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Caffeine is a xanthine alkaloid compound that acts as a stimulant in humans. Caffeine is sometimes called guaranine when found in guarana, mateine when found in mate, and theine when found in tea. It is found in the leaves and beans of the coffee plant, in tea, yerba mate, and guarana berries, and in small quantities in cocoa, the kola nut and the Yaupon Holly. Overall, caffeine is found in the beans, leaves, and fruit of over 60 plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding upon them. Caffeine is a central nervous system (CNS) stimulant, having the effect of temporarily warding off drowsiness and restoring alertness. Beverages containing caffeine, such as coffee, tea, soft drinks and energy drinks enjoy great popularity: caffeine is the world's most widely consumed psychoactive substance. In North America, 90% of adults consume caffeine daily.• Many natural sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine and other substances such as tannins.
Sources | class="toccolours" border="1" width="35%" cellpadding="1" cellspacing="0" style="float: right; clear: right; margin: 2em 0 1em 2em; border-collapse: collapse; font-size: 85%" |- | colspan=3 align=center style="background: Tea is another common source of caffeine. Tea usually contains about half as much caffeine per serving as coffee, depending on the strength of the brew. Certain types of tea, such as black and oolong, contain somewhat more caffeine than most other teas. Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation has a significant impact on tea, and color is a very poor indicator of caffeine content.• Teas like the green Japanese gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little. Chocolate derived from cocoa contains a small amount of caffeine. Chocolate is a weak stimulant, which is mostly due to its content of theobromine and theophylline.• It contains too little of these compounds for a reasonable serving to create effects in humans that are on par with coffee. A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee. Caffeine is also a common ingredient of soft drinks such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 milligrams to 50 milligrams of caffeine per serving. By contrast, energy drinks such as Red Bull contain as much as 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.• History of use
Effects Caffeine is a central nervous system and metabolic stimulant,• Consumption of caffeine does not eliminate the need for sleep: it only temporarily reduces the sensation of being tired. With these effects, caffeine is an ergogenic: increasing the capacity 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 who consumed caffeine compared to control tests.• 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.• The extensive boost shown in the runners is not an isolated case; 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 is sometimes administered in combination with medicines to increase their effectiveness. Caffeine makes pain relievers 40% more effective in relieving headaches and helps the body absorb headache medications more quickly, bringing faster relief.• For this reason, 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. Breathing problems in premature infants, apnea of prematurity, are sometimes treated with citrated caffeine, which is available only by prescription in many countries.• A reduction in bronchopulmonary dysplasia has been exhibited in premature infants treated with caffeine citrate therapy regimens. It is speculated that this reduction in bronchopulmonary dysplasia is tied to a reduction in exposure to positive airway pressure. The only short term risk associated with this treatment is a temporary reduction in weight gain during the therapy.• 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 has a much more significant effect on spiders, for example, than most other drugs do. Overuse Caffeine is a drug that in large amounts, especially over an extended period of time, can lead to a condition termed "caffeinism." Caffeinism usually combines physical addiction with a wide range of unpleasant physical and mental conditions including nervousness, irritability, anxiety, tremulousness, muscle twitching (hyperreflexia), insomnia, and heart palpitations.• (Under a rigid definition of addiction, meaning a process of escalating use, "caffeine dependency" would be a more descriptive term. However, under the widely accepted definition "chronic pattern of behavior that is perceived to be difficult to quit," caffeine may be said to be addictive.) Furthermore, because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease.• However, since both "regular" and decaffeinated coffees have also been shown to stimulate the gastric mucosa and increase stomach acid secretion, caffeine is probably not the only component of coffee responsible.• 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 intoxication An acute overdose of caffeine, usually in excess of 250 milligrams (more than 2-3 cups of brewed coffee), can result in a state of central nervous system overstimulation called caffeine intoxication. The symptoms of caffeine intoxication may include restlessness, nervousness, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irregular or rapid heart beat, and psychomotor agitation.• In cases of extreme overdose, death can result. The median lethal dose (LD50) of caffeine is 192 milligrams per kilogram in rats.• The LD50 of caffeine is dependent on weight and individual sensitivity and estimated to be about 150 to 200 milligrams per kilogram of body mass, roughly 140 to 180 cups of coffee for an average adult taken within a limited timeframe 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 intentional overdosing on caffeine pills.•••• 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. Anxiety and sleep disorders Long-term overuse of caffeine can elicit a number of psychiatric disturbances. Two such disorders recognized by the APA are caffeine-induced sleep disorder and caffeine-induced anxiety disorder. In the case of caffeine-induced sleep disorder, an individual regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention.• Because this condition can mimic organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, or even schizophrenia, a number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated when the treatment for caffeine-induced psychosis would simply be to withhold further caffeine.• A Study in the British Journal of Addiction concluded that caffeinism, although infrequently diagnosed, may afflict as many as one person in ten of the population.• Metabolism Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. After ingestion it is distributed throughout all tissues of the body and is eliminated by first-order kinetics.• The half-life of caffeine — the time required for the body to eliminate one-half of the total amount of caffeine consumed at a given time — 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 3-4 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 when its half-life can increase 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.• Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system (specifically, the 1A2 isozyme) into three metabolic dimethylxanthines,• which each have their own effects on the body: Each of these metabolites is further metabolized and then excreted in the urine. Mechanism of action Caffeine acts through multiple mechanisms involving both action on receptors and channels at the cell membrane, as well as intracellular action on Calcium and cAMP pathways. By virtue of its purine structure it can act on some of the same targets as adenosine related nucleosides and nucleotides, like the cell surface P1 GPCRs for adenosine, as well as the intracellular Ryanodine receptor which is the physiological target of cADPR (cyclic ADP ribose), and cAMP-phosphodiesterase (cAMP-PDE). However the action is antagonistic in some cases and agonistic in some others. The principal mode of action of caffeine is as an antagonist of adenosine receptors in the brain.• The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them (a "false transmitter" method of antagonism). The reduction in adenosine activity results in increased activity of the neurotransmitter dopamine, largely accounting for the stimulatory effects of caffeine. Caffeine can also increase levels of epinephrine/adrenaline,• possibly via a different mechanism. Acute usage of caffeine also increases levels of serotonin, causing positive changes in mood. The inhibition of adenosine may be relevant in its diuretic properties. Because adenosine is known to constrict preferentially the afferent arterioles of the glomerulus, its inhibition may cause vasodilation, with an increase in renal blood flow (RBF) and glomerular filtration rate (GFR). This effect, called competitive inhibition, interrupts a pathway that normally serves to regulate nerve conduction by suppressing post-synaptic potentials. The result is an increase in the levels of epinephrine and norepinephrine/noradrenaline released via the hypothalamic-pituitary-adrenal axis.• Epinephrine, the natural endocrine response to a perceived threat, stimulates the sympathetic nervous system, leading to an increased heart rate, blood pressure and blood flow to muscles, a decreased blood flow to the skin and inner organs and a release of glucose by the liver. Caffeine is also a known competitive inhibitor of the enzyme cAMP-phosphodiesterase (cAMP-PDE), which converts cyclic AMP (cAMP) in cells to its noncyclic form, allowing cAMP to build up in cells. Cyclic AMP participates in the messaging cascade produced by cells in response to stimulation by epinephrine, so by blocking its removal caffeine intensifies and prolongs the effects of epinephrine and epinephrine-like drugs such as amphetamine, methamphetamine, or 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. Caffeine (and theophylline) can freely diffuse into cells and causes intracellular calcium release (independent of extracellular calcium) from the calcium stores in the Endoplasmic Reticulum(ER). This release is only partially blocked by Ryanodine receptor blockade with ryanodine, dantrolene, ruthenium red, and procaine (thus may involve ryanodine receptor and probably some additional calcium channels), but completely abolished after calcium depletion of ER by SERCA inhibitors like Thapsigargin (TG) or cyclopiazonic acid (CPA). The action of caffeine on the ryanodine receptor may depend on both cytosolic and the luminal ER concentrations of Ca2+. At low millimolar concentration of caffeine, the RyR channel open probability (Po) is significantly increased mostly due to a shortening of the lifetime of the closed state. At concentrations >5 mM, caffeine opens RyRs even at picomolar cytosolic Ca2+ and dramatically increases the open time of the channel so that the calcium release is stronger than even an action potential can generate. This mode of action of caffeine is probably due to mimicking the action of the physiologic metabolite of NAD called cADPR (cyclic ADP ribose) which has a similar potentiating action on Ryanodine receptors. Caffeine may also directly inhibit delayed rectifier and A-type K+ currents and activate plasmalemmal Ca2+ influx in certain vertebrate and invertebrate neurons. The metabolites of caffeine contribute to caffeine's effects. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline, the second of the three primary metabolites, acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and efficiency. The third metabolic derivative, 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. Tolerance and withdrawal Because caffeine is primarily an antagonist of the central nervous system's receptors for the neurotransmitter adenosine, the bodies of individuals who regularly consume caffeine adapt to the continual presence of the drug by substantially increasing the number of adenosine receptors in the central nervous system. This increase in the number of the adenosine receptors makes the body much more sensitive to adenosine, with two primary consequences.• Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. 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. Withdrawal symptoms — possibly including headache, irritability, and an inability to concentrate — 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, can relieve the pain symptoms, as can a small dose of caffeine.• Most effective is a combination of both an analgesic and a small amount of caffeine. Currently caffeine withdrawal is recognized as meriting further study by the Diagnostic and Statistical Manual of Mental Disorders for DSM-IV, although research demonstrating its clinical significance means that it will likely be included as an Axis-1 disorder in the DSM-V.• Extraction of pure caffeine Caffeine extraction is an important industrial process and can be performed using a number of different solvents. Benzene, chloroform, trichloroethylene and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost and flavor, they have been superseded by the following main methods: Water extraction Coffee beans are soaked in water. The water, which contains not only caffeine but also many other compounds which contribute to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with a good flavor.• Coffee manufacturers recover the caffeine and resell it for use in soft drinks and medicines. Supercritical carbon dioxide extraction Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine (as well as many other organic compounds), and is safer than the organic solvents that are used for caffeine extraction. The extraction process is simple: CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, CO2 is in a "supercritical" state: it has gaslike properties which allow it to penetrate deep into the beans but also liquid-like properties which dissolve 97-99% of the caffeine. The caffeine-laden CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis. Extraction by nonhazardous organic solvents Organic solvents such as ethyl acetate present much less health and environmental hazard than previously used chlorinated and aromatic solvents. The hydrolysis products of ethyl acetate are ethanol and acetic acid, both nonhazardous in small quantities. Another method is to use triglyceride oils obtained from spent coffee grounds. Relative content: comparison of different sources | |||||||||||||||||||||
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