|Molecular formula||C 8 H 10 N 4 O 2|
colorless and odorless solid
|External identifiers / databases|
|Mechanism of action|
1.23 g cm −3 (18 ° C)
236 ° C (sublimation from 178 ° C)
20 hPa (80 ° C)
|As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .|
Caffeine or caffeine (also Tein , Teein or Thein , formerly also caffeine ) is an alkaloid ( purine alkaloid ) from the group of xanthines . It is one of the psychoactive substances with a stimulating effect .
Caffeine is a component of stimulants such as coffee , tea , cola , mate , guarana , energy drinks and (in smaller quantities) cocoa that stimulates the nerves . In chemically pure form it occurs as a white, odorless, crystalline powder with a bitter taste.
At Goethe's suggestion , the pharmacist and chemist Friedlieb Ferdinand Runge examined coffee beans with the aim of finding the active substance in coffee. In 1819, Runge succeeded for the first time in isolating pure caffeine from coffee beans. He can therefore be seen as the discoverer of caffeine. Independently of Runge, the French pharmacists Pierre Joseph Pelletier , Joseph Bienaimé Caventou and Pierre-Jean Robiquet also succeeded in isolating the caffeine together in 1821. In 1832, Christoph Heinrich Pfaff and Justus von Liebig were able to determine the empirical formula C 8 H 10 N 4 O 2 with the help of combustion data. The chemical structure was adopted by Ludwig Medicus in 1875 as 1,3,7-trimethylxanthine. Emil Fischer was able to confirm the structure that was initially only assumed through the first synthesis of caffeine. The mechanism of action was only successfully researched in the 20th century.
The active ingredient contained in green tea and black tea , often referred to as "Tein", "Thein" or "Teein" in colloquial language, is also caffeine. This previously common distinction between caffeine from coffee and tein from tea is based on the different release of alkaloid in the human organism: Caffeine from coffee is bound to a chlorogenic acid - potassium complex, which immediately releases caffeine after roasting and contact with gastric acid acts quickly. Caffeine from tea, on the other hand, is bound to polyphenols , whereby the alkaloid is only released in the intestine. The effect then occurs later and lasts longer.
The first medical applications were the use as a stimulant ( stimulant ) and diuretic and (as already coffee since the 18th century) as a drug to treat respiratory disorders in bronchial asthma (The breathless stimulating or atemanaleptische and bronchodilator effect was in 1912 by Jakob Pál described) .
Caffeine is the main active ingredient in coffee. In addition to the seeds of the coffee bush, it is also found in over 60 other plants, such as the tea bush , guarana , the mate bush and the kola nut . The active substances theophylline and theobromine , which are chemically closely related to caffeine , can also be found in numerous plant species. Depending on the type, unroasted coffee beans contain around 0.9–2.6% caffeine; 1.3–2.0% remains after roasting. The Coffea arabica varieties contain less alkaloid than the Coffea robusta types. Fermented and dried tea leaves, so-called black tea , contain - like unfermented green tea - around 3–3.5% caffeine.
Caffeine can be obtained by extraction from tea leaves or coffee beans, for example with a Soxhlet attachment . It is produced in large quantities in the industrial decaffeination of coffee, using either dichloromethane , ethyl acetate or supercritical carbon dioxide as extraction agents. In addition, caffeine is mainly produced industrially using grape synthesis .
Caffeine is a common name given to the substance because it is found in coffee. According to the systematic IUPAC nomenclature, the full name is 1,3,7-trimethyl-2,6-purindione, a short form 1,3,7-trimethylxanthine - after the chemical derivation of caffeine from xanthine . It belongs to the group of naturally occurring purines ( purine alkaloids ), just like the structurally similar dimethylxanthines theophylline and theobromine .
