Standing Surgery

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The Pharmacology of Local Anesthetics

Thomas K. Day, DVM,* and Roman T. Skarda, DVM, PhDt

Surgery in standing horses may require the use of local anesthesia, in part or as the only form of analgesia. Since the first local anesthetic, cocaine, was discovered, there have been advances in the development of local anesthetics and a proliferation of the number of.local anesthetics available to the practitioner. Owing to differing pharmacology, these anesthetics vary in potency, duration of action, and toxicity. An understanding of the pharmacology of clinically successful local anesthetics used for equine standing surgery is required to make a rational selection of a local anesthetic to meet the needs of the particular surgery. Specific techniques for application of local anesthetics are described in the article by Gaynor and Hubbell elsewhere in this issue.

PHYSIOLOGY Basic Electrophysiology The peripheral nerve membrane is a semipermeable structure that separates a potassium-rich intracellular solution from a sodium-rich extracellular solution. This large ionic gradient across the membrane results in an electrochemical resting potential between -70 and - 90 m V (negative inside relative to outside). This is termed an inactive or polarized membrane. The semipermeable membrane consists of a lipid bilayer with protein dispersed between the two lipid layers. There are a series of pores in the membrane controlled by "gates" that open and close under the electrical influence of the membrane, allowing the passage of ions. Electrical impulses trigger a series of events that allow the "gates" to open, resulting in a rapid From the Department of Veterinary Clinical Sciences, The Ohio State University College of Veterinary Medicine, Columbus, Ohio 'Resident in Anesthesiology tDiplomate, American College of Veterinary Anesthesiologists; Associate Professor Veterinary Clinics of North America: Equine Practice-Vol. 7, No.3, December 1991

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DAY AND ROMAN T. SKARDA

inward flow of sodium ions. This increases the electrical gradient to a value of +40 mY. This is termed activation or depolarization of the membrane and is carried along the peripheral nerve fiber. Shortly after depolarization, potassium ions move out of the intracellular fluid, returning the membrane to resting potential and closing sodium channels. Local anesthetics exert their effect by inhibiting the rapid inward flow of sodium ions, thereby inhibiting depolarization of the membrane. Anatomy and Function of Nerve Fibers Nerve fibers are classified into three groups (A, B, and C) on the basis of size, function, and degree of myelinization (Table 1). Myelinated nerves transmit impulses more rapidly with the assisstance of breaks in the myelin called nodes of Ranvier. Impulses are not generated in nerve membranes ensheathed in myelin and "skip" to each node of Ranvier, resulting in faster transmission than in nonmyelinated nerve fibers.4 A-fibers are large, myelinated somatic nerves; they are further classified, in decreasing size, as alpha, beta, gamma, and delta. The A-alpha fibers relate to motor function, proprioception, and reflex activity. A-beta fibers transmit touch and pressure impulses. A-gamma fibers control muscle tone, and the Adelta fibers subserve pain and temperature functions and signal tissue decay. B-fibers are thinly myelinated preganglionic nerves that innervate vascular smooth muscle. B-fiber stimulation results in vasoconstriction. These nerves are important in vasomotor and pain functions during spinal and perineural anesthesia. 4 C-fibers are nonmyelinated postganglionic fibers that subserve pain and temperature transmission. B- and C-fibers are 1 to 3 j.Lm in diameter, whereas A-fibers vary in size from A-alpha (12-20 j.Lm) to A-delta (1-7 j.Lm)4 (Table 1). Physiology of Pain The exact mechanism of pain transmission is unknown. Two theories are the "gate control" theory and the specificity theory. The "gate control" theory suggests that information about the presence of injury is transmitted to the central nervous system by peripheral nerves. Small diameter fibers, such as A-delta and C-fibers, respond only to nociceptor (specific receptor for pain) stimulation. 12 The specificity theory suggests that specialized cutaneous receptors (nociceptors) and neural pathways exist for each modality of sensation from cutaneous stimulation. 15 There is a specific role for thinly myelinated A-delta and nonmyelinated C-fibers in signaling pain sensation. 4 In addition, artificial electrical stimulation of peripheral nerves produces pain sensation only when A-delta and C-fibers are stimulated. 23 A-delta fibers transmit sharp, well-localized nociception, and C-fibers respond to dull, burning, diffusely localized nociception. 14 Mechanism of Action Local anesthetics block nerve conduction by preventing the increase in membrane permeability to sodium ions. 1 The exact mechanism is not known. Many agents such as phenol and alcohol can block sodium channels. Local anesthetics reversibly block transmission. Two current theories of the exact mechanism of action are the membrane expansion and specific

