Psychopharmacology (1981) 75:9-15 Psycho pharmacology 9 Springer-Verlag 1981 Acute Extrapyramidal Side Effects: Serum Levels of Neurolepfics and Anticholinergics Larry Tune and Joseph T. Coyle Departments of Neuroscience, Pharmacology and Experimental Therapeutics and Psychiatry and The Behavioral Sciences, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205, USA 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 anticholiner- gics, 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 mea- sured 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 - Schizophrenia - Serum drug levels Drug induced acute extrapyramidal side effects (EPS) includ- ing Parkinsonian symptoms, dystonic reactions and aka- thesia are a major problem in the clinical management of patients receiving neuroleptic medications (Ayd 1961; Donlon and Stenson 1976; Van Putten 1974; Freedman and DeJong 1961). The neurophysiologic basis for neuroleptic- Offprint requests to." J. T. Coyle, Department of Neuroscience Johns Hopkins University School of Medicine 725 North Wolfe Street Baltimore, Maryland 21205, USA induced EPS is fairly well understood and results from their blockade of postsynaptic dopamine receptors in the corpus striatum (Calne et al. 1975; Inch and Brimblecombe 1974; Racagni et al. 1976; Sethy and Van Woert 1973). As a consequence, striatal chlinergic neurons, whose activity is regulated by the dopaminergic afferents are disinhibited, causing excessive stimulation of post-synaptic muscarinic receptors. Congruent with this specific synaptic relationship between dopaminergic terminals and cholinergic neurons in the striatum, muscarinic receptor antagonists reverse many of the symptoms caused by impaired striatal dopaminergic tone (Ahmed and Marshall 1962; Sethy and Van Woert 1973). In spite of our understanding of the molecular basis of these neuroleptic-induced EPS and their attenuation by muscarinic antagonists, currently there is little information about the role that serum levels of the anticholinergics play in controlling neuroleptic-induced EPS. Recently, we described a radioreceptor assay (Tune and Coyle 1980) for measuring serum levels of anticholinergics, which is based upon the specific binding of [3H]_quinuclidinyl benzilate, a potent muscarinic antagonist, to rat brain muscarinic receptors (Yamamura and Snyder 1974). With this assay, a significant inverse relationship between the concentration of anticholinergic drugs in serum and the severity of EPS in patients receiving substantial doses of neuroleptics was demonstrated. In spite of this statistically compelling correlation, nearly 30 % of neuroleptic treated patients with low or undetectable serum levels of anti- cholinergics experienced no EPS. This disparity has raised the question whether serum neuroleptics or other factors may have factiously biased the results. Accordingly, in the present study, we have more closely examined the relationships among EPS, serum anticholinergic levels and serum neurolep- tic levels as measured by radioreceptor assays. In additon, factors affecting the serum levels of anticholinergics were further defined, including protein binding and dose relationships. Materials and Methods Patients. Subjects were all patients treated at the Henry Phipps Psychiatric Clinic of the John Hopkins Hospital between July, 1978 and May, 1980. Informed consent was obtained from all participants according to a protocol approved by the Medical School IRK A total of 109 patients were studied. Eighty two of the patients were hospitalized in the inpatient unit and thus received medication from the nursing staff; 27 of the patients were receiving treatment in the outpatient Continuous Treatment Clinic. 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