Caffeine

Caffeine, found naturally in coffee, tea, and chocolate, and as an additive in soft drinks and various medicinal remedies, is the most popular drug in the world. Caffeine a drug? Most people recognize two types of drugs. The first type includes chemicals such as aspirin and penicillin that can be purchased at the drugstore and are used to treat illnesses. And the second type includes substances such as heroin, cocaine, nicotine, and alcohol that people take to relax, to invigorate themselves, or to escape from reality.

Technically, a drug is a chemical substance used to prevent or cure disease or to enhance a person's physical or mental welfare. In fact, people use caffeine for all of these purposes and caffeine can do all of these things, though usually in a very limited way.

Though caffeine is a chemical used both for medical and non-medical reasons, most often it is used non-medically for its stimulating effect on mood and behavior. Drugs that are taken primarily to alter mood or change behavior are known as psychoactive drugs. Heroin, cocaine, marijuana, nicotine, alcohol, and caffeine are all psychoactive drugs.

Most of the known caffeine-yielding plants were probably discovered and used approximately 600,000 to 700,000 years ago, during the early Stone Age, or Paleolithic times. Paleolithic people chewed the seeds, bark, and leaves of many plants and they probably associated the chewing of parts of caffeine-containing plants with the resulting changes in mood and behavior. Eventually, caffeine was cultivated and consumed to banish fatigue, prolong wakefulness, and elevate mood.

Initially, Paleolithic people may have ground the caffeine-containing plant material to a paste and used it to aid digestion. Only much later was it discovered that by infusing the plant in hot water, a liquid could be created that when ingested produced greater effects. (This is true because more caffeine is extracted from a plant substance at higher temperatures.) This discovery led to the origin of all the caffeine containing beverages, including mate, guarana, yoco infusion, cassina, kola tea, coffee, tea, and cocoa.

Sources of caffeine

Not all of the caffeine derived from coffee and tea plants ends up in coffee mugs and tea cups. A considerable amount is extracted from low-quality coffee beans and tea leaves or is collected as a by-product of the decaffeination of coffee and tea. This caffeine is used in soft drinks and in medicines.

The beans used to produce coffee grow on only three species. Coffea arabica, native to Ethiopia, is now cultivated chiefly in Brazil and Colombia; Coffea robusta, native to Saudi Arabia, is now cultivated chiefly in Indonesia, Brazil, and many parts of Africa; and Coffea liberica, native to Liberia, is currently cultivated in Africa. Tea leaves used in brewing tea grow on a single species, Camellia sinensis, native to China and India where it is still chiefly cultivated. Wild species of both genuses grow abundantly-Coffea in Africa and Camellia in the Yunnan province of China, where a plant over 90 feet tall and 1,800 years old has been reported.

The other commercially valuable plant sources of caffeine are cocoa beans and kola nuts, produced mainly in Africa, and mate leaves, guarana seeds, and yoco bark, all of which grow in South America. Only mate is consumed in any quantity, and then only in Paraguay, Uruguay, and Argentina.

To understand why certain plants have evolved to contain caffeine, researchers have focused on how this chemical compound might benefit these plants. One idea is that caffeine containing plants gain extra protection from attack by bacteria, fungi, and insects. Caffeine is known to inhibit the actions of bacteria and fungi, and to cause sterility in certain insects, which decreases the insect population. In addition, because caffeine gets into the surrounding soil, it may inhibit the growth of weeds that might otherwise destroy the plants. Obviously, a plant containing a substance that gives it this kind of protection will have a higher survival rate than one that either has a smaller amount or none at all.

However, if caffeine were to harm the plant itself this advantage would be lost. In fact, caffeine containing plants do have mechanisms for protecting themselves against the caffeine's poisonous effects. For example, coffee plants produce and store the caffeine in coffee seedlings, away from the sites of cell division, which is very sensitive to toxic substances. But caffeine may still eventually kill the coffee plants that produced it. As a caffeine-bearing bush or tree ages, the soil around it becomes increasingly rich in caffeine that it has absorbed from the accumulation of the plant's fallen leaves and berries. It is partially because of this that coffee plantations tend to degenerate after 10 to 25 years.

