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Some Interesting Experiences in the Clinical Pharmacology of the Eye
SOME INTERESTING EXPERIENCES IN T H E CLINICAL PHARMACOLOGY OF T H E E Y E B Y DAVID I. MACHT, M.D.,
P H A R . D . , L I T T . D . , F.A.C.P.
BALTIMORE
Four interesting experiences are recounted in each of which a prescription properly prepared from chemicals conforming to required standards as proven by subsequent tests produced unexpected results in the eyes of the patient. A solution of pilocarpine 2% with eserine yi% produced mydriasis. A solution of homatropine hydrobromide producing ex treme and prolonged mydriasis was found to be contaminated with atropine. Pharmacologic tests were necessary in this connection, being much more delicate than any chemical test. A pilocarpine solution of high purity was found irritating to the eyes of a patient be cause of unusual sensitization to small differences in hydrogen ion concentration. Read before the Ophthalmological Section of the Baltimore City Medical Society Feb. 26, 1931.
Introduction The present communication is a di rect result of a happy concatenation of circumstances which it may be well to enumerate by way of introduction. In the first place, the writer is a specialist in pharmacology but not exclusively of the theoretic type. While he has been extensively engaged in the study of abstract and fundamental problems pertaining to pharmacology and toxi cology, he has always been particularly interested in the clinical applications of the subject, in other words, in practical pharmacotherapeutics and toxicology. In the second place, the author hap pens to occupy a unique position in pharmacology because, on the one hand, he is a lecturer in pharmacology at the Johns Hopkins University and, on the other hand, he is at the same time the director of a pharmacological research laboratory maintained by a well-known pharmaceutical concern. In this way he has exceptional oppor tunity of coming in contact with the two professions which are most inti mately interested in pharmacology, namely, medicine and pharmacy. In the third place, it happens that the phar maceutical firm, of which he is phar macological director, maintains a highgrade retail prescription department and when difficulties of a pharmaco logical or toxicological nature happen to crop up, such problems are fre quently referred to him for his opinion and advice. It is in connection with the prescription department that the pres ent experiences have been encountered. Curiously enough, in the last four 726
years, during which time thousands upon thousands of prescriptions have been filled by this pharmacy, there have been more questions raised in connection with medicaments com pounded for the treatment of eyes than with those pertaining to any other branch of medicine. Experience 1 A prescription by Dr. C. A. C , for Mrs. J. C. H., calling for eye drops con taining eserine, one-half of a grain, and pilocarpine, four grains to the half ounce, was presented at the pharmacy and duly compounded. Soon after the medicine was employed by the patient, she complained that it did not act prop erly ; and the physician confirmed her findings. Instead of effecting miosis or constriction of the pupil, the drops pro duced a dilatation of the patient's eye; and Dr. C , who tried the same medi cine on himself, obtained the same re sult. On reporting this peculiar action of the drops to the prescription depart ment, another bottle of the same medi cine was immediately prepared accord ing to the directions on the prescrip tion ; and these drops also produced di latation of the pupil. The crystalline in gredients employed in compounding the prescription were then submitted to a chemist for identification. The chemist reported that, as far as he was able to determine by ordinary chemical tests, the eserine salicylate gave the chemical reactions of eserine salicylate and the pilocarpine hydrochloride gave the chemical reactions of pilocarpine hydrochloride. He could not say defi-
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nitely whether impurities of a mydri- sacs, no constriction of the pupil was atic nature were present either in the produced and, in fact, some of the ani solutions or in the original crystalline mals exhibited a definite mydriasis. In salts of the alkaloids. The whole mat stillation of the solution made from the ter was then referred to the pharma new bottle of pilocarpine hydrochlo cologist for his opinion. ride, however, produced a very marked The first step in the pharmacological miotic or constricting effect in both investigation was to test the original cats and rabbits. It may be stated, drops in regard to their effect on the however, that when large doses of the pupil of the cat's eye. Two drops of the unsatisfactory pilocarpine solution were solution, instilled into the conjunctival repeatedly instilled into the eyes of the sac of a cat, produced mydriasis. When cats, a very slight constriction was fi the solution was tested on the rabbit's nally produced in some of the animals. eye, the same result was obtained. A This, however, could not be obtained fresh prescription compounded from with small doses of that solution. the same ingredients again caused a A further comparison of the two similar reaction. It was then decided to specimens of pilocarpine hydrochloride investigate separately all the samples was then made by