Local anesthetic agents: Pharmacology

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Local anesthetic agents: Pharmacology

Terese T. Horlocker, MD

Local anesthetic agents consist of three major chemical moieties (Figure 116-1): a lipophilic aromatic ring, a hydrophilic tertiary amine, and an ester or amide linkage. Changes in the amine or ring chemical structure result in marked alterations in lipid/aqueous solubility, potency, and protein binding. Local anesthetics are classified into two major groups based on the linkage between the lipophilic and hydrophilic components: amino esters and amino amides. Though they exert their effect by the same mechanism, they are metabolized differently (esters in the blood by pseudocholinesterase; amides by normal hepatic pathways) and have different allergic potential (ester greater than amide). The most commonly used local anesthetic agents and their physiochemical properties are described in Table 116-1.

Table 116-1

Physicochemical/Biologic Properties of Local Anesthetic Agents

  Physicochemical Properties Biologic Properties  
Agent pKa* (25° C) Protein Binding (%) pH, Plain Solutions† Equieffective‡ Anesthetic Concentration Approximate Anesthetic Duration (min) Site of Metabolism Onset‡ Recommended Maximum Single Dose (mg)
Procaine 9.05 6 5-6.5 2 50 Plasma, liver Fast 500
Chloroprocaine 8.97 ? 2.7-4 2 45 Plasma, liver Fast 800 (1000 with epinephrine)
Tetracaine 8.46 75.6 4.5-6.5 0.25 175 Plasma, liver Fast (spinal anesthesia) 20
Lidocaine 7.91 64 6.5 1 100 Liver Intermediate 300 (500 with epinephrine)
Mepivacaine 7.76 77 4.5 1 100 Liver Intermediate 400 (500 with epinephrine)
Prilocaine 7.9 55       Liver, extrahepatic tissue Intermediate 400 (600 with epinephrine)
Etidocaine 7.7 94 4.5 0.25 200 Liver Fast 400 with epinephrine
Bupivacaine (and levobupivacaine) 8.16 96 4.5-6 0.25 175 Liver Slow 175 (225 with epinephrine)
Ropivacaine 8.2 95 4.5-6 0.5 175 Liver Slow 225 (300 with epinephrine)

image

*pH corresponds with 50% ionization.

†Epinephrine-containing solutions have a pH that is 1-1.5 units lower than the pH of plain solutions.

‡When used for a brachial plexus block.

Adapted from Mather LE, Tucker GT. Properties, absorption, and disposition of local anesthetic agents. In: Cousins MJ, Carr DB, Horlocker TT, Bridenbaugh PO, eds. Neural Blockade in Clinical Anesthesia and Management of Pain. 4th ed. Philadelphia, Lippincott Williams & Williams, 2009:48-95; and Rosenberg PH, Veering BT, Urmey WF. Recommended doses of local anesthetics: A multifactorial concept. Reg Anesth Pain Med. 2004;29:264-275.

image
Figure 116-1 Chemical configuration of procaine, lidocaine, and bupivacaine.

Physiochemical properties

Local anesthetics are weak bases with pKa values greater than 7.4. Because the free bases are poorly water soluble, local anesthetics are dispensed as hydrochloride salts. The resulting solutions are acidic with pH values of 4 to 7.

In solution, the local anesthetics exist in equilibrium as ionized and nonionized forms (Figure 116-2). The nonionized (lipid-soluble) base crosses the axonal membrane and, once intracellular, in a more acidic environment, ionizes. The ionized (water-soluble) cation is responsible for neural blockade.

image
Figure 116-2 Local anesthetic substructure. (From O’Brien JE, Abbey V, Hinsvark O, et al. Metabolism and measurement of chloroprocaine, an ester-type anesthetic. J Pharm Sci. 1979;68:75-78.)

Potency is related to lipid solubility—the more lipid soluble the agent is, the more drug enters the axon. Speed of onset is related to pKa as the pKa affects how rapidly the drug ionizes. (Note, however, that the onset of procaine and 2-chloroprocaine blockade [pKa < 9] is rapid because of a high solution concentration and, thus, a greater diffusion gradient.) Duration of action is related to protein binding, which influences blood concentrations and, therefore, how quickly drug is taken up at the site of injection into the blood.

Physiologic disposition

The local anesthetic drugs are absorbed after injection of the local anesthetic agent at the site of administration. Very little metabolism of the ester compounds occurs at the site of injection, but once absorbed, they are metabolized in the blood, and the amides, in the liver. Only small amounts of either are excreted unchanged in the urine.

