Dexmedetomidine: A Novel Sedative-Analgesic Agent

Since the first report of clonidine, an α2-adrenoceptor agonist, the indications for this class of drugs have continued to expand. In December 1999, dexmedetomidine was approved as the most recent agent in this group and was introduced into clinical practice as a short-term sedative (<24 hours). α2-Adrenoceptor agonists have several beneficial actions during the perioperative period. They decrease sympathetic tone, with attenuation of the neuroendocrine and hemodynamic responses to anesthesia and surgery; reduce anesthetic and opioid requirements; and cause sedation and analgesia. They allow psychomotoric function to be preserved while letting the patient rest comfortably. With this combination of effects, α2-adrenoceptor agonists may offer benefits in the prophylaxis and adjuvant treatment of perioperative myocardial ischemia. Furthermore, their role in pain management and regional anesthesia is expanding. Side effects consist of mild to moderate cardiovascular depression, with slight decreases in blood pressure and heart rate. The development of new, more selective α2-adrenoceptor agonists with improved side effect profiles may provide a new concept for the administration of perioperative anesthesia and analgesia. This review aims to give background information to improve understanding of the properties and applications of the novel α2-adrenoceptor agonist, dexmedetomidine.

[1]  M. Caron,et al.  Multiple second messenger pathways of alpha-adrenergic receptor subtypes expressed in eukaryotic cells. , 1990, The Journal of biological chemistry.

[2]  Perioperative sympatholysis. Beneficial effects of the alpha 2-adrenoceptor agonist mivazerol on hemodynamic stability and myocardial ischemia. McSPI--Europe Research Group. , 1997, Anesthesiology.

[3]  M. Maze,et al.  The Pharmacokinetics and Hemodynamic Effects of Intravenous and Intramuscular Dexmedetomidine Hydrochloride in Adult Human Volunteers , 1993, Anesthesiology.

[4]  L. Goldman,et al.  Effect of mivazerol on perioperative cardiac complications during non-cardiac surgery in patients with coronary heart disease: the European Mivazerol Trial (EMIT). , 1999, Anesthesiology.

[5]  D. Stanski,et al.  Dexmedetomidine Decreases Thiopental Dose Requirement and Alters Distribution Pharmacokinetics , 1994, Anesthesiology.

[6]  R. Aantaa,et al.  Effect of clonidine and dexmedetomidine premedication on perioperative oxygen consumption and haemodynamic state. , 1997, British journal of anaesthesia.

[7]  Reduction of the Minimum Alveolar Concentration of Isoflurane by Dexmedetomidine , 1997, Anesthesiology.

[8]  M Anttila,et al.  Reversal of the Sedative and Sympatholytic Effects of Dexmedetomidine with a Specific α2-Adrenoceptor Antagonist Atipamezole: A Pharmacodynamic and Kinetic Study in Healthy Volunteers , 1998, Anesthesiology.

[9]  R. Eglen,et al.  Assessment of the role of α2‐adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice , 1997, British journal of pharmacology.

[10]  L. Hall,et al.  "Xylazine"--a new sedative for horses and cattle , 1969, Veterinary Record.

[11]  P. Duke,et al.  Effects of Clonidine on Narcotic Requirements and Hemodynamic Response during Induction of Fentanyl Anesthesia and Endotracheal Intubation , 1986, Anesthesiology.

[12]  F. Prinzen,et al.  Beneficial effects of dexmedetomidine on ischaemic myocardium of anaesthetized dogs. , 1996, British journal of anaesthesia.

[13]  P. Talke,et al.  Dexmedetomidine Does Not Alter the Sweating Threshold, But Comparably and Linearly Decreases the Vasoconstriction and Shivering Thresholds , 1997, Anesthesiology.

[14]  A. Lehtinen,et al.  Effect of intravenously administered dexmedetomidine on pain after laparoscopic tubal ligation. , 1991, Anesthesia and analgesia.

[15]  M. Maze,et al.  Ventilatory effects of clonidine alone and in the presence of alfentanil, in human volunteers. , 1992, Anesthesiology.

[16]  J. Savola,et al.  Characterization of the selectivity, specificity and potency of medetomidine as an alpha 2-adrenoceptor agonist. , 1988, European journal of pharmacology.