means of other phar of eserine and pilocarpine in stock. macological tests. It is well known that Three specimens of eserine salicylate pilocarpine is a powerful stimulant of were found on hand, and a one per cent intestinal contractions, an effect pro solution of each was prepared and ex duced through its pressor or stimulat amined in respect to its miotic proper ing effect on the myoneural junctions ties. It was found that the three speci of the parasympathetics. Again, pilo mens of eserine all differed in their mi- carpine hydrochloride, through its otic potency when two drops of a one stimulating effect on the vagus nerve per cent solution of each were tested on endings, is known to produce an in the cat's or the rabbit's eye. One speci hibition or slowing of the heart beat. men, which was old, produced very Moreover, pilocarpine exhibits a very little constriction of the pupil: the characteristic sialogogic effect. Experi other two were both miotic in their ac ments were performed by the writer tion, but one of the solutions, which on rabbits with injections of five milli had been prepared from a tablet tri grams of the old and new pilocarpine turate of eserine salicylate, was not hydrochloride solutions, respectively, quite as effective as the other, prepared and the effects upon the salivary secre from crystalline eserine salicylate. tion, the heart rate, and intestinal An examination of the pilocarpine movements were observed. Thus it hydrochloride found in stock was very was found that there was a definite and much more interesting and important. marked difference between the two Two specimens of pilocarpine hydro- specimens of pilocarpine hydrochlo chloride were studied, one of which ride. The fresh, miotic-producing pilo had been used for preparing the "un carpine engendered a powerful stimu satisfactory" eye drops in question and lation of intestinal movements, a the other, which had been taken from marked slowing of the heart beat, and a new bottle that had not been used a profuse salivary flow. The pilocar before and was opened for the first pine hydrochloride from which the un time for the purposes of the present in satisfactory eye drops were made, on vestigation. A one per cent solution of the other hand, was much weaker than each of the specimens of pilocarpine the other specimen in all these re hydrochloride was prepared and stud spects. ied on the eyes of cats and rabbits in Having definitely established that two series of experiments, and in each the ingredients of the unsatisfactory case the results obtained were quite eye drops were not of the required decisive. When two drops of the un pharmacological potency and, more satisfactory pilocarpine hydrochloride particularly, that the pilocarpine hy were instilled into the conjunctival drochloride exhibited anomalous phar-
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macodynamic effects, the author wrote a polite letter to the well-known chemi cal firm manufacturing these alkaloids and called their attention to the mat ter. The reply received was of an ex tremely interesting nature. The manu facturers thanked the writer for calling their attention to the unsatisfactory pilocarpine specimen and stated that they had received a similar complaint concerning an ounce bottle of pilocar pine hydrochloride from a Washington physician, who wrote that the alkaloid behaved abnormally in a patient's eyes. They immediately took steps to inves tigate the material from Washington and found that all the physical and chemical properties agreed with the latest published figures, namely: the melting point was 204-5° C.; the speci fic rotatory power was found to be + 91°; and all the other chemical tests made with the alkaloid complied with the requirements of the United States Pharmacopoeia. In addition to the fore going tests, they examined the material for the presence of foreign mydriatics such as atropine, homatropine, scopolamine, cocaine, etc., as well as for other salts of the alkaloids, all with negative results. They then turned to the bio logical behavior of the compound and found, just as the present writer has discovered, that when two drops of a one per cent solution were instilled into the conjunctival sac of a cat's eye, a marked mydriasis was produced. The conclusions which we may therefore draw from this experience are that there must be some modification in the internal structure of this particular sample of pilocarpine hydrochloride, which is responsible for its abnormal pharmacological behavior. Further more, it may be inferred that it is well to include a regular routine assay of pi locarpine before putting it on the mar ket. The present writer has been especial ly interested in this case because it em phasizes a scientific truth not suffi ciently known to the majority of phy sicians and even laboratory investiga tors. Physiological and pharmacologi cal tests are often very much more sensitive and delicate than chemical or
