Advertisement

Psychopharmacology

, Volume 51, Issue 1, pp 15–22 | Cite as

Anticholinergic properties of antipsychotic drugs and their relation to extrapyramidal side-effects

  • Anthony C. Sayers
  • Hans R. Bürki
  • Walter Ruch
  • Helmuth Asper
Animal Studies

Abstract

The effects of haloperidol, alone and in combination with atropine, were compared with the effects of clozapine, alone and in combination with physostigmine, in a variety of tests commonly used to characterize neuroleptic compounds. It was found that clozapine in combination with physostigmine did not present the profile of activity of a classical neuroleptic agent; neither did haloperidol in combination with atropine present that of clozapine. In fact, some effects of haloperidol (catalepsy) were antagonized by atropine, while others (induction of striatal DA-receptor hypersensitivity) were enhanced. It is concluded that the interaction between dopaminergic and cholinergic systems in the striatum is highly complex, and that a neuroleptic possessing both potent DA-receptor blocking and muscarinic anticholinergic activity, while being less likely to cause parkinsonism in patients, would be more likely to induce tardive dyskinesias.

Key words

Clozapine Anticholinergic action Tardive dyskinesias Atropine Haloperidol 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Andén, N. E., Roos, B. E., Werdinius, B. On the occurrence of homovanillic acid in brain and cerebrospinal fluid and its determination by a fluorimetric method. Life Sci. 2, 448–458 (1963)Google Scholar
  2. Angst, J., Bente, D., Berner, P., Heimann, H., Helmchen, H., Hippius, H.: Das klinische Wirkungsbild von Clozapin (Untersuchung mit dem AMP-System). Pharmakopsychiat. 4, 201–211 (1971)Google Scholar
  3. Asper, H., Baggiolini, M., Bürki, H. R., Lauener, H., Ruch, W., Stille, G.: Tolerance phenomena with neuropleptics. Catalepsy, apomorphine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol. Europ. J. Pharmacol. 22, 287–294 (1973)Google Scholar
  4. Bürki, H. R., Ruch, W., Asper, H.: Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat. Psychopharmacologia (Berl.) 41, 27–33 (1975)Google Scholar
  5. Bürki, H. R., Ruch, W., Asper, H., Baggiolini, M., Stille, G.: Effect of single and repeated administration of clozapine on the metabolism of dopamine and noradrenaline in the brain of the rat. Europ. J. Pharmacol. 27, 180–190 (1974)Google Scholar
  6. Clement-Cormier, Y. C., Kebabian, J. W., Petzold, G. L., Greengard, P.: Dopamine-sensitive adenylate cyclase in mammalian brain: a possible site of action of antipsychotic drugs. Proc. nat. Acad. Sci. (Wash.) 71, 1113–1117 (1974)Google Scholar
  7. DeMaio, D.: Preliminary clinical evaluation of a new neuroleptic agent: HF-1854. In: The present status of psychotropic drugs. Pharmacological and clinical aspects, Proc. of the VI Intern. Congress of the Collegium Internationale Neuro-Psychopharmacologicum. Tarragona, Spain, April 1968. A Ceretti and T. Bové, eds., pp. 485–488. Amsterdam: Excerpta Medica Foundation 1969 (Intern. Congress Series No. 180)Google Scholar
  8. Gross, H., Langner, E.: Das Wirkungsprofil eines chemisch neuartigen Breitbandneuroleptikums der Dibenzodiazepingruppe. Wien. med. Wschr. 116, 814–816 (1966)Google Scholar
  9. Iversen, L. L., Horn, A. S., Miller, R. J.: Structure-activity relationships for interactions of agonist and antagonist drugs with dopamine-stimulated adenylate cyclase of rat brain—a model for CNS dopamine receptors? Int. Symp. on “Antipsychotic drugs, pharmacodynamics and pharmacokinetics”. Stockholm: Wenner-Gren Center 1974Google Scholar
