Adrenaline

ADRENALINE, the active principle from the adrenal medulla, a derivative of pyrocatechin, orthodioxyphenyl-ethanol-methylamine (OH C₆H₃OH \CH.OH-CH₂.NH.CH₃). Its synonyms: suprarenin, epinephrine, paranephrin, epirenan, sphygmogenin, methyl-amino-ethanol-pyrocatechin, etc. Adrenaline was first obtained in crystalline form by Takamine and Aldrich in 1901. Properties: Adrenaline is a light, white, fine-crystalline powder with a bitter taste, sparingly soluble in cold water, easily soluble in hot water, in alkalis and acids; with the latter it forms salts; it is insoluble in absolute alcohol, ether, and chloroform; dry adrenaline does not change, but when heated to 212° it decomposes; aqueous solutions of adrenaline react alkaline and are easily oxidized in air; sunlight promotes the alteration of adrenaline; but adrenaline is insensitive to X-rays and thorium rays (V. Salle and Domarus); upon oxidation of adrenaline, its aqueous solutions are colored successively pinkish, pink, red, and, finally, brown; metal salts accelerate the oxidation of adrenaline solutions; in particular, with ferric chloride, adrenaline is colored emerald-green, which soon changes to dirty-brown, and with iodine—to bright red; gold chloride is reduced by adrenaline. Most enzymes rapidly oxidize adrenaline, but it resists the action of pepsin and pancreatin (Bouche). Blood and blood serum to a certain extent protect adrenaline from oxidation. Adrenaline is excellently adsorbed by animal charcoal. With phosphomolybdic, phosphotungstic, picric, and tannic acids, adrenaline does not produce a precipitate, just as it does not with mercuric chloride or with iodine-mercury dissolved in potassium iodide. The method of obtaining adrenaline from the adrenal glands of higher vertebrates was developed by Fürth, and the synthesis of adrenaline was first proposed by Stolz and Flacher; in this process, adrenaline is obtained first as optically inactive, and then it is converted into the acid salt of tartaric acid; this compound is split into dextro (d) and levo (l)-rotatory salt of tartaric acid adrenaline; and from these two salts, d- and l-adrenaline can be isolated in pure form using ammonia. The rotation power of l-adrenaline according to Pauly [α] = -50.4°; l-adrenaline is identical to natural adrenaline obtained from the adrenal glands. Its hydrochloride salt is used in medicine. The presence of adrenaline in solutions and other media can be established by color reactions that occur during the changes of adrenaline. Adrenaline is determined in its nearly neutral solutions (1:100,000) using a diluted solution of ferric chloride (Vulpian's reaction for chromogen) by the appearance of an emerald-green color. Bayer increased the sensitivity of this reaction 20-fold by adding sulfanilic acid to the solution. However, Battelli points out the inaccuracy of the data from this method. Adrenaline reduces potassium dichromate to chromium peroxide CrO₂, a substance of dark-brown, almost chocolate color. Sulfanilic acid increases the sensitivity of this reaction as well. This method is especially suitable for indicating the presence of adrenaline in the so-called "chromaffin" tissue that contains it. Also, adrenaline is determined in tissues by the Kutscher-Aichbergen method using an ammoniacal silver solution. O. Folin determines adrenaline by reducing phosphotungstic acid with it, based on the coloring of the resulting lower oxides to an intense blue color. The reaction is very sensitive (1:200,000). However, even with this method, errors in the determination of adrenaline can be very significant. Therefore, for colorimetric quantitative determinations of adrenaline, weak oxidizing agents or corresponding catalysts are also used, which cause rapid oxidation of adrenaline and, consequently, the coloring of its solutions pink. The amount of adrenaline is determined by comparing the intensity of the color in the test solution with the color of a standard adrenaline solution. For quantitative determinations of adrenaline, according to the indicated Vulpian principle, it has been proposed to add an excess of iodine solution to the test adrenaline solution and perform back-titration of the excess iodine with thiosulfate, and Kraus and Frankel with Allers introduced determination with iodic acid. The sensitivity of the reaction with iodine is high (1:200,000), with iodic acid and with sulfanilic acid—even higher (1:500,000). Russmann brought the sensitivity of the reaction to 1:50 million by combining the iodic and sulfanilic acid test with the mercuric chloride test, first introduced by Comessati. Ewins used a potassium persulfate solution for the oxidation of adrenaline; the adrenaline solution turns distinctly pink at a concentration of 1:5,000,000. More accurate and convenient are the methods of biological determination of adrenaline, and among them the pharmacological one, in which the