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Dexmedetomidine ? a novel sedative agent

Dexmedetomidine – A Novel Sedative Agent Michael Alpha-2 adrenoceptor agonists have been used in veterinary anesthesia practice for many years. However, despite the knowledge that these agents reduce the release of norepinephrine and therefore have anesthetic properties, there use in humans has been very limited. Alpha-2 receptors are located presynaptically in sympathetic nerve endings and in noradrenergic neurons in the CNS. The receptors in the locus coeruleus area of the upper brain stem and the substantia gelatinosa mediate the sedative effects. The imidazoline group of drugs (clonidine, medetomidine, dexmedetomidine, and mivazerol) has been the most thoroughly investigated as sedative, analgesic and anesthetic agents. Medetomidine has been used extensively in large animal veterinary practice with good success. The D-enantiomer, dexmedetomidine, has now been developed for clinical use in humans, and is a very potent and specific alpha-2 adrenoreceptor agonist. The Orion – Farmos Group in Finland, first synthesized it in 1986. Dexmedetomidine is extensively and rapidly metabolized into inactive metabolites that are mainly excreted in the urine. It is a lipophilic compound, which is extensively distributed in the tissues, with a half-life of 6 minutes. The elimination half-life is 2 hours. z Dexmedetomidine
selectively acts on
alpha2-adrenoceptors
(in the brain and CNS)1

Compound
selectivity
Dexmedetomidine
Medetomidine
Clonidine
I-medetomidine
1. Dyck, Shafer. Anaesth Pharm Review.1993;1.
Dexmedetomidine produces both sedative and analgesic properties by its agonist effects on the alpha-2 receptors in the brain and spinal cord. CEREBRUM
z Sites of action
Brain (locus ceruleus)
Spinal cord
Autonomic nerves
Sedation/hypnosis
CEREBELLUM
Anxiolysis
Analgesia
VENTRICLE
LOCUS
CERULEUS

z Autonomic nerves
Spinal Cord
Ð Sympathetic activity
– Ð BP, Ð HR
Dexmedetomidine was first introduced as an anesthetic sparing agent, and was demonstrated to reduce isoflurane requirements by up to 90% when delivered as an infusion during general surgery. It also may have a neuroprotective role as improved neurological outcome has been shown in a rat model of brain ischemia. It may also have a useful role in managing the patient undergoing a drug or alcohol withdrawal process. Cardiovascular System. The intravenous administration of dexmedetomidine causes a decrease in heart rate, a transient increase in blood pressure due to peripherally mediated alpha – 2 receptor vasoconstriction. This is followed by a decrease in blood pressure as a result of a centrally mediated reduction in sympathetic tone. This reduction in sympathetic tone may have a beneficial cardioprotective effect in reducing the hemodynamic response to intubation or light anesthesia. Another alpha-2 agonist, mivazerol has been demonstrated to reduce episodes of myocardial ischemia in patients undergoing peripheral vascular surgery. The reduction in peri-operative oxygen consumption, as a result of these hemodynamic effects, may be very useful in protecting patients with coronary artery disease undergoing surgery. Respiratory System Although dexmedetomidine is a powerful sedation agent with analgesic properties, it does not produce respiratory depression at clinically effective doses. This distinguishes this agent from virtually all other sedatives and provides for a unique safety factor in its use. Neuroendocrine System The neuroendocrine response to stress is blunted by dexmedetomidine, as a result of its inhibition of sympathetic outflow and reduction in plasma catecholamines. It does not have any effect on ACTH secretion at therapeutic doses, unlike etomidate, another imidazole derivative drug. Sedation in the ICU The advantages of a drug that provides sedation, anxiolysis and analgesia, without respiratory depression, makes it ideal for use in the intensive care unit. Dexmedetomidine can facilitate the extubation process by attenuating the hemodynamic responses and by not causing respiratory depression. This allows it to be continued after extubation providing continuity in the sedation therapy. Multiple studies have demonstrated its efficacy in this area. Another novel advantage of this agent is that the deeply sedated patient may be aroused and demonstrate normal cognitive ability. Therefore a neurological assessment could be performed whenever required. Sedation without cognitive impairment may have far-reaching effects von reducing the morbidity in ICU patients. The time on mechanical ventilation and therefore the time spent in ICU may be reduced by the clinical advantages offered by dexmedetomidine. Conclusion The unique molecular pharmacology of this alpha-2 agonist provides sedation and analgesia without respiratory depression in a controlled manner by intravenous infusion. These properties may lend themselves to many areas of sedation and conscious sedation therapy.

Source: http://5jsnacc.umin.ac.jp/Dexmedetomidine.pdf

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Yu YC* , He SJ*, Chen S, Fu YH, Preferential electrical coupling regulates Brown KN, Yao XH, Ma J, Gao KP, neocortical lineage-dependent microcircuit Sosinsky GE, Huang K, Shi SH* Zhu XM, Dai YQ, Sun CG, Cheng induced hemorrhage after stroke in mice YN, Zheng P, Zhao BQ* Emerging roles of Nrf2 and phase II antioxidant Chen J* , Zhang F* Wang Q, Yue XF, Qu WM* , Tan R, Morphine inh

Microsoft word - rd040-03.doc

RESOLUCIÓN DEFENSORIAL N° 040-2003/DP 18 de diciembre de 2003 VISTO: El Informe Defensorial N° 78 “La anticoncepción oral de emergencia”1, elaborado por la Adjuntía para los Derechos de la Mujer. ANTECEDENTES: Primero.- Queja interpuesta por el Comité Consultivo en Anticoncepción de Emergencia El 20 de mayo de 2002, el Comité Consultivo en Anticoncepción de Emer

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