Local anesthetics

Local anesthetics

Clinical data
Pharmacodynamics
Pharmacokinetics
Physical and chemical data
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Local anesthetics are the defining medication class for regional and local anesthesia. They transiently inhibit sensory, motor, and autonomic nerve function depending on location/route of administration and dosage.

Contraindications

Absolute contraindications

• Local anesthetic allergy:
  • True hypersensitivity reactions to local anesthetics (due to IgG or IgE antibodies) are rare
  • Esters are more likely to induce allergic reactivity, especially if compound (procaine or benzocaine) is a derivative of p-aminobenzoic acid (PABA), a known allergen.

Precautions

Drug interactions:

• Succinylcholine and ester local anesthetics both depend on pseudocholinesterase for metabolism, but there is no evidence that this competition has clinical importance. However, pseudocholinesterase inhibitors (organophosphate poisons) and patients with low pseudocholinesterase activity (low dibucaine number) may have decreased metabolism of ester local anesthetics.
• Drugs that decrease hepatic blood flow (H2 receptor blockers, b-blockers) may decrease amide local anesthetic clearance.

Pharmacology

Pharmacodynamics

Mechanism of action

Local anesthetics target voltage-gated sodium channels. Local anesthetic binding to the α subunit prevents channel activation and sodium influx through the channel, resulting in decreased sodium conductance across the membrane. Thus, the threshold for excitation and impulse conduction in the nerve increases, and the rate of rise and magnitude of the action potential decreases. Impulse conduction velocity is also slowed. Of note, this does not alter the resting membrane potential.

Local anesthetics have greatest affinity for the Na channel in the open or inactivated state as opposed to the resting state. Thus, depolarization favors local anesthetic binding.

Sensitivity of nerve fibers to local anesthetics depends on axonal diameter and myelination. Larger, faster-conducting fibers (Aα) are less sensitive to local anesthetics than smaller, slower fibers (Aδ). Additionally, small, unmyelinated C fibers are more resistant than larger myelinated fibers.

Adverse effects

• Systemic absorption
• Local Anesthetic Systemic Toxicity (LAST)

Pharmacokinetics

Absorption of local anesthetics depends on route of administration. The rate of systemic absorption and rise of blood local anesthetic concentration is highly dependent on the vascularity of the site of infection. In general, IV > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous. Presence of additives, such as epinephrine, can decrease amount of systemic absorption and prolong the duration of the effect at the intended site. Lastly, absorption is affected by lipid solubility of the local anesthetic; more lipid-soluble agents (also highly tissue bound) are more slowly absorbed than less lipid-soluble agents.

Chemistry and formulation

Local anesthetics consist of a lipophilic group and a hydrophilic gropu connected by an ester or amide linkage. Thus, there are two major classifications of local anesthetics: esters and amides.

• Esters are predominantly rapidly metabolized by pseudocholinesterases and their water soluble metabolites are excreted in the urine.
• Amides are metabolized by p450s in the liver, and the rate depends on the agent but is overall slower than ester hydrolysis. Decreases in hepatic function or liver blood flow will reduce rate of amide metabolism and predispose these patients to risk of systemic toxicity.

Local anesthetics are weak bases. Their onset depends on their lipid solubility and their pKa. Local anesthetics with a pKa closest to physiologic pH will have a greater fraction of nonionized base that more readily permeates the nerve sheath membrane to bind to the Na channel, hence facilitating a more rapid onset of action. Duration of action correlates with potency and lipid solubility. Highly lipid-soluble local anesthetics have longer duration of action as they more slowly diffuse from a lipid-rich environment to the aqueous bloodstream. In general, less potent, less lipid-soluble agents also have faster onset than more potent, more lipid-soluble agents.