Modelling the cardiovascular effects of ephedrine

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.

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.

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).

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.