traces even when large quantities have been ingested, while on the injected intravenously are exhaled by the lungs in large part, while

Transcription

1 ON THE EXHALATION OF DRUGS BY THE LUNGS. BY ARTHUR R. CUSHNY. (From the Pharmacological Laboratory, University College, London.) THE exhalation of vapours by the lungs has not been the subject of systematic observations hitherto, and no definite statement is to be found in the literature as to the factors involved in it apart from the volatility of the substances eliminated by this passage. As regards individual substances, some results have been recorded; thus MagnusL found that ammonia is not excreted by the living lung and also fails to be absorbed from the air passages, and he considers the living pulmonary epithelium to be impermeable by ammoniia. A number of observers have demonstrated that ethyl alcohol is eliminated by the lungs only in traces even when large quantities have been ingested, while on the other hand it is well known that some of the higher alcohols can be detected in the breath, when comparatively small amounts have been absorbed. Poh 12 has recently shown that in the dog and cat, and to a smaller extent in the rabbit, amylene hydrate and tertiary butyl alcohol injected intravenously are exhaled by the lungs in large part, while isoamyl alcohol and methyl alcohol ingested in the same way appear only in traces in the breath. In one experiment he found isopropyl alcohol also excreted by the lungs in considerable quantity. Pohl seems disposed to consider it a general rule that primary alcohols are excreted only in traces by the lungs, while secondary and tertiary alcohols are mainly eliminated in this way except in so far as they enter into combinations (e.g. with glycuronic acid) and are oxidised in the tissues. This view seems to involve the conception that the exhalation of these bodies is determined by their capacity for undergoing some chemical combinations in the excreting cells rather than by their more 1 Arch. f. exp. Path. u. Pharm. XLVIII., p Arch. f. exp. Path. u. Pharm. Schmiedeberg Festschr. p PH. XL. 2

2 18 A. R. CUSHArY. obvious physical properties, that is that the pulmonary endothelium actually secretes these bodies actively. This would be analogous to Bohr's theory of the interchange of the respiratory gases. From this point of view the examination of the process of exhalation seemed to promise to throw some light on other more complex secretory processes, and I have therefore made a number of experiments as to the relative amount of some volatile substances eliminated by the lungs. It may be stated at once that the results indicate that the physical characters alone determine this way of elimination. These experiments were performed on cats which were anaesthetised with large doses of ethyl urethane injected hypodermically. The drugs were injected through the jugular vein, and the amount exhaled through a tracheal cannula was determined. For this purpose the tracheal cannula was attached to a pair of valves, which pernitted the free inspiration of air while the expired air passed through a collecting tube to a small bladder of varnished gold beaters' skin. From this it passed to four small flasks arranged as washbottles in series. The resistance offered by these was too great to be overcome by the respiratory muscles and the last washbottle was therefore connected with a suction pump which was regulated so as to just keep the bladder empty. The amount of air breathed was measured by a gasmeter interposed between the washbottles and the suction pump. The respiration remained quite normal to all appearance for hours. The washbottles contained water generally, but for some experiments alcohol was used as a better absorbent for the vapour examined. The two washbottles nearest the animal were generally.examined together, the third and fourth separately; the fourth was merely a control and was never found to contain any organic body. The substances examined fall into two groups one with boiling points lying between 56 and 660, acetone (560), chloroform (62 ), and methyl alcohol (660), the other with boiling points lying between 770 and 85, ethyl acetate (770), methylethyl-ketone (78 ), ethyl alcohol (780), isopropyl alcohol (81.30) and ethylene chloride (850). Some difficulty was found in the quantitative estimation of the small amounts of these bodies exhaled. In every case preliminary estimations were made to test the adequacy of the methods employed, but it is unnecessary to record the results here. Acetone. The elimination of acetone in the breath is a familiar clinical observation, but Schwarz' first showed how large a part it plays in the excretion of this substance. He further noted that its 1 Arch. f. exp. Path. u. Pharm. XL. p

