PHARMACOLOGICAL ACTION OF TETRA-ALKYL-AMMONIUM COMPOUNDS. 509 



of these substances to account for this variability in pharmacological action. Both 

 substances are hygroscopic and consequently very soluble in water ; they ionise 

 readily, although not with equal facility ; they have the same constitutional form ; 

 and they react in the same way to other chemical substances. Tetra-ethyl- 

 ammonium chloride is somewhat the less stable of the two, but this would suggest 

 greater pharmacological activity rather than less ; and that it is not a cause of the 

 difference is proved by the fact that the iodide, which is more stable, shows the same 

 difference in pharmacological action from that of tetra-methyl-ammonium iodide. It 

 has been suggested that the explanation lay in the variable hydrolysis which the two 

 substances undergo in the blood, but no experimental evidence has been brought 

 forward to support this view, and the available evidence seems directly opposed to 

 it. The differences in ionisation, notwithstanding recent theories of muscular con- 

 traction, seems to me insufficient to explain the phenomenon, especially as it is still 

 observed to an almost equal degree when equi-conductivity solutions are employed. 

 Nor is the difference apparently due to variability in the penetration of the 

 two substances into muscle cells, although in isotonic solution tetra-methyl- 

 ammonium chloride appears to penetrate less readily than sodium chloride or tetra- 

 ethyl-ammonium chloride. This was determined, according to the method of Loeb 

 and Overton, by immersing muscles in hypertonic, isotonic, and hypotonic solutions 

 and noting the differences in weight before and after immersion. But that it is not 

 a factor of moment seems to me to be proved by the activity of dilute solutions of 

 tetra-methyl-ammonium chloride, and by the fact that hypertonic solutions of tetra- 

 ethyl-ammonium chloride, which penetrate less easily, do not produce the contracture 

 induced by tetra-methyl-ammonium chloride. 



The difference in pharmacological action might be attributed to the methyl 

 groups. Similar marked differences are known to be associated with the action of 

 other methyl and ethyl compounds, and in this connection it is interesting to note 

 that Buchheim and Loos # found strychnine etho-sulphate and nicotine etho-sulphate 

 less powerful than the corresponding metho-compounds. Brunton and Cash t also 

 conclude from their study of substituted ammonium salts that "the methyls are 

 more active than the corresponding ethyls," but that " the methyls, amyls, and ethyls 

 are more effective than the corresponding di- and tri-compounds." As stated in a 

 previous paper, Brunton and Cash did not find great differences in the activity of the 

 tetra-methyl as compared with the tetra-ethyl compounds in the series they investi- 

 gated, and the order of toxicity for rabbits is given as (l) the tetra-ethyls and tetra- 

 methyls, (2) the tri-ethyls and tri-methyls, (3) the di-ethyls and di-methyls, (4) the 

 amyls, ethyls, and methyls.J It is questionable, however, if this series of compounds 

 is strictly comparable to the series under consideration, in which all the hydrogen 

 atoms of the ammonium radical are replaced by alkyl groups. Apart from the fact 



* hoc. cit., pp. 208, 230. 



t Trans. Roy. Soc. Lond., clxxv. pt. i. p. 221 (1884). % Ibid., p. 211. 