The structure of caffeine consists of a double ring with several substituents on the outside. This double ring in the core corresponds to the basic structure of the purine. It consists of two rings, a 6-ring and a 5-ring, each containing two nitrogen atoms. On the outside there is a double bonded oxygen atom at C-2 and C-6. In the case of caffeine, there is still a methyl group (-CH 3 ) at N-1, N-3 and N-7 . There is also isocaffeine , in which one of the methyl groups is not attached to N-7 but to N-9. Of the three methyl groups, theophylline lacks the one at N-7, the theobromine lacks the one at N-1.
Under normal conditions, pure caffeine is a white, odorless, crystalline powder with a bitter taste. Caffeine occurs in two enantiotropic polymorphic crystal forms. The β-form (low-temperature form), which is stable at room temperature, converts to the α-form (high-temperature form) at 141 ° C. This melts at 236 ° C. The reverse conversion from α- to β-form is kinetically inhibited, so that the α-form can be metastable for weeks at room temperature. The connection is easily sublimable (from 178 ° C). The solubility depends on the temperature:
|water||at normal temperature||21.74 g / l|
|at 80 ° C||181.82 g / l|
|Ethanol||at normal temperature||15.15 g / l|
|at 60 ° C||45.45 g / l|
|acetone||20.00 g / l|
|chloroform||181.82 g / l|
When caffeine crystallizes from water, it forms a crystalline hydrate in the form of long needles. Stoichiometrically , the hydrate in the crystal lattice contains 0.8 mol of water per mol of caffeine.
Xanthine derivatives such as caffeine are called weak bases because they can take up protons through their nitrogen atoms. However, solutions of xanthine derivatives are not alkaline. Xanthine derivatives are counted among the alkaloids. Alkaloids are generally all physiologically active, low molecular weight nitrogen-containing compounds, in particular of a vegetable nature.
The caffeine citrate is also used pharmaceutically in addition to the caffeine base, a caffeine-citric acid mixture (ASK, nomenclature by IUPAC : 1,3,7-trimethyl-3,7-dihydro-2 H -purine-2,6-dione + 2-hydroxypropane -1,2,3-tricarboxylic acid) has the empirical formula C 14 H 18 N 4 O 9 , a molar mass of 386.31 g · mol -1 , and the CAS number 69-22-7. It is a white crystalline powder, soluble 1: 4 in hot water (dissociation), 1:25 in ethanol 96%.
The main effects of caffeine are:
- Stimulation of the central nervous system
- Increase in the force of contraction of the heart
- Increase in heart rate (increase in pulse)
- Bronchial dilatation ( bronchodilation )
- Weak diuretic ( diuretic ) effect by inhibiting the return resorption of water from the primary urine
- Effect on blood vessels: Caffeine has a constricting effect on vessels in the brain, expanding on those in the periphery
- Slight increase in blood pressure
- Stimulation of the peristalsis of the intestine
- Inhibition of muscle contractions in the walls of the female fallopian tubes and thus obstruction of the passage of fertilized egg cells into the uterus , with the possible consequence of delayed conception for the woman
- Promote glycogenolysis and lipolysis
While caffeine has a relatively broad spectrum of activity, in low doses it is primarily a stimulant . This is generally understood to be a substance with a stimulating effect on the psyche, which increases drive and concentration and eliminates symptoms of fatigue. A distinction is made between a stimulating and an exciting effect of caffeine, although a higher dose is required for the latter. At low doses, the central stimulating effect of caffeine emerges almost exclusively, so it mainly affects basic psychological functions such as drive and mood. A higher dose also stimulates the respiratory center and circulation.
While higher caffeine concentrations also affect the motor brain centers, the caffeine in lower concentrations mainly affects the sensory parts of the cerebral cortex . This increases attention and concentration; the increase in storage capacity and fixation ( mnestic functions) facilitates the learning process. With the elimination of signs of fatigue, the need for sleep decreases. The increase in blood pressure is small and disappears with long-term use; an effect can only be observed again after the caffeine intake has been discontinued for at least 24 hours. The mild increase in blood pressure is caused by the central nervous stimulation (excitation of the vasomotor center); a simultaneous lowering of the peripheral resistance counteracts this in a compensatory manner. The mood can increase to slight euphoria . As a result of the establishment of associations , the reaction times are shortened, which leads to an acceleration of the psychological pace. At the same time, there is an - only minimal - deterioration in dexterity, especially in tasks that require exact timing or complicated visuomotor coordination . Caffeine owes its broad spectrum of activity to several components that intervene in certain cell processes at the molecular level. Caffeine can cross the blood-brain barrier almost unhindered and its stimulating effect mainly develops in the central nervous system .
