PHARMACOLOGICAL ACTION OF TETRA-ALKYL-AMMON1UM COMPOUNDS. 515 



respiratory paralysis roughly in proportion to their power of paralysing the myo- 

 neural junction, and although the effect on the irritability of the nerves supplying 

 the muscles of respiration was not investigated, except in the case of tri-methyl- 

 ethyl-ammonium chloride, which was found to act similarly to tetra-methyl-ammonium 

 chloride, there can be little doubt from the parallelism mentioned that the mode of 

 action on the respiration is the same in all cases. Since the first paper was issued, 

 Loevenhart * has published a short note in which he says, " Immediately following 

 death from large doses of tetra-methyl-ammonium chloride, due to paralysis of the 

 respiration, it was found that the phrenic nerve endings are fully active, and no 

 support was found for Marshall's view that the temporary stoppage of the respira- 

 tion is clue to paralysis of the endings of the phrenic nerve. The conclusion was 

 reached that the action of tetra-methyl-ammonium chloride on the respiration is 

 entirely central." As no details of the experiments have been published it is difficult 

 to criticise this statement, but I venture to point out that the method adopted by 

 Loevenhart is not adapted to the end in view. When the irritability of the phrenic 

 and other nerves supplying the anterior part of the body is followed after an 

 injection of tetra-methyl-ammonium chloride, it is found to run parallel with the 

 respiratory effect ; whereas an injection made so that the respiratory centre receives 

 a larger concentration and the muscles a smaller concentration of the drug is 

 followed by a smaller effect on the respiration. Moreover, as already stated, the 

 paralysing influences of this series of alkyl-ammonium compounds on the respiration 

 runs parallel with their paralysing action on the myo-neural junction. It is difficult 

 to avoid the conclusion that the temporary respiratory paralysis produced by this 

 substance is partly, I believe, largely peripheral in origin. An interesting com- 

 mentary on Loevenhart' s method appears in the same journal a few pages later than 

 his note. Auer and Meltzer found that ether inhalations are capable of profoundly 

 affecting the peripheral motor mechanism and producing a curare-like action. 

 Githens and Meltzer f in consequence investigated the nature of the cessation of the 

 respiration in deep ether anaesthesia. They determined the irritability of the phrenic 

 nerves and diaphragm at the time of cessation of respiration induced by ether, and 

 found that " some time after complete stoppage of spontaneous respirations indirect 

 stimulation of the phrenic nerve, as well as direct stimulation of the diaphragm, cause 

 still a fairly good contraction of that muscle. On the other hand, it is evident that 

 the phrenic nerve and the diaphragm lose a good deal of their irritability in the 

 course of ether anaesthesia, and that the toxic action upon the peripheral respiratory 

 mechanism begins at an early stage of the etherisation." 



The action of these tetra-alkyl-ammonium compounds on the circulation is 

 apparently somewhat complex. Tetra-methyl-ammonium chloride stimulates the 

 vagal mechanism, and my experiments, in contradistinction to those of Iodlbauer,| 



* Journ. of Pharmacol, and Therap., v. p. 516 [1914]. + Ibid., p. 523. 



I Arch, internal, de pharmacod., vii. p. 183 [1900]. 



