Local Anesthetics and Topical Analgesics

Ashley Wong

Naum Shaparin

Introduction

Local anesthetics have been used since the 19th century for their anesthetic properties.¹ Local anesthetics are drugs that bind to sodium channels on nerves and reversibly block propagation of action potentials. The first discovered anesthetic, cocaine, was used by indigenous people living in the Andes mountains who noted a numbing sensation when they chewed on coca leaves.² Years later, cocaine was isolated from the coca plant and refined for use in ophthalmic surgeries. Since then, several synthetically derived local anesthetics have been developed to be used in the clinical setting. There is a wide range of uses for local anesthetics, therapeutically and diagnostically. Local anesthetics are used in multiple clinical settings including for peri-op anesthesia and to treat a variety of acute or chronic pain syndromes. This chapter will provide a description of the mechanism of action, pharmacokinetics, clinical use, and potential toxicity associated with local anesthetics.

Mechanism of Action

The mechanism underlying all local anesthetics is their capacity to reversibly bind to sodium (Na⁺) channels on nerves. This allows inhibition of neuronal impulse propagation and generation of action potentials that are responsible for nerve conduction and ultimately can lead to abolished sensation and motor function.

Action Potential Physiology

Consistent with all biological cell membranes, the neuronal membrane is made up of an amphipathic phospholipid bilayer. Dispersed throughout this bilayer are embedded protein channels that span the thickness of the membrane. These channels create a conduit between the intracellular and extracellular environments and allow efficient passage of essential molecules across the layer when polarity, gradient, or size impede natural diffusion. Voltage-gated Na⁺ channels play a critical role in triggering nerve action potentials and local anesthetic mechanism of action.

The electrical resting potential of a neuron is around −70 mV, where the negative implies an overall negative intracellular environment compared to the extracellular environment. As a stimulus reaches the target cell, the permeability of the Na⁺ channel increases, which allows an influx of Na⁺ into the cell. If the electrical differential reaches a threshold, which is usually around −55 mV, an action potential is created and an increase amount of Na⁺ influx into the cell occurs. This allows further propagation of the signal down a nerve. Local anesthetics work by binding to these Na⁺ channels to block action potential creation.

The Na⁺ channel is made up of specific protein subunits and functional domains. Local anesthetics reversibly bind to the inner protein subunit of the Na⁺ channel and prevent the channel from opening.³ Once a local anesthetic binds to the Na⁺ channel, a change in membrane permeability to Na⁺ occurs, impeding the influx of more sodium through the channel and inhibiting the generation of action potentials. There is no change in overall resting membrane potential or sodium concentration gradient.⁴ Clinically, we use this to our advantage to block impulse conduction of sensation and create local anesthesia. Local anesthetics can exert this function on any type of nerve, in any part of the body.

Differential Nerve Blockade

Different nerve fiber types have varying sensitivity to local anesthetics. Generally, small diameter nerve fibers are more susceptible to nerve blockade compared to larger diameter fibers. Small sympathetic nerve fibers are blocked first followed by the small, myelinated A-delta fibers that mediate pain and temperature. Then, large myelinated A-gamma, A-alpha, and A-beta nerves, which contribute to touch, pressure, and motor function, are blocked last.⁵ This is the general mechanism behind differential nerve block using local anesthetics. Typically, upon administration of local anesthetic, sympathetic function is impaired first. Therefore, vasodilation and its clinical manifestations are the first marker of a successful local anesthetic block. As the local anesthetic block progresses, patients will then feel a loss of pain sensation, followed by the loss of temperature, touch, pressure, vibration, and then lastly, motor function. Clinically, this becomes relevant in situations where preferential blockade of sensory nerve fibers over motor fibers are desired, such as during labor.