amount of adrenaline is determined by the height of blood pressure in a rabbit (Elliott). Our pharmacopoeia also uses this method. The method of Oliver and Schäfer, consisting of passing fluid through the vessels of the hind limbs of a frog, was tested by Läwen and Trendelenburg for the quantitative determination of adrenaline in preparations. Pisemsky, in the laboratory of N. P. Kravkov, used the vessels of a rabbit's ear for the same purpose. Lewandowsky proposed determining the amount of adrenaline by changes in the pupil of mammals, Stewart—by the movements of a rabbit's intestine, Frankel—by the contractions of the uterus or, even better, the uterine horn of a female rabbit. The indicated methodology for quantitative determinations of adrenaline rests on the physiological property of this hormone to cause irritation of the sympathetic nervous system upon entering the blood from the places of its formation. Oliver and Schäfer pointed to such a property when they determined that an extract from the adrenal medulla, introduced into the organism, sharply increases blood pressure and at the same time reduces the volume of organs. These authors also clarified that the cause of the changes in the organism is the action of the preparation on the terminal apparatus of the sympathetic nervous system. Lewandowsky established that in this case, sympathetic nerve endings are irritated, and Langley and Elliott, having significantly increased the scope of such facts, already in relation to pure adrenaline, determined that it acts similarly to electrical stimulation on the endings of the sympathetic nerve in smooth muscles and glands, thus causing either an enhancement or a depression of the organ's function. Zondek considers the cause of the irritating action of adrenaline to be a disturbance of the equilibrium of calcium and potassium cations in the cells, and Burridge believes that adrenaline strongly increases the sensitivity of cellular colloids of muscle tissue to calcium. Adrenaline, acting on capillaries and small arteries, causes a particularly sharp constriction of vessels at the site of injection, their spasmodic contraction; therefore, the mucous membrane or skin into the thickness of which the adrenaline solution was injected becomes bloodless, becomes very pale, and does not bleed or bleeds little during incisions. With the general action of adrenaline, vessels, especially of the abdominal organs and mesentery (area of the splanchnic nerve), constrict, while the vessels of the lungs, containing only vasodilators, and the coronary vessels of the heart dilate (Kravkov, Markwalder, and E. H. Starling); the state of the vessels of the brain under the influence of adrenaline can be different: Biedl and Reiner, Berezin, and others observed constriction of the vessels of the brain, while Spina observed dilation. Acting on vascular tone, adrenaline, in addition, also excites and strengthens their independent rhythmic contractions (Kravkov, Soloveychik). In general, the influence of adrenaline on vessels is expressed by an increase in blood pressure, which also increases because adrenaline acts on the heart, irritating the cardiac fibers of the sympathetic nerve, on the one hand, causing an increase in heart rate, and on the other—strengthening the muscular contractions of the heart. Sometimes, however, a vagotonic pulse is also observed. Adrenaline also exerts an effect on other organs with smooth musculature: it dilates the pupil by irritating the endings of the sympathetic nerve in the radial muscle of the iris, if the nerves have been previously severed; bronchial musculature also relaxes from the irritation of sympathetic nerve endings in it by adrenaline; in the intestinal tract, where the sympathetic nerve contains partly inhibitory, partly excitatory fibers, the influence of adrenaline is expressed differently: the tone of the entrance to the stomach, peristalsis of the stomach and intestines weaken, and, conversely, the closure of the pylorus, the ileocecal valve, and the internal anal sphincter is strengthened, sometimes even to spasmodic contraction; the smooth musculature of the gallbladder relaxes, the spleen contracts, the urinary bladder relaxes; the uterus, especially the pregnant one, contracts (Kurdinovsky); the smooth muscles that raise the hair contract. Pigment cells, also innervated by fibers of the sympathetic system, contract from adrenaline (Kravkov). The excitability of striated musculature is increased by adrenaline (Gruber). The function of glands under the influence of adrenaline also changes: in sweat glands, it decreases, in all probability, due to the simultaneously occurring constriction of skin vessels; however, in some animals, adrenaline causes increased sweating; thus, Frontier observed strong sweating from adrenaline in horses. The function of salivary, lacrimal, and mucous glands is sharply increased by adrenaline.

