Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 26. Local Anesthetics

Local Anesthetics: Introduction

Local anesthesia is the condition that results when sensory transmission from a local area of the body to the CNS is blocked. The local anesthetics constitute a group of chemically similar agents (esters and amides) that block the sodium channels of excitable membranes. Because these drugs can be administered by injection in the target area, or by topical application in some cases, the anesthetic effect can be restricted to a localized area (eg, the cornea or an arm). When given intravenously, local anesthetics have effects on other tissues.

Chemistry

Most local anesthetic drugs are esters or amides of simple benzene derivatives. Subgroups within the local anesthetics are based on this chemical characteristic and on duration of action. The commonly used local anesthetics are weak bases with at least 1 ionizable amine function that can become charged through the gain of a proton (H+). As discussed in Chapter 1, the degree of ionization is a function of the pKa of the drug and the pH of the medium. Because the pH of tissue may differ from the physiologic 7.4 (eg, it may be as low as 6.4 in infected tissue), the degree of ionization of the drug will vary. Because the pKa of most local anesthetics is between 8.0 and 9.0 (benzocaine is an exception), variations in pH associated with infection can have significant effects on the proportion of ionized to nonionized drug. The question of the active form of the drug (ionized versus nonionized) is discussed later.

Pharmacokinetics

Many shorter-acting local anesthetics are readily absorbed into the blood from the injection site after administration. The duration of local action is therefore limited unless blood flow to the area is reduced. This can be accomplished by administration of a vasoconstrictor (usually an -agonist sympathomimetic) with the local anesthetic agent. Cocaine is an important exception because it has intrinsic sympathomimetic action due to its inhibition of norepinephrine reuptake into nerve terminals. The longer-acting agents (eg, bupivicaine, ropivicaine, tetracain) are also less dependent on the coadministration of vasoconstrictors. Surface activity (ability to reach superficial nerves when applied to the surface of mucous membranes) is a property of certain local anesthetics, especially cocaine and benzocaine (both only available as topical forms), lidocaine, and tetracaine.

Metabolism of ester local anesthetics is carried out by plasma cholinesterases (pseudocholinesterases) and is very rapid for procaine (half-life, 1-2 min), slower for cocaine, and very slow for tetracaine). The amides are metabolized in the liver, in part by cytochrome P450 isozymes. The half-lives of lidocaine and prilocaine are approximately 1.5 h. Bupivacaine and ropivacaine are the longest-acting amide local anesthetics with half-lives of 3.5 and 4.2 h, respectively. Liver dysfunction may increase the elimination half-life of amide local anesthetics (and increase the risk of toxicity).

Acidification of the urine promotes ionization of local anesthetics; the charged forms of such drugs are more rapidly excreted than nonionized forms.

Mechanism of Action

Local anesthetics block voltage-dependent sodium channels and reduce the influx of sodium ions, thereby preventing depolarization of the membrane and blocking conduction of the action potential. Local anesthetics gain access to their receptors from the cytoplasm or the membrane (Figure 26-1). Because the drug molecule must cross the lipid membrane to reach the cytoplasm, the more lipid-soluble (nonionized, uncharged) form reaches effective intracellular concentrations more rapidly than does the ionized form. On the other hand, once inside the axon, the ionized (charged) form of the drug is the more effective blocking entity. Thus, both the nonionized and the ionized forms of the drug play important roles—the first in reaching the receptor site and the second in causing the effect. The affinity of the receptor site within the sodium channel for the local anesthetic is a function of the state of the channel, whether it is resting, open, or inactivated, and therefore follows the same rules of use dependence and voltage dependence that were described for the sodium channel-blocking antiarrhythmic drugs (see Chapter 14). In particular, if other factors are equal, rapidly firing fibers are usually blocked before slowly firing fibers. High concentrations of extracellular K+ may enhance local anesthetic activity, whereas elevated extracellular Ca2+ may antagonize it.

FIGURE 26-1

Schematic diagram of the sodium channel in an excitable membrane (eg, an axon) and the pathways by which a local anesthetic molecule (Drug) may reach its receptor. Sodium ions are not able to pass through the channel when the drug is bound to the receptor. The local anesthetic diffuses within the membrane in its uncharged form. In the aqueous extracellular and intracellular spaces, the charged form (Drug+ ) is also present.

Pharmacologic Effects

Nerves

Differential sensitivity of various types of nerve fibers to local anesthetics depends on fiber diameter, myelination, physiologic firing rate, and anatomic location (Table 26-1). In general, smaller fibers are blocked more easily than larger fibers, and myelinated fibers are blocked more easily than unmyelinated fibers. Activated pain fibers fire rapidly; thus, pain sensation appears to be selectively blocked by local anesthetics. Fibers located in the periphery of a thick nerve bundle are blocked sooner than those in the core because they are exposed earlier to higher concentrations of the anesthetic.

TABLE 26-1 Susceptibility to block of types of nerve fibers.

Fiber Type Function Diameter (m) Myelination Conduction Velocity (m/s) Sensitivity to Block Type A Alpha Proprioception, motor 12-20 Heavy 70-120 + Beta Touch, pressure 5-12 Heavy 30-70 ++ Gamma Muscle spindles 3-6 Heavy 15-30 ++ Delta Pain, temperature 2-5 Heavy 12-30 +++ Type B Preganglionic, autonomic <3 Light 3-15 ++++ Type C Dorsal root Pain 0.4-1.2 None 0.5-2.3 ++++ Sympathetic Postganglionic 0.3-1.3 None 0.7-2.3 ++++

Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 10th ed. McGraw-Hill, 2007.

