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Caffeine

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For other uses, see the chemical substance caffeine.
Caffeine
Caffeine
General
Systematic name 1,3,7-trimethylxanthine
Other names trimethylxanthine
theine
mateine
guaranine
methyltheobromine
Molecular formula C8H10N4O2
SMILES O=C1C2=C(N=CN2C)N(C(=O)N1C)C
Molar mass 194.19 g/mol
Appearance Odorless, white needles or powder
CAS number [58-08-2]
Properties
Density and phase 1.2 g/cm3, solid
Solubility in water Slightly soluble
Melting point 234 - 236.5 °C
Boiling point 178 °C (sublimes)
Acidity (pKa) 10.4
Hazards
MSDS External MSDS
Main hazards May be fatal if inhaled, swallowed
or absorbed through the skin.
NFPA 704 Template:Nfpa
Flash point N/A
RTECS number EV6475000
Except where noted otherwise, data are given for
materials in their standard state (at 25 °C, 100 kPa)
Infobox disclaimer and references

Caffeine, or theine, is a xanthine alkaloid found in the leaves and beans of the coffee tree, in tea, yerba mate, guarana berries, and in small quantities in cocoa, the kola nut and the Yaupon holly. In plants, caffeine acts as a natural pesticide that paralyzes and kills many insects feeding upon them.

Caffeine is a central nervous system (CNS) stimulant, having the effect of warding off drowsiness and restoring alertness. Caffeine-containing beverages, such as coffee and tea, enjoy great popularity, making caffeine the world's most popular psychoactive substance.

Sources of caffeine

Caffeine is the most widely used psychoactive substance in the world.

Caffeine is a plant alkaloid, found in numerous plant varieties. The most commonly used of which are coffee, tea, and to some extent cocoa. Other, less commonly used, sources of caffeine include the plants yerba maté and guarana, which are sometimes used in the preparation of teas and, more recently, energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these plants.

The world's primary source of caffeine is the bean of the coffee plant, from which coffee is brewed. Caffeine content in coffee varies widely depending on the variety of coffee bean and the method of preparation used, but in general one serving of coffee ranges from about 40 mg for a single shot of espresso to about 100 mg for strong drip coffee. Generally, dark roast coffee has less caffeine than lighter roasts since the roasting process reduces caffeine content of the bean.

Tea is another common source of caffeine in many cultures. Tea generally contains somewhat less caffeine per serving than coffee, usually about half as much, depending on the strength of the brew, though certain types of tea, such as black and oolong, contains somewhat more caffeine than most other teas.

Caffeine is also common in soft drinks such as cola prepared from the kola nut. Soft drinks typically contain about 15 mg to 40 mg of caffeine per serving. By contrast, energy drinks such as Red Bull contain as much as 80 mg of caffeine, which is produced synthetically.

Chocolate derived from cocoa is a weak stimulant, mostly due to its content of theobromine and theophylline, but it also contains a small amount of caffeine [1]. However, chocolate contains too little of these compounds for a reasonable serving to create effects in humans that are on par with coffee.

Finally, caffeine may also be purchased in most areas in the form of a pill that containing from 50 mg to 200 mg. Caffeine pills are regulated differently among various nations. For example, the European Union requires that a warning be placed on the packaging of any food whose caffeine exceeds 150 mg per litre. In many other countries, however, caffeine is classified as a flavouring and is unregulated.

Caffeine equivalents

In general, each of the following contains approximately 200 mg of caffeine:

  • One 200 mg caffeine pill (in some countries these are 100 mg, in the UK these are 50 mg)
  • Two 1-fluid ounce shots of espresso from robusta beans (2 fluid ounces (0,59 dl) total)
  • Two 8-fluid ounce containers of regular coffee (16 fluid ounces (4.73 dl) total)
  • Five 8-fluid ounce cups of black tea (40 fluid ounces (1.18 l) total)
  • Five 12-fluid ounce cans of soda (60 fluid ounces total (1.77 l), although these can vary widely in content)
  • Ten 8-fluid ounce cups of green tea (80 fluid ounces (2.36 l) total)
  • One and a half pounds (0,68kg total) of milk chocolate
  • Fifty 8-fluid ounce cups of decaffeinated coffee (400 fluid ounces (11.82 l) total)

History of caffeine use

Although tea has been consumed in China for thousands of years, the first documented use of caffeine in a beverage for its pharmacological effect was in the 15th Century by the Sufis of Yemen, who used coffee to stay awake during prayers. In the 16th Century there were coffee houses in Cairo and Mecca, and in the 17th Century coffee houses opened for the first time in Europe.

In 1819, relatively pure caffeine was isolated for the first time by the German chemist Friedrich Ferdinand Runge. According to the legend, he did this at the instigation of Johann Wolfgang von Goethe (Weinberg & Bealer 2001).

Effects of caffeine

Caffeine has a significant effect on spiders, which is reflected in their web construction.

Caffeine is a central nervous system stimulant, and is used both recreationally and medically to restore mental alertness when unusual weakness or drowsiness occurs. It is important to note, however, that caffeine cannot replace sleep, and should be used only occasionally as an alertness aid.