[17]  A. Iggo,et al.  An α2 receptor mediates the selective inhibition by noradrenaline of nociceptive responses of identified dorsal horn neurones , 1985, Brain Research.

[18]  J. Halter,et al.  Induction of Defective Insulin Secretion and Impaired Glucose Tolerance by Clonidine Selective Stimulation of Metabolic Alpha-adrenergic Pathways , 1978, Diabetes.

[19]  S. Umemura,et al.  Renal alpha 2-adrenoceptors and the adenylate cyclase-cAMP system: biochemical and physiological interactions. , 1987, The American journal of physiology.

[20]  P. Pagel,et al.  Dexmedetomidine Produces Similar Alterations in the Determinants of Left Ventricular Afterload in Conscious Dogs before and after the Development of Pacing-induced Cardiomyopathy , 1998, Anesthesiology.

[21]  P. Housmans Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium. , 1990, Anesthesiology.

[22]  E. Kharasch,et al.  Influence of dexmedetomidine and clonidine on human liver microsomal alfentanil metabolism. , 1991, Anesthesiology.

[23]  H. Scheinin,et al.  The analgesic action of dexmedetomidine — a novel α 2-adrenoceptor agonist — in healthy volunteers , 1991, Pain.

[24]  R. Ahlquist,et al.  A study of the adrenotropic receptors. , 1948, The American journal of physiology.

[25]  M. Koulu,et al.  Effects of dexmedetomidine, a selective α2‐adrenoceptor agonist, on hemodynamic control mechanisms , 1989, Clinical pharmacology and therapeutics.

[26]  M. Maze,et al.  Effects of Dexmedetomidine, a Novel Imidazole Sedative‐Anesthetic Agent, on Adrenal Steroidogenesis: In Vivo and In Vitro Studies , 1991, Anesthesia and analgesia.

[27]  J. G. Lee,et al.  Direct coronary and cerebral vascular responses to dexmedetomidine. Significance of endogenous nitric oxide synthesis. , 1992, Anesthesiology.

[28]  H. Scheinin,et al.  The analgesic action of dexmedetomidine--a novel alpha 2-adrenoceptor agonist--in healthy volunteers. , 1991, Pain.

[29]  M. Aibiki,et al.  Effects of dexmedetomidine, an alpha2-adrenoceptor agonist, on renal sympathetic nerve activity, blood pressure, heart rate and central venous pressure in urethane-anesthetized rabbits. , 1998, Journal of the autonomic nervous system.

[30]  R. Aantaa,et al.  Dexmedetomidine as an Anesthetic Adjunct in Coronary Artery Bypass Grafting , 1997, Anesthesiology.

[31]  N. Maekawa,et al.  The effects of clonidine and dexmedetomidine on human neutrophil functions. , 1999, Anesthesia and analgesia.

[32]  W. Hoffman,et al.  Dexmedetomidine improves neurologic outcome from incomplete ischemia in the rat. Reversal by the alpha 2-adrenergic antagonist atipamezole. , 1991, Anesthesiology.

[33]  M. Scheinin,et al.  Dexmedetomidine Premedication for Minor Gynecologic Surgery , 1990, Anesthesia and analgesia.

[34]  M. Lamy,et al.  Perioperative Sympatholysis: Beneficial Effects of the alpha2 ‐Adrenoceptor Agonist Mivazerol on Hemodynamic Stability and Myocardial Ischemia , 1997 .

[35]  Judith E. Hall,et al.  The Effects of Increasing Plasma Concentrations of Dexmedetomidine in Humans , 2000, Anesthesiology.

[36]  Judith E. Hall,et al.  Sedative, Amnestic, and Analgesic Properties of Small-Dose Dexmedetomidine Infusions , 2000, Anesthesia and analgesia.

[37]  L. Way,et al.  Long-term cardiac prognosis following noncardiac surgery , 1992 .

[38]  W. Browner,et al.  Long-term cardiac prognosis following noncardiac surgery. The Study of Perioperative Ischemia Research Group. , 1992, JAMA.

[39]  M. Singer,et al.  Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit , 1999, Anaesthesia.

