The metabolism of the methyl purins, of which group caffein is a member, appears to vary with the quantity ingested. The manner in which the methyl group is liberated by the cell protoplasm is said[259] to determine the amount of stimulus which the tissues receive from these substances. The xanthin group is almost without any excitatory action, and its metabolic end products are constant. Perhaps the variation in the excretions of unchanged methylpurins is dependent upon the amount of total reactive energy they invoke.
Baldi[260] found that caffein in small doses increases muscular excitability in dogs and frogs. The spinal and muscular hyperic excitability produced by caffein is, in his opinion, due to the methyl groups attached to the xanthin nucleus. Fredericq[261] states that caffein increases the irritability of the cardiac vagus and accelerates the appearance of pseudofatigue of the vagus which is produced by prolonged stimulation of the nerve. The action of caffein on the mammalian heart has also been investigated by Pilcher,[262] who found that, following the rapid intravenous injection of caffein, there is an acute fall of blood pressure; and with a maximal quantity of caffein, 10 milligrams per kilogram, the cardiac volume and the amplitude of the excursions are usually unchanged. With larger quantities, the volume progressively increases and the amplitude of the excursion decreases.
Salant[263] found that the intravenous injection of 15 to 25 milligrams of caffein per kilogram in animals was followed by a fall of blood pressure amounting to 7 to 35 percent in most cases, which was transitory, although in some animals it remained unchanged. A moderate rise was rarely observed. Caffein aids the action of nitrates, acetanilid, ethyl alcohol and amyl alcohol, and increases the toxicity of barium chloride. In a very thorough study of the toxicity of caffein which he made with Reiger,[264] a greater toxicity of about 15 to 20 percent by subcutaneous injection than by mouth, and but about one-half this when injected peritoneally, was found. Intramuscularly the toxicity is 30 percent greater than subcutaneously. In making the tests on animals, they found that individuality, season, age, species, and certain pathological conditions caused variation in the toxic effect of the administered caffein. Low protein diet tends to decrease resistance to caffein in dogs, and a milk or meat diet does the same for growing dogs. Caffein is not cumulative for the rabbit or dog.
As a result of experiments on the action of caffein on the bronchiospasm caused by peptone (Witte), silk peptone, B-imidoazolyl-ethylamin, curare, vasodilation, and mucarin, Pal[265] concluded that caffein stimulates certain branches of the peripheral sympathetic and is thus enabled to widen the bronchi or remove bronchiospasm.
According to Lapicque[266], caffein produces a change in the excitability of the medulla of the frog similar to that produced by raising the temperature of the nerve centers. Schürhoff[267] has pointed out that the continued use of large quantities of caffein will produce cardiac irregularity and sleeplessness.
Cochrane[268] cited three cases where caffein was hypodermically administered in cases of acute indigestion, etc., and concluded that the cases prove that caffein, or a compound containing it as a synergist, does indirectly make the injection of morphia a safe proceeding, and directly increases the force of the heart and arterial tension. However, Wood[269] found that medium doses of caffein do not produce any marked rise in blood pressure, and cause a reduction in pulse rate. He attributes the contradictory results which prior investigations gave, to employment of unusually large doses and to inaccurate experimental methods.
Caffein was found by Nonnenbruch and Szyszka[270] to have a slight action toward accelerating the coagulation time of the blood, being active over several hours. It inhibits coagulation in vitrio. Its action in the body apparently rests on an increase of the fibrin ferment. There is no reason to believe that the behavior is dependent on a toxic action, but there is probably an action on the spleen; for in several rabbits from which the spleen was removed, no action was observed.
Experiments conducted by Levinthal[271] gave no positive information as to the formation of uric acid from caffein in the human organism. The elimination of caffein has also been studied by Salant and Reiger[272], who found that larger amounts of caffein are demethylated in carnivora than in herbivora, and resistance to caffein is inversely as demethylation, caffein being much more toxic in the former class. In a similar investigation, Zenetz[273] observed that caffein is very slightly eliminated from the system by the kidneys, and that its action on the heart is cumulative; therefore he concludes that it is contra-indicated in all renal diseases, in arterio-sclerosis, and in cardiac affections secondary to them. The inaccuracy of these conclusions regarding the non-elimination of caffein and those of Albanese,[274] Bondzynski and Gottlieb[275], Leven[276], Schurtzkwer[277], and Minkowski[278], has been shown by Mendel and Wardell[279], who point out that many of these experimenters worked with dogs, in which the chief end-product of purin metabolism is not uric acid, but allantoin. They observe that the increase in excretion of uric acid after the addition of caffein to the diet seems to be proportional to the quantity of caffein taken, and equivalent to from 10 to 15 percent of the ingested caffein. The remainder of the caffein is probably eliminated as mono-methylpurins.
Regarding the alleged cumulative action of caffein, Pletzer[280], Liebreich,[281] Szekacs[282], Pawinski,[283] and Seifert[284] all concluded from their investigations that the action of caffein is usually of brief duration, and does not have a cumulative effect, because of its rapid elimination; so that there is no danger of intoxication.
Dr. Oswald Schmiedeberg says: