AGING INCREASES PHARMACODYNAMIC SENSITIVITY TO THE HYPNOTIC EFFECTS OF MIDAZOLAM

The effect of aging on the pharmacodynamics of midazolam was investiga ted in a double-blinded study involving 39 consenting patients ranging in age from 39 to 77 yr. Midazolam was infused intravenously (TV) usi ng a pharmacokinetic model-driven drug infusion device to achieve a pl asma midazolam concentration that was held constant for the 10-min dur ation of the study. Blood samples were obtained from the radial artery at 5 and 10 min for subsequent measurement of the plasma midazolam co ncentrations. With the 10-min sample, the patients were also assessed for the presence or absence of responsiveness to verbal command. To en sure that the pharmacodynamic end-point was assessed under the conditi on of a relative steady-state effect-site midazolam concentration, onl y those patients (n = 33) in whom the plasma midazolam concentration a t 10 min was within 30% of the measured concentration at 5 min were in cluded in the subsequent data analyses. Logistic regression was used t o fit the verbal command response/no response data to a mathematical m odel that included patient age and the plasma midazolam concentration measured at 10 min. Cp(50), the steady-state plasma midazolam concentr ation at which 50% of patients would be expected not to respond to a s pecific stimulus (e.g., verbal command), was calculated as a function of age from the parameterized logistic model. The midazolam Cp,, for r esponse to verbal command decreased significantly (P = 0.034) with inc reasing patient age, demonstrating that aging increases pharmacodynami c sensitivity to the hypnotic effects of midazolam independent of phar macokinetic factors.