physical tests for certain powerful drugs. Professor Reid Hunt recently gave a remarkable illustration of this fact in a brief article published in Science 1 , in which he states that one milligram of acetylcholine dissolved in five hundred thousand gallons of blood could easily cause a distinct fall of blood pressure in a cat and that even smaller concentrations of acetylcholine could affect the beating of a frog's heart. Again, the uterus of a virgin guinea pig will respond to such dilute concentrations of histamine as could not be estimated quantitatively by even the most refined microchemical meth ods; and the very highly potent com pound "A" obtained by Professor Abel from the posterior lobe of the pituitary gland is forty or more times more pow erful in this respect, as shown by tests on the isolated uterus and on certain preparations of the urinary bladder 2 . Hatcher is able by biological means to determine minute quantities of strych nine much more readily than by chemi cal methods 3 ; and Macht and Ander son have found delicate pharmacologi cal methods extremely useful in de tecting differences in activity of drugs produced by polarized light 4 . Experience 2 In this case the advice of the pres ent writer was sought by a druggist who filled a prescription which did not act satisfactorily. The prescription called for a solution of homatropine hydrobromide for mydriatic purposes and was filled in a routine way. When the eye drops were used by the patient however, the result was an extreme mydriasis or dilatation of the pupil which lasted for nearly a week. The ophthalmologist suspected the pres ence of another mydriatic. An exami nation of the eye drops by a chemist was unsatisfactory and could not es tablish with certainty the presence of atropine in the solution. When it was submitted to the present writer, how ever, the problem was very easily solved. A standard solution of homa tropine hydrobromide was prepared and another standard solution of
CLINICAL PHARMACOLOGY OF THE EYE atropine hydrobromide was prepared. These were tested pharmacologically on the eyes of various animals and compared with the action of the sus pected solution. It was noted very quickly that the homatropine mydriasis was of much shorter duration than that produced by the solution of atropine. The extreme dilatation produced by homatropine in cats has worn off, for the most part, at the end of twentyfour hours and disappears completely in forty-eight hours. The mydriasis pro duced by atropine, however, lasts for several days and sometimes a week or longer. The suspected eye drops were found to produce a long-lasting mydri asis very much like that of atropine, and the conclusion was inevitable that the homatropine had been contami nated largely by atropine. The pharmacological tests described above are useful in differentiating be tween the action of atropine and homatropine. Macht has investigated the comparative pharmacology of these two alkaloids several years ago and shown that the mechanism of action of the two is not the same 5 . The mydri asis produced by atropine, which is chemically tropine tropate, is due ex clusively to the paralytic effects of the drug on the parasympathetic nerve end ings of the oculomotor nerve supplying the pupil of the eye. Again, compara tive tests with atropine and homatro pine on the parasympathetic paralysis produced on the vagus nerve of the heart revealed that Komatropine is very much weaker than atropine in this re spect. Further experiments on the ef fects of the two alkaloids on smooth muscle revealed that homatropine, at least to some extent, has a direct ac tion on the muscle substance, this be ing due to its peculiar chemical struc ture. Homatropine is chemically the tropine salt or ester of mandelic acid. Mandelic acid, being closely related to benzaldehyde and various benzyl com pounds, exerts in common with those compounds, an antispasmodic effect on smooth muscle fibers. A comparison of atropine and homatropine solutions on smooth muscle will therefore reveal a quantitative difference in their action,
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which may be useful in differentiating them. Experience 3 The potency of homatropine prepa rations in the writer's experience is a variable one. In this connection, the present instance is a good illustration. The chief pharmacist of a government hospital consulted the writer in regard to difficulties he had incurred through the filling of an ophthalmological pre scription. The order called for a solu tion of homatropine and, having sev eral samples of homatropine in stock, he selected one of these at random for filling the prescription. Soon after the pharmacist was censured for making an error in compounding the prescrip tion because the dilatation of the pu pils produced by his eye drops lasted several days. Here again, the question arose in regard to the confusion of atropine with homatropine, and the present writer was asked to throw some light on the subject. Four differ ent samples or vials of homatropine were in stock of the pharmacy in ques tion. One of these was a German homatropine; the other three samples were different specimens of English homatropine. These four different specimens were compared with the chemically pure homatropine in the writer's laboratory and with a chemi cally pure atropine hydrobromide solu tion. It was found that each of the homatropines was different in regard to its mydriatic activity. The three English homatropines differed from each other and the German one was different from the English samples. Some of these homatropine specimens were very powerful mydriatics and were evidently contaminated with more or less atropine. An examination of the melting points of the various specimens and some of the other sim ple chemical properties was of very little help in distinguishing one from the other. The differences, however, were quite marked and easily detect able when a pharmacological examina tion was undertaken. This was made in two ways: on the one hand, by tests on eyes of various animals and, on the