Bile secretion is increased by adrenaline according to Langley, but Camus denies this; pancreatic secretion drops, the amount of gastric juice decreases, but the amount of hydrochloric acid in it increases; adrenaline does not affect the secretion of mammary glands; urine output in rabbits increases sharply, and sugar appears in the urine; in humans, with large doses of adrenaline, urine output decreases, while with small doses it increases. Most authors regarding the mechanism of adrenaline glycosuria express the hypothesis that adrenaline acts on those peripheral sympathetic nerve fibers which, during a sugar puncture, cause the effect of its irritation from the center. Therefore, the appearance of a large amount of sugar in the urine cannot be explained solely by the mobilization of liver glycogen and its release in large quantities into the blood. Glycosuria from adrenaline is linked to the increased formation of adrenaline itself in the adrenal glands, similar to what happens during electrical stimulation of the celiac nerve, which is considered the secretory nerve of the adrenal glands, and with a decrease in chromaffin substance in the adrenal medulla after a sugar puncture (Kahn). On the other hand, the constriction of arterial vessels in the liver by adrenaline also represents a condition that alters the breakdown and assimilation of glycogen in the liver with a simultaneous increased formation of acids in the body or their reduced breakdown, which may bring forward the factor of increased sugar formation in the question of the mechanism of glycosuria from adrenaline. If an excess of adrenaline causes glycosuria, then the loss of another hormone, the pancreatic hormone, causes diabetes (Mering, Minkowski); and in the question of carbohydrate metabolism, attention is always paid to the interrelation of the functions of the adrenal glands and the pancreas, namely, to their antagonistically regulating role, which determines the balance of carbohydrate metabolism. This antagonism is even more pronounced because the pancreatic hormone inhibits the sympathetic nerve, while adrenaline excites it. Glycosuria from adrenaline lasts only a few hours. Adrenaline has no direct effect on the endings of the parasympathetic nervous system, but with strong excitation of the sympathetic apparatus by adrenaline, a weakening of the excitability of the nerves of the parasympathetic system can occur as a secondary phenomenon. Work by Kolm and Pick has proven on an excised frog heart the excitation of vagus nerve endings by adrenaline, but this phenomenon is regarded as a 'perverted' action. One can also note the onset of increased excitability from small doses of adrenaline in motor nerve endings and depression in them from stronger doses. The brain and spinal cord are depressed by adrenaline; adrenaline does not affect the vasomotor center, but it excites the vagus nerve centers and respiratory centers (Gruber). Metabolism upon injection of adrenaline changes as follows: the Ca content in the body falls, the amount of Na and K in the urine increases significantly (Faltau), and Cl decreases; the alkaline-acid balance is disturbed towards increased acidity due to an increase in acetic, lactic, and oxybutyric acids in the blood, as well as acetone; in humans, the content of lactic and phosphoric acids in the urine increases; combustion processes proceed more energetically, the amount of exhaled carbon dioxide and absorbed oxygen increases; more uric acid and allantoin are excreted in the urine, as well as creatinine; urea, however, is excreted sometimes more than normal, sometimes less, depending on the size of the adrenaline dose. Absorption of adrenaline upon subcutaneous administration occurs slowly, the cause of which is the strong constriction of vessels by adrenaline, therefore the lethal dose of adrenaline upon subcutaneous injection (4–20 mg per kilogram in different animals) is very far from the dose introduced directly into the blood (0.1–0.8 mg). The fate of adrenaline introduced into the body is far from clarified, despite the fact that we know the property of adrenaline to decompose easily. Upon subcutaneous administration, adrenaline remains relatively long undecomposed at the site of its introduction; in muscles, in the lungs, and in the blood, adrenaline decomposes little, but the excess of adrenaline disappears from the blood very quickly; the decomposition of adrenaline occurs energetically in the capillary network; the main site of destruction is the liver and intestines (O'Connor). The chemistry of adrenaline destruction is still far from clear, although the majority of