Caffeine adenosine receptor

Caffeine adenosine receptor (antagonistic) phosphodiesterase inhibitor... 

W 0 (X X w High dose T Ca++ permeability in sarcoplasmic reticulum and T cAMP by inhibiting phosphodiesterase. Stimulates CNS, constricts cerebral arterioles, induces diuresis, stimulates heart, bronchodilates. Prolonged apnea in pre-term infants (unlabeled use). Included in some over-the counter analgesic preps, particularly headache remedies. Insomnia, restlessness, anxiety neurosis, nausea, tachycardia, diuresis. 

Beyond Viagra, there are a number of other PDE inhibitors that are used clinically. In fact, the classic drugs papaverine and dipyridamole were used clinically before their effects on PDEs were known. Caffeine and theophylline (a compound found in tea) are also PDE inhibitors. However, all of these drugs most likely have multiple targets, making conclusions regarding the roles of PDEs in processes that are sensitive to these agents difficult to interpret. Certainly, some of their effects are due to their actions on adenosine receptors. 

Caffeine binds to adenosine receptors in the brain, preventing adenosine from inducing sleep or opening blood vessels. Caffeine also increases levels of dopamine, the neurotransmitter associated with pleasure. This is the chemical mechanism for addiction. The response to adenosine competition causes increased adrenaline flow. 

The body responds to chronic presence of caffeine by increasing the number of adenosine receptor sites. This may be one of the reasons for the increased tolerance (and decreased efficacy as a stimulant) to caffeine in heavy coffee and tea drinkers. 

The often severe headaches, common in caffeine withdrawal, appear to be caused by vasodilation of cerebral blood vessels. This action is probably mediated by the action of the methylxanthines on adenosine receptors. 

Three major mechanisms of action have dominated as possible explanations for the ergogenic potential of caffeine in the enhancement of exercise performance. These three mechanisms involve (1) the mobilization of intracellular calcium from the sarcoplasmic reticulum of skeletal muscle, (2) the increase of cyclic-3 ,5 -adenosine monophosphate (cAMP) by the inhibition of phosphodiesterases in muscles and adipocytes, and (3) the competitive antagonism of adenosine receptors, primarily in the central nervous system (CNS).8 9... 

Zhang, Y. and Wells, J., The effects of chronic caffeine administration on peripheral adenosine receptors, Journal of Pharmacology and Experimental Therapeutics, 254, 757, 1990. 

The main mechanism of action of caffeine occurs via the blockade of adenosine receptors in the CNS. Adenosine is an autacoid, which is involved in the modulation of behavior, oxygenation of cells, and dilatation of cerebral and coronary blood vessels and indirectly inhibits the release of dopamine. The blockade of adenosine receptors by caffeine increases the activity of dopamine, which is implicated in the effects of caffeine (91). The question that arises from this observation is to know whether or not adenosine antagonists hold potential for the treatment of Parkinsonism, and further study on the adenosine receptor antagonists from medicinal plants should be encouraged. A possible source for such agents could be the medicinal flora of Asia and the Pacific, among which is the family Sapindaceae. 

Virus, R. M., Ticho, S., Pilditch, M. Radulovacki, M. (1990). A comparison of the effects of caffeine, 8-cyclopentyltheophylline, and alloxazine on sleep in rats. Possible roles of central nervous system adenosine receptors. Neuropsychopharmacology 3 (4), 243-9. 

Although caffeine is known to mobilize intracellular calcium, to inhibit phosphodiesterase activity, and to increase in vitro 5-HT and NE concentrations in the brainstem (Garrett and Griffiths 1997 Berkowitz et al. 1970 Carter et al. 1995 Solinas et al. 2002), it is now widely accepted that the mechanism of action of caffeine on wakefulness, at least at the dose range produced by voluntary caffeine intake, is via the antagonism of adenosine receptors. 

Caffeine The psychostimulant found in colfee, tea and a wide variety of carbonated soft drinks. Chemically related to the purine neurotransmitter adenosine, the drug blocks adenosine receptors in the nervous system. 

Sawynok J. (1995). Pharmacological rationale for the clinical use of caffeine. Drugs. 49(1) 37-50. Sawynok J. (1998). Adenosine receptor activation and nociception. Eur J Pharmacol. 347(1) 1-11. Schlaepfer TE, Strain EC, Greenberg BD, Preston KL, Lancaster E, Bigelow GE, Barta PE, Pearlson GD. (1998). Site of opioid action in the human brain mu and kappa agonists subjective and cerebral blood flow effects. Am J Psychiatry. 155(4) 470-73. 

The plasma concentrations of caffeine in the rats exposed to the 0.25 and 1.0 mg ml solutions were within the range of those fonnd in typical users of caffeinated beverages. Caffeine may weakly stimnlate dopamine mechanisms via its antagonist action at adenosine receptors (Herrera-Marschitz et al. 1988 Casas et al. 1989 Ferre et al. 1992 Fredholm et al. 1999), and in small doses it may have enhanced the dopaminergic component in the nicotine discriminative stimulns through an effect... 

