The influence of pregnancy on drug action: Concentration–effect modelling with propranolol

The physiological changes of pregnancy have been shown to alter the disposition of some drugs. However, there are no data on the possible influence of pregnancy or its complications on drug effect. We have applied drug concentration-effect analysis to determine whether pregnancy influences the action of propranolol. Twelve women with pregnancy induced hypertension were studied during the third trimester and again 2-3 months post partum. On each occasion propranolol (10 mg) was given intravenously and measurements of heart rate, blood pressure and whole blood propranolol concentration were determined over the ensuing 8 h. Pregnancy did not alter propranolol disposition. Clearance was 0.63 +/- 0.18 and 0.71 +/- 0.24 litre h-1 kg-1, and volume of distribution at steady state was 4.02 +/- 2.98 and 3.07 +/- 1.58 litres/kg during and after pregnancy respectively. There was no fall in blood pressure over the period of the acute study. The reduction in heart rate (beats/min per ng of propranolol/ml) was greater during compared with after pregnancy: -0.61 +/- 0.23 and -0.39 +/- 0.19 respectively (F = 6.64; df 1.9; P less than 0.03). There was no relationship between blood pressure or pretreatment heart rate and the slope of the concentration-effect relationship. We conclude that pregnancy can significantly alter drug effect in the absence of any pharmacokinetic changes. These findings suggest that therapeutic ranges established in non-pregnant patients may not be applicable during pregnancy.