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Dexmedetomidine is a selective alpha-2 adrenergic agonist which provides sedative effects, analgesia, and reduction in sympathetic activity. Dexmedetomidine binds to the alpha-2a subset of receptors present in the brain (locus coeruleus) and spinal cord and has inhibitory effects, functioning through activated G-proteins to reduce levels of norepinephrine and adenosine triphosphate release. This results in reduction of pain signaling at the level of the spinal cord, hypnosis at the level of the locus coeruleus, and an overall reduction of central nervous system sympathetic activity. At high doses or with rapid IV infusion, dexmedetomidine loses some of its selectivity and has effects at peripheral alpha-2b receptors which results in vasoconstriction and acts on alpha-1 adrenergic receptors which further constricts vessels. However, in general, dexmedetomidine has minimal alpha-1 activity at a ratio of about 1:1600 when compared to alpha-2 receptors and is considered highly selective for alpha-2.
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STRUCTURE AND HISTORY
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Dexmedetomidine is a water-soluble imidazole compound and a pharmacologically active dextro-isomer of medetomidine, a potent alpha-2 agonist used in veterinary medicine. Clonidine was the first alpha-2 agonist synthesized in the early 1960s and was used as a treatment for nasal congestion, hypertension, and alcohol abuse. Clonidine’s early use in anesthesia was as an anesthetic adjunct for myocardial infarction or intrathecal anesthesia. Dexmedetomidine was approved by the Federal Drug Agency (FDA) in 1999 as a selective alpha-2 agonist for short-term medication (<24 hours) for analgesia and sedation in the intensive care unit (ICU). It is now widely used as a premedication, as an anesthetic adjunct for general and regional anesthesia, and as a postoperative sedative and analgesic.
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PHARMACOKINETICS AND PHARMACODYNAMICS
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The administration forms of dexmedetomidine include intravenous, intramuscular, transdermal, and intranasal. Off-label use includes using dexmedetomidine as an adjunct to local anesthetics in regional blocks.
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Intravenous dexmedetomidine has a large volume of distribution of about 118 L and is 94% protein bound. The mean elimination half-life of dexmedetomidine is one and a half to 3 hours for intravenous administration and 5 to 6 hours for intramuscular administration. IV infusion has linear, concentration-dependent kinetics. Intranasal formulations have an estimated bioavailability of 65% with great variability range: 35%–93%.
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Dosing intravenous dexmedetomidine is dependent on the clinical setting. In the ICU, intravenous dexmedetomidine is dosed based on the Richmond Agitation Sedation Scale (RASS) or clinical sedative effect. Dosing intravenous infusion for monitored anesthesia care ranges from 0.2 to 1 μg/kg/h. Off-label intravenous infusion rate for maintenance of anesthesia typically ranges from 0.1 to 0.8 μg/kg/h. Higher infusion doses have been used but have been shown not to add to clinical efficacy. A loading dose can be administered and typically consists of 0.5 to 1 μg/kg over 10 minutes. Loading doses are not always recommended, however, due to the hemodynamic concerns associated with rapid intravenous administration as discussed below.