| Elsa-Grace Giardina, MD |
Aug 12, 1999 |
The methylated xanthine derivative caffeine (1,3,7- trimethylxanthine) is widely distributed in nature as a plant alkaloid. Consumed in coffee, tea, and soft drinks, caffeine is the most widely used pharmacologically active substance in the world and its exposure dates from ancient history to the present. Exposure to caffeine is generally of long duration, virtually throughout the life of most consumers and the prevalence of exposure is very high (more than 80 percent) in most countries.
Caffeine has a number of physiologic effects on the cardiovascular and central nervous systems that may assume clinical importance. These responses will be reviewed here.
PHARMACOKINETICS ！ Caffeine is absorbed after oral, rectal, or parenteral administration, and maximal concentration is achieved in one hour [1]. Oral bioavailability is almost 100 percent; food ordinarily slows the rate of absorption but does not limit the extent. Caffeine is distributed into all body compartments; it crosses the placenta and passes into breast milk. The apparent volume of distribution is between 0.4 and 0.6 L/kg and less than 40 percent is bound to plasma proteins.
Metabolism primarily occurs in the liver by demethylation and oxidation, with less than 5 percent being recovered in the urine unchanged. The major metabolic pathway in humans is through the formation of paraxanthine (1,7-dimethylxanthine), leading to the principal urinary metabolites, 1-methylxanthine, 1-methyluric acid, and an acetylated uracil derivative. A minor pathway involves the formation of theophylline and theobromine and their subsequent metabolism.
The average half-life in plasma is five hours, with a range of three to seven hours. The half-life may increase twofold in the last trimester of pregnancy, but is somewhat shorter in children (three to four hours) [2]. However, there is marked interindividual variation in the rate of elimination due to genetic and environmental influences. In most patients, the drug obeys first-order kinetics, while zero-order kinetics occur at higher concentrations because of saturation of metabolic enzymes.
There are several factors that influence the plasma caffeine concentration, but the main determinants are the elimination half-life and time since the drug was last consumed. Since the half-life in humans is about five hours, and the drug is usually consumed in separate doses throughout the day, the plasma caffeine concentration is normally highest in the late afternoon and lowest in the early hours upon awakening [3,4]. Overnight abstinence of 8 to 12 hours leads to significant depletion of systemic caffeine by early morning, rendering the subject sensitive to its effects when reexposure occurs [4]. The main sources of caffeine and the amount found in typical sources in the United States are listed in Table 1 (show table 1).
There is an association between plasma levels of caffeine and toxicity and the activity of hepatic cytochrome CYP1A2. A study of 120 normal healthy volunteers found that CYP1A2 activity, gender, and smoking influenced the toxicity of caffeine; in particular females and nonsmokers who experienced toxic effects had a lower caffeine N3-demethylation index (a measure of CYP1A2 activity) compared to females and nonsmokers who did not experience toxicity [5].
EFFECTS ON THE CENTRAL NERVOUS SYSTEM ！ Caffeine is a potent stimulant of the central nervous system (CNS) and persons ingesting caffeine usually experience less drowsiness and less fatigue than others; there is also an increase in basal metabolic rate [6]. The major mechanism underlying these effects is thought to be antagonism of the adenosine receptors [7]. Signs of excess CNS stimulation include nervousness or anxiety, restlessness, insomnia, tremors and tingling sensations. At still higher doses, convulsions may occur [1,3,8].
EFFECTS ON THE HEART ！ Caffeine can affect cardiovascular hemodynamics as well as the electrophysiologic properties of the heart.
Molecular mechanisms ！ A number of molecular mechanisms have been detected in vitro for methylxanthines, but only some which take place at reasonably low concentrations are involved in the responses observed in vivo. These include:
• Inhibition of phosphodiesterase, which results in an elevation in myocardial cyclic AMP and a positive inotropic action on the myocardium
• Inhibition of adenosine receptors, possibly preventing the negative inotropic effect elicited by adenosine [9]
• Facilitation of norepinephrine release from sympathetic nerve endings [10]
• Increase in intracellular calcium, which is mediated at high doses of caffeine by inhibition of calcium reuptake into the sarcoplasmic reticulum and at low doses by calcium release from the sarcoplasmic reticulum [11].
