ISA Thanjavur and ISA Thiruvarur invite FRIDACE Dexmedetomidine

ISA Thanjavur and ISA Thiruvarur invite – FRIDACE Dexmedetomidine Dr. S. Parthasarathy MD. , DA. , DNB, MD (Acu), Dip. Diab. , DCA, Dip. Software statistics. Ph. D ( physiology) IDRA, FICA www. painfreepartha. com

Chemistry • Dexmedetomidine hydrochloride; Dexmedetomidine HCL; • 4 -((S)-alpha, 2, 3 -trimethylbenzyl)imidazole monohydrochloride Eight times more specific for alpha 2 receptors than clonidine

Physiology Alpha 2 receptor agonist There are three types of alpha two( α 2 a, α 2 b, α 2 c) receptors α 2 a- sedation, analgesia , sympatholysis α 2 b- spinal analgesia , peripheral vasoconstriction α 2 c – modulation of cognition, sensory processing, mood changes

Pictures from the net for closed academic purpose only

Usually levo isomer is good but inverse here • Levo medetomidine – useless

How does it act ? • Αlpha 2 stimulation • • Decreased CAMP Potassium efflux Nerve hyper polarization Decreased calcium entry

Alpha 2 is presynaptic and alpha 1 is post synaptic

Pharmacokinetics • Following intravenous administration, dexmedetomidine shows rapid distribution phase with a distribution half life of six minutes and a terminal elimination half life (t 1/2) of approximately two hours • Oral ? ? But nasal and sublingual use is proved • Nasal 1 - 2 µg/kg has an onset of 20 minutes • Cytochrome p 450 glucorinidation and hydroxylation and excreted through kidneys

Dexmed Adrenergic agonists Dopamine Phenyleph Dopamine Clonidine Dobutamine Isoprenaline Oxymetazoline Noradrenaline Terbutalin norad Adrenaline Alpha 1 Ephedrine Beta Alpha 2 Beta 1 Beta 2 Ephedrine Beta 3

Clinical applications

Perioperative hemodynamics • 0. 25 – 1 µg/kg - Blunted Pressor response to intubation • Better intraop hemodynamics • No reflex tachycardia as inhalational agents • 0. 5 µg/kg blunted extubation response also • Hypotension and bradycardia are the common side effects • Used for Deliberate hypotension

Dexmedetomidine is an effective and safe agent for controlled hypotension mediated by its central and peripheral sympatholytic action.

In cardiac • Dexmedetomidine in addition to blunting the hemodynamic response to endotracheal intubation also reduces the extent of myocardial ischemia during cardiac surgery • Decrease pulmonary hypertension in MVR cases

Perioperative analgesia • 0. 8 µg/kg doses decreased morphine requirements by 60 % in major cases. • Infusion of 0. 4 µg/kg/hour decreased opioids by 66% in the 24 hour period • Superior to clonidine but duration only two hours • Nausea and vomiting less Why? ? • opioids less !!

Perioperative analgesia (continued) • Analgesic effects of Dex were associated with more incidence of postoperative bradycardia • But usually – asymptomatic • Beware of combined beta blockers – increased stroke incidence • Dexmed on chronic pain or hyperalgesia – not established

Awake fiber optic intubation • Routine midaz or opioids • Respiratory depression in compromised airways • But dexmed – OK • Loading dose with continued infusion • Sympatholysis , analgesia, sedation --- yes • But some decreased salivary secretion effect ? ? !!

Adjunct to GA • Stress reduction equivalent to epidural in some studies • When epidural is risky ? ? • Decreased dosage requirement of propofol on induction and TIVA • Decreased dosage – rocuronium

Sedation is OK ? ? • Dexmedetomidine does not cause respiratory depression. • This fact can be utilized in sedating morbidly obese patient thereby avoiding respiratory depression caused by narcotics • High dose dexmedetomidine (3 mcg/kg IV load over 10 minutes with an infusion of 1 mcg/kg/hour) has been used successfully for sedation of children undergoing MRI. ( BRADY ? )

On the CNS surgery side ? ? • Dexmedetomidine provides stable cerebral hemodynamics • NO sudden increase in ICP during intubation, extubation, and head pin insertion. • It attenuates neurocognitive impairment (delirium and agitation) allowing immediate neurological evaluation. • Some neuroprotective effects postoperative

Special • awake craniotomy for the resection of tumors or epileptic foci in eloquent areas, • the implantation of deep brain stimulators for Parkinson’s disease • No interference with neuro monitoring

Dexmeditomedine has high lipophilicity and so it passes through placenta but it disappears very fast. Cautious in pregnancy and lactation Intrathecal also – risk Vs benefit

Loco regionals - in nerve blocks • Dexmed shortens onset • Prolongs sensory and motor blockade • Duration prolonged by more than 16 hours extra with 150 mic. gm of dexmed • Not due to CNS effects or vasoconstriction • But probably hyperpolarization is the mechanism • But IV also prolongs nerve blocks !! • Hypotension and bradycardia remains

Neuraxial blockade • • 1 µg/kg – epidural – prolongs sensory and motor blockade No without major side effects Caudal additive in children – good results • 10 – 3µg single dose combining with spinal local anesthetics – similar results • IV dexmed can prolong sensory and mainly analgesic effects of spinal local anesthetics

Biers block • 0. 3µg/kg addition • Better and prolonged analgesia • Reduced local anesthetics • Possible protection from CNS and cardiac toxicity • But done and proved only in upper limbs

Postoperative period • Intra articular dexmedetomidine in patients undergoing arthroscopic knee surgery improves the quality and duration of postoperative analgesia • antihyperalgesic effect when administered locally after bilateral third molar surgery • Preemptive local infiltration dexmed for hernia surgery !! • Dexmed decreases the incidence of sevoflurane emergence delirium in pediatrics

Some potential uses ? ? • used successfully in the treatment of withdrawal from benzodiazepines, opioids, alcohol, and recreational drugs • Management of tetanus in ICU. • As an anti shivering agent. ? • Dexmedetomidine is superior to tramadol for shivering treatment, due to higher effective rate of shivering control, earlier onset of action and lesser recurrence of shivering with higher incidence of sedation and lower incidences of nausea and vomiting. However, dexmedetomidine is also associated with higher incidences of hypotension and bradycardia than tramadol • preventing ethanol induced neuro degeneration

• - Pediatric sedation • Rectal: 0. 3 -0. 5 mg/kg/dose PR 30 -45 min before procedure. • 3 mic/kg intranasal 40 minutes before for pediatric sedation

Side effects • hypotension, hypertension, bradycardia, dry mouth and nausea. • fever, rigors, cyanosis, muscle weakness. • Rarely arrhythmias, AV Block, cardiac arrest, • T-wave inversion, pulmonary edema, tachycardia, angina bronchospasm pectoris, respiratory depression, syncope, neuropathy, paresthesia, paresis, hyperkalaemia, lactic acidosis and hyperglycaemia.

Antagonist ? ? • pharmacological effects of dexmedetomidine can be reversed by α 2 -AR antagonist atipamezole, combination of dexmedetomidine and atipamezole can provide titratable form of sedation in the future. • Upto 30 mg / subject dose in humans – no major problems

Summary What is it ? Pharmacokinetics Receptors uses - hemodynamics , cvs cns , regionals analgesia sedation, pediatrics etc • Potential uses • Antagonist • •

Thank u all • Long live ISA • FRIDACE again next week