Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction

Objective: To determine whether age-dependent pharmacokinetic and pharmacodynamic alterations account for a more pronounced response to benzodiazepines among elderly patients. Methods: Twelve young patients and 10 elderly patients received an intravenous dose of 0.05 or 0.03 mg/kg midazolam, respectively, before third molar extraction. Postoperative pain was treated with 30 mg dihydrocodeine. Serum concentrations of midazolam and sedative effects were monitored with visual analog scales and choice reaction time measurements for 6 hours. Test values above baseline were integrated, and pharmacokinetic-pharmacodynamic analysis was performed. Heart rate, blood pressure, arterial oxygen saturation, and amnesia also were assessed. Results: There were no significant age-dependent differences in disposition of midazolam between young and elderly patients (apparent volume of distribution, 1.3 +/- 0.2 versus 1.1 +/- 0.4 L/kg; half-life, 3.3 +/- 1.5 hours versus 3.7 +/- 2.2 hours; total body clearance, 451 +/- 186 ml/min versus 343 +/- 137 ml/min). However, higher values of area under the effect curve (AUEC) and AUEC divided by area under the serum concentration-time curve (AUC) (sensitivity index) were observed among the elderly as follows: AUEC for reaction time (AUEC(RT)) (573 versus 261; p = 0.042), AUEC for visual analog scale (AUEC(VAS)) (37.7 versus 14.4; p = 0.011), AUEC(RT)/AUC (6.3 versus 1.8; p = 0.007), and AUEC(VAS)/AUC (0.40 versus 0.11; p = 0.009) compared with the young group. Likewise, mean concentration at half-maximal effect for sedation was lower (p = 0.025) among older patients (20.5 +/- 3.3 ng/ml) than among younger (29.7 +/- 6.6 ng/ml) patients. Amnesia was observed among 86% of patients and oxygen saturation was always 95% or more of basal value. There were no age-related differences in concentration of dihydrocodeine and its active metabolite dihydromorphine, but dihydromorphine levels were much lower in three intermediate metabolizers (445 to 879 fmol/L) and especially in five poor metabolizers (65 to 498 fmol/L) than among extensive metabolizers of cytochrome P450 2D6 (1604 to 6490 fmol/L). Conclusions: Elderly patients are more sensitive to the sedative action of midazolam than young patients, and the sensitivity is caused by age-dependent pharmacodynamic alterations. The age-adjusted doses used are both effective (for sedative amnesia) and safe (in terms of arterial oxygen saturation, heart rate, and blood pressure).