Dexmedetomidine

dexmeditomidine

1. DR. SAI DIVYA.V JNR. CONSULTANT,MRNH DEPARTMENT OF ANESTHESIOLOGY. DEXMEDETOMIDINE

2. HISTORY It was introduced in clinical practice in the United States in 1999 and approved by the FDA only as a short-term (<24 hours) sedative for mechanically ventilated adult ICU patients. Dexmedetomidine is a more selective α 2 agonist with a 1600 greater selectivity for the α 2 receptor compared with the α 1 receptor.

3. PHYSICOCHEMICAL CHARECTERISTICS MOLECULAR WEIGHT :200.28G/MOL CHEMICAL FORMULA : C13 H16N2 SYSTEMIC NAME:(S)-4-[1-(2,3DIMETHYLPHENYLETHYL]-3H-IMIDAZOLE

4. Dexmedetomidine is the s- enantiomer of medetomidine .(which was formerly used in veternary medicine) It shows a high ratio of specificity for the α 2 receptor ( α 2 /α 1 1600 : 1) compared with clonidine (α 2 /α 1 200 : 1), making it a complete α 2 agonist. Dexmedetomidine belongs to the imidazole subclass of α 2 receptor agonists, similar to clonidine . It is freely soluble in water and has a pKa of 7.1 Available as clear isotonic solution of 100mcg/ml with 9mg of NaCl

5. METABOLISM AND PHARMACOKINETICS it undergoes almost complete biotransformation with very little unchanged form in urine and feces biotransformation involves bith direct glucorinidation and cytochrome p 450 mediated metabolism major metabolic pathways are direct N -glucoronidation to inactive metabolites,hydroxylation and N- methylation. 94% protein bound concentration ratio between whole blood and plasma is 0.66. clearence varies with hepatic impairment but slightly with renal impairment.

6. Metabolism and Pharmacokinetics Dexmedetomidine has profound effects on cardiovascular variables and may alter its own pharmacokinetics. Dexmedetomidine displays nonlinear pharmacokinetics . Its pharmacokinetics in volunteers is best described by a three-compartment model . These pharmacokinetic parameters apparently are unaltered by age or weight or renal failure, but clearance is a function of height. The elimination half-life of dexmedetomidine is 2 to 3 hours, with a context-sensitive half-time ranging from 4 minutes after a 10-minute infusion to 250 minutes after an 8-hour infusion

7. in patients with severe renal disease the sedative effect is stronger as a result of lower degree of protein binding no clinically relevant cytochrome p 450 mediated drug interactions have been found

8. PHARMACOLOGY Dexmedetomidine is a nonselective α 2 agonist. Alpha 2 adrenoreceptors are membrane-spanning G proteins . Intracellular pathways include inhibition of adenylate cyclase and modulation of ion channels. Three subtypes of α 2 adrenoreceptors have been described in humans: α 2A , α 2B , and α 2C Postsynaptic located α 2 adrenoreceptors in peripheral blood vessels produce vasoconstriction, whereas presynaptic α 2 adrenoreceptors inhibit the release of norepinephrine , potentially attenuating the vasoconstriction. The overall response to α 2 adrenoreceptors agonists is related to the stimulation of α 2 adrenoreceptors located in the CNS and spinal cord. These receptors are involved in the sympatholysis , sedation, and antinociception effects of α 2 adrenoreceptors .

9. PHYSIOLOGY OF ALPHA2RECEPTORS

10. INDICATIONS As a premedicant . for monitored anesthesia care. Sedation in pediatric patients. Pre medicant in ophthalmic surgery. For maintenance of anesthesia. awake craniotomies with functional testing and electrocorticography . anesthetic adjunct or sedative agent for patients who are susceptible to narcotic-induced respiratory depression or sleep apnea. titratable sedation, sympatholysis , and analgesia without significant respiratory depression. Originally approved as a sedative in the ICU.

