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On the Absorption of Drugs and Poisons From the Bladder and the Urethra. I. Absorption of Apomorphin and Morphin
ON THE ABSORPTIO N OF DRUGS AND POISONS FROM THE BLADDER AND THE URETHRA
I.
ABSORPTION OF APOMORPHIN AND MORPHIN
DAVID I. MACHT From the Pharmacological Laboratory, Johns Hopkins University, and the James Buchanan Brady Urological Institute, Baltimore '
A large number of drugs is employed in genito-urinary practice in the treatment of the bladder and the urethra: some as antiseptics, some as styptics, some as local anesthetics and sedatives and still others as stimulants of the mucous membranes and for other purposes. The general belief among the profession is that the drugs or reagents thus exhibited or administered exert a purely local or topical effect, and that absorption from the bladder or urethra into the systemic circulation is rare and, if taking place, is but slight in degree and of no practical importance. In connection with an investigation concerning the absorption of various drugs and poisons through devious and unusual channels or portals of entry such as the eye, the vagina, etc. (1), the author has undertaken an inquiry into the possibility of systemic absorption of pharmacological agents and the degree of such absorption in various parts of the urinary tract. The results have turned out to be of considerable interest not only from the purely pharmacological but also from the practical clinical point of view, and it was therefore deemed desirable to report them in this place. In the present communicatio n the problem of absorption from the bladder and urethra will be taken up. In a later paper the question of absorption from the ureters and the pelvis of the kidney will be dealt with. METHOD
In the present research the study of absorption from bladder and urethra was confined to male animals. Dogs were found to 43
44
DAVID I. MACHT
be ideal subjects for this purpose because, in the first place, the histological structure of the urethra and bladder in the dog is practically the same as that in man, and secondly, because the vesical and urethral sphincters in this animal are so powerfully developed that it is very easy to confine the action of a drug to the bladder or urethra at the pleasure of the experimenter. If a fine catheter, with a side opening and a wire guide, is passed through the urethra of a male dog into its bladder and is left in position, the internal sphincter contracts so firmly around it that any fluid injected through the catheter into the bladder is practically confined to that cavity alone, and does not permeate into the urethra. Indeed in some dogs it is almost impossible to pass a catheter into the bladder at all on account of the excessive irritability and spasmodic contraction of the sphincter muscles. If, on the other hand, it is desired to limit the action of a drug to the urethral mucosa only and not to the bladder, all that is necessary is to insert the catheter as far as the external sphincter, in which case a fluid injected through the catheter under moderate pressure will merely irrigate the urethra and flow out again externally without penetrating either the posterior urethra or the bladder. The conditions just described hold good for the great majority of dogs. In exceptional cases, of course, the sphincters may not be so well developed or may not contract so tightly, thus preventing a sharp differentiation in applying the drug to the bladder or urethra. APOMORPHIN AND MORPHIN AS INDICATORS OF ABSORPTION
In a paper on the absorption of drugs from the eye (2) the author has shown that apomorphin offers a very convenient method of determining the absorption or non-absorption of drugs from various surfaces into the general system in unanesthetized animals. A little apomorphin solution or powder introduced into the conjunctiva! sac of a dog was shown to be followed in a few minutes by violent emesis. Inas-
ABSORPTION OF APOMORPHI N AND MORPHIN
45