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other hand, by a special method de vised by the author in which he com pared the relative toxicity of the vari ous specimens for the growth of living seedlings of Lupinus albus, in other words, by the phytopharmacological methods he has developed in recent years 6 . Experience 4 This is a very remarkable case which strikingly illustrates the delicacy of cer tain biological reactions. Dr. H. B. J., a well-known physician of this city, having a tendency to glaucoma, has been in the habit of instilling into his eye sacs a solution of pilocarpine. One day, on having his prescription re newed at the pharmacy of Hynson, Westcott and Dunning, Inc., the pa tient experienced a novel effect, which he promptly brought to the attention of the druggists. He returned the drops with the statement that they were "liquid fire" when applied to his eyes. A fresh solution of eye drops was com pounded according to specifications but with the same results; and the pa tient, becoming vexed, had a third quantity of the same prescription pre pared in a small drug store, not far from his residence. These last drops, he claimed, were perfectly bland and satisfactory. W h a t was the solution of the riddle? Chemical examination of the ingredi ents revealed that they were of the highest chemical purity obtainable; the care in compounding the prescription had been most meticulous; and no ex planation was apparently available on either chemical or pharmaceutical grounds. The matter was referred to the present writer for investigation. Solutions from the various specimens in stock were prepared and tested on animals. All of these pilocarpine sam ples were found to be very efficient in regard to their miotic properties and, as far as could be determined from animal experiments, none of them pro duced any irritation of the conjunctiva. These specimens were also tested on several healthy patients and were found to produce miosis or constric tion and no particular irritation of the
eye. On pondering over the case, the author conceived the idea that possibly through very prolonged use of the eye drops, the patient might have become sensitive to very slight differences in the physicochemical properties of the solution, more particularly in regard to their hydrogen ion concentration. Ac cordingly, the hydrogen ion concentra tion of various solutions of pilocarpine was determined and it was found that when the best and most efficient pilo carpine specimen was dissolved in dis tilled water, the pH was 5.10. When, however, the same pilocarpine was dis solved in tap water, which is distinctly alkaline in Baltimore, the pH was 5.35. It was then suggested that the eye drops in this particular prescription be buffered so as to make their hydrogen ion concentration a little more alkaline. As soon as this was done and the eye drops were sent to Dr. J., he reported as follows: "I want to tell you that the drops which Dr. Macht has prepared for me are perfectly bland and satisfac tory, and I have used them entirely without irritation in my eyes." It was obvious that the patient's conjunctival mucous membranes had become so sen sitive that they could detect compara tively small differences in the hydro gen ion concentration of collyria. The lesson taught by this case is that ex treme accuracy in compounding of pre scriptions, instead of being a virtue, may sometimes be a real source of ir ritation. The druggist "around the cor ner," who dissolved his non-too-pure pilocarpine in ordinary tap water, pre pared a solution which was not so acid and therefore not so irritating as that prepared by the very careful pharma cist who, using chemically pure pilo carpine dissolved in double distilled water, produced eye drops of a slightly more acid reaction. Summary The cases described above are pre sented because of their interest as emphasizing the following practical points: 1. The occurrence of abnormal physiological effects after the use of certain important alkaloids in ophthal-
CLINICAL PHARMACOLOGY O F T H E EYE
mological practice, more particularly, of eserine and pilocarpine. 2. The great variations in potency and effectiveness of various specimens of homatropine on the market. 3. The importance of applied phar macology in connection with ophthalmologieal therapeutics. 4. The extreme delicacy of certain pharmacological tests as compared with physical and chemical examina tion of powerful drugs, especially in 1
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regard to the detection of contamina tions and variations in their therapeu tic potency. 5. The importance of constantly bearing in mind the idiosyncrasies and extreme sensitiveness on the part of patients to even very small differences in the composition of prescriptions. Pharmacological Research Laboratory, Hynson, Westcott and Dunning.
References
Hunt: Science, 1930, v. 72, p. 526. 'Abel, Rouiller and Geiling: Jour. Pharmacol, and Exper. Therap., 1923, v. 22, p. 289. ' Hatcher: American Druggist, 1929, v. 79, p. 22. 'Macht and Anderson: Jour. Amer. Chem. Soc, 1927, v. 49, p. 2017. 'Macht: Archives Internationales de Pharmacodynamie et de Therapie, 1922, v. 27, p. 175. 'Macht: Science, 1930, v. 71, p. 302.
