Caffeine, or 1,3,7-trimethylxanthine, is related structurally to uric acid. It is metabolized by demethylation and oxidation. The major human pathway results in paraxanthine (1,7-dimethylxanthine), leading to the principal urinary metabolites, L-methylxanthine, 1-methyluric acid, and an acetylated uracil derivative. Minor degradation pathways involve the formation and metabolism of theophylline and theobromine. No evidence exists to suggest that methylxanthines are converted to uric acid or that their ingestion can exacerbate gout.

The rate of elimination of methylxanthines varies from one individual to another, depending on both genetic and environmental factors, and 4-fold differences are not uncommon. In most cases, metabolism obeys first-order elimination kinetics within the therapeutic range. At higher concentrations, however, zero-order kinetics occur with the saturation of metabolic enzymes. This prolongs the decline of caffeine concentrations.

The metabolism of methylxanthines is also influenced by the presence of other agents or specific diseases. For example, cigarette smoking and oral contraceptives produce a small but appreciable increase in methylxanthine clearance. The half-life of theophylline can be prolonged significantly in patients with hepatic cirrhosis, congestive heart failure, or acute pulmonary congestion; values exceeding 60 hours have been reported.

Caffeine has a half-life in plasma of 3-7 hours; this increases approximately 2-fold in women who are in the later stages of pregnancy or are long-term users of oral contraceptive steroids.

Cellular basis of action

The diverse effects of methylxanthines are probably attributable to the following 3 basic cellular actions, listed in order of increasing importance:

Translocations of intracellular calcium

Increasing accumulation of cyclic nucleotides

Adenosine receptor blockade

The ability of methylxanthines to inhibit cyclic nucleotide phosphodiesterases is often cited to explain their therapeutic effects; however, strong evidence for this theory is lacking. Plasma caffeine concentrations that raise blood pressure are below the threshold for phosphodiesterase inhibition. Thus, phosphodiesterase inhibition is probably not important to the therapeutic effects of methylxanthines.

At high concentrations (0.5-1 mmol/L), caffeine interferes with the uptake and storage of calcium by the sarcoplasmic reticulum in striated muscles. This action can account for the observations that such concentrations of caffeine increase the strength and duration of contractions in both skeletal and cardiac muscles. Similar actions can enhance secretion in certain tissues. However, they are unlikely to play an important role at therapeutic concentrations.

In vitro, methylxanthines (at concentrations of approximately 0.2 mmol/L or higher) generally cause relaxation of vascular smooth muscles in the presence of various stimulators of contraction (eg, norepinephrine and angiotensin). Although this relaxation probably results from a reduction of the cytosolic calcium concentration, it is unclear to what extent methylxanthines can alter calcium binding and transport, either directly or indirectly, by altering cyclic nucleotide metabolism.

Thus, adenosine receptor blockade appears to be the predominant mode of action. Methylxanthines act as competitive antagonists at adenosine receptors at concentrations well within the therapeutic range. The effects of exogenous adenosine frequently oppose those of methylxanthines, and in some experimental settings, removing ambient adenosine (by adding adenosine deaminase) can reproduce the actions of methylxanthines. Plasma concentrations of caffeine that raise blood pressure are within the range for antagonism of adenosine receptors.

Several other caffeine actions that have received relatively little attention to date might prove to be important for certain methylxanthine effects. These include their potentiation of inhibitors of prostaglandin synthesis and the possibility that methylxanthines reduce the uptake or metabolism of catecholamines in nonneuronal tissues.

Effects on central nervous system

Most of the pharmacologic effects of adenosine in the animal brain can be suppressed by relatively low concentrations of circulating caffeine (less than 100 µmol/L, the equivalent of 1-3 cups of coffee). Adenosine decreases the neuronal firing rate and inhibits both synaptic transmission and the release of most neurotransmitters. Caffeine also increases the turnover of many neurotransmitters, including monoamines and acetylcholine.

The A1 and A2a adenosine receptors are the subtypes primarily involved in the caffeine effect, with A2b and A3 receptors playing only a minor role. The A1 receptors are linked negatively to adenyl cyclase, whereas the A2a receptors are linked positively to this enzyme. Adenosine A1 receptors are distributed widely throughout the brain, with high levels in the hippocampus, cerebral and cerebellar cortex, and thalamus.

Conversely, A2a receptors are located almost exclusively in the striatum, nucleus accumbens, and olfactory tubercle. In the latter regions, A2a receptors are coexpressed with enkephalin and dopamine D2 receptors in striatal neurons. Direct evidence exists for a central functional interaction between adenosine A2a and dopamine D2 receptors. Indeed, administration of adenosine A2a receptor agonists decreases the affinity of dopamine for D2 receptors in striatal membranes.

Interaction between adenosine A2a receptors and dopamine D2 receptors in the striatum might underlie some of the behavioral effects of methylxanthines. By antagonizing the negative modulatory effects of adenosine receptors on dopamine receptors, caffeine leads to inhibition and blockade of adenosine A2 receptors, causing potentiation of dopaminergic neurotransmission. The latter interaction might explain the adenosine receptor antagonist–induced increase in behaviors related to dopamine (eg, caffeine-induced rotational behavior).

Clinical studies of central nervous system arousal

In a Dutch study, 11 patients who received either caffeine (250 mg) or placebo were asked to attend selectively to stimuli of a specified color (red or blue) and to react to the presence of a target in the attended category. [3] Reactions were faster in the caffeine group, but no intergroup differences in strategy were observed. Caffeine thus appeared to be associated with a higher overall arousal level, better processing of attended and unattended information, and more rapid motor processes. In addition, there is a growing body of evidence that caffeine has a significant effect on the sleep-wake cycle and on circadian rhythm. [4, 5]

Quinlan et al reported 2 studies evaluating different caffeine levels and different caffeine sources. [6] In study 1, tea and coffee were prepared at different strengths, and control subjects received water or no drinks. Both tea and coffee yielded mild autonomic stimulation and mood elevation. Neither the source (tea or coffee) nor the dose significantly influenced the effects of the caffeine, despite a 4-fold variation in the dose. Greater beverage strength was correlated with greater increases in diastolic blood pressure (DBP) and significant arousal.

In study 2, only the caffeine level was manipulated, with varying amounts of caffeine added to water or decaffeinated tea. [6] Systolic blood pressure (SBP), DBP, and skin conductance were increased in the caffeine group, and heart rate and skin temperature were reduced in those who received water. A significant dose-response relation to caffeine was documented only for SBP, heart rate, and skin temperature. Although caffeine significantly affected arousal, no dose-response effects could be consistently demonstrated.

In a double-blind controlled study of younger experienced drivers, Reyner and Horn found that 200 mg caffeine (delivered via coffee) reduced early morning driver sleepiness for about 30 minutes after sleep deprivation and for about 2 hours after sleep restriction. [7] In the caffeine group, sleep incidents were significantly reduced for the first 30 minutes, and subjective sleepiness was reduced for 1 hour.

In a placebo-controlled study of the effects of caffeine on learning and retrieval sessions, Herz et al found that whereas caffeine 5 mg/kg reliably increased arousal, it did not affect any emotional characteristics related to pleasure, nor did it have any effect on memory. [8]

Overusing paracetamol-caffeine-aspirin (PCA) powders affects regional brain glucose metabolism in persons with chronic migraine. Increased metabolism in the right insula may be associated with recurrently overusing of PCA powders. [9]