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Clinical Trial
. 2004 May;57(5):552-62.
doi: 10.1111/j.1365-2125.2003.02062.x.

Modelling the cardiovascular effects of ephedrine

Adam M Persky  1 , N Seth Berry, Gary M Pollack, Kim L R Brouwer
Affiliations
Clinical Trial

Modelling the cardiovascular effects of ephedrine

Adam M Persky et al. Br J Clin Pharmacol. 2004 May.

Abstract

Aims: Recent reports have called into question the safety of ephedra supplements especially with regards to their cardiovascular effects. The purpose of this analysis was to characterize, via pharmacokinetic/pharmacodynamic modelling, the cardiovascular effects of ephedrine, the main active ingredient of ephedra, in apparently healthy, overweight volunteers.

Methods: In a randomized, double-blind, crossover, placebo-controlled study, eight subjects received either placebo, 0.25, 0.5 or 1.0 mg kg(-1) ephedrine sulphate by mouth with a 7-day washout between treatments. Plasma ephedrine concentrations, heart rate and blood pressure were determined for 8 h postdose.

Results: The pharmacokinetics of ephedrine were best described by a one-compartment model with first-order absorption and elimination. The percentage change in heart rate was described by a linear model with a resulting slope of 0.14%.l microg(-1) (CV = 59%). The percentage change in systolic blood pressure demonstrated clockwise hysteresis, and a sigmoidal tolerance model was used to describe the data. The mean maximum predicted effect (Emax) was 53.7% (CV = 41%) with an EC50 of 107 microg.l(-1) (CV = 65%) and an inhibitory maximum (Imax) of 39.8% (CV = 60%). Tolerance developed with a mean half-life of 15 min (range 6-140 min).

Conclusions: This is the first study to apply a comprehensive pharmacokinetic/pharmacodynamic model to the cardiovascular effects of orally administered ephedrine. Although systolic blood pressure increases quickly after administration, the increase is nearly abolished by compensatory mechanisms.

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Figures

Figure 1
Figure 1
Intra-day (diurnal) variability in semirecumbent (a) heart rate and (b) systolic blood pressure during the placebo condition (mean ± SD, n = 8)
Figure 2
Figure 2
Schematic of the tolerance model used to describe the effects of ephedrine on systolic blood pressure. ka, the absorption rate constant; CL/F, the apparent oral clearance; Cp, plasma concentration; k1i, rate constant for tolerance development; ki0, rate constant for the disappearance of tolerance; Ci, hypothetical ‘inhibitor’ concentration
Figure 3
Figure 3
Plasma ephedrine concentration (mean ± SD, n = 8)-time profile after 0.25 ([Image: see text] , 0.5 (○) and 1.0 (•) mg kg−1 oral dosing. Data were modelled simultaneously with a one-compartment model incorporating a lag time, assuming first order absorption and elimination (solid line)
Figure 4
Figure 4
Percentage change in heart rate vs ephedrine plasma concentration after oral dosing. (a) mean ± SD, n = 8 for all subjects and doses and (b) representative model fit for one subject (subject 1). Symbols represent actual data and line represents model prediction
Figure 5
Figure 5
Percentage change in systolic blood pressure vs ephedrine plasma concentration after oral dosing of ephedrine sulphate. (a) 0.25 mg kg−1 (grey diamonds), (b) 0.5 mg kg−1 (open circles), (c) 1.0 mg kg−1 (closed circles) and (d) representative model prediction for one subject after each dose (subject 4). Data shown as mean ± SD, n = 8. Symbols represent actual data and line represents model fit
Figure 6
Figure 6
Application of tolerance model for systolic blood pressure after administration of 50 mg ephedrine hydrochloride [11]. (a) Model fit from using pooled pharmacodynamic parameter estimates from this current study and study-specific pooled pharmacokinetic parameter estimates. (b) Model prediction using study-specific pharmacodynamic parameter estimates. Pharmacokinetic values: ka = 1.27 h−1, CL/F = 34.6 l h−1, V/F = 306 l, tlag = 9 min. Data shown as mean ± SD, n = 16. Symbols represent actual data and line represents model fit
Figure 7
Figure 7
Application of tolerance model for systolic blood pressure after administration of ephedra (17.3 mg ephedrine, 5.3 mg pseudoephedrine, 175 mg caffeine) [15] (a) Model fit from using pooled pharmacodynamic parameter estimates from this current study and study-specific pooled pharmacokinetic parameter estimates. (b) Model fit using study-specific pharmacodynamic parameter estimates. Pharmacokinetic values: ka = 1.34 h−1, CL/F = 21.6 l h−1, V/F = 222 l, tlag = 25 min. Data shown as mean ± SD, n = 8. Symbols represent actual data and line represents model fit
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