The Structure of Bupivacaine and How it Relates to Cardiotoxicity and

Lipid RescueBy: Sean Zajdel SRNA

Disclaimer

• Conflict of Interest: None

• I have not received any compensation from anyone associated with Intralipid or any other lipid emulsion or pharmaceutical company for this presentation.

Objectives

• Describe the properties of the chemical structure of bupivacaine

• Explain the potential reasons bupivacaine is associated with increased rates of cardiotoxicity

• Describe the most current theorized mechanism of lipid rescue and how it relates to the properties of bupivacaines chemical structure

Why is this a problem?Medication Amount Cost

Bupivacaine 250 mg $2.72

Levo-Bupivacaine 225mg $75.00

Ropivacaine 200 mg $164.95

(MIMS Medeconomics, 2017; Clint Pharmaceuticals, 2017)

“The basic action of an anesthetic in the body is largely a function of the drug’s chemical structure and the resulting interaction with the cellular receptor complex.”

- John J. Nagelhout, PhD, CRNA, FAAN

Toxic Dose

• Max safe dose = 2.5 mg/kg of bupivacaine• 3 mcg/mL is toxic plasma concentation

(Nagelhout & Plaus, 2014; Hemmings & Egan, 2012; Evers, Maze & Kharasch, 2011)

BupivacaineLipophilic – Intermediate Amide Bond – “Hydrophilic” Tertiary Amine

Amphipathic

(Miller, 2015; Hemmings & Egan, 2012)

Synonyms are Tough• Lipophilic

– Hydrophobic– Water insoluble– Non-polar– Lipid soluble– FAT LOVING

• Hydrophilic– Lipophobic– Lipid insoluble– Polar– Water soluble– WATER LOVING

Amphipathic

Like dissolves/is attracted to LikeLipophilic substances dissolve/are attracted to other lipophilic substances

Hydrophilic substances dissolve/are attracted to other hydrophilic substances

Barash, Cullen & Stoelting, 2014; Hemmings & Egan, 2012; Evers, Maze & Kharasch, 2011)

Degrees of Lipophilicity

Hydrophilic

Almost Completely Lipophilic

“The more potent, lipophiliclocal anesthetics such as bupivacaine, tetracaine, and etidocaine are more cardiotoxic than the less lipophilic agents such as procaine, prilocaine, and lidocaine (Hemmings & Egan, 2012 p. 299).”

Driving it home

HydrophilicLipophilic

Bupivacaine

(Miller, 2015; Hemmings & Egan, 2012)

Phospholipid Bilayer

(Hall, 2016; Miller, 2015; Barash, Cullen & Stoelting, 2014; Nagelhout & Plaus, 2014; Hemmings & Egan, 2012; Evers, Maze & Kharasch, 2011)

(Miller, 2015; Hemmings & Egan, 2012; Bourne, Wright & Royse, 2010; Heavner, 2002)

Bupivacaine Cellular Cardiotoxic Effects

(Hall, 2016; Hemmings & Egan, 2012; Bourne, Wright & Royse, 2010; Heavner, 2002)

Summary of Main Points Before Discussing Lipid Rescue

• Bupivicaine is the most lipophilic local anesthetic due to the long hydrocarbon chain extending from its amine group.

• “Like” dissolves/is attracted to “Like”

What is lipid rescue?

(American Society of Regional Anesthesia and Pain Medicine, 2011)

(Weinberg et al., 1998)

(Burns, 2010)

Components of Lipid Emulsion

(Intralipid)

“Lipid Sink”Theorized Mechanism of Lipid Rescue

“The lipid micelle/chylomicronstructure is the preferred compartment over other body areas for local anesthetic binding (Bourne, Wright & Royse, 2010)”

“Like” dissolves “like”

(Bourne, Wright & Royse, 2010)

CACTTheorized Mechanism of Lipid Rescue

• Carnitine-acylcarnitine transferase (CACT)– Mitochondial transport protein that brings fatty

acids into mitochondrial matrix to create energy– Bupivicaine has been found to block CACT in rats

(Bourne, Wright & Royse, 2010)

(Giudetti et al., 2016; Bourne, Wright & Royse, 2010).

Summary

The EndQuestions?Sean Zajdel SRNAszajdel@ycp.edu

References• AMERICAN SOCIETY OF REGIONAL ANESTHESIA AND PAIN MEDICINE, 2011• Barash, P. G., Cullen, B. F., & Stoelting, R. K. (2014). Clinical anesthesia, 7th edn.• Bourne, E., Wright, C., & Royse, C. (2010). A review of local anesthetic cardiotoxicity and treatment with lipid emulsion. Local

and regional anesthesia, 3, 11.• Burns, S. M. (2010). Use of lipid emulsions for treatment of local anesthetic toxicity: a case report. AANA journal, 78(5), 359.• Evers, A. S., Maze, M., & Kharasch, E. D. (Eds.). (2011). Anesthetic Pharmacology: Basic Principles and Clinical Practice.

Cambridge University Press.• Giudetti, A. M., Stanca, E., Siculella, L., Gnoni, G. V., & Damiano, F. (2016). Nutritional and Hormonal Regulation of Citrate

and Carnitine/Acylcarnitine Transporters: Two Mitochondrial Carriers Involved in Fatty Acid Metabolism. International journal of molecular sciences, 17(6), 817.

• Hall, J. E. (2016). Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia, PA:Elsevier.• Heavner, J. E. (2002). Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Regional anesthesia

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http://www.pathophys.org/physiology-of-cardiac-conduction-and-contractility/• Intralipid, https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/017643s072,018449s039lbl.pdf• Miller, R. D. (2015). Miller's anesthesia (8th ed., Vol. 1). Philadelphia: Elsevier Saunders.• Nagelhout, J. J., & Plaus, K. L. (2014). Nurse anesthesia. Elsevier Health Sciences.• Weinberg, G. L., VadeBoncouer, T., Ramaraju, G. A., Garcia-Amaro, M. F., & Cwik, M. J. (1998). Pretreatment or resuscitation

with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. The Journal of the American Society of Anesthesiologists, 88(4), 1071-1075.

• http://www.mims.co.uk/about-mims• http://www.clintpharmaceuticals.com/01-0116301-bupivacaine-0-point-5-percent-50ml-mdv.html