Advertisement

Psychopharmacology

, Volume 75, Issue 1, pp 9–15 | Cite as

Acute extrapyramidal side effects: Serum levels of neuroleptics and anticholinergics

  • Larry Tune
  • Joseph T. Coyle
Original Investigations

Abstract

An assay technique for measuring anticholinergic drugs in human serum based upon their inhibition of the specific binding of [3H]-quinuclidinyl benzilate to rat brain muscarinic receptors is described. The assay was validated by demonstrating a close correlation (r=0.99) between serum levels of nortriptyline measured by the radioenzymatic assay and a GLC technique. The assay measures free anticholinergics, and under standard assay conditions, approximately 95% of benztropine is bound to serum protein. Marked variation in serum anticholinergic levels in patients receiving the same oral dose was observed, and in individual patients there was a non-linear relationship between increasing oral dose and serum anticholinergic levels.

In a cross-sectional study of 109 patients receiving concurrently neuroleptics and antichlinergics, there was no correlation (r=0.029) between serum neuroleptic levels measured by a radioreceptor assay and extrapyramidal side effects (EPS). In the patients whose serum anticholinergic levels were also determined, there was a significant inverse correlation (r=0.44) between anticholinergic levels and EPS. In this cohort of patients, there was no significant correlation between serum anticholinergic and serum neuroleptic levels (r=0.16) and the ratio of serum anticholinergic to serum neuroleptic was a poor predictor of EPS (r=0.26).

The results suggest a marked variation in sensitivity of patients to the EPS-inducing of neuroleptics; nevertheless, the incidence of EPS decreases with increasing serum levels of anticholinergics. An optimal serum anticholinergic level of 10 pmole atropine equivalent per ml was associated with a low incidence of EPS and is relevant to drug action at the striatal muscarinic receptor.