Local Anesthetic Pharmacology

Most local anesthetics consist of a hydrophilic tertiary amine that attaches to a hydrophobic aromatic ring. These moieties are connected by an intermediate chain. Local anesthetics that are an exception to this include prilocaine, which lacks a tertiary amine and has a secondary amine instead, and benzocaine, which has a primary amine.⁶ The intermediate chain contains either an ester or an amide link, which defines the two classifications of local anesthetics into aminoesters or aminoamides (further discussed later in this chapter). The duration of onset, action, and potency of each local anesthetic is based on multiple factors including pH of surrounding tissue, local anesthetic lipid solubility, concentration, ionization, and pKa.

Lipid solubility and concentration of the local anesthetic determines potency of the anesthetic. The term “hydrophilic” describes greater affinity to water, and therefore, “hydrophobic” describes substances that tend to repel water. Local anesthetics that are highly hydrophobic cross nerve cell membranes easier and can produce a more potent and longer acting blockade than less hydrophobic anesthetics.⁶ Accordingly, increased hydrophobicity will also increase the adverse effects of local anesthetics.

The onset of action is determined by the local anesthetic pKa and the pH of the surrounding tissue. All local anesthetics exist in protonated (ionized) and uncharged (nonionized) forms when placed in physiologic pH conditions (7.35-7.45).⁷ The pKa is used to define the acidity of each local anesthetic in solution. The nonionized forms of local anesthetics are able to penetrate and cross cell membranes easier, resulting in a faster onset of action. The proportion of ionized to nonionized form changes with the pH of the environment it is delivered in. The pH of the surrounding tissue influences the local anesthetic activity by altering the percentage of the base and protonated forms. In inflamed/infected tissue that has a lower pH than normal tissue, local anesthetics become more protonated and penetrate the tissues slower, causing slower onset of action. Addition of sodium bicarbonate to local anesthetics in these situations may raise the pH and allow faster onset of action.

Specific Local Anesthetics

Local anesthetics are typically divided into aminoamides and aminoesters. Aminoamides are much more stable in solution compared to aminoesters. The anesthetics that are classified as aminoamides are lidocaine, mepivacaine, prilocaine, bupivacaine, and ropivacaine. Aminoesters include cocaine, procaine, tetracaine, chloroprocaine, benzocaine. Procaine is known as the prototypic aminoester, and lidocaine is the prototypic aminoamide. An easy way to remember the anesthetics in each group is to know that aminoamides contain letter “i” twice in their name and so does “aminoamides.” A summary of the particular properties of each local anesthetic is detailed in Table 37.1.

Clinical Use

Local anesthetics have numerous uses in clinical practice such as for peripheral nerve blockade for diagnostic and therapeutic purposes, local infiltration, regional anesthesia in perioperative management, neuraxial administration, or topical preparation for analgesia.

TABLE 37.1 LOCAL ANESTHETIC PROPERTIES

	Local Anesthetic Properties
	Classification	Duration of Action	Recommended Max Dosage	Typical Concentrations	Misc.
Lidocaine	Amide	0.5-2 h	400-500 mg	0.5%-2%	The most commonly used LA
Mepivacaine	Amide	1-1.5 h	300-400 mg	0.5%-2%	Typically used in epidural blocks and regional anesthesia
Prilocaine	Amide	0.5-1.5 h	350 mg	0.5%-3%	Often used in dentistry or in combination with lidocaine in EMLA formulation
Ropivacaine	Amide	2-5 h	225 mg	0.2%-0.75%	Long duration but less cardiotoxic than bupivacaine
Cocaine	Ester	Up to 1.5 h	300 mg	4% or 10%	Available in solution for ENT/ophthalmic use
Procaine	Ester	0.5 h	500 mg	1%-2%	Slow onset, short duration
Tetracaine	Ester	2-3 h	20 mg topical	0.25%-1%	Available in solution for ENT/ophthalmic use
Chloroprocaine	Ester	0.25-0.5 h	800 mg	1%-2%	Fast onset, short duration
Benzocaine	Ester	Varies	Varies	Varies	Available in topical cream, ointment, or spray
This table details local anesthetic properties including classification, duration of action, recommended maximum dosing, typical concentrations used, and specific miscellaneous drug facts.