3 EXHALATION BY LUNGS. elimination was comparatively slow when large quantities were injected; when 0-8 g. per kg. was injected it disappeared fromi the breath only in 24 hours, and after 1P7 g. per kg. the elimination ended only after 42 hours. I estimated acetone in the usual way, by adding a tenthnormal iodine solution and potash and titrating the excess of iodine with sodium thiosulphate. Exp. 1. A cat of 2 kg. weight received 1-6 g. acetone intravenously and exhaled in the first hour g., in the second hour g., and in the third hour g. Total in 3 hours g. Exp. 2. A cat of 2 35 kg. weight received 0-8 g. acetone intravenously and exhaled in the next 34 minutes 15 5 mg., in the next 40 minutes mg., in the next 50 minutes 16-4 mg., and in the following hour 18 6 mg. Total exhaled in 3 hours=68-3 mg., 50 c.c. of blood was drawn at the end of the experiment from the carotid, was diluted and acidulated, filtered and distilled with steam. The distillate redistilled contained 5-13 mg. of acetone giving 10-3 mg. in each 100 c.c. of blood at the end of the experiment. Exp. 3. A cat of 4-72 kg. weight received 0-16 mg. acetone intravenously and exhaled in the next 1J hours 7-3 mg. acetone. Acetone thus appears in the breath even when comparatively small quantities ( per kg.) are injected, and larger amounts are eliminated in correspondingly larger measuire. The exhalation proceeds very slowly however, only 8-5 0/0 of that injected being eliminated in three hours when g. per kg. was injected and 14 /, in the same time when 0-8 g. per kg. was injected. The percentage of that injected which is excreted in a given time thus rises with the dose. Chloroform. It is of course common knowledge that chloroform is eliminated mainly by the lungs, and since my experiments were begun the proportion thus got rid of when the drug is injected 'intravenously has been determined for the rabbit by Burkhardt'. He states that over 90 per cent.2 of the chloroform injected intravenouisly in the rabbit is excreted during the anaesthesia, in his experiments within minutes of the beginning of the injection. In my experiments on cats the proportion of the total exhaled was lower than that given by Burkhardt, but apart from this the results are the same, and it is sufficient to give one experiment. The expired air passed through wasbbottles containing alcohol, and the chloroform was estimated by heating the alcohol with an alcoholic solution of soda in a flask with reflux condenser, evaporating off the alcohol and determining the chloride by Volhard's method. The intravenous injection of chloroform 1 Arch. f. exp. Path. u. Pharm. LXI. p There seems to be an arithmetical error in his calculation that per cent. is exhaled during the narcosis

4 20 A. R. C(USHNY. in salt solution was attended with difficulty owing to the repeated failure of the heart and respiration, and the elimination was of course delayed from this cause. Exp. 4. A cat of 3-6 kg. weight received 0 32'g. chloroform in 40 c.e. saline in 15 minutes. The drug exhaled was collected from the beginning of the injection minutes chloroform exhaled was 123x5 mg ,,,,,,,, 54.5,, 60-90,,,,,,,, 45 0,, ,,,,,,,, 34.5,, ,,,,,,, 12-5,, of,,,,, 7 0 to ,,,,,,,, 4,, Total= g. In this experiment nearly 90 per cent. of the chloroform injected was exhaled and a large proportion came off immediately after the injection was made, although both circulation and respiration were much depressed. A certain amount remained in the tissues even after three hours. The large proportion exhaled immediately forms a contrast with the results under acetone, which is not eliminated so rapidly in the beginning, and therefore decreases much more slowly in the expired air. Yet the heart and respiration are much weakened in the earlier stages after chloroform, while no such effects were observed under acetone. The contrast between the two drugs is brought out more clearly when both are injected together and each is estimated separately in the expired air. For this purpose the air was drawn through three bottles containing water and then through two containing alcohol. The acetone was retained in the water, only traces 'reaching the third bottle, while the chloroform was found for the most part in the alcohol, though some remained in the water. Exp. 5. A eat of 2-5 kg. weight received g. chloroform along with 0 5 g. acetone in 50 c.c. saline in the course of twenty minutes. The respiration failed, but was restored by kneading the thorax. The air expired was examined from the beginning of the injection. Time Chloroform exhaled Acetone exhaled mins. in mg. in mg (?) 7 Total in 4 hours

