Local Anesthetic: Pharmacokinetics

CLINICAL PHARMACOLOGY

Pharmacokinetics

In regional anesthesia local anesthetics are typically injected or applied very close to theirintended site of action; thus their pharmacokinetic profiles are much more important determinants of elimination and toxicity than of their desired clinical effect.

A. Absorption

Most mucous membranes (eg, ocular conjunctiva, tracheal mucosa) provide a minimal barrier to local anesthetic penetration, leading to a rapid onset of action. Intact skin, on the other hand, requires a high concentration of lipid-soluble local anesthetic base to ensure permeation and analgesia. EMLA cream consists of a 1:1 mixture of 5% lidocaine and 5% prilocaine bases in an oil-in-water emul-sion. Dermal analgesia sufficient for beginning an intravenous line requires a contact time of at least 1 h under an occlusive dressing. Depth of penetra-tion (usually 3–5 mm), duration of action (usually 1–2 h), and amount of drug absorbed depend on application time, dermal blood flow, keratin thick-ness, and total dose administered. Typically, 1–2 g of cream is applied per 10-cm² area of skin, with a maximum application area of 2000 cm² in an adult (100 cm² in children weighing less than 10 kg). Split-thickness skin-graft harvesting, laser removal of portwine stains, lithotripsy, and circumcision have been successfully performed with EMLA cream. Side effects include skin blanching, erythema, and edema. EMLA cream should not be used on mucous membranes, broken skin, infants younger than 1 month of age, or patients with a predisposi-tion to methemoglobinemia (see Biotransformation and Excretion, below).

Systemic absorption of injected local anes-thetics depends on blood flow, which is determined by the following factors.

1. Site of injection—The rate of systemicabsorption is related to the vascularity of thesite of injection: intravenous (or intraarterial) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.

Presence of vasoconstrictors—Addition of epi-nephrine—or less commonly phenylephrine— causes vasoconstriction at the site of administration. The consequent decreased absorption reduces the peak local anesthetic concentration in blood, facilitates neuronal uptake, enhances the qual-ity of analgesia, prolongs the duration of action, and limits toxic side effects. Vasoconstrictors have more pronounced effects on shorter-acting than longer-acting agents. For example, addition of epi-nephrine to lidocaine usually extends the duration of anesthesia by at least 50%, but epinephrine has little or no effect on the duration of bupivacaine peripheral nerve blocks. Epinephrine and clonidinecan also augment analgesia through activation of α₂-adrenergic receptors.

Local anesthetic agent—More lipid-soluble localanesthetics that are highly tissue bound are also more slowly absorbed. The agents also vary in their intrinsic vasodilator properties.

B. Distribution

Distribution depends on organ uptake, which is determined by the following factors.

Tissue perfusion—The highly perfused organs(brain, lung, liver, kidney, and heart) are respon-sible for the initial rapid uptake (α phase), which is followed by a slower redistribution (β phase) to moderately perfused tissues (muscle and gut). In particular, the lung extracts significant amounts of local anesthetic; consequently, the threshold for sys-temic toxicity involves much lower doses following arterial injections than venous injections (and chil-dren with right-to-left shunts are more susceptible to toxic side effects of lidocaine injected as an antiar-rhythmic agent).

Tissue/blood partition coefficient—Increasinglipid solubility is associated with greater plasma pro-tein binding and also greater tissue uptake from an aqueous compartment.

Tissue mass—Muscle provides the greatest reser-voir for distribution of local anesthetic agents in the bloodstream because of its large mass.

C. Biotransformation and Excretion

The biotransformation and excretion of local anes-thetics is defined by their chemical structure.

1. Esters—Ester local anesthetics are predom-inantly metabolized by pseudocholinesterase(plasma cholinesterase or butyrylcholinesterase). Ester hydrolysis is very rapid, and the water-soluble metabolites are excreted in the urine. Procaine and benzocaine are metabolized to p-aminobenzoic acid (PABA), which has been associated with rare anaphylactic reactions. Patients with genetically abnormal pseudocholinesterase would theoretically be at increased risk for toxic side effects, as metabo-lism is slower, but clinical evidence for this is lacking. Cerebrospinal fluid lacks esterase enzymes, so the termination of action of intrathecally injected ester local anesthetics, eg, tetracaine, depends on their redistribution into the bloodstream, as it does for all other nerve blocks. In contrast to other ester anesthetics, cocaine is partially metabolized (N-methylation and ester hydrolysis) in the liver and partially excreted unchanged in the urine.

2. Amides—Amide local anesthetics are metabo-lized (N-dealkylation and hydroxylation) by micro-somal P-450 enzymes in the liver. The rate of amide metabolism depends on the specific agent (prilo-caine > lidocaine > mepivacaine > ropivacaine > bupivacaine) but overall is consistently slower than ester hydrolysis of ester local anesthetics. Decreases in hepatic function (eg, cirrhosis of the liver) or liver blood flow (eg, congestive heart failure, β blockers, or H₂-receptor blockers) will reduce the metabolic rate and potentially predispose patients to having greater blood concentrations and a greater risk of systemic toxicity. Very little unmetabolized local anesthetic is excreted by the kidneys, although water-soluble metabolites are dependent on renal clearance.

Prilocaine is the only local anesthetic that is metabolized to o-toluidine, which produces met-hemoglobinemia in a dose-dependent fashion. Classical teaching was that a defined minimal dose of prilocaine was needed to produce clini-cally important methemoglobinemia (in the range of 10 mg/kg); however, recent studies have shown that younger, healthier patients develop medically important methemoglobinemia after lower doses of prilocaine (and at lower doses than needed in older, sicker patients). Prilocaine is generally not used for epidural anesthesia during labor or in larger doses in patients with limited cardiopulmonary reserve.

Benzocaine, a common ingredient in topical local anesthetic sprays, can also cause danger-ous levels of methemoglobinemia. For this rea-son, many hospitals no longer permit benzocaine spray during endoscopic procedures. Treatment of medically important methemoglobinemia includes intravenous methylene blue (1–2 mg/kg of a 1% solution over 5 min). Methylene blue reduces met-hemoglobin (Fe³⁺) to hemoglobin (Fe²⁺).