much as apomorphi n is the best known example of a centrallyacting emetic, the conclusion is inevitable that vomiting in such a dog has been produced by the absorption of apomorphi n from the eye through the blood or lymph stream into the general circulation and through its action upon the vomiting center in the brain. In exactly the same manner the author has pointed out that apomorphin is readily absorbed from the vagina (3). Furthermor e, inasmuch as the vomiting center of dogs is almost as sensitive to the action of morphin as to that of its derivative, apomorphin , the introductio n of morphin salts in solution or in powder form into the conjunctiva ! sac or into the vagina of dogs was also followed by prompt vomiting, again indicating the absorption of the drug from those organs into the general circulation. The same alkaloids were utilized in the study of absorption from the bladder and urethra. ABSORPTION FROM THE BLADDER AND URETHRA OF APOMORPHI N AND MORPHIN
If a catheter is gently introduced into the bladder of a male dog in the manner described above, and a solution of apomorphin (0.1 per cent to I per cent) is injected into the bladder and the catheter left in place in order to prevent regurgitatio n of the solution into the urethral canal-abso rption of the drug as evidenced by emesis, is very slow. The dog generally does not vomit for half an hour or longer and sometimes he does not vomit at all. If now the same animal is used on another day and the same strength of apomorphi n solution or even weaker solutions of the alkaloid be employed for the irrigation of its urethra, vomiting promptly follows, generally in from two to five minutes. This marked difference in the absorptive power for apomorphi n between the bladder and urethra has been repeatedly noted by the author in numerous experiment s with various concentrati ons of the drug. It occurs irrespective of whether the bladder contains urine or is empty. The following protocols may serve as illustration s:
DAVID I. MACH T
46
weight 10 kilos. Exper iment of October 11, 1917. Large white dog, cent apomorper 0.5 of cc. 10 er 10.05 a.m. Introd uced into the bladd in place. ter cathe g leavin on, soluti phin hydrochloride tion defeca 10.25 a.m. No vomit ing and no 11.00 a.m. No vomit ing No vomit ing 12.00 m. . Exper iment of October 15, 1917. Same dog as above as the extern al far as ra ureth into uced 11.43 a.m. Soft cathe ter introd cent apom orper 0.1 with gently ted sphinc ter. Irriga es minut two for on soluti de phin hydrochlori 11.45 a.m. Saliva tion 11.48 a.m. Repea ted vomit ing and defecation 6 kilos. IntroExper iment of May 16, 1917. Medium-sized dog, ed 5 cc. of Inject place. in it left and er duced cathe ter into the bladd about occurs ting Vomi de. chlori hydro a 1.0 per cent of apom orphin drug. the of uction forty-five minut es after introd irriga ted with Exper iment May 17, 1917. Same anima l. Ureth ra ing occurs in vomit de; chlori hydro orphin 0.1 per cent solution of apom three minut es.
powe rs Exac tly the same relati onshi p betwe en the absor ptive in case of of the bladd er and ureth ra was found to hold good after a morp hin excep t that vomi ting gener ally took place case of the in than id longe r perio d of time in case of this alkalo need n actio apom orphi n. Furth er discussion of the morp hin not, therefore, be enter ed into in this place. ON THE
COMP ARAT IVE
ABSO RPTIV E
POWE R
OF THE
ANTE RIOR
HRA AND POSTE RIOR PORTI ONS OF THE URET
ing the The dog offers us an oppo rtuni ty not only of study ra, ureth and er bladd the comp arativ e absor ptive prope rties of e arativ comp the but also enabl es us to observe to some exten t the of ns absor ptive powe r of the anter ior and poste rior portio a side with ter cathe A s: follow as ureth ra. This may be done its er, bladd the into ra ureth openi ng is passe d throu gh the urine of rawal withd presence in the bladd er being prove d by ter in this with a syringe. Fluid injec ted throu gh the cathe outw ards positi on natur ally enter s the bladd er and does not flow rawn withd ally gradu now is ter throu gh the ureth ra. The cathe
ABSORPTION OF APOMORPHI N AND MORPHIN
47
to a point where suction with the syringe obtains no more urine, thus indicating that the tip of the catheter is beyond the internal sphincter. If small injections are made the fluid will remain confined to the posterior urethra but as the amount of fluid is increased, the internal sphincter yields and the fluid passes into the bladder. On the other hand when the catheter is withdrawn so far that its tip extends beyond the external sphinctAr, fluid injected under moderate pressure will regurgitate and will come in contact only with the anterior urethra. This fact .offers us a practical method of applying medicamen ts to the posterior or anterior portions of the urethra at will, and in this way the comparativ e absorptive power of these two divisions can be investigate d. By the method above described, the author has found that the absorptive power of the posterior urethra is distinctly greater than that of the anterior. This may be illustrated by the following protocols: Experiment A, December 31, 1917. Black and white clog, 8 kilos. Posterior urethra is irrigated with 0.5 per cent of apomorphin hydrochloride solution so that the fluid runs into the bladder. Vomiting occurs four and a half minutes after the beginning of the injection. Experiment B, January 2, 1918. Same dog. Catheter introduced as far as but not past the external sphincter and the anterior urethra is irrigated with 0.5 per cent of apomorphin hydrochlorid e. Vomiting takes place six and a half minutes after the beginning of the injection. Experiment C, January 5, 1918. Same dog. Ten cubic centimeters of 1.0 per cent solution of apomorphin hydrochlorid e is introduced into the bladder and catheter is left in place. Vomiting does not occur within thirty minutes after introduction of the drug. Experiment 25. Yellow dog, 6 kilos. Irrigation of posterior urethra with apomorphin hydrochlorid e, 0.5 per cent is followed by emesis in three minutes. Irrigation of the anterior urethra in the same dog on another day with same solution strength produces vomiting four and a half minutes after beginning of injection. Ten cubic centimeters 1.0 per cent solution apomorphin hydrochloride introduced into the bladder with catheter left in place produces vomiting in twenty-five minutes.
48
DAVID I. MACHT
Experi'ment 26. Yellow and white dog, 10 kilos. Irrigation of posterior urethra with 0.1 per cent apomorphin hydrochloride produces vomiting in five minutes. Irrigation of anterior urethra on another day with the same per cent solution is followed by vomiting in seven minutes. Introduction of 10 cc. 0.1 per cent solution of apomorphin hydrochloride into the bladder with catheter left in place is not followed by vomiting for an hour. DISCUSSION
From the above described experiment s it will be seen that the bladder and the urethra differ greatly in their absorptive power for apomorphi n and morphin. That this is also true in case of other drugs and poisons will be shown in the next communica tion on the subject. This difference in the absorptive power between the two organs is, as far as the author has been able to gather from the empirical observation s of clinicians, probably also true in clinical experience. How this difference in the absorptive powers between the urethra and the bladder is to be explained is not altogether clear; but the fact that the bladder is devoid of glands on the one hand, and the urethra contains numerous glands, on the other, is probably at least in part responsible for the phenomenon. Equally interesting both from the scientific and the practical clinical point of view is also the difference in .the rapidity of · absorption of apomorphi n and morphin between the anterior and posterior portions of the urethra. This difference is really more marked than is at first seen from the illustrative protocols given above, for it must be borne in mind that the total mucous surface of the posterior urethra is much less than the total mucous area of the anterior one so that even if vomiting were produced by the same solution in the same time from both portions of the urethra, it could be argued that even in such a case the absorption from the posterior urethra was more rapid. The explanation of this phenomeno n is also not quite clear, but it is suggested that it may at least in part be due to the absorption through the .prostatic ducts opening into the posterior urethra.
ABSORPTION OF APOMORPHIN AND MORPHIN
49
SUMMARY
1. Apomorphin and morphin offer a convenient method for the study of absorption from the bladder and the urethra in the unanesthetized animal. 2. Absorption of apomorphin and morphin from the bladder is very slow. 3. Absorption of apomorphin and ~norphin from the urethra is very marked and rapid. 4. Absorption from the posterior portion of the urethra is more efficient and rapid than from the anterior. 5. The above observations are of interest not only from a purely pharmacological point of view, but also from the clinical. REFERENCES (1) MACHT: Proc. Soc. of Exper. Biol. and Med., December, 1917. (2) MACHT: Jour. of Amer. Med. Assoc., 1917, !xviii, p. 1230. (3) MACHT: Jotir. Pharm. and Exper. Therap., 1918, x, 509.