The chemistry of caffeine

Pure caffeine is a bitter-tasting white powder that resembles cornstarch. It is moderately soluble in water at body temperature and readily soluble in boiling water. It was first isolated from coffee in 1820 and from tea in 1827 and given the name theine. Soon thereafter it was recognized that the mood- and behavior-altering properties of both coffee and tea depended upon caffeine.

Caffeine has two technical names. The full name is 3,7- dihydro-1,3,7-trimethyl-1H-purine-2,6-dione. The more commonly used technical name is 1,3,7-trimethylxanthine. Both names describe the chemical structure of the caffeine molecule.

To understand caffeine's effects, a brief introduction to purine and its related compounds is necessary. Purine is the parent compound of all of these chemicals and of many other of the important chemicals found in the body. Upon closer inspection it can be seen that xanthine, or dioxypurine, is purine with two oxygen atoms, and that caffeine, or trimethylxanthine, is xanthine with three methyl groups. A methyl group consists of a carbon atom and three hydrogen atoms. The "1,3,7" in caffeine's technical names refers to the positions of the methyl groups, as numbered in the purine structure.

Purine does not occur in the body in its pure form. When chemicals in the purine family are broken down, xanthine is produced as an intermediate product. The liver further converts xanthine into uric acid, which is found in unusually high levels in humans. Though too much uric acid is associated with the disease known as gout, uric acid is believed to contribute to our living longer than most other mammals.

The two most important purines found in the body are adenine and guanine. These two, together with cytosine and thymine, comprise the four basic letters of the genetic alphabet, or code, found in the cells of all living organisms. Everything a person inherits-from membership in the human species to eye color-is determined by this code. The code is "read" in groups of three purines, each chemically bound to a long strand of molecules. Two strands and their purines make up what is called a DNA, or deoxyribonucleic acid, double helix. Genes are sequences of the groups of three purines found at specific places on the chromosomes, structures composed of DNA.

The duplication of DNA is one of the central processes in the reproduction of cells and whole organisms. Caffeine, because of its similarity to critical parts of the genetic code, can interfere with this process and cause errors in the cells' reproduction. This may result in tumors, cancers, and genetic defects.

Theobromine and theophylline are two dimethylxanthines, or xanthine molecules, that have two rather than three methyl groups. Both dimethylxanthines produce effects similar to caffeine's, though theobromine is considerably weaker, having no more than one -tenth of the stimulating effect of caffeine or theophylline.

Theobromine is found in cocoa products, tea (only in very small amounts), and kola nuts, but is not found in coffee. In cocoa, theobromine's concentration is generally about seven times as great as caffeine's. Because of this, although the caffeine content of cocoa products is relatively low, the actual caffeine-like effects produced by consuming these products will still be significant.

Theophylline, found in very small amounts with caffeine and theobromine in tea, may have a stronger stimulatory effect than caffeine on the heart and on breathing. It is often the drug of choice in treating diseases in which breathing is difficult; such as asthma, bronchitis, and emphysema. The theophylline used in medicine is made from caffeine extracted from coffee or tea.

Caffeine is moderately soluble in water and therefore can be found in the body wherever there is water-which is in most places. Caffeine also readily passes through cell membranes. Because of these properties, after caffeine is ingested it is rapidly and completely absorbed from the stomach and intestines into the bloodstream, which distributes it to all organs of the body, including the brain, the ovaries, and the testes. In addition, when a pregnant woman consumes a caffeine containing food, the drug quickly goes to all of the organs of the unborn child.

In the bloodstream caffeine finally travels to the liver, where, by a process known as metabolism, it is converted into a number of breakdown products known as metabolites, which are eventually excreted in the urine. These metabolites include theobromine, theophylline, and a third dimethylxanthine, known as paraxanthine.

