Caffeine

CAFFEINE, Coffeinum (State Pharmacopoeia of the USSR), an alkaloid found in significant quantities in various plants, namely: about 1.2% in the seeds of Coffea arabica (see Coffee), about 2% in the leaves of Thea chinensis (see Tea), about 4% in the fruits of Paulinia sorbilis, about 1.3% in the leaves of Ilex paraguayensis, about 1.2% in Cola acuminata nuts, and in small quantities in Theobroma Cacao (see Cocoa), Scilla maritima, and others. Since ancient times, wild peoples of various countries, completely independently of one another among various plants, have instinctively chosen for consumption all those that contain caffeine, although in their raw form these plants do not have an attractive taste or smell. At the present time, the most widespread and cultivated are tea and coffee. Caffeine is extracted mainly from tea and during the production of so-called decaffeinated coffee. For the first time in pure form, caffeine was isolated by Runge (1820) from coffee beans. Subsequently, caffeine was also obtained synthetically (Fischer, Ach). Caffeine has the appearance of long, white, silky-shiny crystalline needles, sparingly (1:80) soluble in cold and readily (1:2) in hot water. The solubility in water, besides warming, is significantly increased by the addition of citric acid, salts of benzoic, salicylic, and hydrobromic acids, antipyrine, and many other substances. A solution of caffeine has a neutral reaction and a bitter taste. Chemically, caffeine is such a weak base that it does not change the color of litmus, and its salts dissociate in aqueous solutions. Caffeine gives the murexide reaction, which indicates its close relationship to uric acid and xanthine. The chemical formula of caffeine was first given by Medicus. Caffeine is a derivative of xanthine (dioxypurine) and is trimethylxanthine with the following structural formula: CH₃.N - CO - CO - C - N.CH₃ // \ // CH₃.N - C - N - CH By its chemical composition, caffeine, being a derivative of dioxypurine, is of great interest also in that it stands close to certain metabolic products of the animal organism (xanthine, uric acid). At the base of all these compounds is purine, from which a whole series of bodies originates in such a way that oxygen or amino groups take the places designated by even numbers (2, 4, 6, 8) in the purine formula given below, while alkyl radicals CH₃, C₂H₅, etc., take the places with odd numbers. In the metabolism of the animal organism, xanthine bodies are regarded as degradation products of nucleoproteins, which are the main component of cell nuclei. The process of their formation is conceived in such a way that from nucleoprotein upon its breakdown protein and nucleide are obtained, from the latter protein and nucleic acid, and from it xanthine bodies and thymic acid. Such a relationship of caffeine to the metabolic products of the animal organism cannot but affect the nature of its fate in the latter, placing caffeine in a special position in comparison with many other plant alkaloids; it is possible that certain features of the pharmacodynamic properties of caffeine (low toxicity, lack of habituation to it, difficulty in obtaining a phase of depressive action, etc.) are connected with this. The local irritant action of caffeine is insignificant, but with prolonged use per os of the salicylic double salt, irritation of the gastric mucosa may be observed. Upon contact with proteins of strong concentrations of caffeine, their alteration is observed due to the ability of caffeine to convert myogen into myogen-fibrin (see below). Caffeine has a weak inhibitory effect on bacteria, thanks to which it possesses mildly expressed antiseptic properties. The absorption of caffeine and its double salts from the digestive canal and from subcutaneous tissue occurs rapidly and completely, which explains the speed of onset of its general (resorptive) action. In body tissues, caffeine decomposes easily, losing first one and then the other methyl group, thus passing into demethylated purines, which subsequently undergo further changes, such that up to 80% of the administered caffeine is completely oxidized to urea. About 20% of the administered caffeine is excreted in the urine as di- and mono-methylxanthines. Only a small part of caffeine (up to 8% in humans) is excreted in the urine unchanged. Excretion begins and ends quickly, but traces can be found in the urine even after 2-3 days. There are data suggesting that small amounts of caffeine are excreted into the gastrointestinal tract, from where they are reabsorbed into the blood. Analysis of the caffeine content in various organs shows that it is distributed among them fairly evenly, accumulating perhaps only in slightly greater quantities in the liver. The central nervous system, and especially those parts of the brain associated with psychic functions, is most sensitive to caffeine. The excitatory action of caffeine on the latter appears already upon taking small doses (0.1-0.2). The perception of external impressions and their processing into ideas are facilitated, the course of associative processes is accelerated, the reaction to external stimuli is refined, the number of errors in solving all kinds of problems is reduced, and an sharpening of the sense organs and other manifestations of clearer and more productive brain activity are noted (Kraepelin and others). The excitatory action of caffeine on the brain is particularly pronounced during fatigue, alcohol intoxication, and generally during mild depression of its work by narcotics of the fatty series. As a result of this action, the processes of internal inhibition underlying sleep are reduced; this explains the rapid disappearance of the remnants of a sleepy state in the morning after drinking tea or coffee and, on the other hand, the often noted insomnia when taking caffeine at night. The action starts quickly (after 20-30 minutes), reaches its maximum in 1-3 hours, and lasts 2-7 or more hours depending on the dose and the sensitivity of the given organism. With very small amounts of caffeine (0.03-0.06), clear phenomena of excitation cannot be caught, and only a clearer work of the central nervous system and other organs is noted, which lies at the base of the so-called "tonic" action of caffeine on the organism. While the action on the spinal cord appears only at very large doses of caffeine, moderate excitation of the centers of the medulla oblongata is observed even at therapeutic doses (0.15-0.25 of the double salt subcutaneously). Due to the excitation of the respiratory center, an increase in the frequency of breathing is observed, and its depth does not always increase and may even decrease, because due to the increase in pulmonary ventilation, the tension of CO₂ in the alveoli noticeably decreases. The excitation of the vasomotor center is not manifested to the same degree in the vessels of various regions. Usually, the greatest constriction is observed in the vessels of the digestive tract, whereas, conversely, the vessels of the kidneys, coronary vessels, vessels of the brain, its membranes, retina, liver, and to a lesser extent the skin and lungs, dilate. In those cases where the central action predominates, the vasodilator action is negligibly expressed or absent, or vasoconstriction may even take place (e.g., of the kidneys). The excitation of the vagus nerve centers leads to a slowing of the pulse at low doses of caffeine. At the same time, due to the direct action of caffeine on the heart muscle, the force of its systolic contractions increases, while diastolic relaxation either remains the same or even slightly decreases. The systolic volume of the heart increases due to the increase in systole, while the minute volume either increases slightly or may remain unchanged due to the slowing of the heart rhythm. Due to the dilatation of the coronary vessels and the enhancement of cardiac contractions, the nutrition of the heart muscle itself improves. At the same time, its absolute strength, i.e., the ability to overcome resistance, also increases. Other functions of the heart muscle also increase: its tone and excitability rise, and the conduction of impulses from the Keith-Flack node increases. Blood pressure usually either does not change or rises only to an insignificant degree, because due to the constriction of some and dilatation of other vessels, a redistribution of blood occurs with a significant increase in the speed of its flow, which is facilitated by the increased work of the heart and the dilatation of many vessels. Venous pressure does not change. With large doses of caffeine, an acceleration of cardiac activity is observed, which is explained by the predominance of the action of caffeine on the heart itself (its muscle or ganglia, or the Keith-Flack node, or the endings of the accelerating nerves). In this case, the minute volume may even decrease in view of the reduction in diastolic relaxation and insufficient time for blood inflow to the heart due to its frequent contractions. The described character of caffeine's action significantly distinguishes it from substances of the digitalis group and creates different indications for their use. The excitatory action of caffeine is manifested not only on the heart muscle, but also on skeletal musculature.

Therapeutic doses (0.1–0.15) of caffeine increase the functional activity of striated muscles; their contractions become stronger and more complete due to an increase in extensibility, the latent period is shortened, as a result of which the speed of contractions increases, the excitability of the muscle and its absolute strength (i.e., the ability to overcome resistance) increase; thus, the endurance and working capacity of the muscle are significantly increased, and the phenomena of fatigue in it disappear sooner. The effect on the muscle lasts for several (2–7) hours, manifesting itself especially significantly in the first hour (sometimes working capacity increases 4–5 times). In addition to the direct effect of caffeine on the contractile substance of the muscle and the favorable conditions of its blood supply, the stimulating effect of caffeine on motor processes in the central nervous system undoubtedly plays a role in the indicated action, the coordination of which reaches a high degree due to the excitation of the corresponding centers of the brain. To a lesser extent, this kind of influence of caffeine manifests itself in the form of its "toning" effect on skeletal musculature. - The effect of caffeine on smooth musculature has been studied less: an increase in the movements of the stomach and intestines is noted, sometimes leading in animals to a more rapid emptying of the contents; however, the sensitivity of smooth musculature is significantly lower, so that the indicated phenomena are observed only with the administration of relatively large doses of caffeine. The excretory activity of the kidneys under the influence of caffeine increases significantly. The increase in diuresis proceeds mainly due to its water part, since the excretion of the solid parts