Local Anesthetics and Adjuvant Analgesics

Local anesthetics are synthetic derivatives of cocaine, a plant alkaloid obtained from the leaves of the South American coca plant, and the first local anesthetic to be discovered. Cocaine is a benzoic acid derivative coupled to a tertiary amine compound by an ester linkage. It is a weak base that is poorly soluble in water. Similarly, all local anesthetics contain a lipophilic benzoic acid derivative linked to a hydrophilic tertiary amine by an ester or amide chain and exist in ionized (cationic) and unionized forms (weak base). The lipophilic and hydrophilic components of local anesthetics enable their penetration into both lipid and aqueous membranes. It is this property that permits local anesthetics to traverse perineurium and axonal walls and block neural transmission without affecting cellular function or metabolism. Sodium conductance (i.e., depolarization) is prevented when an adequate concentration and volume of local anesthetic surround the nerve. The external opening of the Na+ channel is not the site of action of local anesthetics. Rather, the lipophilic, uncharged base form of the local anesthetic penetrates the neuronal cell wall and reaches the axoplasm where it exists in equilibrium as both a charged ionized salt and an uncharged base. The relative concentration of these forms depends on the tissue pH and the pKa of the compound. Once in the axoplasm, the charged base or cationic form enters the internal opening of the sodium channel and blocks Na+ conductance.

Local anesthetic metabolism is determined by the chemical linkage ( Fig. 34.1 ). Those with an ester linkage are metabolized by plasma esterases and those with an amide linkage are metabolized in the liver. Compounds with ester linkages are more likely to cause allergic reactions. The degree of lipid solubility of a local anesthetic determines its potency because the neuronal cell wall is a lipid structure. However, the relationship between lipid solubility and potency is not linear. The onset of action of a local anesthetic is correlated with its specific dissociation constant, or pKa, the pH at which 50% of the drug is present as the uncharged base and 50% as the cationic form. Only the unionized base can penetrate the cell wall. All local anesthetics have a pKa greater than 7.4. The lower the pKa of a local anesthetic, the greater the number of uncharged molecules available to traverse the lipid cell membrane, and the more rapid its onset of action.

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Local anesthetic structural classification. (A) Amide linkage of lidocaine (B) and ester linkage of procaine. (From Suzuki S, Gerner P, Lirk P.

Local anesthetics. In: Hemmings HC Jr, Egan TD, eds. Pharmacology and Physiology for Anesthesia . 2nd ed. Elsevier: 2019:390–411.)

The duration of action of a local anesthetic is determined by its protein binding capacity. After traversing lipid membranes, the local anesthetic enters the Na+ channel, a protein structure, to exert its pharmacologic effect. Therefore duration of action is directly correlated with degree of protein binding.

Frequency-dependent blockade is another important characteristic of local anesthetics. Most local anesthetics enter the Na+ channel only when it is open during depolarization. Thus neurons with high-frequency depolarization (i.e., sensory and pain fibers) are more readily blocked than fibers that have low-frequency depolarization (i.e., motor nerves).

Local anesthetic systemic toxicity (LAST) is the most feared complication of using regional anesthesia as it may result in side effects ranging from mild, transient symptoms to permanent disability or even death. Other reactions to local anesthetics include allergies and neurotoxicity. The best treatment of these problems is through prevention. However, this might not always be possible, so it is important to know the consensus statements published by the American Society of Regional Anesthesia and Pain Medicine.

Rare allergic reactions are mainly associated with ester local anesthetics, which are metabolized by plasma esterases to form para-aminobenzoic acid (PABA), the probable allergenic component. PABA is present in sunscreens and it is recommended that ester local anesthetics not be administered to patients with a history of sunscreen allergy. Skin testing is available to diagnose true local anesthetic allergy. The amide local anesthetics are safe in patients with a true allergy to ester anesthetics as cross-reactivity between ester and amide local anesthetics has not been demonstrated.

Every local anesthetic is capable of producing neurotoxicity. However, this complication is rare. True local anesthetic neurotoxicity is usually mild and resolves completely over time. More common is a neuropathy that follows a nerve injury because of needle trauma or a direct intraneural injection of epinephrine-containing local anesthetics in high concentrations. Lidocaine 5% for spinal anesthesia has been a particular concern because of its association with transient neurologic symptoms (TNS). This syndrome is characterized by the appearance of back pain that radiates to the buttocks within 24 hours of the block, the absence of motor and sensory deficits, and resolution within 3 to 10 days. The lowest effective concentration of local anesthetic should be used when performing any regional block.