Introduction: Initially, the clinical application of lipid emulsions (LEs) was parenteral nutrition. Since 2006, LEs have been widely used as an antidote for various intoxications with lipophilic drugs. Despite the widespread use of LEs, there is insufficient information regarding their pharmacokinetics and mechanism of antidote action. That is why detailed knowledge of their pharmacokinetic parameters and complex mechanism of action is particularly important.
Aim: The aim of the study is to make a detailed literature analysis of the pharmacokinetics and of all putative mechanisms of antidote action of LEs.
Materials and Methods: Over 100 literature sources were studied in various databases, including PubMed, ScienceDirect, Research Gate, Google Scholar, and others. These include clinical cases (over 40), laboratory animal experiments (over 20), and medical guidelines and protocols (over 30).
Results: Lipid emulsions have good absorption and 100% bioavailability after intravenous administration. They do not bind to plasma proteins. Lipid emulsions undergo hepatic metabolism similar to chylomicrons. Their plasma half-life is ±10 minutes. The osmolarity of LEs is 270-345 mosm/l. Lipid emulsions cross the blood-brain barrier but do not cross the placental barrier. They are mainly removed from skeletal muscles (47%), splanchnic organs (25%), myocardium (14%) and subcutaneous tissue (13%). LD50 in rats is 67.72 mL/kg and in dogs 135 mL/kg. The maximum single harmless dose for a person (70 kg) is 4000–7000 mL/24 h. The most widely advocated mechanism of non-antidote action of LEs is the lipid uptake phenomenon.
Conclusion: Evidence collected from numerous clinical cases and laboratory experiments shows high efficiency and great therapeutic safety. Lipid emulsions are distinguished by their ability to dissolve and absorb lipophilic xenobiotics. In the blood, LEs prevent their binding to target receptors or, through the concentration gradient, extract them from critical organs, such as the brain and heart. Lipid emulsions have a cardioprotective effect as energy donors for the myocardium. They also exhibit vasoconstriction, which is important for overcoming toxic shock. Therefore, LEs represent an important therapeutic tool in the fight against intoxications with lipophilic drugs, such as anesthetics, psychopharmacology, and cardiovascular drugs.
Herman R, Btaiche I, Teitelbaum DH. Nutrition support in the pediatric surgical patient. Surg Clin North Am. 2011;91(3):511-41. doi: 10.1016/j.suc.2011.02.008.
Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB. Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology. 2006;105(1):217-8. doi: 10.1097/00000542-200607000-00033.
AAGBI Safety Guideline. Management of severe local anaesthetic toxicity. 2010. Available from: https://www.aagbi.org/sites/default/files/la_toxicity_2010_0.pdf
Intralipid. Product monograph. Fresenius Kabi Canada Ltd. 165 Galaxy Blvd, Suite 100 Toronto, ON M9W 0C8. Date of Revision: May 11, 2017. Submission Control No.: 203141. Available from: https://pdf.hres.ca/dpd_pm/00039298.PDF.
Carpentier YA, Dupont IE. Advances in intravenous lipid emulsions. World J Surg. 2000; 24: 1493–7. doi: 10.1007/s002680010267.
Spray JW. Review of intravenous lipid emulsion therapy. J Infus Nurs. 2016;39(6):377-80. doi: 10.1097/NAN.0000000000000194.
Adolph M, Heller AR, Koch T, Koletzko B, Kreymann KG, Krohn K, et al. Lipid emulsions - Guidelines on Parenteral Nutrition, Chapter 6. Ger Med Sci. 2009;7:Doc22. doi: 10.3205/000081.
Van den Brom CE, Bulte CS, Loer SA, Bouwman RA, Boer C. Diabetes, perioperative ischaemia and volatile anaesthetics: consequences of derangements in myocardial substrate metabolism. Cardiovasc Diabetol. 2013; 12:42. doi: 10.1186/1475-2840-12-42.
Carpentier YA, Deckelbaum RJ. In vivo handling and metabolism of lipid emulsions. World Rev Nutr Diet. 2015;112:57-62. doi: 10.1159/000365431.
Kaijser L, Rössner S. Removal of exogenous triglycerides in human forearm muscle and subcutaneous tissue. Acta Med Scand. 1975;197(4):289-94. doi: 10.1111/j.0954-6820.1975.tb04919.x.