authors speak of the oxidation of adrenaline in this process, but there are also facts contradicting this, and Cramer believes that adrenaline loses its poisonous properties due to the appearance in the body, after the introduction of adrenaline, of metabolic products of an aldehydic nature. The therapeutic use of adrenaline is practiced in a whole range of diseases accompanied by a decrease in the tone of the sympathetic nervous system, for example, in bronchial asthma; an asthmatic attack usually terminates after an injection of adrenaline; hyperemic phenomena, swelling, and hypersecretion in the small bronchi weaken, and the contracture of bronchial muscles ceases. In hysterical angina pectoris, in hysterical neurosis of the vagus nerve, and in hypotonic bradycardia, adrenaline, introduced intravenously, excites the sympathetic nerve (Rossiyskiy), including its cardiac branches, as a result of which cardiac activity returns to normal. Heart function is also restored after adrenaline in cases of acute threatening decline of cardiac and respiratory activity during severe collapses, due to surgical shock, anesthesia, hemorrhages, peritonitis (Butkevich, Eskin); in such cases, however, many prefer to inject adrenaline subcutaneously, since intravenous injection of adrenaline is not safe—there are fatal cases, blood pressure rises too quickly, and obstacles to the work of the heart grow at the periphery. Adrenaline is successfully used in gastrointestinal neuroses accompanied by reduced sympathicotonia; in the Rossbach symptom complex, manifesting as periodically occurring hypersecretion of gastric juice (Arinkin and Sirotkin) and headaches; in spastic phenomena along the intestinal tract; and in muscular atony of the intestine. Addison's disease, in view of its presumed etiological connection with disease of the adrenal glands, is usually treated with adrenaline. Adrenaline is also used with benefit in acute infectious diseases (Molchanov), in which blood pressure often falls or asthenic phenomena develop and insufficient function of the adrenal glands is revealed. However, in such cases, one must be careful with adrenaline, since its action in strength and character in acute and contagious diseases can be very diverse; at least, Kravkov and his students (Anichkov, Shkavera, Zakusov, Valdman, and others), investigating the functional state of vessels in various parts of the body in patients with contagious diseases, pointed with certainty to a very unequal reaction of vessels to adrenaline. This question is complicated all the more by the fact that the interrelation of adrenaline with toxins produced in the body during the indicated diseases remains unclarified. The importance of adrenaline is especially great in surgery when performing local anesthesia: it is added to solutions of cocaine, novocaine, alypin, and others, in order to prevent, by the constriction of vessels caused by adrenaline, the absorption of the anesthetic substance taken and, thus, to avoid poisoning the patient, as well as to prolong and partly strengthen the anesthesia by delaying the anesthetic agent at the site of its introduction. When using adrenaline, the surgeon also gains in that in small cavities—in the nose, in the mouth, in the nasopharynx, in canals—due to the constriction of vessels under the influence of adrenaline, the cavity becomes more spacious, bleeding is less, and it becomes easier to operate; therefore, adrenaline is willingly used in otorhinolaryngological, urological, and eye practice. In obstetrics, adrenaline is used to strengthen labor contractions and to stop postpartum hemorrhages from an atonic uterus. Adrenaline is used in cases of poisoning by chloroform, chloral hydrate, salvarsan (to excite cardiac and vascular activity), and morphine (to excite the respiratory center); in the latter case, with very good results. Contraindications to the use of adrenaline are sympathicotonia, arteriosclerosis, aneurysm, glaucoma, pulmonary hemorrhages, pregnancy, glycosuria, and idiosyncrasy. The therapeutic dose of adrenaline for internal and subcutaneous use usually does not exceed 1 cubic centimeter of a solution of adrenaline hydrochloride (1:1,000); for intravenous administration, 1 cubic centimeter is the maximum dose. In the USSR, adrenaline is produced in Moscow by the Institute of Experimental Endocrinology of the People's Commissariat of Health, and in Leningrad by the Organotherapeutic Institute (formerly Pely); the most commonly used foreign preparations of adrenaline are: Adrenaline Takamine Parke Davis & Co.; Paranephrin by E. Merck; Suprareninum syntheticum by M. Lucius u. Brüning.