The acute toxicity of local anesthetics

Abstract

Importance of the field: Systemic toxicity, usually from overdose or intravascular dose, is feared because it mainly affects the heart and brain, and may be acutely life-threatening.

Areas covered in this review: Pharmacological studies of local anesthetic toxicity have largely been reviewed primarily relating to the evaluation of ropivacaine and levobupivacaine during the past decade. This review/opinion focuses more on the principles and concepts underlying the main models used, from chemical pharmacological and pharmacokinetic perspectives.

What the reader will gain: Research models required to produce pivotal toxicity data are discussed. The potencies for neural blockade and systemic toxicity are associated across virtually all models, with some deviations through molecular stereochemistry. These models show that all local anesthetics can produce direct cardiovascular system toxicity and CNS excitotoxicity that may further affect the cardiovascular system response. Whereas the longer-acting local anesthetics are more likely to cause cardiac death by malignant arrhythmias, the shorter-acting agents are more likely to cause cardiac contraction failure. In most models, equi-anesthetic doses of ropivacaine and levobupivacaine are less likely to produce serious toxicity than bupivacaine.

Take home message: Of the various models, this reviewer favors a whole-body large animal preparation because of the comprehensive data collection possible. The conscious sheep preparation has contributed more than any other, and may be regarded as the de facto ‘standard’ experimental model for concurrent study of local anesthetic toxicity ± pharmacokinetics, using experimental designs that can reproduce the toxicity seen in clinical accidents.

Keywords::

• acute toxicity
• cardiovascular system
• chemical properties
• CNS
• experimental models
• local anesthetics
• pharmacokinetic properties

Acknowledgments

The article is based on an invited plenary lecture to the 13th Asian-Australasian Congress of Anesthesiologists, Fukuoka, Japan, 1 – 5 June 2010.

The author wishes to acknowledge the influence of his former colleagues and postgraduate students in shaping many of the ideas developed in this paper and, in particular, the contributions of Drs LA Ladd and SE Copeland.

Notes

This box summarizes key points contained in the article.