The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function

Abstract

Introduction Therapeutic hypothermia is being employed, clinically based, on its neuro-protective benefits. Both critical illness and therapeutic hypothermia significantly affect drug disposition, potentially contributing to drug-therapy and drug-disease interaction. Currently, there is limited written information of the known alterations in drug concentration and response during mild hypothermia treatment and there is a limited understanding of the specific mechanisms that underlie alterations in drug concentrations and the potential clinical importance of these changes. Areas covered A systemic review of the effect of therapeutic hypothermia on drug metabolism, disposition, and response is provided. Specifically, the clinical and preclinical evidence of the effects of therapeutic hypothermia on blood flow, specific hepatic metabolism pathways, transporter, renal excretion, pharmacodynamics and rewarming effect are reviewed. Expert Opinion Available evidence demonstrates that mild hypothermia decreases the clearance of a variety of drugs with apparently little change in drug protein binding. Recent evidence suggests that the magnitude of the change is elimination route specific. Further research is needed to determine the impact of these alterations on both drug concentration and response in order to optimize the hypothermia therapy in this vulnerable patient population.

Use of a Warming Catheter to Achieve Normothermia in Large Burns

“…1 Accord ing to the Committee on Trauma of the American 20 and reduced clearance of drugs. 21 In burn patients, hypothermia has been shown to correlate with the development of acute lung injury and is associated with increased overall morbidity and mortality. [22][23][24] The warming catheter does pose devicespecific risks.…”

Therapeutic hypothermia for stroke: Where to go?

“…The effects of hypothermia on drug metabolism vary according to the route of elimination (Zhou and Poloyac, 2011). Hypothermia inhibits enzymatic activity including that of cytochrome p450 by altering rates of tubular secretion and reabsorption (Zhou and Poloyac, 2011).…”

“…Hypothermia inhibits enzymatic activity including that of cytochrome p450 by altering rates of tubular secretion and reabsorption (Zhou and Poloyac, 2011). Reduced drug clearance has been observed for commonly used medications including vasopressors, opiates, sedatives, volatile anesthetics, neuromuscular blockers, and phenytoin (Polderman, 2009).…”

Conséquences cardiovasculaires de l’hypothermie

“…Les médicaments ayant une voie métabolique active ou une sécrétion tubulaire rénale verront leur concentration plasmatique augmentée, alors que l'hypothermie ne semble pas altérer le flux global (rénal « passif ») ou la liaison aux protéines plasmatiques [79]. Le rôle des cytochromes dans ces modifications toxicologiques semble être important [78].…”