5 EXHALATION BY LUNGS. The animal was bled from the carotid, and the blood was precipitated with mercury perchloride, filtered, washed and distilled at reduced pressure. The distillate was tested for chloroform with negative results, but contained acetone equivalent to 43 mg. per 100 c.a. of blood. In this experiment much less acetone was exhaled than chloroform, though the latter was injected in smaller amount and also has a higher boiling point. The great mass of chloroform came off almost immediately, and, as the concentration in the blood was thus reduced, the elimination fell rapidly to less than half the maximal and then more slowly. The acetone on the other band was exhaled more slowly at first, but fell more slowly, so that when the experiment closed it was being eliminated in larger amounts than the chloroform. The blood at the end of the experiment contained considerable amounts of acetone, while no chloroform could be obtained from it. But the whole of the chloroform had not been exhaled, and it is probable that it may have been in combination in the tissues from which it is only slowly given up to the blood. Methyl alcohol was found to be exhaled only in traces by Pohl in an experiment in which he injected it intravenously. In my experiments the methyl alcohol in the expired air was collected in water and estimrated by the method introduced by Atwater and Benedict for ethyl alcohol Exp. 6. A cat of 2-3 kg. weight received 1-85 g. of methyl alcohol in saline solution injected intravenously and exhaled 13 mg. in 45 minutes. It was then bled, and 30 a.c. of the blood was put in the evaporating tube described later, and about 30 litres warmed air was drawn through it. This carried out with it 14 mg. of methyl alcohol.; Exp. 7. A cat of 1x8 kg. weight breathed through the apparatus for an hour before any injection was made. The washwater through which the expired air passed was distilled at reduced pressure and contained no reducing substance whatever g. of methyl alcohol was then injected intravenously, and the exhalation was collected for two hours. The washwater distilled over gave a trace of reduction, less than that from 1 mg. of methyl alcohol. Methyl alcohol is therefore exhaled only in traces unless when very large quantities are injected. This is not due to its being eliminated in other ways, for it was present in the blood in some quantity at the end of Exp. 6, and Pohl, has shown that it persists in the tissues for at least 3-4 days. Ethyl acetate was taken as a type of the esters with low boiling point. It was collected in water, which was distilled at reduced pressure. The distillate was rendered exactly neutral to phenolphthalein 1 Arch. f. exp. Path. u. Pharm. xxxi. p

6 22 A. R. CUSHIINY. when necessary, and then a known quantity of NaHo 10wa was added and the ester saponified by heating it for several hours under a reflux condenser. It was then titrated back with H2SO4100, and the ethyl acetate was calculated from the amount of sodium acetate formed. Exp. 8. A cat of 3 9 kg. weight was injected with 027 g. ethyl acetate dissolved in saline solution. The exhalation was collected for 40 mins. and contained merely a trace of ethyl acetate. The blood also contained a trace. Exp. 9. A cat of 2 kg. weight received 0 9 g. ethyl acetate. The expired air was passed through water for an hour and was found to contain 9 5 mg. ethyl acetate. 09 g. was now injected, but the respiration failed and could not be re-established. The blood was collected, precipitated with alcohol and filtered. The filtrate distilled contained ethyl acetate in quantities corresponding to 22 mg. in 100 c.c. blood. Ethyl acetate is thus exhaled only in traces, and this may be due to its rapid disappearance from the blood, for in the second experiment the blood drawn immediately after the injection contained comparatively little of the ester. Methyl-ethyl ketone. Schwarz found that this ketone undergoes oxidation in the tissues much more rapidly than acetone, only about 300/, escaping, unchanged when 0-4 g. was given per kg. It was collected in water in my experiments and was estimated in the same way as acetone. Exp. 10. A cat weighing 3 kg. received 0-16g. in salt solution intravenously, and there was exhaled in 1J hrs. 9 1 mg. Exp. 11. A cat weighing 2x7 kg. was injected with 0x25 g. and 12 mg. were collected from the expired air in 2 hours. Ethyl alcohol was examined in only one experiment, as it has been satisfactorily established that only traces escape in the breath. For example, Atwater and Benedict, found that only 2 per cent. of the alcohol ingested escaped oxidation when as much as 70 g. were taken by men, and Bodlander2 states that of c.c. of alcohol given to dogs only 2 e/0 escapes by the lungs. In my experiment the alcohol was collected in water and estimated by Atwater and Benedict's method. Exp. 12. A cat of 2 6 kg. received 0'18 g. ethyl alcohol in saline solution. Only a trace of reducing substance was found in the water through which the expired air passed for an hour. I8opropyl alcohol is stated by Pohl to be exhaled in considerable amount by the lungs. In the one experiment given by him, 1 Memoirs of National Acad. of Sci. Washington viii Arch. f. d. ges. Physiol. xxxii. p

