RISLEY: A Note on Hyoscyamine.
203
A NOTE ON HYOSCYAMINE. By S. D. RISLEY, M.D., PHILADELPHIA.
In the issue of the Philadelphia Medical Times for February, i88i, I published a preliminary statement on the use of the sulphate of hyoscyamine for the purpose of paralyzing the accommodation for the.correction of anomalies of refraction; and in July of the same year presented a paper before the American Ophthalmological Society on " The Comparative Value of the Mydriatics," in which a more extended study of this drug was made. The conclusions in this paper were based upon ninety cases in which the hyoscyamine salt had been employed and careful records made of its influence over the pupil and accommodation, and the results compared with those attending upon the like employment of the'sulphates of atropine and duboisine and the hydrobromate of homatropine. (Vid.: Trans. Am. Oph. Soc., I88I.) The preparation used was a white crystalline salt which, when placed in solution of distilled water, was entirely bland, causing no irritation of the conjunctiva. The salt proved so much superior to the other members of the group, when employed in those cases of refraction error accompanied by retinochoroidal irritation and asthenopia, that during the intervening years I have used it almost to the exclusion of the other mydriatics, except in selected cases, the ground of selection being the absence of any marked tendency to ciliary cramp, or where the eye-ground was in a fa'irly.healthy state and headache was not a prominent symptom. After ten years of additional experience in its daily use, I have not found occasion to- materially alter the conclusions then formulated. The object in the present note is not so much to call attention to its great efficiency as a mydriatic, as to point out the cause of certain irregularities in its action. In the paper already quoted, the fact that some preparations of the drug were not trustworthy was foreshadowed in a single case the rereported, in which the returning accommodation had pursued the same course as though the sulphate of atropine had been employed. The dispensing
204
RISLEY': A Note
on
Hyoxcyammine.
druggist was consulted regarding the variation, and he exhibited the bottle from which the solution had been prepared. It bore the label of Merck's laboratory, and contained an amorphous, semi-fluid, brownish mass, instead of the crystalline salt with which I was familiar, and upon which the original observations had been made. The investigation was not pressed further at that time, but care was taken subsequently to procure the crystalline salt. Of late as the hyoscyamine has come more and more into use, I have experienced increasing inconvenience from the dispensing of inferior preparations. Not only was frequent annoyance experienced by the returning accommodation being delayed beyond the normal time for hyoscyamine, but very frequently the solutions furnished by the druggist caused severe and protracted smarting, in some instances so violent as to preclude a second instillation. When this occurred I found, in each case investigated, that the amorphous salt had been used. I called the attention of Mr. Frank E. Morgan of Philadelphia to these facts and requested information regarding the chemical history of the drug. In reply he placed in my hands a mass of literature on the alkaloids of the Solanacea and a carefully condensed statement which he had kindly prepared. From these sources the following facts, sufficient for my present purpose, were gleaned, and which I desire to present as a preliminary note to a more detailed study of the physiological properties of these alkaloids when employed as mydriatics. I am encouraged to make this brief statement since it seems to furnish a sufficient explanation of the irregularities observed. In the first place, the mydriatic alkaloids extracted from the Solanaceae are very complex, chemically considered, and when subjected to appropriate manipulation, yield a group of isomeric bodies differing more or less widely in their physiological action, although obtained from a common source. It would appear, furthermore, that the method of extraction employed, in the case of belladonna at least, determines whether the product shall be
hyoscyamine or atropine. As found in the market the alkaloids may be placed in two classes, the first of which properly includes those with a simple or homogeneous base and having the common formula, C1 7 H23
RISLEY: A Note on Hyoscyamine.
2105
NO.. To this class belong atropine, crystalline, hyoscyamine, and hyoscine. In the second class are included those having mixed bases, comprising the simple alkaloids of the first class as they are found mixed in the plants of the natural order of the Solanaceae, e. g., the atropa belladonna, duboisia myoporoides, datura stramonium, scopolia japonica, etc. To this class belong the commercial daturine, duboisine, amorphous hyoscyamine, and scopolein. From this statement it becomes obvious that, if the simple isomeric alkaloids do in fact possess different physiological properties, and therefore different fields of usefulness as therapeutic agents, in order to secure this advantage from their employment in the daily routine of professional life, only the pure, or in other words, the carefully separated, alkaloids or their salts should be dispensed, since in using the mixed bases we could only expect to secure an effect which would in some sense be the resultant of their combined properties. In addition to these considerations it has been shown by chemical investigation that these simple bases are liable to conversion under certain methods of treatment. The literature of the subject is extensive and confused, the confusion no doubt in part growing out of ignorance of this liability to conversion. The discovery of the alkaloid hyoscyamine was first announced by Brandes in I820, but it was not successfully separated until 1833, by Geiger and Hesse, and later exhaustive studies were made by Ladenburg, I879-I884, and by W. Will, in I888, in a paper read before the Berlin Chemical Society, which was subsequently translated for the PharmaceuticalJournal and Transactions, for August, I 888. Hyoscyamine has been found in hyoscyamus niger, atropa belladonna, datura stramonium, duboisia myoporoides, and anisodus lundus. It is isomeric with duboisine and atropine and is therefore closely related to the other mydriatics. Indeed W. Will has shown that when appropriate chemical manipulation is employed that hyoscyamine alone can be procured from the belladonna, -and can then be converted into atropine by simply heating it to its melting point, or by treating it with an alkali, or by heat in the presence of hydrochloric acid. One gram of
206
RISLEY: A Note
on
Iyoscyamine.
