Local anesthetic agents: Mechanism of action

Published on 07/02/2015 by admin

Filed under Anesthesiology

Last modified 22/04/2025

Print this page

This article have been viewed 4440 times

CHAPTER 115

Local anesthetic agents: Mechanism of action

Steven R. Clendenen, MD

The mechanism of action of local anesthetic agents is to prevent the transmission of nerve impulses generated by a chemical, mechanical, or electrical stimulus that triggers an action potential.

Anatomy of a nerve cell

Nerve cells communicate with each other through axons, which are elongations of the cell body, and by dendrites. The cell membrane is a hydrophobic lipid bilayer that incorporates ion channels composed of lipoproteins. In contrast to the nerve cells of the central nervous system, many peripheral nerves are enveloped in myelin that is produced by Schwann cells. Gaps known as nodes of Ranvier, located approximately 1 mm apart in the myelin sheath have a high concentration of Na⁺ channels, facilitating saltatory transmission between sequential nodes and increasing the speed of electrical conduction along the axon.

Nerve cell membrane and depolarization

The cell membrane creates a barrier between the Na⁺-rich extracellular fluid and the K⁺-rich intracellular fluid, creating a resting membrane potential of −60 to −90 mV (Figure 115-1). There is constant movement of Na⁺ ions through Na⁺ channels that spontaneously open and close; active transport of Na⁺ out of the cell maintains the resting membrane potential. When an appropriate stimulus of adequate magnitude opens a sufficient number of Na⁺ channels, the surrounding membrane depolarizes (becomes less negative), recruiting additional channel openings—a cascade of open channels allows more Na⁺ to enter the cell, with K⁺ diffusing out of the cell through K⁺ channels to the point that the entire membrane depolarizes, producing an all-or-nothing electrical signal (action potential) that is propagated along the axon. Once the action potential passes, an energy-dependent mechanism reestablishes the concentrations of Na⁺ and of K⁺, restoring the resting membrane potential.

Figure 115-1 Resting membrane and action potentials. (Netter illustration from www.netterimages.com. © Elsevier Inc. All rights reserved.)

Structure of local anesthetic agents

Molecules of local anesthetic agents contain an aromatic lipophilic end, which is connected by an intermediate chain to a hydrophilic tertiary amine (weak base). The intermediate chain is either an amide or an ester linkage; this linkage is the basis for the two different classes of local anesthetic agents (esters and amides), which have similar mechanisms of action but different metabolic pathways. Because the nonionized form of the molecule crosses the cell membrane, compounds that are more lipophilic have a faster onset of blockade. And, because local anesthetic agents are weak bases, compounds with a pK_a close to physiologic pH will have a faster onset of blockade as more molecules remain in the nonionized state. Clearance of the drug from the site of injection and protein binding of local anesthetic agents by α₁-acid glycoprotein also affect the duration of action because it is the concentration of free drug that is available to diffuse across the membrane that determines blockade (Figure 115-2, Table 115-1).

Table 115-1

Chemical and Physical Properties of the Most Commonly Used Local Anesthetic Drugs

Property	Lidocaine	Mepivacaine	Bupivacaine	Ropivacaine	Levobupivacaine
Molecular weight	234	246	288	274	288
pK_a	7.7	7.6	8.1	8.1	8.1
Liposolubility*	4	1	30	2.8	30
Partition coefficient	2.9	0.8	28	9	28
Protein binding (%)	65	75	95	94	95
Equipotency (%)	2	1.5	0.5	0.75	0.5