,.
I.
ABSORPTION OF APOMORPHIN AND MORPHIN
DAVID I. MACHT From the Pharmacological Laboratory, Johns Hopkins University, and the James Buchanan Brady Urological Institute, Baltimore '
A large number of drugs is employed in genito-urinary practice in the treatment of the bladder and the urethra: some as antiseptics, some as styptics, some as local anesthetics and sedatives and still others as stimulants of the mucous membranes and for other purposes. The general belief among the profession is that the drugs or reagents thus exhibited or administered exert a purely local or topical effect, and that absorption from the bladder or urethra into the systemic circulation is rare and, if taking place, is but slight in degree and of no practical importance. In connection with an investigation concerning the absorption of various drugs and poisons through devious and unusual channels or portals of entry such as the eye, the vagina, etc. (1), the author has undertaken an inquiry into the possibility of systemic absorption of pharmacological agents and the degree of such absorption in various parts of the urinary tract. The results have turned out to be of considerable interest not only from the purely pharmacological but also from the practical clinical point of view, and it was therefore deemed desirable to report them in this place. In the present communicatio n the problem of absorption from the bladder and urethra will be taken up. In a later paper the question of absorption from the ureters and the pelvis of the kidney will be dealt with. METHOD
In the present research the study of absorption from bladder and urethra was confined to male animals. Dogs were found to 43
44
DAVID I. MACHT
be ideal subjects for this purpose because, in the first place, the histological structure of the urethra and bladder in the dog is practically the same as that in man, and secondly, because the vesical and urethral sphincters in this animal are so powerfully developed that it is very easy to confine the action of a drug to the bladder or urethra at the pleasure of the experimenter. If a fine catheter, with a side opening and a wire guide, is passed through the urethra of a male dog into its bladder and is left in position, the internal sphincter contracts so firmly around it that any fluid injected through the catheter into the bladder is practically confined to that cavity alone, and does not permeate into the urethra. Indeed in some dogs it is almost impossible to pass a catheter into the bladder at all on account of the excessive irritability and spasmodic contraction of the sphincter muscles. If, on the other hand, it is desired to limit the action of a drug to the urethral mucosa only and not to the bladder, all that is necessary is to insert the catheter as far as the external sphincter, in which case a fluid injected through the catheter under moderate pressure will merely irrigate the urethra and flow out again externally without penetrating either the posterior urethra or the bladder. The conditions just described hold good for the great majority of dogs. In exceptional cases, of course, the sphincters may not be so well developed or may not contract so tightly, thus preventing a sharp differentiation in applying the drug to the bladder or urethra. APOMORPHIN AND MORPHIN AS INDICATORS OF ABSORPTION
In a paper on the absorption of drugs from the eye (2) the author has shown that apomorphin offers a very convenient method of determining the absorption or non-absorption of drugs from various surfaces into the general system in unanesthetized animals. A little apomorphin solution or powder introduced into the conjunctiva! sac of a dog was shown to be followed in a few minutes by violent emesis. Inas-
ABSORPTION OF APOMORPHI N AND MORPHIN
45
much as apomorphi n is the best known example of a centrallyacting emetic, the conclusion is inevitable that vomiting in such a dog has been produced by the absorption of apomorphi n from the eye through the blood or lymph stream into the general circulation and through its action upon the vomiting center in the brain. In exactly the same manner the author has pointed out that apomorphin is readily absorbed from the vagina (3). Furthermor e, inasmuch as the vomiting center of dogs is almost as sensitive to the action of morphin as to that of its derivative, apomorphin , the introductio n of morphin salts in solution or in powder form into the conjunctiva ! sac or into the vagina of dogs was also followed by prompt vomiting, again indicating the absorption of the drug from those organs into the general circulation. The same alkaloids were utilized in the study of absorption from the bladder and urethra. ABSORPTION FROM THE BLADDER AND URETHRA OF APOMORPHI N AND MORPHIN
