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Nine Adrenoceptors:

Nine Adrenoceptors Alpha-1a, Alpha-1b and Alpha-1d Beta-1, Beta-2, Beta-3 Alpha-2a, Alpha-2b ,Alpha-2c, Alpha-2d

a2-adrenoceptorS :

a 2 -adrenoceptorS Found central and peripheral nervous system. Found both pre- and postsynaptically Presynaptic a 2 receptors inhibit the release of noradrenaline and thus serve as an important receptor in the negative feedback control of noradrenaline release. Postsynaptic a 2 receptors are located on liver cells, platelets, and the smooth muscle of blood vessels. Activation of these receptors causes platelet aggregation , and blood vessel constriction.

Alpha-Adrenoceptor Agonists:

Alpha- Adrenoceptor Agonists Norepinephrine Epinephrine Dopamine Tizanidine Clonidine MPV-2426 Mivazerol Guanfacine Guanabenz Medetomidine Dexmedetomidine Alpha 2 Alpha 1

Alpha-2 Agonists:

Alpha-2 Agonists N N H N Cl Cl Clonidine CH 3 CH 3 N N CH 3 H Dexmedetomidine

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A lpha 2A adrenoceptor subtypes appears to couple in an inhibitory fashion to the L-type calcium channel in the locus coeruleus I n the vasculature, the alpha 2B adrenoceptor subtype couples in an excitatory manner to the same effector mechanism .

Hemodynamic effects:

Hemodynamic effects Combination of effects mediated by: Reduction of central SNS activity (alpha-2a) Reduction of presynaptic NE release (alpha-2a and c) Stimulation of VSM cells (alpha-2b) Stimulation of endothelium (alpha-2b) Stimulation of central imidazoline receptors Some vagomimetic activity

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In the heart , the dominant action of alpha-2 agonists is a decrease in tachycardia (through block of the cardio-accelerator nerve) and bradycardia (through a vagomimetic action ). In the peripheral vasculature there is both a vasodilatory action via sympatholysis and vasoconstriction mediated through the receptors in the smooth muscle cells . The mechanism for both the anti-shivering and diuretic actions have yet to be firmly established.


cns The site for the sedative action is in the locus ceruleus of the brainstem principal site for the analgesic action PERIPHERAL SPINAL SUPRASPINAL . M ore co-operative and communicative T he utility of alpha-2 agonists in diagnostic and/or therapeutic settings in which a state of “conscious-sedation” is desirable & can be readily reversible

Titratable form of hypnotic-sedation :

Titratable form of hypnotic-sedation Reversal of the sedative and sympatholytic effects of dexmedetomidine with a specific alpha2-adrenoceptor antagonist atipamezole : a pharmacodynamic and kinetic study in healthy volunteers . Scheinin H et al- Anesthesiology 1998; 89:574-84


shivering E lective ENT surgery under GA the incidence of postoperative shivering 40% E liminated by administering clonidine 1.5 mcg/kg before emergence Intravenous clonidine (1 mcg/kg) reduced the incidence of shivering in patients undergoing knee arthroscopy under epidural anesthesia


PERIOPERATIVE MYOCARDIAL ISCHEMIA Effect of Perioperative sympatholysis on hemodynamic stability and myocardial ischemia P lacebo-controlled dose-ranging study of 300 patients experiencing perioperative sympatholysis with mivazerol , intraoperative myocardial ischemia and postoperative tachycardia were significantly reduced McSPI -EUROPE Research-Anesthesiology 1997; 86:346-63 Group-

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a 2 A ? ? a 2 A a 2 C a 2 A a 2 A Anxiolysis a 2 B a 2 B X a 2 B X

Effects of Alpha-2 Agonists :

Effects of Alpha-2 Agonists Endocrine  NE release  insulin release  cortisol release  GH release Baroreflexes stay intact (reset) Normal response to vasoactive drugs Attenuates stress response

Effects of Alpha-2 Agonists :

Effects of Alpha-2 Agonists No effect on ICP Reduces IOP No effect on relaxants Prolongs local anesthetic action Decreases metabolism Decreases oxygen consumption

Effects of Alpha-2 Agonists:

Effects of Alpha-2 Agonists Dry mouth (awake fibers) Decreases bowel motility Decreases psychomotor performance Not amnestic Slows EEG Prevents opioid induced rigidity Neuro /cardiac protection?