Other Tissues

The effects of these drugs on the heart are discussed in Chapter 14 (see class I antiarrhythmic agents). Most local anesthetics also have weak blocking effects on skeletal muscle neuromuscular transmission, but these actions have no clinical application. The mood elevation induced by cocaine reflects actions on dopamine or other amine-mediated synaptic transmission in the CNS rather than a local anesthetic action on membranes.

Clinical Use

The local anesthetics are commonly used for minor surgical procedures often in combination with vasoconstrictors such as epinephrine. Onset of action may be accelerated by the addition of sodium bicarbonate, which enhances intracellular access of these weakly basic compounds. Articaine has the fastest onset of action. Local anesthetics are also used in spinal anesthesia and to produce autonomic blockade in ischemic conditions. Slow epidural infusion at low concentrations has been used successfully for postoperative analgesia (in the same way as epidural opioid infusion; Chapter 31). Repeated epidural injection in anesthetic doses may lead to tachyphylaxis, however. Intravenous local anesthetics may be used for reducing pain in the perioperative period. Oral and parenteral forms of local anesthetics are sometimes used adjunctively in neuropathic pain states.

Toxicity

CNS Effects

The important toxic effects of most local anesthetics are in the CNS. All local anesthetics are capable of producing a spectrum of central effects, including light-headedness or sedation, restlessness, nystagmus, and tonic-clonic convulsions. Severe convulsions may be followed by coma with respiratory and cardiovascular depression.

Cardiovascular Effects

With the exception of cocaine, all local anesthetics are vasodilators. Patients with preexisting cardiovascular disease may develop heart block and other disturbances of cardiac electrical function at high plasma levels of local anesthetics. Bupivacaine, a racemic mixture of two isomers may produce severe cardiovascular toxicity, including arrhythmias and hypotension. The (S)isomer, levobupivicaine, is less cardiotoxic. Cardiotoxicity has also been reported for ropivicaine when used for peripheral nerve block. The ability of cocaine to block norepinephrine reuptake at sympathetic neuroeffector junctions and the drug's vasoconstricting actions contribute to cardiovascular toxicity. When cocaine is used as a drug of abuse, its cardiovascular toxicity includes severe hypertension with cerebral hemorrhage, cardiac arrhythmias, and myocardial infarction.

Other Toxic Effects

Prilocaine is metabolized to products that include o-toluidine, an agent capable of converting hemoglobin to methemoglobin. Though tolerated in healthy persons, even moderate methemoglobinemia can cause decompensation in patients with cardiac or pulmonary disease. The ester-type local anesthetics are metabolized to products that can cause antibody formation in some patients. Allergic responses to local anesthetics are rare and can usually be prevented by using an agent from the amide subclass. In high concentrations, local anesthetics may cause a local neurotoxic action that includes histologic damage and permanent impairment of function.

Treatment of Toxicity

Severe toxicity is treated symptomatically; there are no antidotes. Convulsions are usually managed with intravenous diazepam or a short-acting barbiturate such as thiopental. Hyperventilation with oxygen is helpful. Occasionally, a neuromuscular blocking drug may be used to control violent convulsive activity. The cardiovascular toxicity of bupivacaine overdose is difficult to treat and has caused fatalities in healthy young adults.

Skill Keeper: Cardiac Toxicity of Local Anesthetics

(See Chapter 14)

Explain how hyperkalemia facilitates the cardiac toxicity of local anesthetics. The Skill Keeper Answer appears at the end of the chapter.

Skill Keeper Answer: Cardiac Toxicity of Local Anesthetics

(See Chapter 14)

Sodium channel blockers (eg, local anesthetics) bind more readily to open (activated) or inactivated sodium channels. Hyperkalemia depolarizes the resting membrane potential, so more sodium channels are in the inactivated state. Conversely, hypercalcemia tends to hyperpolarize the resting potential and reduces the block of sodium channels.

Checklist

When you complete this chapter, you should be able to:

 Describe the mechanism of action of local anesthetics.

 Know what is meant by the terms "use-dependent blockade" and "state-dependent blockade."

 Explain the relationship among tissue pH, drug pKa, and the rate of onset of local anesthetic action.

 List 4 factors that determine the susceptibility of nerve fibers to local anesthetic blockade.

 Describe the major toxic effects of the local anesthetics.

Drug Summary Table: Drugs Used for Local Anesthesia

Subclass Mechanism of Action Pharmacokinetics Clinical Applications Toxicities Amides Articaine Bupivacaine Levobupivacaine Lidocainea Mepivacaine Prilocaine Ropivacaine Blockade of Na+ channels slows, then prevents axon potential propagation

Hepatic metabolism via CYP450 in part Half-lives: lidocaine, prilocaine < 2 h, others 3-4 h Analgesia via topical use, or injection (perineural, epidural, subarachnoid); rarely IV CNS: excitation, seizures CV: vasodilation, hypotension, arrhythmias (bupivacaine) Esters Benzocainea Cocainea Procaine Tetracainea As above, plus cocaine has intrinsic sympathomimetic actions Rapid metabolism via plasma esterases; short half-lives Analgesia, topical only for cocaine and benzocaine As above re CNS actions; cocaine vasoconstricts When abused has caused hypertension and cardiac arrhythmias

aTopical fomulations available.



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