[40]  M. Scheinin,et al.  Intramuscular dexmedetomidine, a novel alpha2‐ adrenoceptor agonist, as premedication for minor gynaecological surgery , 1991, Acta anaesthesiologica Scandinavica.

[41]  G. M. Drew,et al.  Evidence for two distinct types of postsynaptic alpha-adrenoceptor in vascular smooth muscle in vivo. , 1979, British journal of pharmacology.

[42]  E. Kalso,et al.  Effects of Radolmidine, A Novel &agr;2-Adrenergic Agonist Compared with Dexmedetomidine in Different Pain Models in the Rat , 2000, Anesthesiology.

[43]  T. Gordh,et al.  EPIDURAL CLONIDINE PRODUCES ANALGESIA , 1984, The Lancet.

[44]  B. C. Bloor,et al.  Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes. , 1992, Anesthesiology.

[45]  S. Ferreira,et al.  Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances. , 1988, European journal of pharmacology.

[46]  A. Brown,et al.  Receptor-effector coupling by G proteins. , 1990, Biochimica et biophysica acta.

[47]  P. Talke,et al.  The hemodynamic and adrenergic effects of perioperative dexmedetomidine infusion after vascular surgery. , 2000, Anesthesia and analgesia.

[48]  P. Talke,et al.  The effects of dexmedetomidine on neuromuscular blockade in human volunteers. , 1999, Anesthesia and analgesia.

[49]  R. Fragen,et al.  Effect of dexmedetomidine on the minimum alveolar concentration (MAC) of sevoflurane in adults age 55 to 70 years. , 1999, Journal of clinical anesthesia.

[50]  A. Lehtinen,et al.  The effect of intravenously administered dexmedetomidine on perioperative hemodynamics and isoflurane requirements in patients undergoing abdominal hysterectomy. , 1991, Anesthesiology.

[51]  M. Maze,et al.  Dexmedetomidine produces a hypnotic-anesthetic action in rats via activation of central alpha-2 adrenoceptors. , 1989, Anesthesiology.

[52]  M. Scheinin,et al.  Dexmedetomidine, an alpha 2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery. , 1990, Anesthesiology.

[53]  P. Talke,et al.  Postoperative Pharmacokinetics and Sympatholytic Effects of Dexmedetomidine , 1997, Anesthesia and analgesia.

[54]  G. M. Drew,et al.  EVIDENCE FOR TWO DISTINCT TYPES OF POSTSYNAPTIC α‐ADRENOCEPTOR IN VASCULAR SMOOTH MUSCLE in vivo , 1979 .

[55]  M. Maze,et al.  Dexmedetomidine Decreases Cerebral Blood Flow Velocity in Humans , 1993, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[56]  K. Korttila,et al.  Comparison of dexmedetomidine and midazolam sedation and antagonism of dexmedetomidine with atipamezole. , 1993, Journal of clinical anesthesia.

[57]  R. M. Jones,et al.  Effects of dexmedetomidine on isoflurane requirements in healthy volunteers. 1: Pharmacodynamic and pharmacokinetic interactions. , 1999, British journal of anaesthesia.

[58]  H. Takagi,et al.  Noradrenergic inhibition of the release of substance P from the primary afferents in the rabbit spinal dorsal horn , 1985, Brain Research.

[59]  K. Omote,et al.  Serotonergic mediation of spinal analgesia and its interaction with noradrenergic systems. , 1988, Anesthesiology.

[60]  S. Z. Langer,et al.  Presynaptic regulation of catecholamine release. , 1974, Biochemical pharmacology.

[61]  P. Talke,et al.  Effects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgery , 1995, Anesthesiology.

[62]  W. Browner,et al.  Association of Perioperative Myocardial Ischemia with Cardiac Morbidity and Mortality in Men Undergoing Noncardiac Surgery , 1990 .

[63]  M. Scheinin,et al.  Dexmedetomidine attenuates sympathoadrenal responses to tracheal intubation and reduces the need for thiopentone and peroperative fentanyl. , 1992, British journal of anaesthesia.

[64]  M. Weinger,et al.  Dexmedetomidine, a selective alpha 2-agonist, does not potentiate the cardiorespiratory depression of alfentanil in the rat. , 1990, Anesthesiology.

[65]  B. C. Bloor,et al.  Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate. , 1992, Anesthesiology.