- Paraxanthine (84%): Has the effect of increasing lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.
- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.
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| Caffeine |
Caffeine is a bitter, white crystalline xanthine alkaloid and psychoactive stimulant. Caffeine was first isolated from coffee in 1820 by the German chemist Friedlieb Ferdinand Runge and again in 1821 by French chemists Robiquet, Pelletier, and Caventou. Pelletier first coined the word "cafeine", which became the English word "caffeine".
Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants. It is most commonly consumed by humans in infusions extracted from the bean of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut. Other sources include yerba maté, guarana berries, and the yaupon holly.
In humans, caffeine acts as a central nervous system (CNS) stimulant, temporarily warding off drowsiness and restoring alertness. Caffeine is the world's most widely consumed psychoactive substance, but, unlike many other psychoactive substances, is legal and unregulated in nearly all jurisdictions. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks, enjoy great popularity; in North America, 90% of adults consume caffeine daily. The U.S. Food and Drug Administration (FDA) lists caffeine as a "multiple purpose generally recognized as safe food substance".
Caffeine has diuretic properties when administered in sufficient doses to subjects who do not have a tolerance for it. Regular users, however, develop a strong tolerance to this effect, and studies have generally failed to support the common notion that ordinary consumption of caffeinated beverages contributes significantly to dehydration.
The precise amount of caffeine necessary to produce effects varies from person to person depending on body size and degree of tolerance to caffeine. It takes less than an hour for caffeine to begin affecting the body. An oral dose of 200 mg caffeine appears to decrease reaction time by approximately 4 percent within 30 minutes, approximately 15 percent in 30 to 60 minutes and 18 percent in 60-90 minutes. A mild dose wears off in three to four hours. Consumption of caffeine does not eliminate the need for sleep; it only temporarily reduces the sensation of being tired. Caffeine leads to fewer mistakes caused by tiredness in shift workers.
With these effects, caffeine is an ergogenic, increasing a person's capability for mental or physical labor. A study conducted in 1979 showed a 7% increase in distance cycled over a period of two hours in subjects that consumed a considerable amount of caffeine compared to control subjects. Other studies attained much more dramatic results; one particular study of trained runners showed a 44% increase in "race-pace" endurance, as well as a 51% increase in cycling endurance, after a dosage of 9 milligrams of caffeine per kilogram of body weight. Additional studies have reported similar effects. Another study found 5.5 milligrams of caffeine per kilogram of body mass resulted in subjects cycling 29% longer during high-intensity circuits.
Caffeine citrate has proven to be of short- and long-term benefit in treating the breathing disorders of apnea of prematurity and bronchopulmonary dysplasia in premature infants. The only short-term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine.
Caffeine relaxes the internal anal sphincter muscles and thus should be avoided by those with fecal incontinence.
While relatively safe for humans, caffeine is considerably more toxic to some other animals such as dogs, horses, and parrots due to a much poorer ability to metabolize this compound. Caffeine also has a pronounced effect on mollusks and various insects as well as spiders. (See also Effect of psychoactive drugs on animals.)
Caffeine also increases the effectiveness of some drugs. Many over-the-counter headache drugs include caffeine in their formula. It is also used with ergotamine in the treatment of migraine and cluster headaches as well as to overcome the drowsiness caused by antihistamines.
Caffeine may also have hepatoprotective properties. Studies have shown that increased caffeine consumption is associated with less severe liver injury among those at high risk for liver disease, such as those with alcoholism, obesity, or hemochromatosis. The mechanism by which this occurs is not known.
Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals that regularly consume caffeine adapt to the continuous presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. First, the stimulatory effects of caffeine are substantially reduced, a phenomenon known as a tolerance adaptation. Second, because these adaptive responses to caffeine make individuals much more sensitive to adenosine, a reduction in caffeine intake will effectively increase the normal physiological effects of adenosine, resulting in unwelcome withdrawal symptoms in tolerant users.
Caffeine tolerance develops very quickly, especially among heavy coffee and energy drink consumers. Complete tolerance to the sleep disruption effects of caffeine develops after consuming 400 mg of caffeine 3 times a day for 7 days. Complete tolerance to subjective effects of caffeine was observed to develop after consuming 300 mg 3 times per day for 18 days, and possibly even earlier. In another experiment, complete tolerance of caffeine was observed when the subject consumed 750–1200 mg per day while incomplete tolerance to caffeine has been observed in those that consume more average doses of caffeine. In everyday terms, the typical caffeine content of a single cup or mug of tea or coffee is well below the 300 - 400 mg level: an average mug of instant coffee contains approximately 100mg caffeine, the same level as a cup of brewed coffee. An average mug of tea contains 75mg of caffeine.
Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine due to caffeine withdrawal cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. This means caffeine has vasoconstrictive properties. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate, and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression. Together, these effects have come to be known as a "crash".
Withdrawal symptoms—possibly including headache, irritability, an inability to concentrate, drowsiness, insomnia and pain in the stomach, upper body, and joints—may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days, representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Analgesics, such as aspirin, may relieve the pain symptoms, as may a small dose of caffeine.
In large amounts, and especially over extended periods of time, caffeine can lead to a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and mental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia), insomnia, headaches, respiratory alkalosis, and heart palpitations. Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease. Caffeine may also increase the toxicity of certain other drugs, such as paracetamol.
There are four caffeine-induced psychiatric disorders recognized by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS).
Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90), or colloquially the "caffeine jitters". The symptoms of caffeine intoxication are not unlike overdoses of other stimulants. It may include restlessness, fidgetiness, nervousness, excitement, euphoria, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, and psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.
Extreme overdose can result in death. The median lethal dose (LD50) given orally, is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 80 to 100 cups of coffee for an average adult taken within a limited time frame that is dependent on half-life. Though achieving lethal dose with caffeine would be exceptionally difficult with regular coffee, there have been reported deaths from overdosing on caffeine pills, with serious symptoms of overdose requiring hospitalization occurring from as little as 2 grams of caffeine. An exception to this would be taking a drug such as fluvoxamine or levofloxacin, which block the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine dramatically at 5-fold. It is not contraindicated, but highly advisable to minimize the intake of caffeinated beverages, as drinking one cup of coffee will have the same effect as drinking five under normal conditions. Death typically occurs due to ventricular fibrillation brought about by effects of caffeine on the cardiovascular system.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.
Caffeine is found in many plant species, where it acts as a natural pesticide, with high caffeine levels being observed in seedlings still developing foliage but lacking mechanical protection; caffeine paralyzes and kills certain insects feeding upon the plant. High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine is understood to have a natural function as both a natural pesticide and an inhibitor of seed germination of other nearby coffee seedlings, thus giving it a better chance of survival.
One of the world's primary sources of caffeine is the coffee "bean" (which is the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80–100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee. In general, dark-roast coffee has very slightly less caffeine than lighter roasts because the roasting process reduces a small amount of the bean's caffeine content. Arabica coffee normally contains significantly (+/-50%) less caffeine than the robusta variety. Coffee also contains trace amounts of theophylline, but no theobromine.
Tea is another common source of caffeine. Although tea contains more caffeine than coffee (by dry weight), a typical serving contains much less, as tea is normally brewed much weaker. Besides strength of the brew, growing conditions, processing techniques and other variables also affect caffeine content. Certain types of tea may contain somewhat more caffeine than other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.
Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.
Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine. A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee, although some dark chocolate currently in production contains as much as 160 mg per 100g.
Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness. These effects have been borne out by research that shows caffeine use (whether in tablet form or not) results in decreased fatigue and increased attentiveness. These tablets are commonly used by students studying for their exams and by people who work or drive for long hours. One U.S. company is also marketing dissolving caffeine strips as an alternative to energy drinks.
Caffeine is also used pharmacologically to treat apnea in premature newborns and, as such, is one of the 10 drugs most commonly given in neonatal intensive care, though questions are now raised based on experimental animal research whether it might have subtle harmful side-effects.
Use of the kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health". On March 13, 1911, the government initiated United States v. Forty Barrels and Twenty Kegs of Coca-Cola, hoping to force Coca-Cola to remove caffeine from its formula by making claims the product was adulterated and misbranded. The allegation of adulteration was, in substance, that the product contained an added poisonous or added deleterious ingredient: caffeine, which might render the product injurious to health. It was alleged to be misbranded in that the name 'Coca Cola' was a representation of the presence of the substances coca and cola; that the product 'contained no coca and little if any cola' and thus was an 'imitation' of these substances and was offered for sale under their 'distinctive name.' Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.
The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. In the New World, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.
Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as "black bean".
The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink". Archaeologists have found evidence of this use stretch back far into antiquity, possibly dating to Late Archaic times.
Caffeine from coffee or other beverages is absorbed by the stomach and small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body. Peak blood concentration is reached within one hour. It is eliminated by first-order kinetics. Caffeine can also be ingested rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and chlorobutanol and caffeine (for the treatment of hyperemesis).