According to a new study, caffeine should not only increase the ability to concentrate, improve vigilance and alertness , and increase the speed of thought processes, but also improve long-term memory .
Caffeine in luxury foods such as B. in black tea or cola, can be problematic especially for children. B. three cans of cola (depending on the source 65–250 mg or 150–350 mg in 990 ml) contain roughly as much caffeine as two cups of coffee (depending on the source 100–240 mg or 160–240 mg caffeine in 250 ml filter coffee) . A child weighing thirty kilograms can achieve a concentration of 5–12 milligrams of caffeine per kilogram of body weight; a dose sufficient to cause nervousness and sleep disturbance.
Caffeine was on the doping list of the International Olympic Committee from 1984 to 2004 , but the limits were so high that athletes could drink coffee for breakfast. Nevertheless, on July 25, 2000, the Spanish professional cyclist Óscar Sevilla (Team Kelme ) tested "positive" for caffeine and was subsequently excluded from the road world championship by his association. The World Anti-Doping Agency removed the stimulant caffeine from the list of prohibited substances with effect from January 1, 2004. Pasman et al. a. (1995) compared the effects of 0, 5, 9 and 13 milligrams per kilogram of body weight one hour before exercise and found that all doses greater than 0 had a significant performance-enhancing effect in the cycling test (80% Wmax). The lowest dose was below the assessment limit as doping.
The oral LD 50 for a rat is 381 milligrams per kilogram. In humans, the lethal dose is around 10 grams of caffeine (5-30 g), which is about 100 cups of coffee.
Mechanism of action
The effect of caffeine is based on the cellular level as follows: When awake, nerve cells exchange messenger substances and consume energy. This creates adenosine as a by-product. One of the tasks of adenosine is to protect the brain from "overexertion". It attaches itself to certain receptors on the nerve tracts (the adenosine receptors of subtype A2a). If adenosine is bound, this is a signal for the cell to work a little less. This creates a negative feedback effect : the more active the nerve cells, the more adenosine is formed and the more receptors are occupied. The nerve cells work more slowly. The chemical structure of caffeine is similar to adenosine and occupies the same receptors, but does not activate them. Adenosine can no longer dock, and the nerve tracts do not receive a signal - that is why they continue to work even if the adenosine concentration increases. The adenosine receptors are competitively inhibited by caffeine .
Analgesic , i.e. pain-relieving effects of caffeine are discussed. Here, too, the antagonistic effects on the adenosine receptors and the resulting reduced effect of adenosine on the central nervous system are assumed to be the mechanism. Adenosine causes pain at the sensory nerve endings by acting directly on the specific A2 receptors and causing hypersensitivity to pain ( hyperalgesia ).
In higher doses, caffeine prevents the enzymatic breakdown of cyclic adenosine 3 ', 5'-monophosphate . As a second messenger, this plays an important role in the regulation of cellular processes in the human organism . Caffeine inhibits the enzymes, specific phosphodiesterases , which are responsible for breaking down cyclic to acyclic AMP. The inhibited degradation leads to an increase in the cAMP concentration in the cells. Among other things, cAMP leads to the activation of protein kinase A , which in turn mediates a number of functions (depending on the tissue), including the release of glucose in the liver (via gluconeogenesis and glycogen cleavage ) and the production of ATP for muscle contraction in skeletal muscle. In addition, cAMP activates lipases ( HSL , ATGL ) in fat cells to metabolize the fats stored there.
