formed naturally in the
body as a product of the enzymatic breakdown of adenosine triphosphate or S-adenosylhomocysteine. After intravenous (IV) administration, adenosine is almost completely eliminated after a single pass through the coronary circulation. It is rapidly taken up from plasma into red blood cells and blood vessel endothelial cells where it is converted to
adenosine-5'-monophosphate, inosine, or both . Inosine is further degraded to hypoxanthine and uric acid. Methylxanthines -- caffeine or theophylline -- block the adenosine receptor and thus prevent the pharmacologic effect of adenosine on the heart, while dipyridamole potentiates and prolongs the effects

http://bisleep.medsch.ucla.edu/SRS/srs/radulovacki.htm
Then in 1982 while working on my lecture on CNS stimulants in a regular
pharmacology course for medical students, I found a paper by Snyder et al. (1981) describing the newly observed mechanism of action of methylxanthines. The authors said that methylxanthines, i.e., caffeine and theophylline,produce behavioral excitation not by blocking the enzyme phosphodiesterase (as had been universally accepted) but by blocking adenosine receptors. The authors found that micromolar concentrations of theophylline are sufficient to block adenosine receptors and produce behavioral excitation whereas millimolar concentrations of theophylline are needed to block phosphodiesterase. I had no idea what adenosine may be doing in the CNS and my library search produced papers by Phillis et. al. (1979), Phillis and Wu
(1981) and Stone (1981) which showed that general neurophysiological effects of adenosine were inhibitory. Then, in the middle of my lecture to M-2 students I thought: If methylxanthines produce behavioral excitation by blocking adenosine receptors, would stimulation of adenosine receptors produce sleep?


Caffeine from dietary sources (mainly coffee, tea and soft drinks) is the most frequently and widely consumed CNS stimulant in the world today. Because of its enormous popularity, the consumption of caffeine is generally thought to be safe and long term caffeine intake may be disregarded as a medical problem. However, it is clear that this compound has many of the features usually associated with a drug of abuse. Furthermore, physicians should be aware of the possible contribution of dietary caffeine to the presenting signs and symptoms of patients. The toxic effects of caffeine are extensions of their pharmacological effects. The most serious caffeine-related CNS effects include seizures and delirium. Other symptoms affecting the cardiovascular system range from moderate increases in heart rate to more severe cardiac arrhythmia. Although tolerance develops to many of the pharmacological effects of caffeine, tolerance may be overwhelmed by the nonlinear accumulation of caffeine when its metabolism becomes saturated.

This might occur with high levels of consumption or as the result of a
pharmacokinetic interaction between caffeine and over-the-counter or
prescription medications. Thepolycyclic aromatic hydrocarbon-inducible
cytochrome P450 (CYP) 1A2 participates in the metabolism of caffeine as well as of a number of clinically important drugs. A number of drugs, including certain selective serotonin reuptake inhibitors (particularly fluvoxamine), antiarrhythmics (mexiletine), antipsychotics (clozapine), psoralens, idrocilamide and phenylpropanolamine, bronchodilators (furafylline and theophylline) and quinolones (enoxacin), have been reported to be potent inhibitors of this isoenzyme. This has important clinical implications, since drugs that are metabolised by, or bind to, the same CYP enzyme have a high potential for pharmacokinetic interactions due to inhibition of drug metabolism. Thus, pharmacokinetic interactions at the CYP1A2 enzyme level may
cause toxic effects during concomitant administration of caffeine and certain drugs used for cardiovascular, CNS (an excessive dietary intake of caffeine has also been observed in psychiatric patients), gastrointestinal, infectious, respiratory and skin disorders. Unless a lack of interaction has already been demonstrated for the potentially interacting drug, dietary caffeine intake should be considered when planning, or assessing response to, drug therapy. Some of the reported interactions of caffeine, irrespective of clinical relevance, might inadvertently cause athletes to exceed the urinary caffeine concentration limit set by sports authorities at 12 mg/L. Finally,
caffeine is a useful and reliable probe drug for the assessment of CYP1A2 activity, which is of considerable interest for metabolic studies in human populations.