7 EXHALATION BY LUNGS g. was injected into a dog of 6-9 kg. in 20 c.c. saline. In the first hour thereafter 8-6 mg. were exhaled, in the second 12'6 mg. and later mg., making in all 33 mg. or about 750/0 of that injected. In my experiments, the isopropyl alcohol was injected dissolved in saline and the exhalation was collected in water. The isopropyl alcohol contained in it was estimated by Pohl's method, by oxidising it to acetone by potassium bichromate and sulphuric acid and distilling over the acetone which was estimated in the usual way. In some experiments this method was controlled by the use of Atwater and Benedict's and also by Nicloux' method, and all three gave concordant results. Exp. 13. A cat of 1 9 kg. weight received 2-75 g. isopropyl alcohol in saline intravenously. The respiration ceased but returned on kneading the thorax. In 45 minutes, the amount exhaled was 11 mg.; in the next 50 minutes, again 11 mg. and in two hours longer 17 mg. Total exhaled in 3i hours 39 mg. or 1'4 per cent. of that injected. Exp. 14. A cat of 2-4 kg. weight was injected with 1-8g. isopropyl alcohol intravenously. The respiration had to be restored by kneading and remained rather slow throughout the experiment. In 45 minutes the amount collected in the water was 9 5 mg. The animal was now bled, and 30 c.c. of the blood were placed in the evaporating tubes to be described later and thirty litres of air were led through it. The water through which the air passed from the evaporating tubes contained 7 5 mg. isopropyl alcohol. Exp. 15. A cat of 1 5 kg. weight received g. isopropyl alcohol intravenously. The exhalation was collected for two hours, but only a trace of isopropylic alcohol was found. In my experiments isopropylic alcohol was only exhaled to about the same extent as methyl and ethyl alcohol, and in several performed with about the same dose as in Exp. 15; only a trace could be recovered, in fact the water contained only a trace of reducing substance of any kind. This dose represents over three times the amount used by Pohl, and I am quite unable to suggest any explanation of the divergence between our results. It is true that his experiment was done on a dog, while I have used cats exclusively. The isopropyl alcohol I used was supplied by Merck and was redistilled before use. Ethylene chloride is known to be exhaled by the lungs, and was in fact investigated as a substitute for chloroform by Simpson, Snow and Nunneley and warmly recommended by the last. In my experiments it was collected in alcohol, and estimated by heating with alcoholic soda under a reflux condenser, evaporating off the alcohol and titrating the chlorides by Volhard's method. Exp. 16. A cat of 2-5 kg. weight received g. of ethylene chloride dissolved in dilute alcohol. The injection caused failure of the heart and respiration, which were restored with some difficulty. In the course of an hour after the injection there was 23

8 24 A. R. CUSHNY. exhaled g. The animal was then bled and the blood precipitated with much alcohol. The alcoholic fluid waas distilled and examined for ethylene chloride with negative results. Exp. 17. A cat of 2 5 kg. weight received 0-25 g. ethylene chloride in alcohoi and exhaled g. in the course of 30 minutes. Drug Acetone Chloroform Methyl alcohol Ethyl acetate Methyl-ethyl ketone Ethyl alcohol Isopropyl alcohol Ethylene chloride TABLE I. Small doses injected Exhaled Time in gs. in mgs in mins * trace trace trace trace Large doses /_~~ -_ - % Injected Exhaled Time in gs. in mgs. in mins * Partition Boiling coefficient point oil :water : ac 620 oo: : : : : : 1 In Table I, I have summarised the results of these experiments, dividing them into those in which the dose was from 0-15 to 0-3 g. and those in which it was larger. It is obvious that the drugs examined fall into three classes in regard to their exhalation by the lungs, chloroform and ethylene chloride being exhaled in much the largest amount, acetone and methyl-ethyl ketone to a less extent, and the alcohols and ethyl acetate in very small quantities comparatively. All appear in the breath when large doses are injected but in very different ratios. The volatility as measured by the boiling point is obviously of minor importance in determining this method of elimination, for ethylene chloride boiling at 850 is exhaled in larger amounts than any of the others except chloroform. The absence of the alcohols from the expired air is not to be explained by their being eliminated by other channels or to their destruction in the tissues, for considerable quantities could be obtained from the blood, while little or none was being exhaled. In order to appear in the expired air, the constituents must first be capable of entering the cells lining the air passages and it occurred to me that the same principle might hold here as has been suggested by Meyer and Overton for the nerve cells-the solubility in lipoids as compared with that in water. This seems the more plausible in that the an3sthetics, chloroform and ethylene chloride, are exhaled in largest