hyoscyamine in IO solution was converted into atropine by one drop of a soda solution in two hours. As an illustration of the confusion which obtains in the sttudy of these products of the Solanacae it was claimed that at certain seasons of the year only hyoscyamine could be extracted from belladonna, and that at other seasons only atropine, but the later studies of Will renders it probable that this variation in the product of extraction was due to the methods employed. It is plain, therefore, that only by great skill in manipulation can a pure hyoscyamine be obtained, and as a mydriatic at least, none should be employed but the pure crystalized salt. The painful irritation following the instillation of solutions prepared from other preparations, e. g., the amorphous mass, is due to the presence of impurities, either resin coloring matter, or possibly tropine or tropic acid; while the irregularity in the duration of the ciliary paralysis and dilatation of the pupil is due to the presence of atropine, or possibly daturine in the mixed basic salt, a fact, as regards atropine, readily accounted for, since by the method of preparation directed in the Dispensatory, soda is freely used, and the hyoscyamine therefore converted into atropine. Although these alkaloids are isomeric it is interesting to note that while the hyoscyamine has the poWer of rotating a beam of light to the left, atropine possesses no polarizing power. From the foregoing the following conclusions seem justified: First. That in prescribing hyoscyamine or its salts for ophthalmological purposes, only the pure crystals, skillfully prepared, should be employed. Second. That in dispensing- it the solution should be strictly neutral, that only very moderate degrees of heat, if any, should be used, and in filtering the solution, alkaline filtering paper should be avoided. DISCUSSION.
DR. GEORGE C. HARLAN of Philadelphia.- My attention has been called to a statement in the last edition of the U;zited States Dispensatory that recent chemical and pharmacological observations have shown that hyoscyamine, duboisine, and daturine, as found, at any rate, in the shops, are not only isomeric, but are actually one and the same alkaloid under different names.
203
A NOTE ON HYOSCYAMINE. By S. D. RISLEY, M.D., PHILADELPHIA.
In the issue of the Philadelphia Medical Times for February, i88i, I published a preliminary statement on the use of the sulphate of hyoscyamine for the purpose of paralyzing the accommodation for the.correction of anomalies of refraction; and in July of the same year presented a paper before the American Ophthalmological Society on " The Comparative Value of the Mydriatics," in which a more extended study of this drug was made. The conclusions in this paper were based upon ninety cases in which the hyoscyamine salt had been employed and careful records made of its influence over the pupil and accommodation, and the results compared with those attending upon the like employment of the'sulphates of atropine and duboisine and the hydrobromate of homatropine. (Vid.: Trans. Am. Oph. Soc., I88I.) The preparation used was a white crystalline salt which, when placed in solution of distilled water, was entirely bland, causing no irritation of the conjunctiva. The salt proved so much superior to the other members of the group, when employed in those cases of refraction error accompanied by retinochoroidal irritation and asthenopia, that during the intervening years I have used it almost to the exclusion of the other mydriatics, except in selected cases, the ground of selection being the absence of any marked tendency to ciliary cramp, or where the eye-ground was in a fa'irly.healthy state and headache was not a prominent symptom. After ten years of additional experience in its daily use, I have not found occasion to- materially alter the conclusions then formulated. The object in the present note is not so much to call attention to its great efficiency as a mydriatic, as to point out the cause of certain irregularities in its action. In the paper already quoted, the fact that some preparations of the drug were not trustworthy was foreshadowed in a single case the rereported, in which the returning accommodation had pursued the same course as though the sulphate of atropine had been employed. The dispensing
204
RISLEY': A Note
on
Hyoxcyammine.