• Increase in sensitivity of the myofilaments to calcium [12,13]
Although the methylxanthines have a positive inotropic effect, they are not used as primary agents in the treatment of heart failure since the risks and adverse effects from their stimulatory effect on the nervous system and on cardiac rhythm outweigh any potential benefits of increased inotropy.
Electrophysiologic effects ！ High concentrations of caffeine can directly increase the transmembrane calcium current which is responsible for the oscillatory afterpotential (ie, triggered activity) [14,15]. In experimental models, even low concentrations of caffeine can increase triggered activity due to release of calcium from the sarcoplasmic reticulum [12,16].
There is a widespread belief that caffeine, particularly at high doses, is associated with palpitations and a number of arrhythmias, including atrial fibrillation and supraventricular and ventricular ectopy [17]. This putative relationship may result from triggered activity or enhanced sympathetic tone [18]. However, despite the theoretical relationship between caffeine and arrhythmogenesis, there is no evidence in humans that caffeine can provoke any spontaneous arrhythmia or enhance the ability to induce an arrhythmia in the electrophysiologic laboratory [10,19,20,21]. Furthermore, among patients with arrhythmia, caffeine restriction has not been of benefit [22] and the administration of a modest dose of caffeine is not arrhythmogenic, even among patients with known life-threatening ventricular arrhythmia [23].
Hemodynamic effects ！ Caffeine can, in patients who are infrequently exposed, acutely raise the blood pressure (BP) by as much as 10 mmHg [24,25,26]. It can also potentiate (by about 5 mmHg) the rise in blood pressure induced by stress, such as that occurring in the workplace [27]. The increase in vascular resistance associated with these changes also involves the cerebral and coronary circulations [7,28].
The effect of chronic caffeine ingestion is less clear. It does not appear to be associated with an increased incidence of hypertension due to attenuation of the pressor response [29,30,31]. However, there is some evidence that chronic caffeine use can cause a small elevation in blood pressure. A meta-analysis of eleven controlled clinical trials found that coffee ingestion (median dose of five cups per day) increased systolic and diastolic blood pressure by 2.4 and 1.2 mmHg, respectively [32]. Similar reductions in blood pressure may be seen when habitual coffee drinkers either abstain from coffee or switch to decaffeinated coffee [30,33,34]. The hypertensive effect may be more prominent in elderly patients with hypertension [35].
The acute caffeine-induced pressor effect is probably mediated by vasoconstriction resulting from antagonism of endogenous adenosine [7,36]. There may also be a contribution from primary actions on the brain stem or heart, with reinforcement by autonomic reflexes and increased circulating catecholamine concentrations. On the other hand, upregulation of adenosine receptors probably explains the tolerance to chronic caffeine ingestion [36].
The likelihood of a pressor response also appears to be determined by the pharmacokinetics of caffeine in each individual. This was illustrated in a study of normotensive habitual coffee drinkers who ingested coffee after caffeine abstinence of 4.5 individual caffeine half-lives; the ensuing increase in blood pressure was inversely related to the baseline plasma caffeine concentration [37]. Thus, rapid metabolizers of caffeine are more likely to have a pressor response after drinking coffee, despite the phenomenon of adaptation.
Vascular disease ！ There has been considerable controversy about the effects of coffee intake on coronary artery disease. The Health Professionals Study, which prospectively followed 45,589 men over a two year period, found no relationship between coffee, caffeine, and tea intake and the incidence of coronary heart disease or cerebrovascular disease [38].
NUTRITIONAL VALUE ！ Caffeine has no nutritional value and the general benefits that are claimed for the drug, such as enhanced work capacity, are unfounded. Boiled coffee increases serum total and LDL-cholesterol. In one trial, for example, four to six cups of boiled coffee per day for nine weeks raised these values by 18 and 15 mg/dL [0.48 and 0.39 mmol/L], respectively; no changes were cholesterol levels were seen in subjects drinking a similar amount of filtered coffee or no coffee at all [39]. The hyperlipidemic effect is due to coffee lipid compounds (cafestol) which are removed when the beverage is prepared with a paper filter [40].