Concentration-effect relationships of two infusion rates of the imidazoline antihypertensive agent rilmenidine for blood pressure and development of side-effects in healthy subjects.
OBJECTIVE
The aim of this study was to compare the effect profiles of i.v. administered rilmenidine aimed at the same target plasma concentration, but attained with different rates.


METHODS
The study was placebo-controlled, randomized, double-blind, double-dummy, three-way, cross-over in nine healthy volunteers. All subjects randomly received either a fast infusion, a slow infusion or a placebo infusion. The target concentration was set at 8 ng ml-1 with a fivefold difference in the time to reach the maximum concentration. Saccadic eye movements, electroencephalography (EEG), blood pressure and heart rate were measured every half hour. Drug plasma concentrations, adverse events, salivary flow and visual analogue scales were obtained every hour.


RESULTS
Changes in systolic/diastolic blood pressure at the end of the infusion were (mean +/- s.d.) 13.3 +/- 16.4/7.9 +/- 7.5 mmHg with the fast infusion and 16.3 +/- 12.7/10.2 +/- 7.9 mmHg during the slow infusion, compared with 0.0 +/- 13.2/1.3 +/- 8.3 mmHg for the placebo occasion. Decrease of saccadic peak velocity (SPV) at the end of the infusion was 18.0 +/- 5.2% during the fast infusion, 23.0 +/- 7.0% with the slow infusion, and 6.1 +/- 5.2% with placebo. PK/PD analysis showed similar concentration-dependent linear reduction in SPV and blood pressure up to the maximum observed rilmenidine plasma level for both the fast and the slow infusion.


CONCLUSIONS
The rate of infusion of rilmenidine in healthy volunteers does not influence the PK/PD relationship of saccadic eye movements and blood pressure up to the maximum observed rilmenidine plasma concentrations. Rilmenidine causes clear concentration-dependent blood pressure reductions in healthy volunteers.
de Visser
S J
SJ
Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands. sv@chdr.nl
van Gerven
J M
JM
Schoemaker
R C
RC
Cohen
A F
AF
D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004569:Electroencephalography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010080:Oxazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D000077769:Rilmenidine; D012438:Saccades / Q000187:drug effects; D012469:Salivary Glands / Q000187:drug effects / Q000502:physiology
D000959:Antihypertensive Agents; D010080:Oxazoles; D000077769:Rilmenidine