Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion

Abstract

Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

Confusion About Infusion: Rational Volume Limits for Intravenous Lipid Emulsion During Treatment of Oral Overdoses

“…The need for lipemic plasma is based on the accumulating evidence that intravenous lipid emulsion functions both as a scavenging agent to accelerate redistribution of the offending drug [22][23][24][25][26] and as a direct inotrope to improve cardiovascular performance. 22,[27][28][29] The latter mechanism is consistent with the observation that small-volume infusions (40 mL/hour) of 20% Intralipid elevate blood pressure in healthy patients while only moderately increasing triglyceride concentrations.…”

“…The need for lipemic plasma is based on the accumulating evidence that intravenous lipid emulsion functions both as a scavenging agent to accelerate redistribution of the offending drug [22][23][24][25][26] and as a direct inotrope to improve cardiovascular performance. 22,[27][28][29] The latter mechanism is consistent with the observation that small-volume infusions (40 mL/hour) of 20% Intralipid elevate blood pressure in healthy patients while only moderately increasing triglyceride concentrations. [30][31][32] In accordance with these assumptions, we used a physiologically based pharmacokinetic-pharmacodynamic model that has been repeatedly back-tested against physiologic data 22,28,33 to estimate a rational infusion regimen needed to maintain a modestly lipemic plasma.…”

Intralipid in acute caffeine intoxication: a case report

“…ILE may have carried the stimulant drug from the heart and brain to less well-perfused organs (scavenging effect), and then once the concentration of caffeine was sufficiently low, ILE may have acted as a tonic to the depressed heart. Recent studies have suggested that ILE may act as a 'shuttle' to move drugs around the body-and not as a 'sink' that captures and isolates drugs [14][15][16].…”

Intravenous Fat Emulsion (IFE) Improvement of Qt-Interval in Tricyclic Antidepressant Overdose

“…Finally, free fatty acids from the lipids provide a supportive energy source throughout detoxification. 13 These mechanisms of action help us understand how IFE supports cardiac function. However, this proposal of mechanism hasa few caveats when discussing its use specifically in TCA overdose.…”

“…The research undertaken and reviewed by Fettiplace et al 13 looked primary at bupivacaine, a long-acting anesthetic. Bupivacaine acts primary on voltage-gated sodium channels while TCAs have multiple cellular targets, thus their mechanism of toxicity is primarily different.…”