Dexmedetomidine: Sedative and Neuroprotective Mechanisms of Action and New Developments

Dexmedetomidine, the D-enantiomer of medetomidine, is among the most potent sedative drugs known. It is also one of the best understood in terms of its molecular and cellular mechanisms. Its sedative (and probably its neuroprotective) effects are mediated by subtype A of the α2 adrenergic receptor, a G-protein-coupled receptor. Acting as an agonist at this receptor, dexmedetomidine causes numerous intracellular changes that lead, generally speaking, to reduced neuronal excitability. These intracellular eeffects are mediated by a reduction in cyclic AMP concentrations. I will outline the genetic evidence that the α2A adrenergic receptor is the key target for dexmedetomidine. At the cellular level, there is good evidence that dexmedetomidine causes its sedative effects by acting on neuronal pathways in the brain that mediate natural sleep and arousal. The similarities between the EEG patterns of natural sleep and dexmedetomidine sedation will be discussed. I will present the evidence that contrasts the actions of dexmedetomidine with other sedative agents that may account for the arousable nature of the sedation with dexmedetomidine. Although currently used only as a sedative/analgesic, dexmedetomidine may provide some protection over the reported neurotoxicity caused by certain anesthetics in neonates. I will briefly discuss this aspect of dexmedetomidine pharmacology. If time allows I will discuss the synergy that occurs between dexmedetomidine and other sedative/hypnotic drugs.