If a catheter is gently introduced into the bladder of a male dog in the manner described above, and a solution of apomorphin (0.1 per cent to I per cent) is injected into the bladder and the catheter left in place in order to prevent regurgitatio n of the solution into the urethral canal-abso rption of the drug as evidenced by emesis, is very slow. The dog generally does not vomit for half an hour or longer and sometimes he does not vomit at all. If now the same animal is used on another day and the same strength of apomorphi n solution or even weaker solutions of the alkaloid be employed for the irrigation of its urethra, vomiting promptly follows, generally in from two to five minutes. This marked difference in the absorptive power for apomorphi n between the bladder and urethra has been repeatedly noted by the author in numerous experiment s with various concentrati ons of the drug. It occurs irrespective of whether the bladder contains urine or is empty. The following protocols may serve as illustration s:
DAVID I. MACH T
46
weight 10 kilos. Exper iment of October 11, 1917. Large white dog, cent apomorper 0.5 of cc. 10 er 10.05 a.m. Introd uced into the bladd in place. ter cathe g leavin on, soluti phin hydrochloride tion defeca 10.25 a.m. No vomit ing and no 11.00 a.m. No vomit ing No vomit ing 12.00 m. . Exper iment of October 15, 1917. Same dog as above as the extern al far as ra ureth into uced 11.43 a.m. Soft cathe ter introd cent apom orper 0.1 with gently ted sphinc ter. Irriga es minut two for on soluti de phin hydrochlori 11.45 a.m. Saliva tion 11.48 a.m. Repea ted vomit ing and defecation 6 kilos. IntroExper iment of May 16, 1917. Medium-sized dog, ed 5 cc. of Inject place. in it left and er duced cathe ter into the bladd about occurs ting Vomi de. chlori hydro a 1.0 per cent of apom orphin drug. the of uction forty-five minut es after introd irriga ted with Exper iment May 17, 1917. Same anima l. Ureth ra ing occurs in vomit de; chlori hydro orphin 0.1 per cent solution of apom three minut es.
powe rs Exac tly the same relati onshi p betwe en the absor ptive in case of of the bladd er and ureth ra was found to hold good after a morp hin excep t that vomi ting gener ally took place case of the in than id longe r perio d of time in case of this alkalo need n actio apom orphi n. Furth er discussion of the morp hin not, therefore, be enter ed into in this place. ON THE
COMP ARAT IVE
ABSO RPTIV E
POWE R
OF THE
ANTE RIOR
HRA AND POSTE RIOR PORTI ONS OF THE URET
ing the The dog offers us an oppo rtuni ty not only of study ra, ureth and er bladd the comp arativ e absor ptive prope rties of e arativ comp the but also enabl es us to observe to some exten t the of ns absor ptive powe r of the anter ior and poste rior portio a side with ter cathe A s: follow as ureth ra. This may be done its er, bladd the into ra ureth openi ng is passe d throu gh the urine of rawal withd presence in the bladd er being prove d by ter in this with a syringe. Fluid injec ted throu gh the cathe outw ards positi on natur ally enter s the bladd er and does not flow rawn withd ally gradu now is ter throu gh the ureth ra. The cathe
ABSORPTION OF APOMORPHI N AND MORPHIN
47
to a point where suction with the syringe obtains no more urine, thus indicating that the tip of the catheter is beyond the internal sphincter. If small injections are made the fluid will remain confined to the posterior urethra but as the amount of fluid is increased, the internal sphincter yields and the fluid passes into the bladder. On the other hand when the catheter is withdrawn so far that its tip extends beyond the external sphinctAr, fluid injected under moderate pressure will regurgitate and will come in contact only with the anterior urethra. This fact .offers us a practical method of applying medicamen ts to the posterior or anterior portions of the urethra at will, and in this way the comparativ e absorptive power of these two divisions can be investigate d. By the method