Dr.Praful Zinzuwadia M.D.,D.A.

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The use of Alpha() -2 agonists,either alone or in combination,is widespread in anaesthesia pratice. The field has rapidly evoled with the clinical introduction of second generation of Alpha-2 agonist Dexmedetomidine,Denantiomer of Medetomidine,a more selective,specific and efficacious compound than the prototype, Clonidine. Food and Drug Administration had approved Dexmedetomidine for use in humans as a short term(<24 hours)medication for analgesia and sedation in the ICU at the end of 1999. Its application as a premedication, as an anesthetic adjunct for general anaesthesia and regional anaesthesia and as a post operative sedative and analgesic,reveals more beneficial effects.
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Adrenergic Receptors (AR) differentiated into & receptors based on potency of various natural and synthetic catecholamines.

AR seperated into two subtypes -1 &-2, depending on their sensitivity to the -1 selective antagonist Prazosin and -2 selective antagonist Yohimbine. -2 AR futher differentiated into -2a,-2b,-2c. Clonidine is weak partial agonist at 2b,butappeared inactive at -2a & -2c. Dexmedetomidine shown to be full agonist at2c and apartial agonist at-2a & -2b.
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Highly selective -2 agonist,with a relatively high ratio of -2/-1 activity(1620:1 as compared to 220:1 for Clonidine). After I.V. ,the distribution half life is approximately 6 minutes Time to peak effect is 15 minutes. Its volume of distribution is 118L/kg and 94% protein binding. It undergoes complete biotransformation in the liver viaglucuronidase and cytochrome P450 mediated metabolism. The metabolites with no clinical effects,are eliminated in the urine(95%) and feces(5%). The elimination half-life is approx.2 hours. Dose reduction may be needed in patients with hepatic dysfunction and renal function impairment. Drug accumulation does not seem to occur,even with infusions longer than 24 hours.

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Dexmedetomidine,an imidazole compound,displays specific and selective alpha-2AR agonism. The -2 receptors re pre and post synaptic receptors found within the cental and peripheral nervous system. The central -2a receptors are located in the Locus Ceruleus,and the peripheral receptors are situated in the neurons of superficial dorsal horn especially lamina II. Activation of this receptors in the brain and spinal cord inhibits neuronal firing causing hypotension,bradycardia,sedationand analgesia. The response to activation of the receptors in other areas include:decreased salivation,decreased secretion and decreased bowel motility in gastrintestinal tract,

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Contraction of vascular and other smooth muscle;inhibition of renin release;increased glomerular filtration,increased secretion of sodium and water in the kidney,decreased intraocular pressure, decreased insulin release from the pancreas,decreased shivering thresold. Dexmedetomidine retains the ventilatory response to increasing CO2,does not lead to respiratory depression.

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Dexmedetomidine is provided in 1ml and 2ml ampoules(100mcg/ml). It must be diluted in 49 or 48 ml of Normal Saline giving concentration of either2mcg/ml or 4mcg/ml respectively. It must be given in a controlled infusion device. A Loading infusion i.e.1mcg/kg must be given over a 10 minute period.Followed by infusion in the dose of 0.2mcg/kg/hour to 0.7mcg/kg/hour. The loading dose should not be bolused.It has dose dependent -2AR selectivity.In rapid infusion of lower doses both -1and -2 activities are observed. Transinet and paradoxical hypertension may be seen during loading dose infusion.
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In 1999 FDA approved for use as a sedative and supplement to sedation in the ICU. Because of short elimination half life of 2 hour and a linear pharmacokinetic behaviour,make it an ideal drug for intravenous titration . Its unique sedative action mimics normal sleep,an advantage during weaning from mechanical ventilation. It need not to be discontinued after tracheal extubation,for preventing emergence delirium and agitation. ITU patients on dexmedetomidine were clinically sedated,but could be roused when stimulated,and returned to their sleep-like state when left alone.

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Studies are now focusing on the safety and efficacy,beyond 24 hours because of its favourable profile in improving outcome and long term brain functions in critically ill. In a phase IV study,dexmedetomidine for more than 24hr, in dose of 1.4mcg/kg/hr found to be safe and did not produce rebound tachycardia or hypertension when abruptly discontinued. The Maximising Efficacy of Targeted Sedation and Reducing Neurological Dysfunction(MENDS)randomized trial reported an earlier return to a delirium-free cognitive state and more ventilator-free days with Dexmedetomidine when used for 24 to 120 hrs.Above studies indicate long term (>24h)in critically ill patients.

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Recent work has shown that omitting or halving the loading dose eliminates adverse cvs effects but at the same time preserves sedative action.
Caution should be exercised in pts who are volume depleted,vasoconstricted,or have severe heart block. Publication of few cases of asystole after its use,warrants intense vigilence with its use and the need for a large-scale study on its Tachycardia amd arterial hypertension can cause severe problems in many postsurgical patients requiring intensive care,especially during the period of weaning and when transitioning to the awake state,dexmedetomidine reduces this adverse effects.