Relatively high levels of paraxanthine are found in the blood after caffeine has been ingested. However, as the blood passes through the liver again, paraxanthine is itself broken down to 1-methylxanthine. Methylxanthine is the main metabolite of caffeine found in human urine, but typically it accounts for only about one-fifth of the caffeine dose. The remainder is turned into one of at least a dozen other products of caffeine metabolism.

Because caffeine so readily passes in both directions across membranes, it is not easily excreted by the kidneys !into urine. If caffeine were not metabolized to compounds such as 1-methylxanthine that do not pass back across the kidney membrane and into the bloodstream, the caffeine from a cup of coffee would stay in the body for several days.

Frequently the metabolites of a drug have more effect than the drug that was originally ingested. Paraxanthine and, especially, 1-methylxanthine are even more similar to adenine and guanine than caffeine itself. Though it is not yet known exactly how much caffeine's metabolites contribute to caffeine's effects, both paraxanthine and 1-methylxanthine may very well play an important part in this drug's stimulation of the nervous system.

Caffeine's stimulatory effects involve the action of adenosine, a chemical widespread in the body. The adenosine molecule, composed of a purine linked to a type of sugar, is part of a larger molecule that supplies energy necessary for all cell functions.

Adenosine is also an important regulator of body processes, particularly the transmission of signals by nerves. Injection of adenosine or substances that increase adenosine levels can cause lethargy and sleep. Adenosine can also dilate blood vessels, diminish gastrointestinal motility (the gastrointestinal organs' ability to contract), protest against seizures, retard the body's reaction to stress, and lower heart rate, blood pressure, and body temperature.

Adenosine inhibits the release of neurotransmitters, or chemicals that carry messages from one nerve cell to another. To do this it must first bind to specific receptor sites on the cell surface. Because its structure is so similar to adenosine's, caffeine also binds to the receptors, and, in doing so, caffeine prevents adenosine from binding there. Thus, the nerve cells fire more rapidly. Researchers have discovered that both paraxanthine and 1-methylxanthine are even more effective than caffeine in competing with adenosine for adenosine receptors. Therefore, caffeine's brain-stimulating effects may be enhanced by its being metabolized to paraxanthine and 1-methylxanthine.

Caffeine in the body

Drugs such as caffeine that affect behavior and mood usually do so by acting on some of the 50 billion nerve cells in the brain. To reach the brain the molecules of a drug must first get into the bloodstream, which they do by a process known as absorption. This is accomplished in two basic ways. In enteral administration, caffeine's most common form of ingestion, the route includes the gastrointestinal tract-the mouth, throat, stomach, intestines, and rectum.

Parenteral administration bypasses the gastrointestinal tract. Instead, the drug gets into the body via the lungs, skin, ear, or vagina, or by injection. Injections can be made directly into an artery or vein, into a muscle, into the spinal cord, or into some of the body's spaces, such as just under the skin or around the intestines. Though perhaps infrequently, caffeine has been administered through most of these routes.

Injection directly into the bloodstream is obviously the fastest route, but it is often the most dangerous. Some drugs, such as insulin, are not given enterally because they are destroyed by substances in the gastrointestinal tract. Other drugs, such as some of the barbiturates, cannot pass from the gastrointestinal tract into the blood vessels in the wall of the stomach and intestines. Therefore, these drugs are also not given enterally. And because the blood from the stomach and intestines goes to the liver before going to the brain, drugs such as cocaine and heroin, which are broken down very quickly by the liver, are also not effective if given enterally.

Because caffeine is not broken down by the acid in the stomach, it is readily absorbed by the blood vessels in the walls of the stomach and intestines. About one-sixth of a dose of caffeine is absorbed through the stomach walls, and most of the remainder is absorbed through the wall of the duodenum, the first section of the small intestine. In addition, caffeine is metabolized relatively slowly by the liver. These properties make it a suitable drug for enteral administration.

