Local Anesthetics

Ayumi Maeda

Rebecca D. Minehart

I. GENERAL PRINCIPLES

A. Chemistry. Local anesthetics are weak bases whose structure consists of an aromatic moiety connected to a substituted amine through an ester or amide linkage. The pK_a values of local anesthetics are near physiologic pH; thus, in vivo, both charged (protonated) and uncharged (unprotonated) forms are present. The degree of ionization is important because the uncharged form is more lipophilic and is able to gain access to the axon. The clinical differences between the ester and amide local anesthetics involve their potential for producing adverse effects and the mechanisms by which they are metabolized.

1. Esters. Procaine, cocaine, chloroprocaine, and tetracaine. The ester linkage is cleaved by plasma cholinesterase. The half-life of esters in the circulation is very short (about 1 minute). The degradation product of ester metabolism is p-aminobenzoic acid.

2. Amides. Lidocaine, mepivacaine, bupivacaine, etidocaine, and ropivacaine. The amide linkage is cleaved through initial N-dealkylation followed by hydrolysis, which occurs primarily in the liver. Patients with severe hepatic disease may be more susceptible to adverse reactions from amide local anesthetics. The elimination half-life for most amide local anesthetics is 2 to 3 hours.

B. Mechanism of Action

1. Local anesthetics block nerve conduction by impairing propagation of the action potential in axons. They have no effect on the resting or threshold potentials but decrease the rate of rise of the action potential so that the threshold potential is not reached.

2. Local anesthetics interact directly with specific receptors on the Na⁺ channel, inhibiting Na⁺ ion influx. The anesthetic molecule must traverse the cell membrane through passive nonionic diffusion in the uncharged state and then becomes protonated and binds to the axoplasmic side of the sodium channel. K⁺ and Ca²⁺ channels are also found to be blocked by local anesthetics.

3. Physiochemical properties of the local anesthetics affect neural blockade.

a. Lipid solubility. Higher lipophilicity increases potency by increasing the rate of diffusion through axonal membranes and other tissues.

b. Protein binding. More protein binding prolongs the duration of effect.

c. pK_a. Agents with a lower pK_a value will have a faster onset because a greater fraction of these weak bases will exist in the uncharged form at pH 7.4 and thus will more readily diffuse across nerve membranes.

d. pH of the drug solution. Higher pH will speed up the onset by increasing the proportion of molecules in the uncharged form.

e. Drug concentration. Higher concentration speeds up the onset of action due to mass effect.

4. Differential blockade of nerve fibers

a. Peripheral nerves are classified according to size and function (Table 16.1). Traditionally, thin nerve fibers were believed to be more easily blocked than thick ones; however, the opposite susceptibility
has been found. Myelinated fibers are more readily blocked than unmyelinated ones, as myelinated fibers need to be blocked only at the nodes of Ranvier.

TABLE 16.1 Classification of Nerve Fibers

Class	Myelin	Diameter (µm)	Local Anesthetic Sensitivity	Function
A-α	+++	12-20	++	Motor
A-β	+++	5-12	++	Touch/pressure
A-γ	++	1-4	+++	Proprioception/motor tone
A-δ	++	1-4	+++	Pain/temperature
B	+	1-3	++	Preganglionic autonomic
C	+	0.5-1	+	Pain/temperature

b. Differential blockade refers to the fact that a specific concentration of local anesthetic may produce a different intensity of block for pain, temperature sensation, and motor function. This reflects the different sensitivities of nerve fibers to local anesthetics, and it may be due to different ion channel composition or different arrangement of channels within the axon. A dilute solution of local anesthetic cannot be relied upon to block a specific sensory or motor function in a reproducible manner.

5. Sequence of clinical anesthesia. Complete blockade of peripheral nerves usually progresses in the following order:

a. Sympathetic block with peripheral vasodilatation and skin temperature elevation.

b. Loss of pain and temperature sensation.

c. Loss of proprioception.

d. Loss of touch and pressure sensation.

e. Motor paralysis.

6. Pathophysiologic factors affecting the neural block

a. A decrease in the cardiac output reduces the plasma and tissue clearance of local anesthetics, increasing plasma concentration and the potential for toxicity.

b. Severe hepatic disease may prolong the duration of action of amino amides.

c. Renal disease has minimal effect.

d. Patients with reduced cholinesterase activity (newborns and pregnant patients) and patients with atypical cholinesterase may have decreased clearance of ester-type anesthetics, but this will not generally lead to toxicity unless a very high percentage of enzyme activity is lost.

e. Fetal acidosis may cause ionization of local anesthetics and thereby “trap” drug molecules transferred from the mother to the fetus. The increased fetal versus maternal concentration may increase the possibility of fetal toxicity, particularly with amide forms that are not cleared rapidly by the maternal circulation like the ester forms, and therefore reach the fetus in greater concentrations.

f. Pathologic conditions such as sepsis, malignancy, and cardiac ischemia can increase the concentration of the binding protein α₁-acid glycoprotein, and this may decrease the plasma concentration of free local anesthetics.

C. Commercial Preparations

1. Commercially available solutions of local anesthetics are supplied as hydrochloride salts to promote ionization and increase solubility in water. Plain solutions usually are adjusted to pH 6. Those containing epinephrine are adjusted to pH 4 because of the instability of catecholamine molecules at alkaline pH.