of urine (NaCl, nitrogenous substances, etc.), although it increases, does so to a lesser extent. The reaction of urine approaches neutral, since the dilution of urine reduces its acidity and a larger amount of blood alkalis passes through the kidney. Such urine even irritates the urinary tract less than normal; caffeine itself, even in large doses or with prolonged use, does not cause irritation of the kidneys. Therefore, substances of the caffeine group (caffeine, its salts, and especially diuretin, agurin, etc.) are also used in pathological processes in the kidneys. In accordance with the presence of various physiological theories of urine secretion, the mechanism of the diuretic action of caffeine has several explanations (see Diuretics). Briefly, they can be summarized as follows. It is undoubtedly that diuresis increases due to the direct action of caffeine on the kidneys, while its mechanism is explained differently: 1) the direct stimulating action of caffeine on the secretory function of the renal epithelium (von Schröder); 2) an increase in the permeability of the filtering membrane of the renal glomeruli and hence more rapid filtration of liquid parts from the blood (Cushny, Lambie); 3) a decrease or paralysis of the process of reabsorption in the tubules (Sobieranski). In addition, there are indications (Ellinger) that caffeine reduces the ability of blood and tissue colloids to bind water and salts, due to which more "free" water and salts are formed in the organism, which are subjected to increased excretion by the kidneys. Therefore, tissues lose all the more water the greater amount of it they contained (sharp diuresis in dropsy and negligible in dry food). In addition, the state of the blood supply to the kidneys undoubtedly must play a role in caffeine diuresis, but it is not a determining factor, but only an additional one. With the predominance of the central action of caffeine, due to strong excitation of the vasomotor center, a significant constriction of the renal vessels may take place instead of their usual dilation; under these conditions of poor blood supply, the diuretic effect is not observed. Therefore, with diuretin, agurin (see), and other purine derivatives that do not have a pronounced effect on the central nervous system, the diuretic effect is more reliable, strong, and prolonged than with caffeine. In view of this, in the clinic, to enhance diuresis, instead of caffeine, it is preferred to use diuretin, theocin, agurin, or other derivatives of dioxypurine. Frequently, the increase in diuresis goes together with glucosuria in the presence of hyperglycemia. The mechanism of increasing the concentration of sugar in the blood under the influence of caffeine has not yet received sufficient explanation. Metabolism under caffeine does not undergo sharp changes, and only in doses of 0.5–0.65 of Coffeini puri was a small (by 7–23%) increase in basal metabolism noted in humans without an increase in the respiratory quotient. Diuresis, as indicated above, proceeds with an increase in urea excretion; an increased excretion of water by the lungs and skin is also noted. At toxic doses of caffeine, a significant increase in body temperature is observed, the cause of which has not yet been elucidated (stimulating effect on the thermal center, increase in muscle tone, increase in reflex activity, etc.). Coffee and tea apparently possess this action to a somewhat greater extent (the influence of their other constituent parts), since Lichtenfeld and Fröhlich, in experiments on themselves, found an increase in temperature of 0.35° after drinking a cold infusion of coffee (from 22.5 g of its beans). Side effects of the action of caffeine are frequently observed in children, in individuals with increased excitability of the nervous system, with malnutrition, and also in patients with interstitial nephritis and myocarditis even with relatively small doses of caffeine (for example, 0.3 pro die). They are expressed by strong restlessness, strong significant ringing in the ears, insomnia, nausea, vomiting, a sensation of palpitation with a feeling of anguish and fear, etc. Usually, however, large doses per administration (0.5–1.0) are required for the development of symptoms of acute poisoning: strong excitement, sometimes mild delirium, aphasia, hallucinations, fever, tremor of the extremities, dizziness, severe headache; the pulse in this case is full and firm, accelerated or slowed; respiration is sharply accelerated. In very cases - vomiting, severe diarrhea with tenesmus, severe choreic tremor, collapse with a small irregular pulse, drop in blood pressure, cooling of the extremities, dilation of the pupils. In animals (especially cold-blooded ones), the stimulating effect on the spinal cord is much more sharply expressed, which can lead to convulsions and death from asphyxia during them. In frogs (Rana temporaria) at toxic doses of caffeine, a peculiar effect on striated muscles is observed, due to which they become as if hardened; under the microscope, a sharp shortening of the muscle fibrils is visible; they are white and opaque; transverse striation is absent, while longitudinal is more clearly visible; with stronger solutions of caffeine, destructive changes in muscle cells occur. The muscle reaction is acidic. It is believed that the cause of the changes is the transformation of myogen into myogen-fibrin with coagulation of the liquid contents of the muscle sarcolemmas. Lethal doses for humans are so great (apparently about 10 g of Coffeini puri) that