11. EFFECTS ON CNS

12. SEDATION ACTION ON ALPHA 2 RECEPTORS IN LOCUS COERULEUS Analgesic action by acting on receptors at Lc and at spinal cord Decreased action of projections of LC to VLPO nucleus So there is release of GABA and galantin release in tuberomamillary nucleus Sedative effect through endogenous sleep promoting pathways thus generating natural sleep pathways

13. patients have been described as being very easy to wake up and having the ability to follow commands and cooperate while being intubated. this allows for “daily wake up “ tests to be done in a safe fashion. the number of patients experiencing delirium in the ICU is significantly lower compared with propofol or lorzepam or with midazolam.

14. Analgesia The primary site of analgesic action is thought to be the spinal cord . primarily mediated through alpha 2c and 2a receptors in dorsal horn . anaalgesia is due to inhibition of pronociceptive transmitters like substance p and glutamate Systemic use of dexmedetomidine shows narcotic sparing . systemic analgesic effects have been attributed to the confounding sedative effects. The analgesic effect of dexmedetomidine has been compared with remifentanil , dexmedetomidine was less effective in reducing pain than remifentanil .

15. ` advantageous in patients who are prone to postopertaive hypoventialtion dexmed also reduces the MAC of inhaled anasthetics.

16. Central Nervous System Protection and Other Central Nervous System Effects reduces cerebral necrosis and improves neurologic outcome. dexmedetomidine reduced the intracerebral catecholamine outflow during injury and resulted in less neural tissue damage with better neurologic outcome. The neuroprotection may be attributed to modulation of pro apoptotic and antiapoptotic proteins . reduction of the excitatory neurotransmitter glutamate .

17. has a major role in neuro physiological monitoring cortical evoked potential amplitudes abd latencies were minimally affected when used intraoperatively

18. Effects on the Respiratory System reduces minute ventilation . but retains the slope of the ventilatory response to increasing carbon dioxide. no change in arterial oxygenation or pH. Dexmedetomidine also exhibited a hypercarbic arousal phenomenon , which has been described during normal sleep and is a safety feature.

19. Effects on the Cardiovascular System decreased heart rate, decreased systemic vascular resistance and indirectly decreased myocardial contractility, cardiac output, and systemic blood pressure. The hemodynamic effects of a bolus of dexmedetomidine have shown a biphasic response . The incidence of hypotension and bradycardia may be related to the administration of a loading dose . Omitting the loading dose or not giving more than 0.4 µg/kg reduces the incidence of hypotension, or makes it less pronounced. Giving the loading dose over 20 minutes also minimizes the transient hypertension. Generally, these episodes resolved spontaneously or were readily treated without adverse outcome by anticholinergics .

20. INTENSIVE CARE UNIT Dexmedetomidine has advantages over propofol for sedation in mechanically ventilated postoperative patients. Heart rate was slower in the dexmedetomidine group, whereas MAP was similar. The Pa o 2 /F io 2 ratio was significantly higher in the dexmedetomidine group. Time to extubation after discontinuation of the infusion was similar at 28 minutes. Patients receiving dexmedetomidine seemed to have greater recall of their stay in the ICU, but all described this as pleasant overall. Several other studies have confirmed the decreased requirement for opioids (>50%) when dexmedetomidine is used for sedation compared with propofol or benzodiazepines.

21. For sedation in the ICU, loading doses of 0.5 to 1 µg/kg have been used. Omitting the bolus or giving the lower dose has been associated with fewer episodes of severe bradycardia and other hemodynamic perturbations. Infusion rates of 0.1 to 1 µg/kg/hr are generally needed to maintain adequate sedation. Delirium in the ICU is a risk factor for increased length of stay and increased mortality.

22. AS ADJUVANTS frequently used as a adjuvant in central or peripheral neural blockade. as a adjuvant in the range of o.5 mcg/kg to 1mcg/kg many studies showed the intensification and foremost prolongation of sensory blockade

23. other uses as premedicant in the doses of 0.33 to 0.67mcg/kg used to reduce the laryngoscopy response used as a total IV anaesthesia , given in the dose range of about 10 times the dose for sedation employed for addiction treatment- rapid opiod detoxification ,cocaine withdrawal,benzodiazepine and opioid tolerance useful adjumct in awake fiberoptic intubation