The generic name of the cacao tree (Theobroma) means food of the Gods and gives its name to a caffeine-like stimulant, theobromine (a methylxanthine). It has been claimed that the theobromine in chocolate is responsible for its addictive characteristics. This is based on the fact that methylxanthines bind to adenosine receptors in the central nervous system and act as antagonists to this neurotransmitter (Chapter 14). However, another group of substances, the amides formed between ethanolamine and unsaturated fatty acids, are also possible candidates for the title of the chocolate drug . 

Changes in the activity of adenosine receptors have been implicated in the stimulant effects of drugs like caffeine. Carbamazepine exhibits a partial agonist effect on adenosine receptors, and experimental evidence suggests that the reduced reuptake and release of noradrenaline caused by the drug are due to its interaction with these receptors. The precise relevance of these findings to its anticonvulsant and psychotropic effects is presently unclear. 

Purine derivatives with neurotransmitter function are all derived from adenine-containing nucleotides or nucleosides. ATP is released along with acetylcholine and other transmitters, and among other functions it regulates the emission of transmitters from its synapse of origin. The stimulatory effect of caffeine is mainly based on the fact that it binds to adenosine receptors. 

There are a number of possible ways that caffeine can exert its effects, but the most probable action, particularly at concentrations from common consumption, is blockage of the adenosine receptor. Adenosine is a neurotransmitter that produces a calming effect. Caffeine blocks the receptors that are activated by adenosine, which results in stimulation (Figure 4-3). There is additional evidence that over time the cells of the nervous system respond to the blockage of adenosine receptors by increasing or up-regulating the number of adenosine receptors. 

Caffeine is the most widely consumed stimulant drug in the world. It occurs naturally in coffee, tea, and the cola nut and is added to many soft drinks. Many of us consume coffee and soft drinks because of the desirable stimulatory effects produced by caffeine many of us have consumed too much caffeine and felt the consequences. The undesirable effects of caffeine, the agitation, the inability to concentrate, the mild tremors, and the general unpleasantness, are a form of neurotoxicity. Literally your brain, and more specifically, the adenosine receptors in your brain, has too much caffeine. These effects are a reversible form of neurotoxicity. Fortunately, we metabolize caffeine quickly and the undesirable effects end. By experience we have learned how to moderate our caffeine consumption to avoid the unpleasant side effects. A great deal of money is made from the neuroactive and physiological effects of caffeine. You can learn more about this fascinating drug in the chapter on caffeine. 

Table 15.2 provides just a few examples of different neuroactive agents and their mechanism of action. Caffeine, the most widely consumed stimulant drug in the world, works by affecting the adenosine receptor. Adenosine is a naturally occurring depressant, so caffeine works by blocking the depressive actions of adenosine, causing stimulation. 

Caffeine is a known inhibitor of phosphodiesterase. Caffeine has an effect on calcium-mediated signalling namely it causes an increase of cAMP activity. Caffeine also has a competitive effect on the central adenosine receptor and is thought to increase analgesic activity. It is also known to be somewhat effective... 

Use of caffeine has also been recommended to lower the threshold in patients who do not experience an adequate seizure (104,105 and 106). One report, however, found that caffeine appeared to produce neuronal damage in rats receiving ECS (107). Because adenosine may have neuroprotective effects, one postulated mechanism is the ability of methyixanthines (e.g., caffeine, theophylline) to block adenosine receptors. On a positive note, studies have not found a difference in cognitive disruption between patients receiving ECT with or without caffeine (108). Although the implications of the animal data for humans are not clear, and because shorter seizures may be effective in some patients, a conservative approach would be to augment with caffeine only when seizure duration is less than 20 seconds and response is inadequate ( 38). Alternatively, it may be appropriate to switch to BILAT electrode placement or from methohexital to etomidate when UND electrode stimulation produces inadequate seizure duration (even at maximal stimulus intensity) and response is insufficient ( 97, 98). 

Adenosine is a nucleoside that occurs naturally throughout the body. Its half-life in the blood is less than 10 seconds. Its mechanism of action involves activation of an inward rectifier K+ current and inhibition of calcium current. The results of these actions are marked hyperpolarization and suppression of calcium-dependent action potentials. When given as a bolus dose, adenosine directly inhibits atrioventricular nodal conduction and increases the atrioventricular nodal refractory period but has lesser effects on the sinoatrial node. Adenosine is currently the drug of choice for prompt conversion of paroxysmal supraventricular tachycardia to sinus rhythm because of its high efficacy (90-95%) and very short duration of action. It is usually given in a bolus dose of 6 mg followed, if necessary, by a dose of 12 mg. An uncommon variant of ventricular tachycardia is adenosine-sensitive. The drug is less effective in the presence of adenosine receptor blockers such as theophylline or caffeine, and its effects are potentiated by adenosine uptake inhibitors such as dipyridamole. 

Caffeine is a weak diuretic because it nonspecifically and weakly blocks adenosine receptors that participate in the control of proximal tubule Na+ reabsorption in the kidney. A new class of drugs, the adenosine A1 receptor antagonists, have recently been found to have potent vasomotor effects in the renal microvasculature and to significantly blunt both proximal tubule and collecting duct NaCI reabsorption (see under Heart Failure). One of these drugs, rolofylline (KW-3902), should soon receive final Food and Drug Administration (FDA) approval. 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

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