above described, the author has found that the absorptive power of the posterior urethra is distinctly greater than that of the anterior. This may be illustrated by the following protocols: Experiment A, December 31, 1917. Black and white clog, 8 kilos. Posterior urethra is irrigated with 0.5 per cent of apomorphin hydrochloride solution so that the fluid runs into the bladder. Vomiting occurs four and a half minutes after the beginning of the injection. Experiment B, January 2, 1918. Same dog. Catheter introduced as far as but not past the external sphincter and the anterior urethra is irrigated with 0.5 per cent of apomorphin hydrochlorid e. Vomiting takes place six and a half minutes after the beginning of the injection. Experiment C, January 5, 1918. Same dog. Ten cubic centimeters of 1.0 per cent solution of apomorphin hydrochlorid e is introduced into the bladder and catheter is left in place. Vomiting does not occur within thirty minutes after introduction of the drug. Experiment 25. Yellow dog, 6 kilos. Irrigation of posterior urethra with apomorphin hydrochlorid e, 0.5 per cent is followed by emesis in three minutes. Irrigation of the anterior urethra in the same dog on another day with same solution strength produces vomiting four and a half minutes after beginning of injection. Ten cubic centimeters 1.0 per cent solution apomorphin hydrochloride introduced into the bladder with catheter left in place produces vomiting in twenty-five minutes.
48
DAVID I. MACHT
Experi'ment 26. Yellow and white dog, 10 kilos. Irrigation of posterior urethra with 0.1 per cent apomorphin hydrochloride produces vomiting in five minutes. Irrigation of anterior urethra on another day with the same per cent solution is followed by vomiting in seven minutes. Introduction of 10 cc. 0.1 per cent solution of apomorphin hydrochloride into the bladder with catheter left in place is not followed by vomiting for an hour. DISCUSSION
From the above described experiment s it will be seen that the bladder and the urethra differ greatly in their absorptive power for apomorphi n and morphin. That this is also true in case of other drugs and poisons will be shown in the next communica tion on the subject. This difference in the absorptive power between the two organs is, as far as the author has been able to gather from the empirical observation s of clinicians, probably also true in clinical experience. How this difference in the absorptive powers between the urethra and the bladder is to be explained is not altogether clear; but the fact that the bladder is devoid of glands on the one hand, and the urethra contains numerous glands, on the other, is probably at least in part responsible for the phenomenon. Equally interesting both from the scientific and the practical clinical point of view is also the difference in .the rapidity of · absorption of apomorphi n and morphin between the anterior and posterior portions of the urethra. This difference is really more marked than is at first seen from the illustrative protocols given above, for it must be borne in mind that the total mucous surface of the posterior urethra is much less than the total mucous area of the anterior one so that even if vomiting were produced by the same solution in the same time from both portions of the urethra, it could be argued that even in such a case the absorption from the posterior urethra was more rapid. The explanation of this phenomeno n is also not quite clear, but it is suggested that it may at least in part be due to the absorption through the .prostatic ducts opening into the posterior urethra.
ABSORPTION OF APOMORPHIN AND MORPHIN
49
SUMMARY
1. Apomorphin and morphin offer a convenient method for the study of absorption from the bladder and the urethra in the unanesthetized animal. 2. Absorption of apomorphin and morphin from the bladder is very slow. 3. Absorption of apomorphin and ~norphin from the urethra is very marked and rapid. 4. Absorption from the posterior portion of the urethra is more efficient and rapid than from the anterior. 5. The above observations are of interest not only from a purely pharmacological point of view, but also from the clinical. REFERENCES (1) MACHT: Proc. Soc. of Exper. Biol. and Med., December, 1917. (2) MACHT: Jour. of Amer. Med. Assoc., 1917, !xviii, p. 1230. (3) MACHT: Jotir. Pharm. and Exper. Therap., 1918, x, 509.
,.