cases of fatal poisoning have not been noted. Recovery is usually complete within one day, even in severe cases. A slight restlessness and weakness may remain for some time. Assistance in acute poisoning consists in the removal of the poison if it is taken per os, gastric lavage, the administration of substances that depress the central nervous system (bromides, chloral hydrate, alcohol, morphine); it is important to calm the patient as much as possible. - Chronic poisoning is described in individuals consuming excessive amounts of tea. Its symptoms are diverse: restlessness, nervousness, insomnia, tremor, headache, dizziness, palpitation, irregular pulse, often shortness of breath; they depend mainly on caffeine, but also on the aromatic substances in the beverage. On the other hand, loss of appetite, heaviness in the epigastrium after eating, dyspepsia, stomach pains, constipation depend on the tannin contained in the drunk tea. Frequent consumption of coffee produces approximately the same phenomena, but often instead of constipation there is laxation due to the irritating effect on the digestive tract of the volatile oil. Therapeutic use of caffeine is wide and diverse in view of its versatile action. 1. As a general stimulating and tonic agent in mental and physical fatigue, in collapse due to depression of the vasomotor or respiratory centers due to pathological processes in the organism (e.g., infectious diseases) or poisoning with morphine, opium, narcotics of the fatty series (chloroform, alcohol, chloral hydrate, etc.), heavy metals, etc. In the latter cases, caffeine is usually used in the form of very strong hot black coffee or tea, in order to have the synergistic stimulating effect of heat and coffee oils and the metal-precipitating action of tea tannin. 2. In weakening of the activity of the cardiac muscle caused by pathological processes in it or diseases of other organs and tissues (diseases of the respiratory tract, tuberculosis, acute infectious diseases, etc.). The effect on the heart comes on quickly, but does not last long; caffeine cannot completely replace digitalis, but is a good auxiliary agent to it. 3. In spasm of the cerebral vessels and the headache depending on this (spastic migraine), spasm of the coronary vessels (angina pectoris vasomotoria), sometimes in bronchial asthma - counting on the relaxation of the smooth musculature of the vessels (brain, heart) and bronchi. 4.

As a diuretic in kidney lesions and cardiac dropsy, sometimes in combination with central nervous system depressants (chloral hydrate, paraldehyde, luminal, etc.), because caffeine alone usually does not produce a reliable effect. Preparations. 1. Coffeinum purum (for its physical and chemical properties, see above). Used internally in powders, tablets, and pills, 0.06-0.1 2-3 times a day. Maximum doses (State Pharmacopoeia VII): 0.5 pro dosi and 1.5 pro die. 2. Coffeinum natrio-benzoicum—a mixture of about 50% caffeine with sodium benzoate. A white powder, odorless, with a bitter taste. In contrast to pure caffeine, it is easily (1:2) soluble in cold water. Official as a 10% solution for subcutaneous injections, 1-2 cm³ repeatedly. Internally—in powders, 0.1-0.3 pro dosi. Maximum doses (State Pharmacopoeia VII): 1.0 pro dosi and 3.0 pro die. 3. Coffeinum natrio-salicylicum—a mixture of caffeine (about 50%) with sodium salicylate. A white amorphous powder with a bittersweet taste, odorless. Well (1:2) soluble in water; dosage is the same as for the previous one. 4. Coffeinum citricum—a mixture of caffeine (approx. 50%) with citric acid. A white crystalline powder with a bittersweet-sour taste, odorless. Soluble in cold water (1:32) and better (1:4) in hot water. Not used subcutaneously due to the presence of free acid. Given at 0.1-0.3 in solutions. 5. Coffeinum citricum effervescens—effervescent citrated caffeine. A granular mixture of caffeine (approx. 2%) with citric acid, tartaric acid, and sodium bicarbonate. Internally, 4.0-8.0 per dose. 6. Migranin (Hoechst factory)—tablets consisting of 0.09 caffeine, 0.85 antipyrine, and 0.06 citric acid. 1 tablet for headaches. 7. Coffetylin—tablets containing 0.05 caffeine and 0.45 acetylsalicylic acid. A similar other preparation is Caffeospyrin, seu Coffeinum acetylsalicylicum. Used as an antineuralgic and antirheumatic agent. 8. Basicinum—a compound of caffeine with quinine. Xanthine derivatives and their salts have an action similar to caffeine in many respects (see Diuretin, Agurin). M. Nikolaev. Detection of caffeine in forensic cases. When tested for alkaloids, caffeine is extracted with chloroform already from an acidic solution (see Poisons, Isolation) and even more completely upon alkalization with aqueous ammonia. The residue after evaporation of the chloroform extract usually has a characteristic crystalline appearance, representing concentric circles of fused needles. Part of the residue is evaporated on a water bath with chlorine water. Upon adding traces of aqueous ammonia or a diluted sodium hydroxide solution to the red or red-yellow dry residue, a violet coloration appears. The distinction of caffeine (trimethylxanthine) from theobromine (dimethylxanthine) is the solubility of caffeine in carbon tetrachloride and the transfer of caffeine into chloroform from an aqueous solution upon alkalization with sodium hydroxide, which converts theobromine into a sodium derivative insoluble in chloroform. Caffeine sublimes upon careful heating. Quantitatively, caffeine is usually determined by weighing the dry residue.