A 2004 study at Duke University Medical Center in Durham , North Carolina showed that consuming caffeine in combination with eating a meal containing carbohydrates increased blood sugar and insulin levels in people with type 2 diabetes .
If a person ingests large doses of caffeine over a long period of time, the nerve cells change. They react to the missing adenosine signal and form more receptors so that adenosine molecules can bind to receptors again. The nerve cells work more slowly. The stimulating effect of caffeine is therefore severely limited. Such a tolerance develops after 6 to 15 days of heavy caffeine consumption .
If the consumption of caffeine is greatly reduced, withdrawal symptoms can occur (see below), but these are usually short-lived. Caffeine is cheaply and legally available and is the most widely consumed stimulant in the world. It is not clear from the scientific literature whether caffeine is to be regarded as an addictive substance; in any case, it has some similarities with typical addictive substances. The most important ones include the development of tolerance as well as psychological and physical dependence with withdrawal symptoms. Tolerance occurs with not necessarily excessive, but with regular caffeine consumption.
The following withdrawal symptoms were observed in an empirical study: headache, exhaustion, loss of energy, reduced vigilance, drowsiness, decreased satisfaction, depressed mood, difficulty concentrating, irritability and the feeling of being unable to think clearly. In some cases there were also flu-like symptoms. The symptoms set in twelve to 24 hours after the last caffeine consumption, peak after 20 to 51 hours and last about two to nine days. Even a small amount of caffeine leads to relapse.
Symptoms of withdrawal include changes in theta waves in the brain.
In the event of an overdose (doses of over 1 g in adults), symptoms of anxiety and excitement, a strongly accelerated pulse and extrasystoles occur; Charcoal tablets , verapamil and diazepam can be given for therapy .
Caffeine releases calcium 2+ ions from the endoplasmic reticulum (ER) in very high concentrations (from around 10 mM in the outer space of the cell) . This happens through its specific binding to ryanodine receptors . Because of this property, caffeine is used in physiological research. The dose required far exceeds the lethal dose in mammals, which is why caffeine is only used in in vitro experiments.
There are u. a. Drug interactions. This must be taken into account in all examinations. For example, a study by EFSA ( European Food Safety Authority ) indicated that only the consumption of caffeinated beverages was examined and not the effects of caffeine additives in food. Caffeine is absorbed more quickly with carbonated drinks. Caffeine increases the heart rate-increasing effect of sympathomimetics . It counteracts soothing agents such as antihistamines and barbiturates . 50 mg caffeine can have a relative analgesic potency of 1.3 to 1.7 when taking acetylsalicylic acid or paracetamol at the same time (possible savings in painkillers). Disulfiram and cimetidine reduce the breakdown of caffeine in the body. Smoking and barbiturates accelerate the breakdown of caffeine in the body. Theophylline excretion is reduced by caffeine. If antibiotics of the group of gyrase inhibitors ( quinolone antibiotics ) are taken at the same time, the excretion of caffeine and its breakdown product paraxanthin may be delayed. Caffeine can increase potential dependence on ephedrine- type substances .
Precautions for use
People with cirrhosis of the liver (possible caffeine accumulation), people with cardiac arrhythmias such as sinus tachycardias / extrasystoles (possible aggravation), people with hyperthyroidism (possible intensification of the side effects of caffeine) and people with anxiety syndrome (possible intensification) should only take caffeine in low doses.
Caffeine can intensify symptoms of anxiety disorders . Conversely, reducing your caffeine intake can have a symptom-relieving effect.