Caffeine is sometimes administered in combination with medicines to increase their effectiveness, such as with ergotamine in the treatment of migraine and cluster headaches, or with certain pain relievers such as aspirin or acetaminophen. Caffeine may also be used to overcome the drowsiness caused by antihistamines. Breathing problems (apnea) in premature infants are sometimes treated with citrated caffeine, which is available only by prescription in many countries.

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. Template:Fn

Caffeine metabolism

Caffeine is completely absorbed by the stomach and small intestine within 45 minutes of ingestion. It is widely distributed in total body water and is eliminated by apparent first-order kinetics that can be described by a one-compartment open-model system. Continued consumption of caffeine can lead to tolerance. Upon withdrawal, the body becomes oversensitive to adenosine, causing the blood pressure to drop dramatically, which causes headaches and other symptoms.

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system into three metabolic dimethylxanthines, which each have their own effects on the body:

Each of these metabolites is further metabolised and then excreted in the urine.

Mechanism of Action

The caffeine molecule is structurally similar to adenosine, and binds to adenosine receptors on the surface of cells without activating them. 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 (adrenaline) and norepinephrine released from the pituitary gland [2]. 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 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 messenging 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.

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 (Dews et al. 1984).

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 (Ivy et al. 1979). 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 (Graham & Spriet 1991). 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 (Trice & Hayes 1995).

Side effects of caffeine

The minimum lethal dose of caffeine ever reported is 3,200 mg, administered intravenously. The LD50 of caffeine is estimated between 13 and 19 grams for oral administration for an average adult. The LD50 of caffeine is dependent on weight and individual sensitivity and estimated to be about 150 to 200 mg per kg 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. The half-life, or time it takes for the amount of caffeine in the blood to decrease by 50%, ranges from 3.5 to 10 hours. In adults the half-life is generally around 5 hours. However, contraceptive pills increase this to around 12 hours, and, for women over 3 months pregnant, it varies from 10 to 18 hours. In infants and young children, the half-life may be longer than in adults. With common coffee and a very rare half-life of 100 hours, it would require 3 cups of coffee every hour for 100 hours just to reach LD50. Though achieving lethal dose with coffee would be exceptionally difficult, there have been many reported deaths from intentional overdosing on caffeine pills.

Too much caffeine, especially over an extended period of time, can lead to a number of physical and mental conditions. The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) states: "The 4 caffeine-induced psychiatric disorders include caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS)."

An overdose of caffeine can result in a state termed caffeine intoxication or caffeine poisoning. Its symptoms are both physiological and psychological. Symptoms of caffeine intoxication include: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, muscle twitching, rambling flow of thought and speech, cardiac arrhythmia or tachycardia, and psychomotor agitation, gastrointestinal complaints, increased blood pressure, rapid pulse, vasoconstriction (tightening or constricting of superficial blood vessels) sometimes resulting in cold hands or fingers, increased amounts of fatty acids in the blood, and an increased production of gastric acid. In extreme cases mania, depression, lapses in judgment, disorientation, loss of social inhibition, delusions, hallucinations and psychosis may occur. [3]

It is commonly assumed that only a small proportion of people exposed to caffeine develop symptoms of caffeine intoxication. However, because it mimics organic mental disorders, such as panic disorder, generalized anxiety disorder, bipolar disorder, and schizophrenia, a growing number of medical professionals believe caffeine-intoxicated people are routinely misdiagnosed and unnecessarily medicated. Shannon et al (1998) point out that:

"Caffeine-induced psychosis, whether it be delirium, manic depression, schizophrenia, or merely an anxiety syndrome, in most cases will be hard to differentiate from other organic or non-organic psychoses....The treatment for caffeine-induced psychosis is to withhold further caffeine." A study in the British Journal of Addiction declared that "although infrequently diagnosed, caffeinism is thought to afflict as many as one person in ten of the population" (JE James and KP Stirling, 1983).

Because caffeine increases the production of stomach acid, high usage over time can lead to peptic ulcers, erosive esophagitis, and gastroesophageal reflux disease.[citation needed] Furthermore, it can also lead to nervousness, irritability, anxiety, tremulousness, muscle twitching, insomnia, heart palpitations and hyperreflexia [4].

Withdrawal

Individuals who consume caffeine regularly develop a reduction in sensitivity to caffeine; when such individuals reduce their caffeine intake, their body becomes oversensitive to adenosine, with the result that blood pressure drops dramatically, leading to an excess of blood in the head (though not necessarily on the brain), causing a headache. Other symptoms may include fatigue, drowsiness, anxiety and irritability; in extreme cases symptoms may include depression, inability to concentrate and diminished motivation to initiate or to complete daily tasks at home or at work.

Withdrawal symptoms may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually lasts from one to five days. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine.