druggist was consulted regarding the variation, and he exhibited the bottle from which the solution had been prepared. It bore the label of Merck's laboratory, and contained an amorphous, semi-fluid, brownish mass, instead of the crystalline salt with which I was familiar, and upon which the original observations had been made. The investigation was not pressed further at that time, but care was taken subsequently to procure the crystalline salt. Of late as the hyoscyamine has come more and more into use, I have experienced increasing inconvenience from the dispensing of inferior preparations. Not only was frequent annoyance experienced by the returning accommodation being delayed beyond the normal time for hyoscyamine, but very frequently the solutions furnished by the druggist caused severe and protracted smarting, in some instances so violent as to preclude a second instillation. When this occurred I found, in each case investigated, that the amorphous salt had been used. I called the attention of Mr. Frank E. Morgan of Philadelphia to these facts and requested information regarding the chemical history of the drug. In reply he placed in my hands a mass of literature on the alkaloids of the Solanacea and a carefully condensed statement which he had kindly prepared. From these sources the following facts, sufficient for my present purpose, were gleaned, and which I desire to present as a preliminary note to a more detailed study of the physiological properties of these alkaloids when employed as mydriatics. I am encouraged to make this brief statement since it seems to furnish a sufficient explanation of the irregularities observed. In the first place, the mydriatic alkaloids extracted from the Solanaceae are very complex, chemically considered, and when subjected to appropriate manipulation, yield a group of isomeric bodies differing more or less widely in their physiological action, although obtained from a common source. It would appear, furthermore, that the method of extraction employed, in the case of belladonna at least, determines whether the product shall be
hyoscyamine or atropine. As found in the market the alkaloids may be placed in two classes, the first of which properly includes those with a simple or homogeneous base and having the common formula, C1 7 H23
RISLEY: A Note on Hyoscyamine.
2105
NO.. To this class belong atropine, crystalline, hyoscyamine, and hyoscine. In the second class are included those having mixed bases, comprising the simple alkaloids of the first class as they are found mixed in the plants of the natural order of the Solanaceae, e. g., the atropa belladonna, duboisia myoporoides, datura stramonium, scopolia japonica, etc. To this class belong the commercial daturine, duboisine, amorphous hyoscyamine, and scopolein. From this statement it becomes obvious that, if the simple isomeric alkaloids do in fact possess different physiological properties, and therefore different fields of usefulness as therapeutic agents, in order to secure this advantage from their employment in the daily routine of professional life, only the pure, or in other words, the carefully separated, alkaloids or their salts should be dispensed, since in using the mixed bases we could only expect to secure an effect which would in some sense be the resultant of their combined properties. In addition to these considerations it has been shown by chemical investigation that these simple bases are liable to conversion under certain methods of treatment. The literature of the subject is extensive and confused, the confusion no doubt in part growing out of ignorance of this liability to conversion. The discovery of the alkaloid hyoscyamine was first announced by Brandes in I820, but it was not successfully separated until 1833, by Geiger and Hesse, and later exhaustive studies were made by Ladenburg, I879-I884, and by W. Will, in I888, in a paper read before the Berlin Chemical Society, which was subsequently translated for the PharmaceuticalJournal and Transactions, for August, I 888. Hyoscyamine has been found in hyoscyamus niger, atropa belladonna, datura stramonium, duboisia myoporoides, and anisodus lundus. It is isomeric with duboisine and atropine and is therefore closely related to the other mydriatics. Indeed W. Will has shown that when appropriate chemical manipulation is employed that hyoscyamine alone can be procured from the belladonna, -and can then be converted into atropine by simply heating it to its melting point, or by treating it with an alkali, or by heat in the presence of hydrochloric acid. One gram of
206
RISLEY: A Note
on
Iyoscyamine.
hyoscyamine in IO solution was converted into atropine by one drop of a soda solution in two hours. As an illustration of the confusion which obtains in the sttudy of these products of the Solanacae it was claimed that at certain seasons of the year only hyoscyamine could be extracted from belladonna, and that at other seasons only atropine, but the later studies of Will renders it probable that this variation in the product of extraction was due to the methods employed. It is plain, therefore, that only by great skill in manipulation can a pure hyoscyamine be obtained, and as a mydriatic at least, none should be employed but the pure crystalized salt. The painful irritation following the instillation of solutions prepared from other preparations, e. g., the amorphous mass, is due to the presence of impurities, either resin coloring matter, or possibly tropine or tropic acid; while the irregularity in the duration of the ciliary paralysis and dilatation of the pupil is due to the presence of atropine, or possibly daturine in the mixed basic salt, a fact, as regards atropine, readily accounted for, since by the method of preparation directed in the Dispensatory, soda is freely used, and the hyoscyamine therefore converted into atropine. Although these alkaloids are isomeric it is interesting to note that while the hyoscyamine has the poWer of rotating a beam of light to the left, atropine possesses no polarizing power. From the foregoing the following conclusions seem justified: First. That in prescribing hyoscyamine or its salts for ophthalmological purposes, only the pure crystals, skillfully prepared, should be employed. Second. That in dispensing- it the solution should be strictly neutral, that only very moderate degrees of heat, if any, should be used, and in filtering the solution, alkaline filtering paper should be avoided. DISCUSSION.
DR. GEORGE C. HARLAN of Philadelphia.- My attention has been called to a statement in the last edition of the U;zited States Dispensatory that recent chemical and pharmacological observations have shown that hyoscyamine, duboisine, and daturine, as found, at any rate, in the shops, are not only isomeric, but are actually one and the same alkaloid under different names.
