potassium channel activator
Springer Online Journal Archives 1860-2000
Chemistry and Pharmacology
Summary The concentration-effect relationships of pinacidil, a peripheral vasodilator, have been measured in 12 healthy adults who received placebo or pinacidil 25 mg daily for 1 week in a cross-over experiment. Diastolic blood pressure (DBP) and heart rate (HR) were recorded and blood samples were taken on days 1 and 7. Plasma drug concentration-time data were fitted by a biexponential function with zero-order input. The pharmacokinetic model was incorporated into a combined pharmacokinetic-dynamic model (PK-PD) using the Hill equation, which has three parameters: n, the sigmoidicity parameter, Emax the maximum effect and EC50 the concentration which gives 50% of Emax. For ΔDBP, the parameter medians were estimated as n=5, EC50=44.6 ng · ml−1 and Emax=13.5 mm Hg. A hysteresis loop was found when ΔHR was plotted against concentration, which could be fitted by a linear effect compartment model. Simulations showed that experimental ΔDBP points on Day 7 could be predicted from a simulated curve computed by the model using parameters estimated on Day 1. Using the simulation, it was possible to suggest an optimal dosage regimen for pinacidil tablets.
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