Esters

Ester local anesthetic agents are metabolized by pseudocholinesterase (plasma cholinesterase) and partially by red blood cell esterases. Hydrolysis occurs at the ester linkage and yields an alcohol and para-aminobenzoic acid (or a PABA) derivative. Because ester local anesthetics are metabolized by pseudocholinesterase, toxicity and duration of blockade may be prolonged in patients with liver disease, in neonates, or in atypical cholinesterase carriers (Table 116-2).

Table 116-2

Half-life of Chloroprocaine

Study Population/Sample No. of Patients/Specimens Half-life (sec)*
Mothers 7 20.9 ± 5.8
Umbilical cords 7 42.6 ± 11.2
Male control subjects 6 20.6 ± 4.1
Female control subjects 5 25.2 ± 3.7
Homozygous–atypical cholinesterase carriers 10 106.0 ± 45.0

*Data are presented as means ± SD.

Results are from O’Brien JE, Abbey V, Hinsvark O, et al. Metabolism and measurement of chloroprocaine, an ester-type anesthetic. J Pharm Sci. 1979;68:75-78.

Chloroprocaine is hydrolyzed four times faster than procaine, and procaine is hydrolyzed four times faster than tetracaine.

Amides

Amide local anesthetic agents are metabolized by the liver. (Prilocaine is also metabolized by extrahepatic tissues.) Three main routes of biotransformation have been identified: aromatic hydroxylation, N-dealkylation, and amide hydrolysis. Clearance of these agents varies in the following order: levobupivacaine < bupivacaine < ropivacaine < mepivacaine < lidocaine < etidocaine < prilocaine.

Liver disease affects metabolism of amide local anesthetic agents while having minimal effects on ester-linked compounds. In patients with severe cirrhosis, the half-life and volume of distribution of lidocaine are increased, whereas clearance is decreased because of decreased enzyme activity and shunting. Liver enzyme–inducing agents, such as barbiturates, increase the systemic clearance of amide local anesthetic agents.

Because these drugs have neurologic and cardiac toxicity, which is related to blood concentration, epinephrine in concentrations of 2.5 to 5 μg/mL should be added to the local anesthetic solution when large doses are administered, providing there are no contraindications to the use of epinephrine. The vasoconstriction caused by epinephrine decreases perfusion at the site of injection, thereby slowing systemic uptake and decreasing toxicity but also prolonging the duration of action. As a rule, conditions (e.g., end-stage pregnancy, increased age for epidural or spinal anesthesia or analgesia) or diseases (uremia) that may increase the rate of the initial uptake of the local anesthetic agent are indications to reduce the dose in comparison to the dose used for young, healthy, and nonpregnant adults. On the other hand, the reduced clearance of local anesthetic agents associated with renal, hepatic, and cardiac diseases is the most important reason to reduce the dose for repeated or continuous administration (Table 116-3). The magnitude of the reduction should be related to the expected influence of the pharmacodynamic or pharmacokinetic change.

Table 116-3

Lidocaine Disposition in Healthy Patients and Those With Various Diseases

Clinical Condition Half-life (h) Vss (L/kg) Clearance (mL·min−1·kg−1)
Normal 1.8 1.32 10.0
Heart failure 1.9 0.88* 6.3*
Liver cirrhosis 4.9* 2.31* 6.0*
Renal disease 1.3 1.2 13.7

image

Vss, the volume of distribution at steady state.

*Values differ significantly in comparison with normal subjects.

From Thompson P, Melmon KL, Richardson JA, Rowland M. Lidocaine pharmacokinetics in advanced heart failure, liver disease and renal failure in humans. Ann Intern Med. 1973; 78:499-508.

Clinical use of local anesthetic agents

Esters

Benzocaine

Benzocaine is almost insoluble in water. Its use is limited to topical applications, as in orotracheal administration. Methemoglobinemia is an adverse effect associated with the use of benzocaine.

Amides

Prilocaine

The most common application of prilocaine in North America is topical (as a component of EMLA cream [eutectic mixture of lidocaine and prilocaine]). Prilocaine is the least toxic of the amides due to its extrahepatic metabolism, but its use has been associated with methemoglobinemia.

Pure isomeric agents

Because cardiopulmonary collapse has been reported following inadvertent intravascular injection of bupivacaine, scientists sought to identify an alternative amide with less cardiac toxicity (though one that would produce similar neural blockade). Importantly, although local anesthetic agents are typically racemic mixtures of two isomers (enantiomers), animal studies have demonstrated that the (S)− isomer is less cardiotoxic than the (R)− isomer. Consequently, more recently developed long-acting amides (ropivacaine and levobupivacaine) have been marketed as a pure isomeric solution.

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