The effects of amitriptyline, citalopram and reboxetine on autonomic nervous system. A randomised placebo-controlled study on healthy volunteers.
BACKGROUND
In therapeutic use, amitriptyline, reboxetine and citalopram have all been associated with apparent anticholinergic-like side effects (dry mouth, constipation, etc.), despite the very low antimuscarinic activity of reboxetine and citalopram in vitro.


OBJECTIVE
We hypothesised that the spectral analysis of heart rate variability (HRV) might detect differences between amitriptyline, citalopram and reboxetine in their anticholinergic activities following a single peroral administration.


METHODS
In this double-blind, cross-over study, amitriptyline (75 mg), citalopram (20 mg), reboxetine (4 mg) and placebo were randomly given at 1-week intervals to eight healthy male volunteers. Drug and catecholamine concentrations in plasma were determined repeatedly. The drug effect was assessed with periodic recordings of electrocardiogram (ECG) and blood pressure, and with measurements of salivary secretion. The ECG recordings were subjected to spectral analysis of HRV, in which the high frequency (HF) power of R-R interval (RRI) variability was supposed to reflect cardiac parasympathetic tone.


RESULTS
Reboxetine increased heart rate and blood pressure and reduced the HF power of RRI and 3,4-dihydroxyphenylglycol (DHPG) plasma concentrations. Amitriptyline diminished salivary secretion and had a prominent sedative action. Measurements after citalopram did not differ significantly from placebo.


CONCLUSIONS
Reboxetine, despite its low antimuscarinic activity in vitro, had distinct effects on the HF power of RRI, consistent with anticholinergic activity in vivo. Amitriptyline had a measurable anticholinergic effect in the salivary glands, but, surprisingly, not in the heart. We suggest that the sedative effect of amitriptyline could alter cardiac sympathovagal balance and, therefore, counteract the anticholinergic drug effect.
Penttilä
J
J
Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland.
Syvälahti
E
E
Hinkka
S
S
Kuusela
T
T
Scheinin
H
H
D000293:Adolescent; D018759:Adrenergic Uptake Inhibitors / Q000097:blood / Q000494:pharmacology*; D000328:Adult; D000639:Amitriptyline / Q000097:blood / Q000494:pharmacology*; D000704:Analysis of Variance; D001341:Autonomic Nervous System / Q000187:drug effects* / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002395:Catecholamines / Q000097:blood*; D015283:Citalopram / Q000097:blood / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008297:Male; D009025:Morpholines / Q000097:blood / Q000494:pharmacology*; D000077593:Reboxetine; D012472:Salivation / Q000187:drug effects / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000097:blood / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D018759:Adrenergic Uptake Inhibitors; D000639:Amitriptyline; D002395:Catecholamines; D015283:Citalopram; D009025:Morpholines; D000077593:Reboxetine; D017367:Selective Serotonin Reuptake Inhibitors