Anesthetics

Description: Dexmedetomidine is a relatively selective alpha2-adrenoceptor agonist with centrally mediated sympatholytic, sedative, and analgesic effects. In general, dexmedetomidine has similar pharmacological effects to clonidine, another alpha2-adrenoceptor agonist. Dexmedetomidine infusions are used for sedation in the treatment of mechanically ventilated patients in an intensive care setting or as premedication for anesthesia and surgery. Dexmedetomidine has been administered to mechanically ventilated patients prior to extubation, during extubation, and post-extubation. During perioperative use, dexmedetomidine has reduced anesthetic or opioid dosage requirements similar to midazolam, but its use may require vasopressor and/or anticholinergic support to maintain blood pressure and heart rate goals. Infusion of dexmedetomidine benefited perioperative hemodynamic management of surgical patients at high cardiovascular risk undergoing vascular surgery but required greater intraoperative pharmacologic intervention to support blood pressure and heart rate. Dexmedetomidine was approved by the FDA on December 17, 1999.

Mechanism of Action: Dexmedetomidine is a relatively selective, centrally acting, alpha2-adrenoceptor agonist with sympatholytic, sedative, and analgesic properties but without significant ventilatory effects. Selectivity for the alpha2-receptors is observed in animals following slow intravenous (IV) infusion of dosages ranging from 10—300 mcg/kg. Both alpha1 and alpha2 activity is observed following slow IV infusion of very high doses (>=1000 mcg/kg) or with rapid IV administration. Sedation and analgesia occurs following stimulation of central alpha2-adrenergic receptors, which inhibit sympathetic outflow and tone. Sedative effects are observed within 5 minutes following IV dexmedetomidine administration.

Dexmedetomidine, when administered to healthy subjects, causes dose-dependent decreases in systolic and diastolic blood pressure; heart rate is also reduced. A small initial hypertensive response has been observed with IV injection of higher doses. Dexmedetomidine does not alter respiratory rate or oxygen saturation at the recommended dosage. Hemodynamic and catecholamine studies suggest that dexmedetomidine attenuates sympathetic activity during the immediate postoperative period. These sympatholytic effects include reduced heart rate, blood pressure, and plasma catecholamine (e.g., norepinephrine) concentrations. Consistent with alpha2-adrenoceptor agonism, hypotension and bradycardia occur frequently during dexmedetomidine administration. This effect is related to both the dose and the infusion rate.

Pharmacokinetics: Dexmedetomidine is administered by intravenous infusion. It is rapidly distributed to tissues with a rapid distribution phase half-life of approximately 6 minutes and a large volume of distribution. Plasma protein binding is about 94%. The bound fraction of dexmedetomidine is significantly decreased in subjects with hepatic impairment compared to healthy subjects. Dexmedetomidine exhibits linear kinetics in the dosage range of 0.2 to 0.7 mcg/kg/hr when administered by IV infusion for up to 24 hours.

Dexmedetomidine undergoes almost complete biotransformation with minimal unchanged dexmedetomidine excreted in urine and feces. Hepatic metabolism involves both direct glucuronidation and oxidative metabolism. The major metabolic pathways of dexmedetomidine are direct N-glucuronidation to inactive metabolites, aliphatic hydroxylation (mediated primarily by CYP2A6), and N-methylation.

Dexmedetomidine exhibits linear kinetics at therapeutic doses; the terminal elimination half-life (t1/2) is approximately 2 hours. About 95% of the total dose was recovered in the urine and 4% in the feces by nine days following IV administration. No unchanged dexmedetomidine was detected in the urine. Approximately 85% of the total dose recovered in the urine was excreted within 24 hours after the infusion. Metabolites formed by N-glucuronidation, aliphatic hydroxylation, and N-methylation accounted for approximately 34%, 14%, and 18% of the cumulative urinary excretion, respectively. Approximately 28% of the urinary metabolites have not been identified.

•Special Populations: Pharmacokinetic values of dexmedetomidine were similar for patients with a creatinine clearance (CrCl) < 30 ml/min as compared with healthy subjects, but the pharmacokinetic values of the metabolites of dexmedetomidine have not been evaluated in patients with impaired renal function. As dexmedetomidine is extensively metabolized and most of the metabolites are excreted in the urine, metabolites may accumulate upon long-term infusions in patients with impaired renal function (see Contraindications). Also, the mean elimination half life of dexmedetomidine was shorter (113.4 ± 11.3 ml/minute) among 5 patients with a mean CrCl of 20.9 ± 9.3 ml/minute as compared with the value (136.5 ± 13 ml/minute) from 5 patients with a mean CrCl of 122.1 ± 30.8 ml/minute. Theoretically, more free dexmedetomidine may be available for metabolism and renal clearance in patients with significantly impaired renal function due to decreased protein binding.[9443] In subjects with varying degrees of hepatic impairment (Child-Pugh Class A, B, or C), clearance values were lower than in healthy subjects. The mean clearance values for subjects with mild, moderate, and severe hepatic impairment were 74%, 64%, and 53% of those observed in the normal healthy subjects, respectively. Mean clearances for free drug were 59%, 51%, and 32% of those observed in the normal healthy subjects, respectively. Although dexmedetomidine is dosed to effect, dosage reduction may be necessary in patients with hepatic or renal impairment (see Dosage). There were no differences in the pharmacokinetic profile of dexmedetomidine in young (18—40 years), middle-age (41—65 years), and elderly (> 65 years) subjects. No pediatric pharmacokinetic data are available.

References
9443. DeWolf AM, Fragen RJ, Avram MJ, et al. The pharmacokinetics of dexmedetomidine in volunteers with severe renal impairment. Anesth Analg 2001;93:1205—9.



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