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

Introduction: Therapeutic hypothermia is being employed clinically due to its neuro-protective benefits. Both critical illness and therapeutic hypothermia significantly affect drug disposition, potentially contributing to drug-therapy and drug-disease interactions. Currently, there is limited information on 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 function, renal excretion, pharmacodynamics and the effects during rewarming 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 therapeutic hypothermia in this vulnerable patient population.