130 JOHN T. HALSEY 



at least trac<* of epinephrin are excreted in the urine when the drug is 

 administered by other routes. 



Acute Poisoning. As produced in the laboratory, acute poisoning 

 shows great variations in different species. In addition to the circulatory 

 phenomena of high blood-pressure, irregular and violent heart action, and 

 irregularity of respiration, nervous phenomena are prominent. In some 

 species convulsions are followed by coma, in others coma alone develops. 

 In some species the respiration stops before the heart ; in others, the heart 

 is the first to fail. 'Pulmonary edema is an almost constant phenomenon. 

 Post-mortem examination usually shows edema of the lungs. Often there 

 are blood-tinged exudates in various serous cavities, with subpleural, sub- 

 peritoneal, and subpericarclial ecchymoses. The heart is usually in com- 

 plete diastole and often contains clotted blood. Hyperemia of various 

 organs, and hemorrhages in the suprarenals, thymus, and anterior pitui- 

 tary are often found. The kidneys show cloudy swelling and at times 

 there is a parenchymatous nephritis. 



Chronic Poisoning". In laboratory animals the most constant post- 

 mortem finding is the arteriosclerosis to which Josue first called attention. 

 This condition is found in animals, not only when the drug has been ad- 

 ministered intravenously, but also when the subcutaneous, intraperitoneal, 

 or oral routes have been used. Changes in the inner and median layers of 

 the media predominate. Whether or not such changes can result from the 

 use of epinephrin in human beings is uncertain. Brooks and Kaplan, in 

 an autopsy on a patient treated for months with many epinephrin injec- 

 tions, besides arteriosclerotic changes of the usual type, found also plaques 

 which exactly resembled those ascribed to epinephrin. Somewhat similar 

 reports have been made by others. On the other hand, in numerous 

 cases which had undergone long-continued epinephrin treatment,, the post- 

 mortem examination disclosed no such changes. In a case of chronic epi- 

 nephrin poisoning reported recently by Iloxie and Morris, post-mortem 

 examination failed to show arteriosclerosis of the epinephrin type. 



Habituation. Irr laboratory experiments, frequently repeated intra- 

 venous injections are followed, in some animals at least, by progressively 

 smaller effects on the blood-pressure, although, on the other hand, Kretsch- 

 nier found that in rabbits it was possible repeatedly to produce the same 

 effect with a constant dose. The many experiments carried out for the 

 purpose of studying the production of arteriosclerosis have clearly demon- 

 strated the development of a rapid habituation, or increased resistance, so 

 that after a few days several times the originally lethal dose can be borne. 

 The habituation, or lessened susceptibility, manifests itself not only in 

 respect to the hemodynamic effects, but also in connection with the glyco- 

 suric action. It is also a common clinical experience that many asthmatic 

 patients more or less rapidly develop a tolerance to this drug, but for- 

 tunately in many the development of such tolerance is very slow or does 