P H A R . D . , L I T T . D . , F.A.C.P.
BALTIMORE
Four interesting experiences are recounted in each of which a prescription properly prepared from chemicals conforming to required standards as proven by subsequent tests produced unexpected results in the eyes of the patient. A solution of pilocarpine 2% with eserine yi% produced mydriasis. A solution of homatropine hydrobromide producing ex treme and prolonged mydriasis was found to be contaminated with atropine. Pharmacologic tests were necessary in this connection, being much more delicate than any chemical test. A pilocarpine solution of high purity was found irritating to the eyes of a patient be cause of unusual sensitization to small differences in hydrogen ion concentration. Read before the Ophthalmological Section of the Baltimore City Medical Society Feb. 26, 1931.
Introduction The present communication is a di rect result of a happy concatenation of circumstances which it may be well to enumerate by way of introduction. In the first place, the writer is a specialist in pharmacology but not exclusively of the theoretic type. While he has been extensively engaged in the study of abstract and fundamental problems pertaining to pharmacology and toxi cology, he has always been particularly interested in the clinical applications of the subject, in other words, in practical pharmacotherapeutics and toxicology. In the second place, the author hap pens to occupy a unique position in pharmacology because, on the one hand, he is a lecturer in pharmacology at the Johns Hopkins University and, on the other hand, he is at the same time the director of a pharmacological research laboratory maintained by a well-known pharmaceutical concern. In this way he has exceptional oppor tunity of coming in contact with the two professions which are most inti mately interested in pharmacology, namely, medicine and pharmacy. In the third place, it happens that the phar maceutical firm, of which he is phar macological director, maintains a highgrade retail prescription department and when difficulties of a pharmaco logical or toxicological nature happen to crop up, such problems are fre quently referred to him for his opinion and advice. It is in connection with the prescription department that the pres ent experiences have been encountered. Curiously enough, in the last four 726
years, during which time thousands upon thousands of prescriptions have been filled by this pharmacy, there have been more questions raised in connection with medicaments com pounded for the treatment of eyes than with those pertaining to any other branch of medicine. Experience 1 A prescription by Dr. C. A. C , for Mrs. J. C. H., calling for eye drops con taining eserine, one-half of a grain, and pilocarpine, four grains to the half ounce, was presented at the pharmacy and duly compounded. Soon after the medicine was employed by the patient, she complained that it did not act prop erly ; and the physician confirmed her findings. Instead of effecting miosis or constriction of the pupil, the drops pro duced a dilatation of the patient's eye; and Dr. C , who tried the same medi cine on himself, obtained the same re sult. On reporting this peculiar action of the drops to the prescription depart ment, another bottle of the same medi cine was immediately prepared accord ing to the directions on the prescrip tion ; and these drops also produced di latation of the pupil. The crystalline in gredients employed in compounding the prescription were then submitted to a chemist for identification. The chemist reported that, as far as he was able to determine by ordinary chemical tests, the eserine salicylate gave the chemical reactions of eserine salicylate and the pilocarpine hydrochloride gave the chemical reactions of pilocarpine hydrochloride. He could not say defi-
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727
nitely whether impurities of a mydri- sacs, no constriction of the pupil was atic nature were present either in the produced and, in fact, some of the ani solutions or in the original crystalline mals exhibited a definite mydriasis. In salts of the alkaloids. The whole mat stillation of the solution made from the ter was then referred to the pharma new bottle of pilocarpine hydrochlo cologist for his opinion. ride, however, produced a very marked The first step in the pharmacological miotic or constricting effect in both investigation was to test the original cats and rabbits. It may be stated, drops in regard to their effect on the however, that when large doses of the pupil of the cat's eye. Two drops of the unsatisfactory pilocarpine solution were solution, instilled into the conjunctival repeatedly instilled into the eyes of the sac of a cat, produced mydriasis. When cats, a very slight constriction was fi the solution was tested on the rabbit's nally produced in some of the animals. eye, the same result was obtained. A This, however, could not be obtained fresh prescription compounded from with small doses of that solution. the same ingredients again caused a A further comparison of the two similar reaction. It was then decided to specimens of pilocarpine hydrochloride investigate separately all the samples was then made by means of other phar of eserine and pilocarpine in stock. macological tests. It is well known that Three specimens of eserine salicylate pilocarpine is a powerful