Table 1. Classification of Nerve Fibers and Order of Neural Blockade A-ALPHA

Function

Diameter (u) Degree of Myelination Priority of blockade Signs of blockade

Somatic motor proprioception reflex activity

12-20 Heavy

5 Ataxia, recumbency

A-BETA

A-GAMMA

A-DELTA

Touch and pressure sensation

Maintenance of muscle tone

5-12 Moderate

Moderate

Light

3 Flaccid muscle

An~lgesia, loss of

4 Loss of sensation to touch an'd pressure

Nociception and temperature sensation

~

B

Vasoconstriction (preganglionic sympathetic)

Light

Nociception and temperature sensation (postganglionic sympathetic) 0.3-1.3 None

1 Vasodilation, increased skin temperature

2 Analgesia, loss of temperature sensation

2-5 2

temperature sensation

C

1-3

Data from deJong RH: Clinical physiology of local anesthetic action. In Cousins MJ, Bridenbaugh PO (eds): Natural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia, JB Lippincott, 1980, p 54.

~ ....

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T.

SKARDA

receptor theories. The membrane expansion theory suggests that local anesthetics are absorbed into the membrane, increasing fluidity and causing expansion. 19 This expanded membrane closes sodium channels, preventing depolarization. The specific receptor theory suggests that the dissociation of local anesthetic alters electrical forces across the membrane. The degree of blockade depends on the amount of ionized local anesthetic cation at specific receptors at or near the sodium channel, preventing sodium influx. 19 The order and degree of neural blockade correlates with diameter and type of nerve fiber and degree of myelinization (Table 1). The first nerve fibers blocked are the B-fibers, resulting in vasodilation and increased skin temperature. A-delta and C-fibers are blocked next, relieving pain. The last nerves blocked are A-gamma, A-beta, and A-alpha, which produces loss of proprioception, touch and pressure sensation, and motor activity, respectively. A common misinterpretation regarding nerve blockade is that the area that is blocked is completely void of all nerve transmission. Differential blockade actually occurs and refers to the removal of the perception of pain with retention of motor activity and, possibly, pressure sensation as a result of blockade of some fibers and not others. The insulating properties of myelin limit local anesthetic access to nerve membranes except at the nodes of Ranvier. A myelinated nerve must be blocked 8 to 10 mm to stop nerve impulse transmission, because nerve impulses can effectively "jump" over two or three nodes and continue the impulse. 4 Furthermore, thick myelinated fibers are less readily blocked than thin fibers.4 Heavily myelinated A-alpha fibers, responsible for motor activity and proprioception, may not concurrently be blocked when the Adelta and C-fibers transmitting pain are blocked. Also, A-beta and A-gamma fibers that transmit touch and pressure may not be blocked. This explains why an animal can respond to pressure but not to pain while under local anesthesia. PHARMACOLOGY Fate of Local Anesthetics Local anesthetics, as the name implies, are deposited at or near the desired site of action. Unlike other drugs administered parenterally or orally, local anesthetics do not rely on the systemic circulation for their action. The systemic circulation does, however, playa role in concentration of local anesthetic at the site. Uptake into the systemic circulation is the route by which local anesthetics are cleared from the site and exert toxic effects on various organ systems. A balance between local disposition and systemic absorption determines the local therapeutic effects as well as potential systemic toxic effects (Fig. 1). An in depth discussion of each variable is beyond the scope of this article; however, it is important to realize that after injection oflocal anesthetics, there are multiple interactions that determine the effectiveness and potential onset of toxic side effects . Physical and Chemical Properties of Local Anesthetics