Regular consumption of high doses is not recommended because of the possible occurrence of caffeinism . While some researchers, based on studies on mice, advise avoiding caffeine during pregnancy, the American College of Obstetricians and Gynecologists, in a recommendation issued in 2010, considers a daily dose of 200 milligrams of caffeine to be safe. A Brazilian study found that moderate caffeine consumption during pregnancy and breastfeeding in the first three months of life does not seem to affect the sleep of infants. A study by EFSA ( European Food Safety Authority ), which examined the consumption of beverages containing caffeine and is based on observations on around 66,000 people, comes to the conclusion that a caffeine intake of up to 400 mg per day (this corresponds to approximately 5.7 mg / kg body weight for a person weighing 70 kg) can be classified as harmless. Guideline values were also determined for pregnant women, nursing mothers and children: for pregnant and nursing women, caffeine intake from all sources of up to 200 mg per day is harmless for the fetus over the entire day. For children and adolescents, the guideline value levels off at 3 mg / kg body weight and is considered harmless at this dosage.
For Pharmacoepidemiology of caffeine are studies of the effect of caffeine on blood lipid status of national examinations in the population of the Federal Republic of Germany. Among other things, an increase in triglycerides in the blood serum was demonstrated in test subjects who used caffeine-containing drugs. Results were also published on the influence of caffeine on the glucose and magnesium content of the serum. Thereafter, higher glucose levels and decreased magnesium levels were measured in the sera of test subjects who used caffeine-containing drugs.
Mutagenic effect on lower organisms
Caffeine can have a mutagenic effect on bacteria , fungi and algae ; this is probably caused by the inhibition of repair mechanisms of the DNA in these living things. Such an effect has not yet been demonstrated in higher animals or humans.
The metabolism of caffeine is species-specific . In humans, around 80% of the caffeine ingested is demethylated to paraxanthine by the enzyme cytochrome P450 1A2 and another 16% is converted into theobromine and theophylline in the liver . Further partial demethylation and oxidation result in urate and uracil derivatives. About a dozen different caffeine metabolites can be extracted from the urine , but less than 3% of the caffeine originally ingested. The main waste products in the urine Di - and mono methylxanthine and mono-, di- and Trimethylharnsäure .
The pharmacokinetics of caffeine depend on many internal and external factors. The absorption of caffeine via the gastrointestinal tract into the bloodstream occurs very quickly and almost completely: about 45 minutes after absorption, practically all of the caffeine is absorbed and is available for the metabolism ( bioavailability : 90–100%). The maximum plasma concentration is reached 15-20 minutes after ingestion of the caffeine. The administration of 5-8 mg caffeine / kg body weight results in a plasma caffeine concentration of 8-10 mg / l. The biological half-life of caffeine in plasma is between 2.5 and 4.5 hours (other sources speak of 3–5 hours) in healthy adults. In contrast, the half-life increases to an average of 80 hours (36–144 h) for newborns and to well over 100 hours for premature babies . The half-life of caffeine is reduced by 30–50% in smokers , while it doubles in women taking oral contraceptives . In women who are in the last trimester of pregnancy , it increases to 15 hours. It is also known that drinking grapefruit juice before caffeine intake increases the half-life of caffeine, as the bitter substance in grapefruit inhibits the metabolism of caffeine in the liver . In breastfeeding mothers, coffee consumption of less than two cups a day has no effect on the infant's nightly sleep behavior.
Chromatographic methods are preferred for the analysis of caffeine. In particular, gas chromatography , HPLC and the coupling of these separation techniques with mass spectrometry are able to guarantee the required specificity and sensitivity in the analysis of complex matrices in physiological research and in food chemistry analysis. In pharmaceutical analysis , thin-layer chromatography is also used for the qualitative and quantitative determination of caffeine. Also enzyme immunoassay (EIA) for the routine analysis of serum - or urine samples are available. In cases of doubt, the results obtained can be checked using GC-MS or HPLC-MS methods.
Use in food and luxury foods
Isolated natural or synthetic caffeine is added to some soft drinks (cola drinks), energy drinks and confectionery because of its stimulating effect.
Adjuvant pain and migraine therapy
Caffeine increases the analgesic potency of acetylsalicylic acid or paracetamol by a factor of 1.3 to 1.7 so that their dose in combination drugs can be reduced accordingly. Such caffeine-containing combination pain relievers are also particularly indicated in the treatment of migraine headaches.
