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Related post: 212 MANUAL OF PHARMACOLOGY portional to the effusion, sets in promptly, and ceases when the drug is withdrawn. It is therefore especially useful for two or three days at the beginning of the more slowly acting but more permanent digitalis treat- ment. Caffein is the least active of the series. It may be given in the doses of 0.3 Gm. (5 grains) of citrated caffein, in watery solutions, three times a day, but Taylor found at least 0.5 Gm., four times daily, neces- sary for a full effect. Theobromin (i Gm. or 15 grains of theobromin-sodium-salicylate, or diuretin, in water, four times a day) has the advantage of producing a better diuretic effect with the least side effects. Taylor found that a daily dose of 30 grains produced very little effect; 40 grains a moderate diuresis; but 80 grains (5 Gm.) were required to secure the maximum efficiency. This quantity, when divided into four doses, was well tole- rated. It has also been used intravenously, 20 c.c. of 5 per cent., Neuhof, 1913 ; but it is doubtful whether this is justified. Theophyllin (theophyllin- sodium-acetate, or theocin) is the most powerful, but has been charged with sometimes causing renal irritation. Its dose is 0.3 Gm. = 5 grains, three times per day, administered in hot tea. In renal or hepatic effusions, the efficiency is less certain. In acute or chronic parenchymatous nephritis, there is often no response whatever, while chronic interstitial nephritis usually responds (J. Miller, 1912); but unless the dosage is very small and carefully watched, the toxic side ac- tions may set in, and the renal condition grow worse. Theophyllin and theobromin may cause renal irritation; it would therefore be better to avoid the methyl xanthins when the kidneys are acutely irritated. In anuria, the methyl xanthins are generally ineffective. Christian et al., 1915, state that diuretics are generally ineffective in chronic nephritis, unless there is edema. They would therefore be of little use against nephritic toxemia. Absorption, Fate and Excretion. Caffein is readily and completely absorbed: none appears in the feces even after large doses. Only a small fraction is excreted unchanged in the urine. This excretion starts and is mainly completed promptly, but traces may continue for two or three days (Salant and Rieger, 1912). A somewhat larger fraction loses a part of its methyl groups, and appears in the urine as di- and mono-methyl- xanthins. It is not known whether this is effected by oxidation or hydroly- sis. The remainder up to 80 per cent. is completely oxidized to urea. Practically none of the caffein is converted into uric acid (which is largely the fate of hypoxanthin and of xanthin) . Theobromin undergoes changes similar to caffein, but a larger fraction (32 per cent.) escapes decomposition. The greater part leaves as hetero- xanthin. Quantitative Excretion. The quantity of caffein which is excreted unchanged varies with the dose and with different animals, being only i per cent, in carnivora, less than 8 per cent, in man, and 6 to 20 per cent, in rabbits (Rost, 1895; Salant and Rieger, 1912). The relative quantity of the various mono- and dimethyl-xanthins also varies in differ- ent animals, representing 10 to 40 per cent, of the caffein (Albanese, 1895; Bondzynski and Gottlieb, 1895, Krueger and Schmidt). The literature has been summarized by Bloch, 1906. The demethylation is retarded by alcohol (Salant and Phelps, 1912). Emory and Salant, 1909, report experiments on the decomposition of caffein in the liver. A trace appears in the stomach, intestines and in the bile (Salant and Rieger). The gastro-intestinal excretion is higher when the kidneys are excised (Salant and Rieger, 1913). The loss of methyl groups occurs in pretty much all organs (J. Schmidt, 1910). CAFFEIN AND OTHER METHYL-XANTHINS 213 Toxicology. The fatal dose of caffein is so large (presumably about 10 Gm.), 1 that no fatal case of poisoning is on record; but doses above i Gm. may produce alarming symptoms, and even therapeutic doses may cause unpleasant side actions. With larger doses, the pulse is full and hard, quickened or slowed, with palpitation and precordial distress (sometimes anginal attacks). The head is heavy, throbbing, confused; often intense headache and great anxiety. Restlessness and excitement, insomnia (sometimes mild delirium, aphasia, fever). Vertigo, nausea, general discom- fort, fatigue, weakness (sometimes burning in the throat, gastric distress, heat flashes, perspiration, insensible pharynx, swollen tongue, ringing in the ears, flashes in eyes). Tremors of jaws, hands and feet, and muscular stiffness. Quickened, embarrassed respiration. Increased micturition (sometimes ardor urinae and erection). In very severe cases, there is vomiting (sometimes violent diarrhea and tenesmus); violent choreic tremors. Collapse, with small, irregular arrhythmic pulse, cold extremi- ties, dilated pupils. Consciousness is usually intact, but there may be delirium. Toxic Effects on Animals. The symptoms in animals correspond fairly to those observed in man: restlessness and increased reflexes; increased respiration, vomiting and diarrhea; muscular weakness. Then: clonic or tetanic convulsions, during which respiration may stop, with or without resumption; exhaustion and increasing paralysis; death in one to four hours. The fatal dose lies about 0.15 Gm. per kilogram. Dogs and cats are somewhat more susceptible than rabbits and guinea pigs. The dose by mouth is but little larger than the intravenous dose, except in rabbits (Salant and Rieger, 1910, 1912). Young mice are more resistant than old. The effects in birds are similar (Brill); in frogs they are modified by the onset of rigor. The toxicity is diminished by temperature above 98F. At 45F. the muscular effects predominate; while the convulsions become more prominent as the temperature is increased (Salant, Recovery is usually complete within a day, even when the symptoms were violent. Some restlessness and weakness may remain for a time. It is claimed (Kunkel) that large therapeutic doses have been followed by nephritic urine, but on the other hand, daily doses of 1.25 Gm. have often been given without detriment (Becher, 1884). Idiosyncrasy toward caffein is marked, as every one knows. Children and nervous and weak- ened individuals appear to be relatively more susceptible. Overdoses should be avoided, especially in myocarditis. Treatment. This would consist in evacuation and narcotics bromid, alcohol, chloral, or morphin. The principal indication would be to reas- sure the patient. Theobromin and theophyllin, in excessive doses or in susceptible in- dividuals, may produce toxic effects similar to caffein: headache, nausea, vomiting, epileptic spasms, albuminuria, gastric hemorrhage, etc. (Robert, Schmiedeberg, Seifert). These manifestations are, however, rare. In epileptic patients, Buy Dexamethason large doses of theophyllin are said to have produced attacks (Schlesinger, 1905). Chevalier, 1914, claims that some commer- cial theobromins contain toxic impurities; this requires more confirmation. PREPARATIONS CAFFEIN GROUP * Cajfeina, U.S.P., B.P.; Caffein (Thein); C 8 Hi N 4 O2 + H 2 O. A feebly basic alka- loid, usually prepared from tea. White, silky, needle-crystals; odorless; bitter taste.
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