Molecular Structure. Local anesthetics consist of a lipophilic group and hydrophilic group connected by an intermediate chain. This structure

493

THE PHARMACOLOGY OF LOCAL ANESTHETICS

Bulk flow of drug

Diffusion into

Metabolism

ne~!_e---,

(ePidl"'""!!....a_I)__ Local Injection .. anesthetic

Local disposition

i

Systemic absorption

t

Vascular activity (vasoconstriction)

Protein binding

Vascular supply

Drug di stribution Systemic disease

Figure 1. Factors influencing local distribution and systemic absorption of local anesthetics.

is similar to the structure of the axonal membrane where the local anesthetics act; outer layers are hydrophilic and inner layers are lipophilic. The local anesthetic therefore orients itself with each portion of the lipid bilayer. The lipophilic portion consists of an aromatic ring and provides lipid solubility to each molecule and the ability to penetrate and cross cellular membrane barriers. The hydrophilic portion contains the amino groups that allow the molecule to be ionized. The intermediate chain consists of a carbonyl group of an ester or amide linkage. Historically, local anesthetics are classified by the amide or ester linkage. Cocaine, an ester-type local anesthetic, was the first identified. Procaine, chloroprocaine, and tetracaine were synthesized as other ester-type drugs. The introduction of amide-type local anesthetics began with the synthesis of lidocaine. Other local anesthetics of the amide-type include prilocaine, mepivacaine, bupivacaine, etidocaine, dibucaine, and ropivacaine. Ionization. Most local anesthetics are weak bases and are supplied as mildly acidic hydrochloride salts to improve solubility and stability. In solution, local anesthetics exist as

Equation 1

B nonionized base

BH+

+ H + ionized a cation

The proportion of Band BH + depend on the dissociation constant Ka represented by

Equation 2 where the parentheses represent concentrations, or more accurately, activities. Rearranging equation 2 and remembering that Ka is a constant, the impact of acidosis and alkalosis can be illustrated

Equation 3

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The amount of ionized cation (BH+) is proportional to the hydrogen ion activity (H+). The amount of non ionized base (B) is inversely proportional to the hydrogen ion activity. The nonionized base is necessary for penetration of the axonal nerve membrane. Local anesthetics penetrate membranes less in acidotic areas, such as infected wounds, and therefore are less effective in these areas. It is not known which portion of the dissociated molecule is the active form (produces local anesthesia). Once the molecule is across the membrane, both the ionized base and the ionized cation probably contribute to activity.u Further rearranging equation 2 with logarithms produces the familiar Henderson-Hasselbalch equation pKa

Equation 4

=

(B)

pH

log (BH+)

The exact proportions of non ionized base and ionized cation could be derived if pH and pKa were known. Most local anesthetics have pKa values ranging from 7.6 to 9.1 that are higher than physiologic pH (7.4). Table 2 lists selected local anesthetics, pKa values, and proportion of non ionized base present at physiologic pH and in the presence of acidosis. Duration of Action and Potency. The duration of action and potency of local anesthetics are directly related to lipid solubility and protein binding. The more potent drugs are those that are more lipid soluble. Examples are (1) addition of a butyl group to the lipophilic portion of procaine forms tetracaine, which is 11 times more potent than procaine, and (2) addition of a butyl group to the aromatic portion of mepivacaine forms bupivacaine, which is 30 times more potent than mepivicaine. Protein binding and vasoactivity are primary determinants of duration of action. Local anesthetics that are highly protein-bound bind to membrane protein, increasing duration of action. Table 3 summarizes local anesthetics' onset and duration of action, potency, trade names, and manufacturers.

Table 2. Dissociation Constants (pK.) and Percent of Nonionized Base of Local Anesthetics at Physiologic pH (7.4) and in Acidosis (pH