  10. Janssen, P. A. J., Niemegeers, C. I. C., Jagenau, A. H. M.: Apomorphine-antagonism in rats. Arzneimittel-Forsch. 10, 1003–1005 (1960)Google Scholar
  11. Karobath, M. E.: Tricyclic antidepressive drugs and dopamine-sensitive adenylate cyclase from rat brain striatum. Europ. J. Pharmacol. 30, 159–163 (1975)Google Scholar
  12. Karobath, M., Leitich, H.: Antipsychotic drugs and dopamine-stimulated adenylate cyclase prepared from corpus striatum of rat brain. Proc. nat. Acad. Sci. (Wash.) 71, 2915–2918 (1974)Google Scholar
  13. Kiloh, L. G., Smith, J. S., Williams, S. E.: Antiparkinson drugs as causal agents in tardive dyskinesia. Med. J. Aust. 2, 591–593 (1973)Google Scholar
  14. Laduron, P.: Limiting factors in the antagonism of neuroleptics on dopamine-sensitive adenylate cyclase. J. Pharm. Pharmacol. 28, 250–251 (1976)Google Scholar
  15. Litchfield, J. T., Jr., Wilcoxon, F.: A simplified method of evaluating dose-effect experiments. J. Pharmacol. exp. Ther. 96, 99–113 (1949)Google Scholar
  16. Miller, R. J., Hiley, C. R.: Antimuscarinic properties of neuroleptics and drug-induced parkinsonism. Nature (Lond.) 248, 596–597 (1974)Google Scholar
  17. Miller, R. J., Iversen, L. L.: Effect of psychoactive drugs on dopamine (3,4-dihydroxyphenylethylamine)-sensitive adenylate cyclase activity in corpus striatum of rat brain. Trans. Biochem. Soc. 554th Meeting London, Vol. 2, pp. 256–259 (1974)Google Scholar
  18. Morpurgo, C.: Effects of antiparkinson drugs on a phenothiazine-induced catatonic reaction. Arch. int. Pharmacodyn. 137, 84–90 (1962)Google Scholar
  19. Rubovits, R., Klawans, H. L., Jr.: Implications of amphetamine induced stereotyped behaviour as a model for tardive dyskinesias. Arch. gen. Psychiat. 27, 502–507 (1972)Google Scholar
  20. Sayers, A. C., Bürki, H. R., Ruch, W., Asper, H.: Hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia (Berl.) 41, 97–104 (1975)Google Scholar
  21. Snyder, S. H., Greenberg, D., Yamamura, H. I.: Antischizophrenic drugs and brain cholinergic receptors. Arch. gen. Psychiat. 31, 58–61 (1974)Google Scholar
  22. Stille, G., Ackermann, H., Eichenberger, E., Lauener, H.: The pharmacological properties of a potent neurotropic compound from the dibenzo-thiazepine group. Int. J. Neuropharmacol. 4, 375–391 (1965)Google Scholar
  23. Stille, G., Lauener, H., Eichenberger, E.: The pharmacology of 8-chloro-11-(4′-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4] diazepine (clozapine). Farmaco, Ed. prat. 26, 603–625 (1971)Google Scholar
  24. Thornton, W. E., Thornton, B. P.: Tardive dyskinesia from the major tranquillizers. J. Florida med. Ass. 60, 24–26 (1973)Google Scholar
  25. Van Rossum, J. M., Janssen, P. A. J., Boissier, J. R., Julou, L., Loew, D. M., Møller-Nielsen, O., Munkvad, I., Randrup, A., Stille, G., Tedeschi, D. H.: Pharmacology. In: Modern problems of pharmacology, Vol. 5, The neuroleptics, D. P. Bobon, P. A. J. Janssen, and J. Bobon, eds., pp. 23–70. Basel: Karger 1970Google Scholar

Copyright information

© Springer-Verlag 1976

Authors and Affiliations

  • Anthony C. Sayers
    • 1
  • Hans R. Bürki
    • 1
  • Walter Ruch
    • 1
  • Helmuth Asper
    • 1
  1. 1.Research Institute Wander, a Sandoz Research UnitWander Ltd.BernSwitzerland

Personalised recommendations