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I t can be used as sedative supplementation to regional anaesthesia. Compared with propofol,as a supplement to regional anaesthesia,the target sedation level took longer to achieve with Dexmedetomidine(25 minutes versus 10 minutes){Avian S.R. et al;Anaes&Anal.2002,95,461 Use of Dexmedetomidine, resulted in greater sedation,lower B.P., and improved analgesia in the recovery room,when compared with propofol. Time to Post Anaesthesia Care Unit(PACU) discarge was not different.

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Due to its faster onset of action,faster recovery and discharge times,a new role as a sole agent for procedural sedation is fast emerging. FDA approved this drug to be used as a SedativeAnalgesic and/or total anaesthetic in adults and paediatric population undergoing small minimally invasive procedures,with or without tracheal intubation. It is a safe sedative alternative to benzodiazepine/opoid combination or propofol,in multitude pf procedures because of its analgesic,cooperative sedation and lack of respiratory depression effects.
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Sedation,anxiolysis and antisialogogue actions are attractive attributes in apremedication agent. Dexmedetomidine not only offers anxiolysis,sedation and analgesia,but also helps in attentuating the stress response to tracheal intubation/extubation.,and emergence from anaesthesia. Another benefit as premedication is its ability to pontentiate the anaesthetic action of other agents,and to reduce its requirements during surgery. Dexmedetomidine can be administered by the relatively noninvasive buccal or nasal route,because of its high bioavailability. Buccal route ensures more compliance and better absorption(upto 82%) in younger children than i.v..Studies evaluating the efficacy,safety,optimal dosage of buccal route in children have found a dose of 3-4mcg/kg,one hour before surgery.
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Preliminary studies report better sedation at parental seperation and induction of anesthesia with 1mcg/kg intranasal dexmedetomidine when given 30-45 minutes prior to surgical procedure as compared to oral midazolam. The technique causes no discomfort,relatively quick,simpleand may have benefits overtransmucosal route and rectal administration . The nasal route is also effective in adults in the dose of 1mcg/kg given 45 min. before surgery. More studies are needed to evalute the effects of premedication routes on various outcome measures.,like preop.anxiety level,induction time,emergence excitation,postop analgesic requirments,postop behavior disturbance.
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Dexmedetomidine is used as a part of multimodal anesthetic regimen. Dexmedetomidine have been shown to attentuate stressinduced sympathoadrenal response,protecting the patient from noxious sympathetic stimulation and haemodynamic changes during intubation/extubation,as well as duing surgical procedure. It has minimum alveolar concentration(MAC) and opiate sparing properties,which helps in decreasing inhalational anesthetic and opoid requirments by upto 90%. It reduces Recornium requirements during Sevofluranr anesthesia,there by potentially reducing the risk of muscle weakness during emergence. It significantly attentuates postoperatve pain,thereby reducing analgesic requirements in immidiate post-op period.
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Pneumoperitoneum is produced isby administration of CO2 during laproscopic surgical procedures. Both pneumoperitoneum and co2,causes adverse cardiovascular effects,this effect is attributed to increase plasma level of norepinephrine,epinephrine and activation of renin-angiotensin-aldosterone system. All these changes and reverse Trendelenburg position contribute to elevated arterial pressure,increased systemic and pulmonary vascular resistance and reduced cardiac output. Dexmedetomidine significantly reduces the release of catecholamines specially norepinephrine,tereby stabilizing the changes in arterial pressure,heart rate and cardiac output.
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Certain neurosurgical procedures require a haemodynamically stable,comfortable,sedated patient who is awake and cooperative enough to perform neuromotor and neurocognitive tests on demand. Dexmedetomidine achieves this desired neurophysiologic profile,in a dose of 0.2 to 0.5 mcg/kg/hour. There are published reports of its usage in various neurosurgical procedures like awake craniotomies,deep brain stimulation,surgery near speech areas,minimally invasive endoscopic procedures,steretactic interventions,intraoperative imaging,etc.
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Dexmedetomidine blunt hemodynamic variability during surgery and recovery,mayy exert anti-ischemic effects in the peri-operative setting and early postoperative period. Successful use of Dexmedetomidine for sedation during vascular and cardiac surgery has been reported due to its cardio-protective modulation of sympathetic tone and maintenance of myocardial oxygen supply/demand ratio with consequent less perioperative ischemia. However, patients who depend on a high level of sympathetic tone or have reduced left ventricular function(Less E.F.) might not tolerate the decrease in sympathetic tone.
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Respiratory co morbidities in morbid obesity may profoundly impact the anesthetic management of these patients. The ideal anesthetic would produce minimal respiratory depression while offering adequte pain relief. Dexmedetomidine has been used successfully in general anesthesia to reduce opoid and volatile anesthetic requirements without causing any cardiorespiratory depression and rnsuring faster,neuromuscular recovery and smooth emergence. It also significantly attentyates postoperative pain.
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An emerging application,is its role in facilitating awake fiber-optic intubation(AFOI) in difficult airway situations. Successful AFOI necssitates maintenance of a clear dry airway,with spontaneous ventilation,such that the airway is secured without any discomfort to the patient and complication like upper airway obstruction,respiratory depression and aspiration are avoided. Dexmedetomidine provides an ideal solution in critically compromised airways. Series of case reports document its efficacy in a dose of 0.5to1mch/kgasa bolus followed by infusion of 0.2 to 0.7mcg/kg/hr with no evidence of respiratory depression.

