The influence of age on the pharmacokinetics and pharmacodynamics of bemetizide and triamterene: a single and multiple dose study

Diuretics are a frequent cause of adverse drug effects in the elderly, many times involving drug–drug interactions. In addition, multiple chronic diseases, age-dependent pharmacokinetic and pharmacodynamic changes, and a decreased homeostatic capacity often complicate diuretic therapy in the elderly. The pharmacokinetics (area under the plasma concentration–time curve: AUC; peak concentration in plasma: cmax; time to reach peak concentration: tmax; terminal half-life: t1/2) and pharmacodynamics (urine flow rates and renal excretion rates of Na+ at 1, 3, and 6 h after oral administration) of a fixed combination of 25 mg bemetizide and 50 mg triamterene were investigated in 15 elderly patients (age 70–84 years) and 10 young volunteers (age 18–30 years) after a single dose (day 1) and after multiple doses (at steady state, day 8). Compared with the young volunteers, mean plasma concentrations of bemetizide, triamterene, and the active triamterene metabolite were significantly higher in the elderly volunteers. These elevated plasma levels occurred after single dose and were even more pronounced after multiple dose in the elderly. While plasma concentrations and AUC of bemetizide, triamterene, and the active metabolite of triamterene were increasing in correlation to age of subjects and duration of therapy, urine flow and renal Na+ excretion rates were decreasing at the same degree. At steady state conditions, practically no effect on urine flow and Na+ excretion rates could be observed in the elderly patients (in contrast to the young volunteers) for the first 8 h after administration of bemetizide and triamterene. The lower the measured (endogenous) creatinine clearance was in all subjects, the higher were the plasma concentrations of bemetizide and triamterene, and the lower was the effect on pharmacodynamics (i.e. urine flow and renal Na+ excretion rates). The glomerular filtration rate, known to be lower in the elderly (a priori), was apparently decreased at higher levels of bemetizide and triamterene in the elderly, which may explain why there was no diuretic and saluretic effect after multiple dose in the elderly patients.