2. Antimicrobial preservatives (paraben derivatives) are added to multidose vials. Only preservative-free solutions should be used in spinal, epidural, or caudal anesthesia to prevent potentially neurotoxic effects from preservatives.

3. Antioxidants (sodium metabisulfite, sodium ethylenediaminetetraacetic acid [EDTA]) may be added to slow breakdown of local anesthetics.

II. CLINICAL USES OF LOCAL ANESTHETICS

The choice of local anesthetic must take into account the duration of surgery, regional technique used, surgical requirements, the potential for local or systemic toxicity, and any metabolic constraints (Tables 16.2 and 16.3).

A. Combinations of Local Anesthetics

1. Chloroprocaine-bupivacaine, lidocaine-bupivacaine, and mepivacaine-bupivacaine mixtures are reported to have a rapid onset and long duration; however, it has been shown with chloroprocaine-bupivacaine mixtures that the onset is slower than chloroprocaine, but the duration is shorter than bupivacaine when administered epidurally in obstetrics. The systemic toxicity appears to be additive.

2. Eutectic mixture of local anesthetics (EMLA) cream is a mixture of 2.5% lidocaine and 2.5% prilocaine for use as a topical skin anesthetic. It must be applied to unbroken, healthy skin for at least 30 minutes for an effect.

B. Epinephrine

1. Epinephrine may be added to local anesthetics for the following reasons:

a. To prolong the duration of anesthesia. This varies with the specific agent and its concentration as well as the type of regional block.

b. To decrease systemic toxicity by decreasing the rate of absorption of anesthetic into the circulation, thus minimizing peak blood levels of local anesthetics. Addition of 5 µg for every mL of local anesthetic decreases systemic absorption by up to one third.

c. To increase intensity of the block by a direct α-agonist effect on antinociceptive neurons in the spinal cord.

d. To provide local vasoconstriction and decrease surgical bleeding.

e. To assist in detection of intravascular injections (see Chapter 16, section III.C.2.b).

2. Adding epinephrine (to make a 1:200,000 solution, or 5 µg/mL) to plain solutions of local anesthetics just before administration permits the use of a solution with a high pH, which speeds up the onset of the block. A 1:200,000 dilution is achieved by adding 0.1 mL of 1:1,000 (1 mg/mL) epinephrine (with a tuberculin syringe) to 20 mL of local anesthetic solution.

3. The maximum dose of epinephrine should not exceed 10 µg/kg in pediatric patients and 5 µg/kg in adults to avoid ventricular arrhythmias.

4. Epinephrine should not be used in peripheral nerve blocks in areas with poor collateral blood flow (e.g., digits, penis, and nose) or in intravenous regional techniques. Caution is advised in patients with severe coronary artery disease, arrhythmias, uncontrolled hypertension, and hyperthyroidism.

TABLE 16.2 Clinical Uses of Local Anesthetics

Anesthetics	pK_a	Onset	Duration^a	Relative Toxicity	Officially Recommended Highest Doses (mg)^b	Clinical Use/Comments
Esters
Procaine (Novocaine)	8.9	Slow	Short	Low	500 (600)	Infiltration, spinal Allergic potential
Chloroprocaine (Nesacaine)	9.1	Fast	Short	Low	800 (1,000)	Infiltration, nerve blocks, epidural, spinal Rapid hydrolysis in plasma
Tetracaine (Pontocaine)	8.5	Slow	Long	High	10 (20)	Spinal, topical
Benzocaine	2.5	Moderate	Short	n/a^c	n/a^c	Exclusively for topical use Methemoglobinemia
Amides
Lidocaine (Xylocaine)	7.9	Fast	Medium	Medium	300 (500)	All types of local and regional anesthesia
Prilocaine (Citanest)	7.7	Fast	Medium	Medium	400 (600)	Infiltration, nerve blocks, epidural Methemoglobinemia
Mepivacaine (Carbocaine)	7.6	Fast	Medium	Medium	400 (550)	Infiltration, nerve blocks, epidural, spinal
Bupivacaine (Marcaine, Sensorcaine)	8.1	Moderate	Long	High	175 (225)	All types of local and regional anesthesia Lower concentration provide differential sensory/motor block
L-Bupivacaine (Chirocaine)	8.1	Moderate	Long	High	150 (n/a)	All types of local and regional anesthesia S-isomer of bupivacaine—probably less cardiac toxicity than bupivacaine
Ropivacaine (Naropin)	8.1	Moderate	Long	High	225 (n/a)	Infiltration, nerve blocks, epidural S-isomer enantiomer of bupivacaine—less cardiac toxicity than bupivacaine
Etidocaine (Duranest)	7.7	Moderate	Long	High	300 (400)	Infiltration, nerve blocks, epidural Motor greater than sensory blockade
^aDuration of dose depends on site of administration and proximity to vasculature (see Table 15.3). ^bDose in epinephrine-containing solution in parenthesis. The maximum dose to be employed as a single injection should be determined on the basis of the status of the patient and the type of regional anesthetic technique to be performed. ^c20% spray has a high risk of methemoglobinemia and has been removed from practice by many hospitals in the United States.