Effects on fetuses and newborn children

There is some evidence that caffeine may be dangerous for fetuses and newborn children. In animal studies, caffeine intake during pregnancy has been demonstrated to have teratogenic effects and increase the risk of learning problems and hyperactivity in rats and mice, respectively. The applicability of these results to human infants is disputed since the concentrations involved were high and rodents are more susceptible to most mutagens. In a 1985 study conducted by scientists of Carleton University, Canada, children born by mothers who had consumed more than 300 mg/d caffeine (about 3 cups of coffee or 6 cups of tea) were found to have, on the average, lower birth weight and head circumference than the children of mothers who had consumed little or no caffeine. In addition, use of large amounts of caffeine by the mother during pregnancy may cause problems with the heart rhythm of the fetus. For these reasons, some doctors recommend that women largely discontinue caffeine consumption during pregnancy and possibly also after birth until the newborn child is weaned.

The negative effects of caffeine on the developing fetus can be attributed to the ability of caffeine to inhibit two DNA damage response proteins known as Ataxia-Telangeictasia Mutated (ATM) or ATM-Rad50 Related (ATR). These proteins control much of the cells ability to stop cell cycle in the presence of DNA damage, such as DNA single/double strand breaks and nucleotide dimerization. DNA damage can occur relatively frequently in actively dividing cells, such as those in the developing fetus. Caffeine is used in laboratory setting as an inhibitor to these proteins and it has been shown in a study by Lawson et al. in 2004, that women who use caffeine during pregnancy have a higher likelyhood of miscarriage than those who do not. Since the dosage rate of self-administration is difficult to control and the effects of caffeine on the fetus are related to random occurance (DNA damage), a minimal toxic dose to the fetus has yet to be established.

The dangers of caffeine pills

Caffeine pills are often used by college students and shift workers as a convenient way to fight sleep, and are often considered harmless. However, like any medication, caffeine can be harmful or deadly in sufficient quantities. The LD50 of caffeine, as determined by animal studies, is 10,000 mg, equal to 50 average caffeine pills.

Periodically, caffeine pills come under media fire in connection with the death of a college student due to a large overdose of caffeine. One example is the death of a North Carolina student, Jason Allen, who swallowed most of a bottle of 90 such pills [5], equivalent of about 250 cups of coffee. A few other deaths by caffeine overdose have been known, almost always in the case of massive pill consumption.

Extraction of pure caffeine

Anhydrous (dry) USP grade Caffeine

It is very difficult to know the exact amount of caffeine in a particular drink that is not automatically prepared. The amount of caffeine in a single serving of coffee varies considerably due to many variables. Concentration can vary from bean to bean within a given bush; preparation of the raw bean will affect concentration, as well as multiple variables involved in brewing.

Extracting caffeine takes some time, about two hours, and requires chemicals unavailable for everyday use and equipment for distillation and sublimation. To extract caffeine, one must mix the beverage one wants to extract the caffeine from with a solvent possessing a high affinity for caffeine and a different density. Chloroform is known to possess both these properties, however industry prefers using the much less toxic ethyl acetate.

Caffeine will migrate to the solvent in which it is most soluble, and it is more soluble in chloroform than water. Using a separating funnel, one should take about 30 ml of chloroform and 200 ml of the beverage from which one wants to extract the caffeine and agitate for about two minutes. The bottom phase will be the chloroform and the caffeine, so one will keep this phase. Repeating this step about five times should ensure extraction of most of the caffeine.

The next step is a distillation using a standard distillation column where one gets rid of most of the chloroform. Finally, one has to sublimate the remaining chloroform under vacuum. If the result is a fine white powder, one's extraction has succeeded.

References

  • Weinberg BA, Bealer BK. The world of caffeine. New York & London: Routledge, 2001. ISBN 0-415-92722-6.
  • Template:Fnb Noever, R., J. Cronise, and R. A. Relwani. 1995. Using spider-web patterns to determine toxicity. NASA Tech Briefs 19(4):82. Published in New Scientist magazine, 27 April 1995.
  • JE James and KP Stirling, "Caffeine: A Summary of Some of the Known and Suspected Deleterious Habits of Habitual Use," British Journal of Addiction, 1983;78:251-58.
  • Hughes JR, McHugh P, Holtzman S. "Caffeine and schizophrenia." Psychiatr Serv 1998;49:1415-7. Fulltext. PMID 9826240.
  • Shannon MW, Haddad LM, Winchester JF. Clinical Management of Poisoning and Drug Overdose, 3rd ed.. 1998. ISBN 0721664091.
  • Diagnostic and Statistical Manual of Mental Disorders ISBN 0890420610
  • Trice, I., and Haymes, E. (1995). "Effects of caffeine ingestion on exercise-induced changes during high intensity, intermittent exercise". International Journal of Sports Nutrition. 37-44.
  • Tarnopolsky, M. A. (1994). "Caffeine and endurance performances". Sports Medicine (Vol. 18 Ed. 2): 109 – 125.
  • Ivy, J., Costill, D., Fink, W. et al. (1979). "Influence of caffeine and carbohydrate feedings on endurance performance". Medical Science Sports Journal (Vol. 11). 6-11.
  • Dews, P.B. (1984). "Caffeine: Perspectives from Recent Research". Berlin: Springer-Valerag.

Caffeine as an ergogenic aid

Caffeine toxicity

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