The speed with which caffeine gets from the mouth into the bloodstream depends on a number of factors. Absorption is slower, for example, when the stomach is full or after prolonged fasting. Usually a single dose of caffeine passes into the bloodstream within 36 minutes of administration.

Blood containing caffeine flows from the gastrointestinal tract to the liver and then to the heart, from where it is circulated quickly throughout the body, including through the brain. The process whereby a drug spreads throughout the body is known as distribution. Caffeine is distributed to all of the body's water-approximately 42 liters, or 60% of total body weight, in an adult male. Of this 42 liters of water, only 6 liters is in blood. Most of it-about 28 liters-is found in the cells of the body that make up the brain, muscles, and other tissues and the remainder is found between the cells. Because, unlike some drugs, caffeine is relatively insoluble in fat, it does not accumulate in body fat, a substance in which it could be stored for long periods.

The effect of a given amount of drug is directly related to the weight of the person or animal receiving the drug. This is because a heavier body will generally contain more water and therefore dilute a given drug dose more. The result is a lower drug concentration in the blood reaching the brain and the other organs where the drug has its effects. It is the drug's concentration in the blood that generally determines how strong an effect will be.

Each time caffeine-containing blood passes through the liver, a small portion of the caffeine is metabolized. The caffeine removed from the blood is replaced by more of the drug returning from the body's other fluids. This process continues until eventually all of the caffeine has been metabolized by the liver.

The metabolism of caffeine is a complex process involving more than a dozen known metabolites, or products. Details of the process have become clear only in recent years, brought on by the advent of powerful equipment for distinguishing closely related chemicals and by the development of sophisticated techniques for labeling parts of the caffeine molecule and tracing their fate in the body.

The main metabolite of caffeine metabolism is 1,5 dimethylxanthine, known as paraxanthine. During later passes through the liver the paraxanthine is metabolized, producing, among other chemicals, 1-methylxanthine, which is the main metabolite of caffeine excreted in urine.

The strength of caffeine's effect on the body depends largely on the concentration of the drug in the blood circulating through the brain. This concentration reaches a peak between 30 and 60 minutes after caffeine is taken by mouth, after most of the caffeine has been absorbed from the gastrointestinal tract, and before much of it is metabolized by the liver.

Caffeine continues to have an effect as long as it remains in the blood. The critical factor is the metabolizing activity of substances in the liver known as enzymes. A lower rate of metabolism means the drug remains in the body and produces its effects longer. The half-life of caffeine-the amount of time it takes for the liver to remove half of the amount that has been ingested-varies considerably from individual to individual. The usual adult half-life ranges from 2.5 to 10 hours, averaging about 4 hours. Most of the drug is removed from the body within 12 hours. Men and women tend to have similar average rates of caffeine metabolism, as do people of all ages. Because of the liver's role in caffeine metabolism, most kinds of liver disease, particularly liver disease related to alcohol abuse, increase caffeine half-life.

Use of other drugs can dramatically affect the rate of caffeine metabolism. On an average, smokers, whose caffeine half-life is approximately 3 hours, metabolize caffeine 50% faster than nonsmokers. Thus, smokers experience the effect of a given cup of coffee for a shorter period of time than do nonsmokers. In addition, caffeine and nicotine have opposite effects on the neurotransmitter adenosine. Perhaps smokers tend to drink more coffee than nonsmokers in order to compensate for these effects.

Some of the variability in rates of caffeine metabolism is inherited. Asians, for example, appear to metabolize caffeine differently and more slowly than Caucasians. Some of the variability, however, may be the result of experience with caffeine. Regular caffeine users may metabolize caffeine more quickly, though this has not yet been proven.

The rate of caffeine metabolism declines during pregnancy, particularly during the last few weeks. It returns to normal levels in the mother a few days after giving birth.