The biological half-life of caffeine—the time required for the body to eliminate one-half of the total amount of caffeine—varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. In healthy adults, caffeine's half-life is approximately 4.9 hours. In women taking oral contraceptives, this is increased to 5–10 hours, and in pregnant women the half-life is roughly 9–11 hours.
Caffeine can accumulate in individuals with severe liver disease, increasing its half-life up to 96 hours. In infants and young children, the half-life may be longer than in adults; half-life in a newborn baby may be as long as 30 hours. Other factors such as smoking can shorten caffeine's half-life. Fluvoxamine (Luvox) reduced the clearance of caffeine by 91.3%, and prolonged its elimination half-life by 11.4-fold; from 4.9 hours to 56 hours.
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (to be specific, the 1A2 isozyme) into three metabolic dimethylxanthines, each of which has its own effects on the body:
Each of these metabolites is further metabolized and then excreted in the urine.
Some quinolones, including ciprofloxacin, exert an inhibitory effect on the cytochrome P-450 enzyme CYP1A2, thereby reducing clearance, and thus increasing blood levels of tizanidine and methylxanthines (e.g.caffeine).
There is also research which suggests that alcohol inhibits the metabolism of caffeine in the liver, especially by influencing its demethylation to other dimethyl- and monomethylxanthines.
Caffeine readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors. The caffeine molecule is structurally similar to the aglycone of adenosine, adenine, and is capable of binding the adenosine receptors on the surface of cells without activating them (an "antagonist" mechanism of action), thereby acting as a competitive inhibitor.
Adenosine is found in every part of the body, because it plays a role in the fundamental ATP-related energy metabolism and is necessary for RNA synthesis, but it has special functions in the brain. There is a great deal of evidence that concentrations of brain adenosine are increased by various types of metabolic stress including anoxia and ischemia. The evidence also indicates that brain adenosine acts to protect the brain by suppressing neural activity and also by increasing blood flow through A2A and A2B receptors located on vascular smooth muscle. By counteracting adenosine, caffeine reduces resting cerebral blood flow between 22% and 30%. Caffeine also has a generally disinhibitory effect on neural activity. It has not been shown, however, how these effects cause increases in arousal and alertness.
Adenosine is released in the brain through a complex mechanism. There is evidence that adenosine functions as a synaptically released neurotransmitter in some cases, but stress-related adenosine increases appear to be produced mainly by extracellular metabolism of ATP. It is not likely that adenosine is the primary neurotransmitter for any group of neurons, but rather that it is released together with other transmitters by a number of neuron types. Unlike most neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in a voltage-controlled manner, but the possibility of such a mechanism has not been completely ruled out.
Several classes of adenosine receptors have been described, with different anatomical distributions. A1 receptors are widely distributed, and act to inhibit calcium uptake. A2A receptors are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lower densities. There is evidence that A 2A receptors interact with the dopamine system, which is involved in reward and arousal. (A2A receptors can also be found on arterial walls and blood cell membranes.)
Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be more specifically involved in control of the sleep-wake cycle. Robert McCarley and his colleagues have argued that accumulation of adenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that the effects may be mediated both by inhibition of wake-promoting neurons via A1 receptors, and activation of sleep-promoting neurons via indirect effects on A2A receptors. More recent studies have provided additional evidence for the importance of A2A, but not A1, receptors.
Some of the secondary effects of caffeine are probably caused by actions unrelated to adenosine. Like other methylated xanthines, caffeine is both a
1. competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity.
2. nonselective adenosine receptor antagonist (see above).
Phosphodiesterase inhibitors inhibit cAMP-phosphodiesterase (cAMP-PDE) enzymes, which convert cyclic AMP (cAMP) in cells to its noncyclic form, thus allowing cAMP to build up in cells. Cyclic AMP participates in activation of protein kinase A (PKA) to begin the phosphorylation of specific enzymes used in glucose synthesis. By blocking its removal, caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, and methylphenidate. Increased concentrations of cAMP in parietal cells causes an increased activation of protein kinase A (PKA), which in turn increases activation of H+/K+ ATPase, resulting finally in increased gastric acid secretion by the cell. Cyclic AMP also increases the activity of the funny current, which directly increases heart rate. Caffeine is also a structural analogue of strychnine and, like it (though much less potent), a competitive antagonist at ionotropic glycine receptors.
Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency.
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