9 EXHALATION BY LUNGS. amounts. The partition coefficients between olive oil and water were therefore taken and a fair agreement appears between the rate of exhalation and the coefficient except in the case of acetone (see Table I last column) which is taken up by olive oil to a much less extent than the alcohols wbile it is exhaled much more readily. This exception however is sufficient to throw doubt on the view that the exhalation is governed by the relation which appears to determine the permeation into the nerve cells. This view was definitely negatived by experiments in which the rate of evaporation of these bodies from water wa-s examined. For this purpose a glass tube 125 cm. in length and bent on itself twice was filled wth glass beads and attached to the collecting bottles used in the animal experiments. 100 c.c. of water containing the drug to be examined were poured into this evaporating tube which was then sunk in a large bath of water kept at a temperature of The other end of the evaporating tube was attached to a long rubber tube which was also sunk in the bath in order that the air drawn through the apparatus might be warmed before it reached the liquid. After the whole had stood for some time so as to take the temperature of the bath, 30 litres of air were drawn through slowly, and bubbled through the solution and then through the collecting flasks. The substances evaporated in this way appeared in quantities similar to those obtained in the experiments on animals (Table II). TABLE II. Amount evaporated Percentage in gs. in mgs. Acetone Methyl alcohol 0' Ethyl alcohol 008 8a Isopropyl alcohol Chloroform Much larger quantities of acetone evaporated from water than of the alcohols, and these three are fairly equal in value though isopropyl alcohol is slightly more readily vaporised than methyl alcohol, and this 25

10 26 A. R. CUSHNY. again rather more readily than ethyl alcohol. Practically the whole of the chloroform passed over in the air. The analogy between the exhalation and evaporation from water at body temperature is especially striking in an experime-nt in evaporation in which 0-2 g. acetone was used along with 0'25 g. chloroform in 50 c.c. of water and the two components were estimated in the same way as in Exp. 5 (p. 20). The experiment was divided into four stages in each of which 2-5 litres of air were drawn through the tube and the vapour of each of which was analysed separately. First 2-5 litres carried over 165 mgs. chloroform and 13 mgs. acetone. Second 2-5,,,, 13,,,, 10 Third 2-5,,,, 32,,,, 18 Fourth 2 5,,,, 6-5,,,, 17,, Total These results bear a close resemblance to those obtained in Exp. 5. The increase in both the chloroform and the acetone shown in the third period may have arisen from the temperature of the bath being higher. Another experiment in which chloroform and acetone were evaporated from blood gave similar results. These results from the evaporation of volatile substances from water show such a close analogy with those obtained from the examination of the exhalation from the lungs in animals, that it seems unnecessary to assume any other factor in the latter than the purely physical one. And my experiments lend no support to the view that the pulmonary cells exercise any selection of these substances, or in fact play any r6le except a purely passive one in exhalation. The composition of the vapour from a mixture of two volatile fluids depends on several factors, which have been only partially investigated'. When the fluids are quite immiscible the composition of the distillate is independent of the proportions of the original components as each is volatilised independently. And the more nearly they approach this condition, the less does the distillate resemble the fluid. In exhalation from the lungs the vapour arises from a mixture of water and the substance injected, and the less soluble the latter is in the plasma, the more may the composition of the exhalation depart from that circulating through the lungs. Thus though the water exhaled is a snmall fraction of that in the blood, the chloroform exhaled may formi a much larger fraction of 1 See Young's Fractional Distillation, London, 1903.

11 EXHALATION BY LUNGS. that in the circulation, since chloroform may be taken as almost immiscible with water. When the two fluids are miscible, the principles determining the composition of the vapour are more obscure, but apparently that arising from a mixture of two nearly related chemical substances' depends more upon the composition of the original fluid than that arising from less closely analogous substances; thus the concentration of the vapour from dilute methyl alcohol appears to be determined entirely by the degree of dilution. Thus the proportion of methyl alcohol to water vapour in the breath can scarcely rise above the relative proportion in which they occur in the blood, and the amount of water of the blood which is exhaled being limited, a correspondingly small fraction of the methyl alcohol in the body finds this way of escape. The same holds true for ethyl and the other lower alcohols, while the higher members become less closely analogous in composition to water and at the sanme time less miscible with it and may therefore be exhaled in this way. Acetone while completely miscible with water is not so nearly related in constitution and its evaporation and exhalation are thus less dependent on its concentration in the blood. This is also true of the ketones, which at the same time are less soluble in water. The failure of ammonia to be exhaled from the blood does not seem analogous to that of the retention of alcohols, and may be due to the endothelium being impermeable by it as Magnus suggests, or perhaps to its forming actual combinations with the proteins. SUMMARY. 1. The exhalation of volatile substances from the lungs is exactly analogous to their evaporation from solutions in water, and the pulmonary cells seem to be purely passive in the process. 2. The amount of any substance which is eliminated by exhalation is dependent not so much on its volatility as measured by the boiling point as on its miscibility with water and its chemical affinity with water. The less the solubility and the more distant the affinity, the larger the amount exhaled. 1 In the case of the alcohols at any rate, the water actually forms a loose combination as is shown by the heat evolved on mixing them. 27