stimulant of were found on hand, and a one per cent intestinal contractions, an effect pro solution of each was prepared and ex duced through its pressor or stimulat amined in respect to its miotic proper ing effect on the myoneural junctions ties. It was found that the three speci of the parasympathetics. Again, pilo mens of eserine all differed in their mi- carpine hydrochloride, through its otic potency when two drops of a one stimulating effect on the vagus nerve per cent solution of each were tested on endings, is known to produce an in the cat's or the rabbit's eye. One speci hibition or slowing of the heart beat. men, which was old, produced very Moreover, pilocarpine exhibits a very little constriction of the pupil: the characteristic sialogogic effect. Experi other two were both miotic in their ac ments were performed by the writer tion, but one of the solutions, which on rabbits with injections of five milli had been prepared from a tablet tri grams of the old and new pilocarpine turate of eserine salicylate, was not hydrochloride solutions, respectively, quite as effective as the other, prepared and the effects upon the salivary secre from crystalline eserine salicylate. tion, the heart rate, and intestinal An examination of the pilocarpine movements were observed. Thus it hydrochloride found in stock was very was found that there was a definite and much more interesting and important. marked difference between the two Two specimens of pilocarpine hydro- specimens of pilocarpine hydrochlo chloride were studied, one of which ride. The fresh, miotic-producing pilo had been used for preparing the "un carpine engendered a powerful stimu satisfactory" eye drops in question and lation of intestinal movements, a the other, which had been taken from marked slowing of the heart beat, and a new bottle that had not been used a profuse salivary flow. The pilocar before and was opened for the first pine hydrochloride from which the un time for the purposes of the present in satisfactory eye drops were made, on vestigation. A one per cent solution of the other hand, was much weaker than each of the specimens of pilocarpine the other specimen in all these re hydrochloride was prepared and stud spects. ied on the eyes of cats and rabbits in Having definitely established that two series of experiments, and in each the ingredients of the unsatisfactory case the results obtained were quite eye drops were not of the required decisive. When two drops of the un pharmacological potency and, more satisfactory pilocarpine hydrochloride particularly, that the pilocarpine hy were instilled into the conjunctival drochloride exhibited anomalous phar-
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macodynamic effects, the author wrote a polite letter to the well-known chemi cal firm manufacturing these alkaloids and called their attention to the mat ter. The reply received was of an ex tremely interesting nature. The manu facturers thanked the writer for calling their attention to the unsatisfactory pilocarpine specimen and stated that they had received a similar complaint concerning an ounce bottle of pilocar pine hydrochloride from a Washington physician, who wrote that the alkaloid behaved abnormally in a patient's eyes. They immediately took steps to inves tigate the material from Washington and found that all the physical and chemical properties agreed with the latest published figures, namely: the melting point was 204-5° C.; the speci fic rotatory power was found to be + 91°; and all the other chemical tests made with the alkaloid complied with the requirements of the United States Pharmacopoeia. In addition to the fore going tests, they examined the material for the presence of foreign mydriatics such as atropine, homatropine, scopolamine, cocaine, etc., as well as for other salts of the alkaloids, all with negative results. They then turned to the bio logical behavior of the compound and found, just as the present writer has discovered, that when two drops of a one per cent solution were instilled into the conjunctival sac of a cat's eye, a marked mydriasis was produced. The conclusions which we may therefore draw from this experience are that there must be some modification in the internal structure of this particular sample of pilocarpine hydrochloride, which is responsible for its abnormal pharmacological behavior. Further more, it may be inferred that it is well to include a regular routine assay of pi locarpine before putting it on the mar ket. The present writer has been especial ly interested in this case because it em phasizes a scientific truth not suffi ciently known to the majority of phy sicians and even laboratory investiga tors. Physiological and pharmacologi cal tests are often very much more sensitive and delicate than chemical or