Side Effects:

Side Effects Sinus pause/arrest Orthostatic hypotension/Rebound hypertension on withdrawal Dry mouth Vasoconstriction

Clonidine Vs Dexmedetomidine:

Clonidine Vs Dexmedetomidine Clonidine Selectivity: 2:1 200:1 t1/2  8 hrs1 PO,IV,patch,epidural Antihypertensive Analgesic adjunct Less cost 19 Dexmedetomidine Selectivity:  2 : 1 1620:1 t 1/2  2 hrs Intravenous Sedative-analgesic Primary sedative More cost




CLONIDINE C 9 H 9 Cl 2 N 3


CLONIDINE Pharmacokinetic data Bioavailability 75-95% Protein binding 20-40% Metabolism Hepatic to inactive metabolites Half-life 12-33 hours Excretion urine (40-50%)


CLONIDINE--INDICATIONS Antihypertensive drug Neuropathic pain Opioid , alcohol and nicotine detoxification Sleep hyperhidrosis Anxiety and panic disorder Attention-deficit hyperactivity disorder (ADHD) Insomnia Relief of menopausal symptoms. Tourette syndrome Migraine Restless Legs Syndrome

Clonidine Mechanism of action:

Clonidine Mechanism of action The hypotensive effect Agonist action on presynaptic α-2 receptors , Down-regulator on the amount of norepinephrine released in the synaptic cleft Clonidine binds to imidazoline receptors with a much greater affinity than α-2 receptors. Agonism on the I 1 -receptor ( imidazoline receptor ), which mediates the sympatho -inhibitory actions of imidazolines to lower blood pressure. stimulating α 2 receptors in the brain, which decreases cardiac output and peripheral vascular resistance , lowering blood pressure


CLONIDINE -ANALGESIA Direct inhibitory effects of α2-AR agonists on the conduction of Aδ and C sensory fibers inhibition of I h ( hyperpolarization -activated) currents and (perhaps) inhibition of tetrodotoxin -resistant Na + channels accounts for the potentiation of the intensity and duration of perineural local anesthetics.

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Dexmedetomidine :

Dexmedetomidine Dextro (s) isomer of medetomidine Introduced 1999 Approved for short term sedation by FDA –USA 27

Dexmedetomidine :

Dexmedetomidine Dextro (s) isomer of medetomidine Introduced 1999 Approved for short term sedation by FDA –USA 28

Dexmedetomidine :

Dexmedetomidine An intravenous anesthetic agent Selective α 2 receptor agonist. ( 2 : 1 1620:1) Provides -Sedation - Anxiolysis -Analgesia 29

Dexmedetomidine :

Dexmedetomidine No respiratory depression. Mild antihypertensive effects Decrease the need for other analgesic medications such as opioids 30

Mechanism of Action of Dexmedetomidine:

Mechanism of Action of Dexmedetomidine 31 NE release decreased Binding on alpha2 receptor Inhibit Firing rate & Substance P release SEDATION, SYMPATHOLYSIS ANALGESIA ANALGESIA


PHARMACOLOGICAL POFILE Rapid redistribution: 6 min Elimination half-life: 2 h Protein binding: 94% Metabolism: biotransformation in liver to inactive metabolites + excreted in urine No accumulation after infusions 12-24 h Pharmacokinetics similar in young adults + elderly 32

Mechanism for the Hypnotic Effect:

Mechanism for the Hypnotic Effect Hyperpolarization of locus ceruleus neurons –  2A -Adrenoreceptor subtype Activation of K + channels Inhibition of Ca ++ channels Inhibition of adenylyl cyclase  Firing rate of locus caeruleus neurons  Activity in ascending noradrenergic pathway

Difference from other sedatives:

Difference from other sedatives Patients sedated, but, arousable , alert, and to respond without uncomfortable They may quickly return to sedation again Even if the elimination half-life of DMET is short (i.e., 2-3 hours), the analgesic-sparing effect observed after a preoperative or an intraoperative administration usually lasts up to 24 hours, with the anxiolytic , sedative, and thymoanaleptic properties implicated as being partly responsible for this effect 34

Hemodynamic effects of Dexmedetomidine:

Hemodynamic effects of Dexmedetomidine Reduces sympathetic activity-reduction in HR & BP No rebound effects 35

Respiratory effects of Dexmedetomidine:

