Local Anesthetics

Alisa C. Thorne

The clinically useful local anesthetics are either amino amides or amino esters. These agents are effective when applied topically, injected subcutaneously, or injected in the area of major peripheral nerves.

MECHANISM OF ACTION

Local anesthetics cause a blockade in nerve condition. The local anesthetic diffuses passively through the neuronal cell membrane in the nonionic state, becomes charged, and blocks the sodium channel within the neuron. With sodium conductance inhibited, threshold potential is not reached and an action potential is not generated.

PHARMACOLOGY

The molecular structure of local anesthetic agents consists of an aromatic moiety at one end, an amine moiety at the other end, and an intermediate chain between. The latter contains either an amide or an ester linkage, allowing local anesthetics to be classified as either amides or esters. Commonly used esters are procaine (Novocain), chloroprocaine, tetracaine, and cocaine. Commonly used amides are lidocaine, mepivacaine, prilocaine, bupivacaine (Marcaine), and etidocaine. Differences in the metabolism of local anesthetics, their stability in solution, and differences in allergenicity are all related to the presence of an ester or amide linkage.

Metabolism

Esters undergo hydrolysis in the plasma by pseudocholinesterase, whereas the amides are metabolized in the liver. The rate of metabolism of local anesthetics is related to the number of additional carbon atoms on the aromatic or amine side of the molecule.

Stability in Solution

Esters are unstable in solution. Amides are stable in solution.

Allergenicity

Esters are also more likely to cause allergenic reactions than amides. A true allergic reaction to lidocaine is extremely rare, although many patients will state, incorrectly, that they have such an allergy.

Potency and Toxicity

Potency and toxicity are determined by the structure of the aromatic and the amine group.

ANESTHETIC PROFILE

The profile of a particular local anesthetic agent is related to its lipid solubility, protein binding, acid strength (pKa), and vasodilator activity.

Potency

Anesthetic potency is determined primarily by the degree of lipid solubility. The local anesthetic molecule must penetrate the nerve cell membrane to have an effect. In vitro, hydrophobicity alone determines the potency of a given local anesthetic. In clinical settings, however, other factors, such as vasodilatory activity and the tissue redistribution properties of the different local anesthetics, influence potency to some extent.

Onset of Action.

The onset of action is primarily a result of the pKa, but the dose and the concentration are also factors. In vitro studies confirm the relationship between pKa of a local anesthetic compound and the onset of anesthesia. Lidocaine has a pKa of 7.4 and a more rapid onset of action than tetracaine, which has a pKa of 8.6.

Duration of Action.

In the clinical arena, the duration of local anesthesia is principally influenced by the vasodilator effects of the individual drugs. With the exception of cocaine, all local anesthetics cause some degree of vasodilation. The greater the degree of vasodilation, the greater the amount of the drug that is absorbed by the vascular system, leaving less drug to act on the nerve cell. Therefore, the degree of vasodilation is inversely related to the duration of action. See the section “Addition of Epinephrine.”

Duration and Potency Summary.

In summary, agents with low potency and short duration are procaine (Novocain) and chloroprocaine; agents with moderate potency and duration are lidocaine (Xylocaine), mepivacaine, and prilocaine; agents with a high potency and a long duration are tetracaine, bupivacaine (Marcaine), and etidocaine.

Effect of Total Dose

Other factors determine a local anesthetic agent’s activity in the clinical setting. Total dose is probably the single most important factor in determining satisfactory local anesthesia. Also, as mentioned earlier in the section “Onset of Action,” the greater the dose, other factors being equal, the faster the onset of action.

Addition of Epinephrine

The addition of vasoconstrictors is another factor determining the performance of the local anesthetic. Epinephrine markedly prolongs the duration of action of all local anesthetics when used for local infiltration or peripheral nerve blocks. By decreasing the rate of vascular absorption, vasoconstrictors cause a higher concentration of local anesthetic molecules to be available to act on the nerve cell membrane.

Epinephrine is frequently used in combination with local anesthetics at concentrations of 1:100,000 or 1:200,000. In fact, epinephrine is probably equally effective at much lower doses (1:1,000,000) and might decrease the danger of an intravascular injection.

Location of Injection

The anatomy of the site of injection also has a role in determining the activity of a local anesthetic. Intradermal injection allows for the most rapid onset of action but the shortest duration of these agents, whereas brachial plexus block injections yield some of the longest durations and slowest onsets of action seen with local anesthetics. Although intradermal injection provides the most rapid onset, it is more painful than subcutaneous injection.

PERIPHERAL NERVE BLOCKS

There are two general types of peripheral nerve blockade: major and minor. Blocks of individual nerves, such as radial nerve block, are referred to as minor, and blocks of two or more nerves or a plexus of nerves are called major nerve blocks. A wide variety of local anesthetics can be used for minor nerve blocks. The drug is usually selected based on the duration of anesthesia that is required. The duration of action of minor nerve blockade is prolonged by the addition of epinephrine to the local anesthetic solution.

A commonly used major nerve block is the brachial plexus (or axillary) block (see Chapter 71). Although the onset of action for minor nerve blocks is generally rapid for all the local anesthetics, there are differences in onset between the various anesthetic agents when major nerve blocks are performed. Epinephrine, in general, will prolong the duration of brachial plexus blockade. The longer acting local anesthetics do not demonstrate as much prolongation of action with epinephrine as do the shorter acting agents. Tables 12.1 and 12.2 show the maximal dose, onset, and duration of action of the commonly used local anesthetics for minor and major nerve blocks.

TOPICAL ANESTHESIA

Topical anesthesia is increasingly important in pediatric intravenous insertion and is used by some surgeons to lessen the discomfort of injectables such as Restylane and Botox. These topical agents will provide dermal anesthesia if applied far enough in advance but do nothing to lessen the burning associated with subcutaneous injection.

Eutectic mixture of local anesthetics (EMLA) is a combination of 25 mg lidocaine and 50 mg prilocaine per gram of EMLA. L-M-X4 contains 4% lidocaine per gram. These formulations decrease pain secondary to intravenous insertion and also provide adequate analgesia for split-thickness skin graft harvesting. L-M-X4 may have a slightly faster onset but both preparations are best applied between 30 and 60 minutes prior to the procedure and are best covered with an occlusive dressing such as Tegaderm or OpSite.

Several other topical local anesthesia preparations are available that provide brief periods of anesthesia when they are applied to mucous membranes or abraded skin. The most common local anesthetic agents used topically are lidocaine, dibucaine, tetracaine, and benzocaine.

TABLE 12.1 DOSAGE AND DURATION CHARACTERISTICS OF THE LOCAL ANESTHETICS WHEN USED FOR MINOR NERVE BLOCKS (E.G., MEDIAN NERVE BLOCK AT THE WRIST)

		PLAIN SOLUTIONS			EPINEPHRINE-CONTAINING SOLUTIONS
▪	DRUG	▪ USUAL CONCENTRATION (%)	▪ USUAL VOLUME (ML)	▪ DOSAGE (MG)	▪ AVERAGE DURATION (MIN)	▪ AVERAGE DURATION (MIN)
	Procaine	2	5-20	100-400	15-30	30-60
	Chloroprocaine
	Lidocaine
	Mepivacaine	1	5-20	50-200	60-120	120-180
	Prilocaine
	Bupivacaine	0.25	5-20	12.5-50	180-360	240-480
	Etidocaine	0.5	5-20	25-100	120-240	180-420
Reprinted with permission from Strichartz GR, Covino BG. Local anesthetics. In: Miller RD, ed. Anesthesia. 4th ed. New York, NY: Churchill Livingstone; 1994.