Pharmacokinetics - Neonatal Intensive Care Drug Manual

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Neonatal Intensive Care Drug Manual
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bet | 157/654 | Sana | 03.01.2022 | Hajmi | 1,5 Mb. | | #14803 |
Pharmacokinetics
Dexmedetomidine is an α2-adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2-receptors with an α2: α1 ratio of 1620:1. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2-receptors in the locus coeruleus. Hemodynamic effects include transient hypertension, bradycardia, and hypotension resulting from the drug’s peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine is rapidly distributed and is mainly hepatically metabolised into inactive metabolites by glucuronidation and hydroxylation (cytochrome P450 enzymes). A high inter-individual variability in dexmedetomidine pharmacokinetics has been described. Body size, hepatic impairment, and presumably plasma albumin and cardiac output have a significant impact on dexmedetomidine pharmacokinetics. Dexmedetomidine is eliminated mainly through biotransformation by the liver with an extraction ratio of 0.7 reported. Less than 1% is excreted unchanged with metabolites being excreted renally (95%) and faecally (4%). Direct N-glucuronidation accounts for about 34% of dexmedetomidine metabolism. An elimination half-life of 2.1–3.1 hours is reported in healthy volunteers, and 2.2 to 3.7 hours in ICU patients. The sedative effect of dexmedetomidine is concentration dependent, with plasma concentrations between 0.2 and 0.3 ng/mL resulting in significant and rousable sedation in adults, and unarousable deep sedation at plasma concentrations above 1.9 ng/mL. [2]
In neonatal pharmacokinetic studies, where 20 ventilated infants with a median PMA of 44 weeks (range, 33-61) on a median maximum dexmedetomidine infusion dose during the study period of 1.8 μg/kg/hour, younger PMA was a significant predictor of lower clearance. Infants with a history of cardiac surgery had ~40% lower clearance, and infants with PMA of 33 to 61 weeks and body weight of 2 to 6 kg, the estimated clearance and volume of distribution were 0.87 to 2.65 L/kg/hour and 1.5 L/kg, respectively.[26] Preterm neonates had lower weight-adjusted plasma clearance (0.3 vs. 0.9 L/hour/kg) and an increased elimination half-life (7.6 vs. 3.2 hours) than term neonates. Premature neonates were reported to be adequately sedated with dexmedetomidine alone, although doses up to 0.2 microgram/kg/hour were not sufficient in most term neonates.[3] In a pharmacokinetic study [4, 5] in 95 children aged 1 week to 14 years and weight 3.1 to 58.9 kg, clearance maturation increases from 18.2 L/hour/70 kg at birth in a term neonate to reach 84.5% of the mature value by 1 year of age. Children given an infusion after cardiac surgery had 27% reduced clearance compared to a population given a bolus dose. Simulation of published infusion rates that provide adequate sedation for intensive care patients found a target therapeutic concentration of between 0.4 and 0.8 microgram/L. A recommended dose regimen based on the target concentration range of 0.4–0.8 μg/L was considered safe and efficacious, and consisted of a standard loading dose 0.6 microgram/kg = 2.9 microgram/kg/hour over 10 minutes, a maintenance dose for general sedation 0.33 microgram/kg/hour for neonates and 0.4 microgram/kg/hour for 3 month infants, and a maintenance dose for postoperative cardiac infusion of 0.24 microgram/kg/hour and 0.29 microgram/kg/hour for 3 month infants. [4, 5]
In a dose escalation study in full-term neonates and infants requiring mechanical ventilation after open heart surgery, dexmedetomidine clearance was significantly diminished in full-term newborns and increased rapidly in the first few weeks of life. Typical clearance post cardiac surgery increased from 10 mL/min/kg (34 mL/min) for a full term newborn, 18.2 mL/min/kg (69 mL/min) at 2 weeks, to 18.4 mL/min/kg (77 mL/min) at 1 month. A continuous infusion of up to 0.3 μg/kg/hour in neonates and 0.75 μg/kg/hour in infants was well tolerated after open heart surgery. [27]
Conclusion: Dexmedetomidine has reduced clearance and a longer half-life in preterm compared to term infants, and term infants compared to older infants. [3-5] Whereas doses up to 0.2 microgram/kg/hour may be sufficient in most preterm neonates, infusion rates of 0.33 microgram/kg/hour for neonates and 0.4 microgram/kg/hour for 3 month infants are recommended. Lower infusion rates are recommended for infants undergoing cardiac surgery [4, 5] and with concomitant use of other sedatives or analgesics.
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