Cardiac Depression Induced by Cocaine or Cocaethylene Is Alleviated by Lipid Emulsion More Effectively Than by Sulfobutylether‐β‐cyclodextrin

Abstract

Objectives Cocaine intoxication leads to over 500,000 emergency department visits annually in the USA and ethanol co-intoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-β-cyclodextrin (Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion which exhibits multi-modal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. Methods For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a non-recirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure (LVDP), maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (−dP/dtmax), rate-pressure product (RPP = heart rate*LVdevP), and line pressure were monitored continuously during the experiment. A dose-response to cocaine (10, 30, 50, and 100 μM) and cocaethylene (10, 30, 50 μM) was generated in the absence or presence of either 0.25% lipid emulsion, or sulfobutyl-β-cyclodextrin. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. Results Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and −dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. Sulfobutyl-β-cyclodetrin alone evoked a mild cardio-depressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 μM; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). Conclusions A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart whil...

Effect of Intravenous Lipid Emulsion on Clozapine Acute Toxicity in Rats

“…Investigations and case reports about this novel benefit of ILE result in adding it into Guidelines for the Management of Severe Local Anesthetic Toxicity [4–6]. ILE has been shown to have positive impacts toxicity resulted in lipophilic drugs overdose through some case reports and animal studies [7, 8]. Acute antipsychotic drug poisoning is one of the most important reasons for referring to the hospital [9, 10].…”

The Mechanisms Underlying Lipid Resuscitation Therapy

“…Cocaine, cocaethylene, 39 and bupivacaine (unpublished data from the same set of experiments as the prior citation) all inhibit CACT in an uncompetitive manner, and thus, increasing the fatty-acid substrate concentration cannot completely overcome the inhibition of mitochondrial uptake. In an intact rat model of bupivacaine toxicity, cardiac output does not recover until myocardial drug concentrations fall below channel-blocking (and CACT blocking) thresholds 9 (Fig.…”

“…34,37 The reduction in ATP production results from less fatty-acid oxidation because bupivacaine (and other local anesthetics) block fatty-acid transport into the mitochondria via inhibition of carnitine acylcarnitine translocase (CACT). 38, 39 Other studies indicate that bupivacaine inhibits respiratory chain complexes 1 and 3, leading to increased reactive oxygen species (ROS) production. 40 Supplementation of rabbit isolated atria with ATP overcomes the inhibition of contractility produced by bupivacaine, leading some to hypothesize that a reduction in ATP is the primary driver of toxicity in vivo.…”

Insulin Signaling in Bupivacaine-induced Cardiac Toxicity

“…Further, local-anesthetics inhibit mitochondrial carnitine exchange in experimental models 37,38 and supplementation of ATP can overcome bupivacaine toxicity in myocardial cells 39 . Beyond energy production, a number of clinical and experimental observations comport with the conclusion that local anesthetics modify insulin signaling.…”