Kayipmaz AE, Gulalp B, Benli S, Sezgin N, Dagdeviren A, Helvacioglu F, et al. The effects of a combined treatment of lipid emulsion and conventional therapy on tissues of rats poisoned with methyl parathion. HealthMED. 2014;8 (4):433–41.
Kayipmaz AE, Kavalci C, Bayraktar N, Bacanli D, Aydos TR, Giray TA, et al. Treatment with lipid emulsion decreases high levels of phenytoin in rats. Biomed Res. 2017;25-9.
Stammers J, Stephenson T, Colley J, Hull D. Effect on placental transfer of exogenous lipid administered to the pregnant rabbit. Pediatr Res. 1995;38(6):1026-31. doi: 10.1203/00006450-199512000-00032.
Hiller DB, Di Gregorio G, Kelly K, Ripper R, Edelman L, Boumendjel R, et Reg Anesth Pain Med. 2010;35(2):140-4. doi: 10.1097/aap.0b013e3181c6f5aa.
Kehayova G, Zlateva S, Marinov. Dosage of lipid emulsions as an antidote to lipid-soluble substances. Folia Med, 2021;63(6):913-8. doi: 10.3897/folmed.63.e59216.
Kehayova G, Zlateva S, Zgurova N. Biochemical and histological analysis of rats treated with Verapamil overdose and resuscitated with lipid emulsion. East Eur Sci J. 2020;10(62),part 1:4-8. doi: 10.31618/EESA.2782-1994
Weinberg G, Ripper R, Feinstein D, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine induced cardiac toxicity. Reg Anesth Pain Med. 2003;28:198–202. doi: 10.1053/rapm.2003.50041.
Weinberg GL, Ripper R, Murphy P, Edelman LB, Hoffman W, Strichartz G, et al. Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart. Reg Anesth Pain Med. 2006;31:296–303. doi: 10.1016/j.rapm.2005.02.011.
Van de Velde M, Wouters PF, Rolf N, Van Aken H, Flameng W, Vandermeersch E. Long-chain triglycerides improve recovery from myocardial stunning in conscious dogs. Cardiovasc Res. 1996;32(6):1008–15. doi: 10.1016/s0008-6363(96)00165-4.
Eledjam JJ, de La Coussaye JE, Brugada J, Bassoul B, Gagnol JP, Fabregat JR, et al. In vitro study on mechanisms of bupivacaine-induced depression of myocardial contractility. Anesth Analg. 1989;69(6):732–5.
Kehayova G, Zlateva S, Marinov P, Dimitrova S. Lipid emulsion reduces complications and mortality in patients with severe drug intoxications. J IMAB. 2021;27(4):67-9. doi: 10.5272/jimab.2021Supplement1.
Picard J, Meek T. Lipid emulsion to treat overdose of local anaesthetic: the gift of the glob. Anaesthesia. 2006;61(2):107-9. doi: 10.1111/j.1365-2044.2005.04494.x.
Huang J, Xian H, Bacaneand M. Long-chain fatty acids activate calcium channels in ventricular myocytes. Proc Natl Acad Sci U S A. 1992;89(14):6452–6. doi: 10.1073/pnas.89.14.6452.
Bania TC, Chu J, Perez E, Su M, Hahn IH. Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium, and saline. Acad Emerg Med. 2007;14(2):105–1. doi: 10.1197/j.aem.2006.10.094.
García-Sáinz JA, Vázquez-Prado J, Del Carmen Medina L. Alpha 1-adrenoceptors: function and phosphorylation. Eur J Pharmacol. 2000;389(1):1-12. doi: 10.1016/s0014-2999(99)00896-1.
Murakami K, Whiteley MK, Routtenberg A. Regulation of protein kinase C activity by cooperative interaction of Zn2+ and Ca2+. J Biol Chem. 1987;262(29):13902-6.
Davda RK, Chandler L. Protein kinase C modulates receptor-independent activation of endothelial nitric oxide synthase 1. Eur J Pharmacol. 1994;266(3):237-44. doi: 10.1016/0922-4106(94)90132-5.
Rahman M, Wright JT, Douglas JG. The role of the cytochrome P450-dependent metabolites of arachidonic acid in blood pressure regulation and renal function: a review. Am J Hypertens. 1997;10(3):356–65. doi: 10.1016/s0895-7061(96)00381-0.
Hadley KB, Ryan AS, Forsyth S, Gautier S, Salem N Jr. The essentiality of arachidonic acid in infant development. Nutrients. 2016;8(4):216. doi: 10.3390/nu8040216.
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