Respiratory effects of Dexmedetomidine NO RESPIRATORY DEPRESSION 36 A Comparison of the Sedative, Hemodynamic, and Respiratory Effects of Dexmedetomidine and Propofol in Children Undergoing Magnetic Resonance Imaging Analg -Anesthesia july 2006


SPECIAL CONSIDERATIONS Hypovolemic patients With other vasodilators or negative chronotropic agents dexmedetomidine have an additive effect With renal or hepatic impairment, metabolites may accumulate and dose reductions may be necessary 37


Contraindications Patients with pre-existent severe bradycardia and related bradydysrhythmias (advanced heart block) Patients with impaired ventricular functions (ejection fraction <30%). Infusion over 24 hours? In obstetric procedures , cesarean section deliveries ? 38


DOSAGE 2 ml (200µgs) +48 ml NS Loading dose -0.5µg-1µg/kg over 10 min (36-72 ml /hr) Maintenance -0.3µg-0.7µg/kg/hr[4-9ml/hr] Titration ±0.1µg/kg/hr.-1.25ml/hr 39

Administration of Dexmeditomidine:

Administration of Dexmeditomidine Loading dose 1µg/kg 0.5ml[50µg] diluted as10ml ×10min. Maintenance 0.3-0.6µg/kg/hr 1.5ml[150µg] diluted in 500ml NS solution conc-0.3µg/ml infusion-16 to32drops/min Recovery 10-12mins after cessation. 40

Uses of Dexmeditomidine:

Uses of Dexmeditomidine Bariatric surgery Sleep apnea patients Craniotomy: aneurysm, AVM [hypothermia] Cervical spine surgery Off-pump CABG Vascular surgery Thoracic surgery 41

Uses of Dexmeditomidine:

Uses of Dexmeditomidine Conventional CABG Spine surgery, evoked potentials Head injury Burn Trauma Alcohol withdrawal Awake intubation 42

Clinical Uses of Dexmeditomidine:



SEDATIVE ICU sedation. Procedural sedation -gynecological -urological -burns patients -pediatric patients Sedation during RA OBESE,OSA Patients 44


SEDATIVE As sole sedative during percutaneous carotid artery stenting in a patient with severe chronic obstructive pulmonary disease j p cata; e folch minerva anestesiologica     volume:  75     issn:  1827-1596 publication date:  2009 nov 45


SEDATIVE Preservation of arousability Respiratory-sparing properties -safer conduct of AWAKE FIBEROPTIC INTUBATIONS in difficult airway cases. Vol. 17, no. 1, 2007 international traumacare (ITACCS) 46 FIBROPTIC INTUBATION


ENT SURGERIES Analgesia, adequate sedation and surgical comfort without adverse effects for patients undergoing FESS under LA European Journal of Anaesthesiology : January 2008 - Volume 25 - Issue 1 - p 22-28 47


MONITORED ANESTHESIA CARE Effective baseline sedative for a broad range of surgical procedures Better patient co operation Less opioid requirements Less respiratory depression than midazolam and fentanyl Dr. Keith A. Candiotti, department of anesthesiology, perioperative medicine and pain management, university of miami - Anes -anal may2009 48


PREMEDICATION IV 0.3 - 0.6ug/kg 15mins prior surgery IM 2.5ug/kg 45-90mins prior Effective Stress attenuation Reduces thiopentone doses(±30%) *Miller 7 th edition 49


STRESS ATTENUATION Preoperative a single dose(1µg/kg) result in progressive increases in sedation Blunt the haemodynamic responses during laryngoscopy Reduce opioid and anaesthetic requirements Decrease blood pressure and heart rate as well as the recovery time after the operation Possess neuroprotective effects and attenuates neurocognitive impairment (mainly delirium and agitation) following anesthesia Drugs in R& DVolume 7, Number 1, 2006 , pp. 43-52(10) 50


DMET--EXTUBATION In children undergoing tonsillectomy, the use of an intraoperative infusion of DMET reduced the frequence of severe emergence agitation in comparison with an intraoperative infusion of fentanyl . Patel A, Davidson M, Tran MC, Quraishi H, Schoenberg C, Sant M, Lin A, Sun X: Dexmedetomidine infusion for analgesia and prevention of emergence agitation in children with obstructive sleep apnea syndrome undergoing tonsillectomy and adenoidectomy. Anesth Analg . 2010, 111 :1004–10