Most of the enzymes that metabolize caffeine are not present in the livers of newborn babies. Caffeine in their blood has to be excreted through the urine, which is a slow process-the half-life of caffeine in newborn babies is approximately 85 hours. As the enzymes begin to be produced, the half-life decreases. By 2 months of age the half-life is close to 27 hours, and by 4 months it is 14 hours. At 6 months the infant's caffeine half-life averages between 2 and 3 hours below the adult level. It remains below the adult level until adolescence.

As well as being secreted into milk, caffeine is also secreted from blood into saliva and semen. Compared with the concentration in the user's blood, the concentration in his or her saliva is about 75% and that in semen is about 100%, or approximately equal to the level in the blood.

Except in newborn babies, there is very little elimination of unchanged caffeine. Only small amounts of unmetabolized caffeine are eliminated in feces and in body fluids other than urine, and less than 3% of the ingested caffeine appears unchanged in urine. Most of the caffeine is excreted into the urine in the form of caffeine metabolites. This is done by the kidneys as the blood flows through them at a rate dependent on the amount of urine produced. Even though only a small amount of ingested caffeine appears in urine, the average concentration of caffeine found in urine is relatively high-about 40% higher than in blood-because the actual volume of urine is small compared with that of blood.

The acute effects of caffeine

Caffeine reaches almost every part of the body and therefore has the potential to affect most of the body's functions. In fact, it does produce acute (short-term but often severe) effects on the cardiovascular system (the heart and blood vessels), on the digestive system, on breathing, on energy expenditure, and on urination. This property has also made it possible for caffeine to contribute to the therapeutic treatment of illnesses and diseases. But in addition, this characteristic enables caffeine to exhibit its toxic effects throughout the body. At the extreme, caffeine use can even be fatal.

Two important measures of cardiovascular function are the pressure of the blood as it flows through the arteries (blood pressure) and the heart rate. Blood pressure is of special concern because high blood pressure is an indication of strain on the heart and blood vessels and of possible obstruction somewhere in the circulatory system. Anything that causes or adds to high blood pressure could be dangerous.

A person's blood pressure at any given time depends on two things: the output of blood from the heart and the resistance of the circulatory system to the flow of blood. The output from the heart is determined in part by the rate at which the heart beats. When both the resistance to blood flow and the volume of blood pumped through the system at each heart beat remain constant, blood pressure and heart rate rise and fall together.

Increased heart rate usually accompanies the use of caffeine, although the change is generally small and not statistically significant. In some studies reduced heart rate was found after caffeine administration. Other researchers have reported that caffeine causes an initial decrease and then an increase in heart rate.

Caffeine has been shown to increase the rate of breathing by heightening the sensitivity of the part of the brain that responds to the level of carbon dioxide in the blood. Caffeine can improve the depth of breathing by strengthening the action of the diaphragm, which is the major muscle involved with inhaling and exhaling. One study has found that caffeine could be useful for people with lung disease who suffer from breathlessness.

Caffeine's short-term effects on the body's use of energy might be of interest to people who wish to lose weight. When ingested with a meal, caffeine increases the rate at which the food is converted into usable energy. When caffeine is taken between meals, it causes fats to be transferred from deposits in the cells to the bloodstream. Here, as free fatty acids they can be used as energy by most of the organs of the body.

Caffeine also raises the activity level of the body, which can mean that the energy derived from food is used up in exercise rather than being stored as fat. In addition, caffeine stimulates the temperature-regulating centers of the body, which in turn produces an increase in body temperature. To sustain this change, energy that might have otherwise been deposited as fat is used. Thus, even when the body is at rest a greater amount of food is burned.

Caffeine is a common ingredient in nonprescription diet aids, sometimes also known as appetite suppressants. However, there is no evidence that caffeine does indeed reduce appetite for food.