Treatment of respiratory arrest in the newborn
Caffeine citrate is used under the trade name Peyona to treat primary apnea ( respiratory failure without an apparent cause) in premature babies . Apnea in premature babies refers to stopping breathing for more than 20 seconds. Because there are only a few patients with primary apnea - 32,000 people in the EU - the disease is considered rare and caffeine citrate was designated as an orphan medicine in this indication on February 17, 2003 . Caffeine citrate is given as a solution for infusion (20 mg / ml). The solution can also be swallowed and can be obtained with a prescription .
Further areas of application
Caffeine is indicated in doses of 50 to 200 mg for the short-term elimination of signs of fatigue.
Caffeine sodium salicylate , a salt of caffeine that is better absorbed in the human body than caffeine, was previously used as a circulatory and respiratory stimulant and a diuretic . Today this application is obsolete.
Since April 2014, caffeine citrate has had the status of an orphan drug for the prevention of bronchopulmonary dysplasia .
Caffeine is said to promote hair growth, as was discovered at the Friedrich Schiller University in Jena , which makes it possible to use it in the case of hair loss. However, the caffeine shampoos and tinctures available on the market today have a reputation for making hasty and scientifically unjustified promises about their effectiveness.
Caffeine-containing skin creams are used to tighten and smooth the skin, e.g. B. in cellulite , advertised.
Contents in food, luxury foods and medicines
Products with natural caffeine content:
- A cup of coffee (150 ml from 4 g coffee beans) contains around 40–120 mg.
- One cup of espresso (30 ml) about 40 mg of caffeine.
- A cup of black tea and green tea can contain up to 50 mg, depending on the type of preparation, normally a cup of tea made from 1 g of tea leaves contains 20–40 mg. 100 g of dry tea leaves contain more caffeine than the same amount of roasted coffee beans.
- Guaraná contains 40–90 mg of caffeine per 1 g of dry matter.
- Cocoa contains a little caffeine at around 6 mg per cup, but mostly theobromine .
- In chocolate there is caffeine (milk chocolate about 15 mg / 100 g, dark chocolate with 70% cocoa content about 70 mg up to 90 mg / 100 g with an even higher cocoa content) along with theobromine and other stimulating substances.
Synthetic caffeine is usually added to the following products. In some cases, however, natural caffeine, obtained from coffee decaffeination , is also used. Natural caffeine is often added to so-called wellness products as guarana extract .
- Energy drinks such as Red Bull (about 32 mg / 100 ml), Lipovitan (about 50 mg / 100 ml), power syrup (about 68 mg / 100 ml) or Relentless Energy Shot (160 mg / 100 ml)
- Mate lemonade (about 20-25 mg / 100 ml)
- Cola drinks (formerly with caffeine from the kola nut ) Coca-Cola and Pepsi Cola: 10 mg / 100 ml, Afri-Cola , fritz-kola etc. Ä .: 25 mg / 100 ml
- Coffee candies (about 80–500 mg caffeine per 100 g, about 3.3–8 mg caffeine per candy)
- Caffeinated pain relievers with acetylsalicylic acid or paracetamol or both contain 50 mg of caffeine per single dose
- Caffeine tablets for the short-term elimination of signs of fatigue contain 50–200 mg caffeine
- Scho-Ka-Kola contains 200 mg / 100 g caffeine from cocoa, coffee and kola nut extract
In 1997, scientists declared in an appeal to the Food and Drug Administration that it was important to make the declaration of the caffeine content in food mandatory. Since the end of 2014, according to the Fruit Juice and Soft Drinks Ordinance , beverages with more than 150 milligrams per liter must have the caffeine content in milligrams per 100 milliliters as well as the note “Increased caffeine content. Not recommended for children and pregnant or breastfeeding women ”. This does not apply to tea, coffee and drinks based on them if they have “tea” or “coffee” in their name (for example iced tea). In Germany, soft drinks may contain a maximum of 320 milligrams of caffeine per liter.
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