STRESS ATTENUATION A bolus dose of 1μg/kg over 10 minutes, prior to administration of reversal provided hemodynamic stability associated with extubation D. Jain, R. Khan & M. Maroof The Internet Journal of Anesthesiology. 2009 Volume 21 Number 1 52


ANALGESIC Intravenous Adjuvant in epidural Intra articular IVRA 53


ANALGESIC The primary site of analgesic action is thought to be the spinal cord Both supra spinal and spinal, modulate the transmission of nociceptive signals in the CNS Systemic use of dexmedetomidine shows narcotic sparing Analgesic property similar to remifentanil 54

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Addition of DMET to lidocaine for intravenous regional anesthesia improves the quality of intraoperative anesthesia & Intra- articular administration of DMET decreases the need for postoperative analgesics after arthroscopic knee surgery Al- Metwalli RR, Mowafi HA, Ismail SA, Siddiqui AK, Al- Ghamdi AM, Shafi MA, El- Saleh AR: Effect of intra- articular dexmedetomidine on postoperative analgesia after arthroscopic knee surgery. Br J Anaesth . 2008, 101 :395–9


AS ADJUVANT Intraoperative infusion of dexmedetomidine reduces perioperative & post op analgesic requirements Dr. Alp Gurbet , Uludag , Department of Anesthesiology and Reanimation, University Faculty of Medicine, GorukleCAN J ANESTH 2006 / 53: 7 / pp 646–652 56


ADJUVANT TO REGIONAL ANAESTHESIA IV administration- prolongs the sensory and motor blocks of bupivacaine spinal analgesia with good sedation effect and hemodynamic stability Mahmoud Al-Mustafa, MD, Department of Anesthesia and Intensive Care, Jordan University Hospital, M.E.J. ANESTH 20 (2), 2009 Pre- and intraoperative DMET prolongs the duration of the sensory block of local anesthetics during spinal anesthesia and peripheral nerve block Kaya FN, Yavascaoglu B, Turker G, Yildirim A, Gurbet A, Mogol EB, Ozcan B: Intravenous dexmedetomidine , but not midazolam , prolongs bupivacaine spinal anesthesia. Can J Anaesth . 2010, 57:39–45 57


IV DMET AS ADJUANT ? Postoperatively, intravenous DMET infusion as an adjunct to epidural analgesia allows for better pain control and reduces epidural analgesic consumption after major surgery Akin S, Aribogan A, Arslan G: Dexmedetomidine as an adjunct to epidural analgesia after abdominal surgery in elderly intensive care patients: A prospective, double-blind, clinical trial. Curr Ther Res Clin Exp . 2008, 69 :16–28


DMET-LABOUR ANALGESIA ? Continuous intravenous DMET infusion has been successfully used as an adjunct to unsatisfactory analgesia by systemic opioids in laboring parturients who could not benefit from epidural analgesia High lipophilicity , DMET is retained in placental tissue and passes less readily than clonidine into the fetal circulation and thereby is less susceptible to cause harmful fetal bradycardia . Abu- Halaweh SA, Al Oweidi AK, Abu- Malooh H, Zabalawi M, Alkazaleh F, Abu-Ali H, Ramsay MA: Intravenous dexmedetomidine infusion for labour analgesia in patient with preeclampsia. Eur J Anaesthesiol . 2009, 26 :86–7


ADJUVANT TO REGIONAL ANAESTHESIA 5 μg with spinal bupivacaine in surgical procedures produces prolongantion of duration & better quality of spinal analgesia. American Journal of Applied Sciences 6 (5): 882-887, 2009 60


ADJUVANT TO REGIONAL ANAESTHESIA Addition of dexmedetomidine to LA in IVRA improve the quality of anaesthesia and decreased analgesic requirement Enhances local anesthetic action via alpha 2A receptors European journal of anestheiology (2005), 22 : 447-451 61


AS SOLE ANESTHETIC Awake Thyroidectomy Awake Craniotomy, Laminectomy Awake Laryngoplasty Surgeries for Tracheomalacia Militory med jan 2009 Journal of Clinical Anesthesia - Volume 21, Issue 6 (September 2009 Journal of Clinical Anesthesia - Volume 21, Issue 6 (September 2009 Chicago, IL 60612, USASurgical Neurology 63 (2005) 114–117 62


NON ANESTHETIC USES Opioid/BZD withdrawl Alcohol withdrawl Sedative in sleep deprived patients Antishivering 63

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