Despite the apparent relationship between caffeine's effects and weight loss, and though regular caffeine administration to animals has been shown to contribute to their losing weight, still it is not clear whether, in the long term, caffeine use contributes to weight loss in humans. Even if caffeine proved to be a weight-loss aid, one must consider this drug's other effects before advocating its use for this purpose. Frequently a drug's negative side effects make its use highly undesirable and dangerous. In addition, for a weight-loss program to be successful and lead to permanent weight loss, it must also include a change both in diet and life-style.

Drinking coffee increases the secretion of acid into the stomach, but it may be that, in addition to caffeine, other coffee components produce this effect. Although caffeine stimulates acid secretion, it also reduces the peristaltic action of the stomach, the action that causes the emptying of the stomach's contents into the small intestine. Caffeine also slows down the passage of material through the small intestine, yet speeds its passage through the large intestine.

As well as these effects on the digestive system, coffee and tea also reduce the body's absorption of specific nutrients, particularly iron, an essential mineral. The specific chemical or chemicals that cause the inhibition of iron uptake are not known, but caffeine and the tannins and other components of tea are the most likely agents. In addition to this, caffeine's ability to increase urination-by 30% for up to three hours following ingestion-can cause significant increases in the excretion in urine of calcium, magnesium, and sodium. Though some tolerance does develop to this effect, it could contribute to a deficiency in these minerals.

Caffeine is frequently included in both prescription and nonprescription headache preparations and other pain relievers. The amount is small-much less per tablet than in an average cup of coffee. Exactly why caffeine was first included in these products along with analgesic drugs (pain relievers) such as aspirin and acetaminophen is not known, though it may have been added to counter possible depressant effects of these drugs. Caffeine may also have been included because it is especially effective as a remedy for headaches caused by caffeine withdrawal.

Caffeine has also been used as an aid to fertility. A major cause of human infertility is sperm that are not mobile enough to reach and fertilize the egg. Studies of nonhuman mammals have shown that when caffeine is added to semen it can increase the mobility of their sperm and enhance fertilization. Studies of humans have produced similar findings regarding increased mobility, and at least one recent study suggests that, in fact, fertility too is enhanced by caffeine. According to the findings, women are twice as likely to become pregnant if prior to artificial insemination caffeine is added to the semen of their infertile mates. However, the concentration of caffeine used to achieve this effect is high-approximately 1,500 mg/liter, or more than three times the concentration of caffeine in the average cup of coffee (approximately 436 mg/liter). The possible negative side effects of such high concentrations of caffeine used in this way are not known.

Death from a caffeine overdose has usually involved accidental administration by hospital personnel of caffeine by injection or by tablet, or suicide using caffeine-containing tablets. The lowest dose of caffeine known to have caused death in an adult is 3,200 mg, administered intravenously by a nurse who believed that the syringe contained another drug. Children have died from caffeine overdose after eating many wake-up, weight-control, or other caffeine-containing pills.

The acute fatal dose of caffeine taken by mouth is at least 5,000 mg-the equivalent of about 40 strong cups of coffee consumed in a very short period of time. Thus, death from a coffee "binge" is unlikely. Moreover, caffeine in high doses causes vomiting, which would add to the difficulty of consuming enough beverage to cause death.

The actual cause of death from caffeine poisoning is not known, though in general the toxic (poisonous) effects of a drug are related to the drug's effects at lower doses. A wide variety of effects have been observed in patients who have received about 1,000 mg of caffeine, including the following:

• abnormally fast or deep breathing (hyperventilation)
• rapid heart beat (tachycardia)
• involuntary, uncoordinated muscle contractions (convulsions)
• rapid, uncoordinated twitching of the heart (ventricular fibrillation)
• low levels of potassium in blood (hypokalemia)
• high levels of blood sugar and ketone bodies in urine, as in diabetes (glycosuria and ketonuria)

The prolongation of any of these effects of large doses of caffeine can lead to death. Some physicians have noted that caffeine poisoning resembles the condition that can occur when diabetics do not take insulin or when their insulin fails to regulate the fat and glucose levels in their blood. Among diabetics this condition is the most common cause of early death.

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