PHARMACOKINETICS AND THE PHARMACODYNAMIC ACTION OF MIDAZOLAM IN YOUNGAND ELDERLY PATIENTS UNDERGOING TOOTH EXTRACTION

Objective: To determine whether age-dependent pharmacokinetic and phar macodynamic alterations account for a more pronounced response to benz odiazepines among elderly patients. Methods: Twelve young patients and 10 elderly patients received an intravenous dose of 0.05 or 0.03 mg/k g midazolam, respectively, before third molar extraction. Postoperativ e pain was treated with 30 mg dihydrocodeine. Serum concentrations of midazolam and sedative effects were monitored with visual analog scale s and choice reaction time measurements for 6 hours. Test values above baseline were integrated, and pharmacokinetic-pharmacodynamic analysi s was performed. Heart rate, blood pressure, arterial oxygen saturatio n, and amnesia also were assessed. Results: There were no significant age-dependent differences in disposition of midazolam between young an d elderly patients (apparent volume of distribution, 1.3 +/- 0.2 versu s 1.1 +/- 0.4 L/kg; half-life, 3.3 +/- 1.5 hours versus 3.7 +/- 2.2 ho urs; total body clearance, 451 +/- 186 ml/min versus 343 +/- 137 ml/mi n). However, higher values of area under the effect curve (AUEC) and A UEC divided by area under the serum concentration-time curve (AUC) (se nsitivity 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 h alf-maximal effect for sedation was lower (p = 0.025) among older pati ents (20.5 +/- 3.3 ng/ml) than among younger (29.7 +/- 6.6 ng/ml) pati ents. Amnesia was observed among 86% of patients and oxygen saturation was always 95% or more of basal value. There were no age-related diff erences in concentration of dihydrocodeine and its active metabolite d ihydromorphine, but dihydromorphine levels were much lower in three in termediate metabolizers (445 to 879 fmol/L) and especially in five poo r metabolizers (65 to 498 fmol/L) than among extensive metabolizers of cytochrome P450 2D6 (1604 to 6490 fmol/L). Conclusions: Elderly patie nts are more sensitive to the sedative action of midazolam than young patients, and the sensitivity is caused by age-dependent pharmacodynam ic alterations. The age-adjusted doses used are both effective (for se dative amnesia) and safe (in terms of arterial oxygen saturation, hear t rate, and blood pressure).