physical tests for certain powerful drugs. Professor Reid Hunt recently gave a remarkable illustration of this fact in a brief article published in Science 1 , in which he states that one milligram of acetylcholine dissolved in five hundred thousand gallons of blood could easily cause a distinct fall of blood pressure in a cat and that even smaller concentrations of acetylcholine could affect the beating of a frog's heart. Again, the uterus of a virgin guinea pig will respond to such dilute concentrations of histamine as could not be estimated quantitatively by even the most refined microchemical meth ods; and the very highly potent com pound "A" obtained by Professor Abel from the posterior lobe of the pituitary gland is forty or more times more pow erful in this respect, as shown by tests on the isolated uterus and on certain preparations of the urinary bladder 2 . Hatcher is able by biological means to determine minute quantities of strych nine much more readily than by chemi cal methods 3 ; and Macht and Ander son have found delicate pharmacologi cal methods extremely useful in de tecting differences in activity of drugs produced by polarized light 4 . Experience 2 In this case the advice of the pres ent writer was sought by a druggist who filled a prescription which did not act satisfactorily. The prescription called for a solution of homatropine hydrobromide for mydriatic purposes and was filled in a routine way. When the eye drops were used by the patient however, the result was an extreme mydriasis or dilatation of the pupil which lasted for nearly a week. The ophthalmologist suspected the pres ence of another mydriatic. An exami nation of the eye drops by a chemist was unsatisfactory and could not es tablish with certainty the presence of atropine in the solution. When it was submitted to the present writer, how ever, the problem was very easily solved. A standard solution of homa tropine hydrobromide was prepared and another standard solution of
CLINICAL PHARMACOLOGY OF THE EYE atropine hydrobromide was prepared. These were tested pharmacologically on the eyes of various animals and compared with the action of the sus pected solution. It was noted very quickly that the homatropine mydriasis was of much shorter duration than that produced by the solution of atropine. The extreme dilatation produced by homatropine in cats has worn off, for the most part, at the end of twentyfour hours and disappears completely in forty-eight hours. The mydriasis pro duced by atropine, however, lasts for several days and sometimes a week or longer. The suspected eye drops were found to produce a long-lasting mydri asis very much like that of atropine, and the conclusion was inevitable that the homatropine had been contami nated largely by atropine. The pharmacological tests described above are useful in differentiating be tween the action of atropine and homatropine. Macht has investigated the comparative pharmacology of these two alkaloids several years ago and shown that the mechanism of action of the two is not the same 5 . The mydri asis produced by atropine, which is chemically tropine tropate, is due ex clusively to the paralytic effects of the drug on the parasympathetic nerve end ings of the oculomotor nerve supplying the pupil of the eye. Again, compara tive tests with atropine and homatro pine on the parasympathetic paralysis produced on the vagus nerve of the heart revealed that Komatropine is very much weaker than atropine in this re spect. Further experiments on the ef fects of the two alkaloids on smooth muscle revealed that homatropine, at least to some extent, has a direct ac tion on the muscle substance, this be ing due to its peculiar chemical struc ture. Homatropine is chemically the tropine salt or ester of mandelic acid. Mandelic acid, being closely related to benzaldehyde and various benzyl com pounds, exerts in common with those compounds, an antispasmodic effect on smooth muscle fibers. A comparison of atropine and homatropine solutions on smooth muscle will therefore reveal a quantitative difference in their action,
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which may be useful in differentiating them. Experience 3 The potency of homatropine prepa rations in the writer's experience is a variable one. In this connection, the present instance is a good illustration. The chief pharmacist of a government hospital consulted the writer in regard to difficulties he had incurred through the filling of an ophthalmological pre scription. The order called for a solu tion of homatropine and, having sev eral samples of homatropine in stock, he selected one of these at random for filling the prescription. Soon after the pharmacist was censured for making an error in compounding the prescrip tion because the dilatation of the pu pils produced by his eye drops lasted several days. Here again, the question arose in regard to the confusion of atropine with homatropine, and the present writer was asked to throw some light on the subject. Four differ ent samples or vials of homatropine were in stock of the pharmacy in ques tion. One of these was a German homatropine; the other three samples were different specimens of English homatropine. These four different specimens were compared with the chemically pure homatropine in the writer's laboratory and with a chemi cally pure atropine hydrobromide solu tion. It was found that each of the homatropines was different in regard to its mydriatic activity. The three English homatropines differed from each other and the German one was different from the English samples. Some of these homatropine specimens were very powerful mydriatics and were evidently contaminated with more or less atropine. An examination of the melting points of the various specimens and some of the other sim ple chemical properties was of very little help in distinguishing one from the other. The differences, however, were quite marked and easily detect able when a pharmacological examina tion was undertaken. This was made in two ways: on the one hand, by tests on eyes of various animals and, on the