Key words

Anticholinergics Extrapyramidal side effects Muscarinic receptor Neuroleptics Senizophrenia Serum drug levels 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Ahmed A, Marshall PB (1962) Relationship between anti-acetylcholine and anti-tremorine activity in anti-parkinsonian and related drugs. Br J Pharmacol 18:247–254Google Scholar
  2. Alpert M, Diamond F, Weisenfreund J, Taleporos E, Friedhoff AJ (1978) The neuroleptic hypothesis: a study of the covariation of extrapyramidal and drug effects. Br J Psychiatry 133:169–175Google Scholar
  3. Ayd FJ (1961) A survey of drug-induced extrapyramidal reactions. JAMA 175:1054–1060Google Scholar
  4. Burt DR, Creese I, Snyder SH (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196:326–328Google Scholar
  5. Calne D, Chase TN, Barbeau A (eds) (1975) Dopaminergic mechanisms, vol 9. Raven Press, New YorkGoogle Scholar
  6. Chase TN, Schnur JA, Gordon EK (1970) Cerebrospinal fluid monoamine catabolites in drug-induced extrapyramidal disorders. Neuropharmacology 9:265–268Google Scholar
  7. Creese I, Snyder SH (1977) A simple and sensitive radio-receptor assay. Nature 270:261–263Google Scholar
  8. Davis JM (1974) Dose equivalence of the antipsychotic drugs. J Psychiatr Res 11:65–69Google Scholar
  9. DiMascio A (1976) A controlled trial of amatidine in drug induced extrapyramidal disorders. Arch Gen Psychiatry 33:599–602Google Scholar
  10. Donlon PT, Stenson RL (1976) Neuroleptic-induced extrapyramidal symptoms. Dis Nerv Syst 37:629–635Google Scholar
  11. Eadie MJJ, Tyrer JH (1974) Anticonvulsant therapy. Pharmacological basis and practice, Churchill Livingstone London pp 35–78Google Scholar
  12. Freedman DX, DeJong J (1961) Factors that determine drug-induced akathisia. Dis Nerv Syst 22:69–76Google Scholar
  13. Hansen LB, Elley J, Christensen TR, Larsen NE, Narstoft J, Hridberg EF (1979) Plasma levels of perphenazine and its major metabolites during simultaneous treatment with anticholinergics. Br J Clin Pharmacol 7:75–80Google Scholar
  14. Inch TD, Brimblecome RW (1974) Antiacetylcholine drugs. Int Rev Neurobiol 16:67–144Google Scholar
  15. Innis R, Tune L, Rock R, DePaulo JR, U'Prichard D, Snyder SH (1979) Tricyclic antidepressant radioreceptor assay. Eur J Pharmacol 58: 472–477Google Scholar
  16. Jurgenson A (1975) A gas chromatographic method for determination of amitriptyline and nortriptyline in human serum. Acta Pharmacol Toxicol 36:79Google Scholar
  17. Muller P, Seeman P (1978) Dopaminergic supersensitivity after neuroleptics: time course and specificity. Psychopharmacology 60:1–11Google Scholar
  18. National Institute of Mental Health-Psychopharmacology Science Center Collaborative Study Group (1964) Phenothiazine treatment in acute schizophrenia: Effectiveness Arch Gen Psychiatry 10:246–261Google Scholar
  19. Racagni G, Cheney DL, Trabucchi M, Costa E (1976) In vivo actions of clozapine and haloperidol on the turnover rate of acetylcholine in rat striatum. J Pharmacol Exp Ther 196:323–332Google Scholar
  20. Rehavi M, Maayani S, Sokolovsky M (1977) Tricyclic antidepressants as antimuscarinc drugs: in vitro and in vivo studies. Biochem Pharmacol 26:1559–1567Google Scholar
  21. Richelson E, Divinetz-Romero S (1977) Blockade by psychotropic drugs of the muscarinic receptor in cultured nerve cells. Biol Psychiatry 12:771–782Google Scholar
  22. Rish SC, Hicey LY, Janowsky DS (1979) Plasma levels of tricyclic antidepressants and clinical efficacy. Review of the literature. J Clin Psychiatry 40:4–116Google Scholar
  23. Sethy VH, Van Woert MH (1973) Antimuscarinic drugs — effect on brain acetylcholine and tremors in rats. Biochem Pharmacol 22:2685–2691Google Scholar
  24. Snyder SH, Greenberg D, Yamamura HI (1974) Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry 31:58–61Google Scholar
  25. Snyder SH, Yamamura HI (1977) Antidepressants and the muscarinic acetylcholine receptor. Arch Gen Psychiatry 34:236–239Google Scholar
  26. Spitzer RL, Endicott J, Robins E, Kuriansky J, Gurland B (1975) Preliminary report of the reliability of reserach diagnostic criteria applied to psychiatric case records. In: Sudilovsky A, Gershon S, Beer B (eds). Predictability in psychopharmacology: preclinical and clinical correlations. Raven Press, New York, pp 1–30Google Scholar
  27. Tune LE, Coyle JT (1980) Serum levels of anticholinergic drugs in treatment of acute extrapyramidal side effects. Arch Gen Psychiatry 37:293–297Google Scholar
  28. Tune LE, Creese I, Coyle JT, Pearlson G, Snyder SH (1980a) How neuroleptic serum levels in patients receiving fluphenazine decanoate. Am J Psychiotry 137:80–82Google Scholar
  29. Tune LE, Creese I, DePaulo JR, Slavney PR, Coyle JT, Snyder SH (1980b) Clinical state and serum neuroleptic levels measured by radioreceptor assay in schizophrenia. Am J Psychiatry 137:187–190Google Scholar
  30. VanPutten T (1974) Why do schizophrenic patients refuse to take their drug? Arch Gen Psychiatry 31:67–72Google Scholar
  31. Yamamura HI, Snyder SH (1974) Muscarinic cholinergic receptor binding in the longitudinal muscle of the guinea pig ileum with [3H] quinuclidinyl benzilate. Mol Pharmacol 10:861–867Google Scholar

Copyright information

© Springer-Verlag 1981

Authors and Affiliations

  • Larry Tune
    • 1
    • 2
    • 3
  • Joseph T. Coyle
    • 1
    • 2
    • 3
  1. 1.Department of NeuroscienceJohns Hopkins University, School of MedicineBaltimoreUSA
  2. 2.Department of Pharmacology and Experimental TherapeuticsJohns Hopkins University, School of MedicineBaltimoreUSA
  3. 3.Department of Psychiatry and The Behavioral SciencesJohns Hopkins University, School of MedicineBaltimoreUSA

Personalised recommendations