Kabimidine Mechanism of Action

Pharmacologic Category: Psycholeptics, other hypnotics and sedatives.
Pharmacology: Pharmacodynamics: Mechanism of action and Pharmacodynamic effects: Dexmedetomidine is a selective α 2-adrenoreceptor agonist with sedative and a broad range of pharmacological properties. α 2-selectivity is observed in animals following slow intravenous infusion of low and medium doses (10-300 mcg/kg). Both α1 and α2 activities are observed following slow intravenous infusion of high doses (1000 mcg/kg) or with rapid intravenous administration. The sedative actions of Dexmedetomidine are believed to be mediated primarily by postsynaptic α 2-adrenoreceptors. Dexmedetomidine has a low affinity for beta adrenergic, muscarinic, dopaminergic and serotonin receptors.
Pharmacokinetics: Following intravenous administration, Dexmedetomidine exhibits the following pharmacokinetic characteristics: rapid distribution phase with a distribution half-life (t_½α) of about six minutes; and a terminal elimination half-life (t_½) approximately two hours. 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.
Distribution: The steady-state volume of distribution (Vss) of Dexmedetomidine is approximately 118 liters. The average protein binding is 94% and is significantly decreased in subjects with hepatic impairment.
Metabolism: Dexmedetomidine undergoes almost complete biotransformation with very little unchanged Dexmedetomidine excreted in urine and feces. Biotransformation involves both direct glucuronidation as well as cytochrome P450 mediated metabolism. The major metabolic pathways of Dexmedetomidine are: direct N-glucuronidation to inactive metabolites; aliphatic hydroxylation (mediated primarily by CYP2A6) of Dexmedetomidine to generate 3-hydroxy Dexmedetomidine, the glucuronide of 3-hydroxy Dexmedetomidine, and 3-carboxy Dexmedetomidine, and N-methylation of Dexmedetomidine to generate 3-hydroxy N-methyl Dexmedetomidine, 3-carboxy N-methyl Dexmedetomidine and N-methyl O-glucuronide Dexmedetomidine.
Elimination: The terminal elimination half-life (t_½) of Dexmedetomidine is approximately 2 hours and clearance is estimated to be approximately 39 L/h.
Hepatic Function Impairment: In subjects with varying degrees of hepatic impairment, clearance values are lower than in healthy subjects. It is necessary to reduce the dose depending on the degree of hepatic impairment.
Renal Function Impairment: Dexmedetomidine Hydrochloride pharmacokinetics (C_max, T_max, AUC, t_1/2, CL and V_ss) do not vary in subjects with severe renal impairment (CrCl: <30 mL/min). Since the majority of metabolites are excreted in the urine, it is possible that the metabolites may accumulate upon long-term infusions in patients with impaired renal function.
Elderly: The pharmacokinetic profile of Dexmedetomidine Hydrochloride was not altered by age, however as with many drugs, the elderly may be more sensitive to the effects of Dexmedetomidine.
Children: The pharmacokinetic profile of Dexmedetomidine hydrochloride has not been studied in children.