Summary
Guinea-pigs and rats were tested once every fortnight during a period of 6 weeks for their responses to stimuli producing cough and to stimuli producing a twitch of the skin of the back, and the dose of codeine which depressed these responses in 50% of a group of animals (ED50) was determined. In the conditions of the experiment both the sensitivity of the animals and the effects of codeine were constant.
Then the animals were treated with codeine, once or three times daily, for 6 or 7 weeks, they developed tolerance to its effects on both responses. With rats this tolerance followed the same time course for both actions of codeine studied, but with guinea-pigs the tolerance to its effects in depressing cough developed rapidly, whereas there was little tolerance to its effect on the twitch.
Animals lost their tolerance much more slowly than they acquired it. When guinea-pigs which had developed tolerance to the cough-depressant actions of codeine were left until their sensitivity to it had returned to normal, tolerance could once again be induced but took longer to develop. The onset and decline of tolerance appeared to vary logarithmically with time; the graph of log. ED50 against time was linear.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Literatur
Adler, T. K.: A comparative study of the metabolism of codeine. Dissertation: University of California/Berkeley 1953.
, and M. F. Latham: Demethylation of 14-C-labelled codeine in the rat. Proc. Soc. Exp. Biol. (N. Y.) 73, 401–404 (1950).
Cochin, J., J. Haggart, L. A. Woods, and M. H. Seevers: Plasma levels, urinary and fecal excretion of morphine in non-tolerant and tolerant dogs. J. Pharmacol. exp. Ther. 111, 74–83 (1954).
Conney, A. H., C. Davison, R. Gastel, and J. J. Burns: Adaptive increases in drug-metabolizing enzymes induced by phenobarbital and other drugs. J. Pharmacol. exp. Ther. 130, 1–8 (1960).
Eddy, N. B., and J. G. Reid: Studies of morphine, codeine and their derivatives. VII. Dihydromorphine (paramorphan), dihydromorphinone (dilaudid), and dihydrocodeinone (dicodide). J. Pharmacol. exp. Ther. 52, 468–493 (1934).
Fraser, H. F., H. Isbell, and G. D. van Horn: Norcodeine in man. Fed. Proc. 17, 367 (1958).
Friebel, H., C. Reichle u. A. v. Graevenitz: Zur Hemmung des Hustenreflexes durch zentral angreifende Arzneimittel. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 224, 384–400 (1955).
Irwin, S., and M. H. Seevers: ref. nach Seevers and Woods.
Kasé, Y.: Pharmacological studies on cough reflex. Part. 3: Coughing dog and its application. Jap. J. Pharmacol. 4, 130–135 (1955).
T. Yuizono, T. Yamasaki, T. Yamada, S. Io, M. Tamiya, and I. Kondo: A new potent non-narcotic antitussive, 1-methyl-3-di(2-thienyl)-methylene-piperidine. Pharmacology and clinical efficacy. Chem. pharm. Bull. 7, 372–377 (1959).
Kolb, L., and A. G. Dumez: Experimental addiction of animals to opiates. Publ. Hlth Rep. (Wash.) 46, 698 (1931).
Krueger, H., N. B. Eddy, and M. Sumwalt: The pharmacology of the opium alkaloids. Publ. Hlth Rep. (Wash.) Suppl. 165 (1941).
Kuhn, H. F., u. H. Friebel: (1) Der Nachweis von Codein im Harn. Arch. Pharm. (Weinheim) 296, 232–235 (1963).
(2) Die Ausscheidung von Codein und Codeinmetaboliten im Harn Codeingewöhnter Ratten und Meerschweinchen. Med. exp. 7, 255–261 (1962).
Litchfield, J. T., jr., and F. Wilcoxon: A simplified method of evaluating dose-effect experiments. J. Pharmacol. exp. Ther. 96, 99–113 (1949).
Paerregaard, P.: The liberation of morphine from codeine in man and dog. Acta pharmacol. Kbh. 14, 394–399 (1958).
Reichle, C., u. H. Friebel: Zur Hemmung des Hustenreflexes durch zentral angreifende Arzneimittel. 2. Mitteilung. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 226, 558–562 (1955).
Remmer, H.: Drug tolerance. In: Symposium of enzymes and drug action. 276–300. London: J. & A. Churchill 1962.
Schroeder, W.: Die Verwendung des Vagusschlingenhundes für die Wertbestimmung hustenstillender Substanzen. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 212, 433–439 (1951).
Seevers, M. H.: Adaptation to narcotics. Fed. Proc. 13, 672–684 (1954).
, and L. A. Woods: The phenomena of tolerance. Amer. J. Med. 14, 546–557 (1953).
Takemori, A. E.: (1) Enzymic studies on morphine glucuronide synthesis in acutely and chronically morphinized rats. J. Pharmacol. exp. Ther. 130, 370–374 (1960).
(2) Cellular adaption to morphine in rats. Science 133, 1018–1019 (1961).
Way, E. Leong, and T. K. Adler: The pharmacologic implications of the fate of morphine and its surrogates. Pharmacol. Rev. 12, 383–446 (1960).
Wikler, A.: Mechanisms of action of “Opiates and Opiate Antagonists”. Public Hlth Monogr. 52, 1–38 (1958).
Woods, L. A.: Distribution and fate of morphine in non-tolerant and tolerant dogs and rats. J. Pharmacol. exp. Ther. 112, 158–175 (1954).
Author information
Authors and Affiliations
Additional information
Mit 4 Textabbildungen
Auszugsweise der Dtsch. Pharmakologischen Gesellschaft vorgetragen. Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 243, 305 (1962).
Rights and permissions
About this article
Cite this article
Friebel, H., Kuhn, HF. Gewöhnung an die hustenhemmende Wirkung von Codein. Naunyn - Schmiedebergs Arch 246, 527–537 (1964). https://doi.org/10.1007/BF00246306
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00246306