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other hand, by a special method de vised by the author in which he com pared the relative toxicity of the vari ous specimens for the growth of living seedlings of Lupinus albus, in other words, by the phytopharmacological methods he has developed in recent years 6 . Experience 4 This is a very remarkable case which strikingly illustrates the delicacy of cer tain biological reactions. Dr. H. B. J., a well-known physician of this city, having a tendency to glaucoma, has been in the habit of instilling into his eye sacs a solution of pilocarpine. One day, on having his prescription re newed at the pharmacy of Hynson, Westcott and Dunning, Inc., the pa tient experienced a novel effect, which he promptly brought to the attention of the druggists. He returned the drops with the statement that they were "liquid fire" when applied to his eyes. A fresh solution of eye drops was com pounded according to specifications but with the same results; and the pa tient, becoming vexed, had a third quantity of the same prescription pre pared in a small drug store, not far from his residence. These last drops, he claimed, were perfectly bland and satisfactory. W h a t was the solution of the riddle? Chemical examination of the ingredi ents revealed that they were of the highest chemical purity obtainable; the care in compounding the prescription had been most meticulous; and no ex planation was apparently available on either chemical or pharmaceutical grounds. The matter was referred to the present writer for investigation. Solutions from the various specimens in stock were prepared and tested on animals. All of these pilocarpine sam ples were found to be very efficient in regard to their miotic properties and, as far as could be determined from animal experiments, none of them pro duced any irritation of the conjunctiva. These specimens were also tested on several healthy patients and were found to produce miosis or constric tion and no particular irritation of the
eye. On pondering over the case, the author conceived the idea that possibly through very prolonged use of the eye drops, the patient might have become sensitive to very slight differences in the physicochemical properties of the solution, more particularly in regard to their hydrogen ion concentration. Ac cordingly, the hydrogen ion concentra tion of various solutions of pilocarpine was determined and it was found that when the best and most efficient pilo carpine specimen was dissolved in dis tilled water, the pH was 5.10. When, however, the same pilocarpine was dis solved in tap water, which is distinctly alkaline in Baltimore, the pH was 5.35. It was then suggested that the eye drops in this particular prescription be buffered so as to make their hydrogen ion concentration a little more alkaline. As soon as this was done and the eye drops were sent to Dr. J., he reported as follows: "I want to tell you that the drops which Dr. Macht has prepared for me are perfectly bland and satisfac tory, and I have used them entirely without irritation in my eyes." It was obvious that the patient's conjunctival mucous membranes had become so sen sitive that they could detect compara tively small differences in the hydro gen ion concentration of collyria. The lesson taught by this case is that ex treme accuracy in compounding of pre scriptions, instead of being a virtue, may sometimes be a real source of ir ritation. The druggist "around the cor ner," who dissolved his non-too-pure pilocarpine in ordinary tap water, pre pared a solution which was not so acid and therefore not so irritating as that prepared by the very careful pharma cist who, using chemically pure pilo carpine dissolved in double distilled water, produced eye drops of a slightly more acid reaction. Summary The cases described above are pre sented because of their interest as emphasizing the following practical points: 1. The occurrence of abnormal physiological effects after the use of certain important alkaloids in ophthal-
CLINICAL PHARMACOLOGY O F T H E EYE
mological practice, more particularly, of eserine and pilocarpine. 2. The great variations in potency and effectiveness of various specimens of homatropine on the market. 3. The importance of applied phar macology in connection with ophthalmologieal therapeutics. 4. The extreme delicacy of certain pharmacological tests as compared with physical and chemical examina tion of powerful drugs, especially in 1
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regard to the detection of contamina tions and variations in their therapeu tic potency. 5. The importance of constantly bearing in mind the idiosyncrasies and extreme sensitiveness on the part of patients to even very small differences in the composition of prescriptions. Pharmacological Research Laboratory, Hynson, Westcott and Dunning.
References
Hunt: Science, 1930, v. 72, p. 526. 'Abel, Rouiller and Geiling: Jour. Pharmacol, and Exper. Therap., 1923, v. 22, p. 289. ' Hatcher: American Druggist, 1929, v. 79, p. 22. 'Macht and Anderson: Jour. Amer. Chem. Soc, 1927, v. 49, p. 2017. 'Macht: Archives Internationales de Pharmacodynamie et de Therapie, 1922, v. 27, p. 175. 'Macht: Science, 1930, v. 71, p. 302.