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The greater-2AR selectivity enhances the therapeutic window of Dexmedetomidine in the treatment of acute and chronic pain. Its opiate sparing effect has important implications,for the management of acute postoperative pain and chronicpain states which includes myofascial pain,neuropathic pain,disorders involving spasticity,sympathetically maintained pain such as complex regional pain syndrome(CRPS)and chrnic daily headaches. It is evolving as an adjuvant analgesic,both as intravenous and intrathecal infusion in cancer pain refractory to multiple treatment modalities.
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Pre & intraoperative i.v. Dexmedetomidine prolongs the duration of sensory block in Central Neuraxial Block and Peripheral Nerve Blocks. Postoperatively,I.V. infusion is asociated with a reduction in nausea and vomiting,reducing postoperative morbidity. Evidence suggests that neuraxial administration of Dexmedetomidine produces analgesia as efficiently as Clonidine. As a neuraxial adjuvant 2-AR agonists activate a nuumber of antinociceptive mechanisms,depending on dose and route,however the main site seems to be spinal dorsal horn.
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Experimental animal and human studies of intrathecal Dexmedetomidine as an additive to L.A. have observed dose dependent prolongation of sensory block, in motor block, duration of postoperative analgesia,allowing for a reduced dose of L.A. in high risk patients. In a few dose finding studies,investigators have used 3,5&10mcg of intrathecal Dexmedetomidine,in humans,with favourable results,along with preserved haemodynamic stability and lack of sedation.Only drawback of this drug as supplement to S.A. is increase in the duration of motor block,which may not suit for ambulatory procedures.
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Epdural Dexmedetomidine exhibits synegism with L.A..When epidural Dexmedetomidine used in conjunction with G.A.,it exhibits it potentiation of neuraxial L.A.,decrease in intraoperative anesthetic requirements,prevention of intraop.awareness,improved oxygenation and improved postop.analgesia. Its use in obstetric analgesia is being explored in view of the high lipophilicity. It is retained in the placental tissue,there by resulting in less fetal transfer and a decreased incidence of fetal bradycardia.Continous I.V. infusion has been successfullyused in laboring partureents who could not benefit from epidural analgesia.

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No neurological deficits have been reported till date in studies on both humans and animals during intrathecal/epidural use. There is some evidence of demyelinization of the oligodendrocytes in the white matter,suggesting harmful effects on the myelin sheath when given via epidural route in animal studies. More clinical studies & pathological investigations are needed to validate the efficiency and safety of the optimum intrathecal/epidural dose,for supplementation with L.A. Few clinical studies have evaluted the effect of adding Dexmedetomidine to L.A. in Peripheral Nerve Block(PNB)
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In a randomized double blind trial,shortened the onset time,prolonged the duration of block and postoperative analgesia,when added to levobupivacaine for axillary brachial plexus block. Animal studies have not shown any neurological toxicity,even at higher doses,when applied directly to sciatic nerce models. Dexmedetomidine has also been reported to improve block quality,prolong post-deflation analgesia,and decrease tourniquet pain when used as an additive to lignocaine in Intravenous Regional Anesthesia(IVRA). It is used in a dose of1mcg/kg intraarticularly during arthroscopic procedures.
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An novel theraeutic role of dexmedetomidine is its use for opoid/benzodiazepine withdrawl insedated pediatric patients during mrchanical ventilation in critical areas. It has potential for treatment for agitation and alcohol withdrawl in alcoholic patients after brain trauma,who require reliable,serial neurological testing to monitor the course of their traumatic brain injury Dexedetomidine has shown neuroprotective effecs in animal models of hypoxic-ischemic injury,making it a therapeutic option for prevention and treatment of delirium,shivering or post anesthesia emergence.
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The teratogenic effects ,have not been adquately studied,so should be used during pregnancy only if the benefits justify the risk to the fetus. The adverse effects include hypotension,bradycardia,nausea,hypoxia,dry mouth. Overdose may cause first degree or second degree atrioventricular block.By omiting or reducing the loading dose,adverse effect can be reduced No study has descibed the long termuse,but adaptive changes and withdrawl syndrome like those seen with the use of clonidine can be expected. All effects of dexmedetomidine could be antagonized by 2 adrenoreceptor antagonist Atipamezole.
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Dexmedetomidine is emerging as therapeutic agent eith an efficacious,safe profile. It has various application,with promising delivery routes. Its clinical applications in adults and children include premedication,as a part of multimodal anesthetic regimn,regional anesthesia,sedation,monitored anesthesia care,procedural sedation,prevention/treatment of emergence delirium,alcohol withdrawl,& shivering and the list continues to grow. It appears to have promising future in the field of neuroprotection,cardioprotection and renoprotection especially in children. The novel therapeutic uses of this Alpha2 AdrenoReceptor agonist can be put safely into practice .

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