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  • image Voltage-gated sodium (Na) channels are membrane-associated proteins that comprising one large α subunit, through which Na ions pass, and one or two smaller β subunits. Na channels exist in (at least) three states—resting (nonconducting), open (conducting), and inactivated (nonconducting). Local anesthetics bind and inhibit a specific region of the α subunit, preventing channel activation and the Na influx associated with membrane depolarization.

  • image Sensitivity of nerve fibers to inhibition by local anesthetics is influenced by axonal diameter, myelination, and other factors.

  • image Clinical local anesthetic potency correlates with octanol solubility and the ability of the local anesthetic molecule to permeate lipid membranes. Potency is increased by adding large alkyl groups to a parent molecule. There is no clinical measurement of local anesthetic potency that is analogous to the minimum alveolar concentration (MAC) of inhalation anesthetics.

  • image Onset of action depends on many factors, including lipid solubility and the relative concentration of the nonionized, more lipid-soluble free-base form (B) and the ionized more water-soluble form (BH+), expressed by the pKa. The pKa is the pH at which there is an equal fraction of ionized and nonionized drug. Less potent, less lipid-soluble agents (eg, lidocaine or mepivacaine) generally have a faster onset than more potent, more lipid-soluble agents (eg, ropivacaine or bupivacaine).

  • image Duration of action correlates with potency and lipid solubility. Highly lipid-soluble local anesthetics have a longer duration of action, presumably because they more slowly diffuse from a lipid-rich environment to the aqueous bloodstream.

  • image In regional anesthesia local anesthetics are typically applied close to their intended site of action; thus their pharmacokinetic profiles in blood are important determinants of elimination and toxicity and have very little to do with the duration of their desired clinical effect.

  • image The rates of local anesthetic systemic absorption and rise of local anesthetic concentrations in blood are related to the vascularity of the site of injection, and generally follow this rank order: intravenous (or intraarterial) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.

  • image Ester local anesthetics are metabolized predominantly by pseudocholinesterase. Amide local anesthetics are metabolized (N-dealkylation and hydroxylation) by microsomal P-450 enzymes in the liver.

  • image In awake patients rising local anesthetic concentrations in the central nervous system produce the premonitory signs of local anesthetic intoxication.

  • image Major cardiovascular toxicity usually requires about three times the local anesthetic concentration in blood as that required to produce seizures.

  • image Unintended intravascular injection of bupivacaine during regional anesthesia may produce severe cardiovascular toxicity, including left ventricular depression, atrioventricular heart block, and life-threatening arrhythmias such as ventricular tachycardia and fibrillation.

  • image True hypersensitivity reactions (due to IgG or IgE antibodies) to local anesthetics—as distinct from systemic toxicity caused by excessive plasma concentrations—are uncommon. Esters appear more likely to induce an allergic reaction, especially if the compound is a derivative (eg, procaine or benzocaine) of p-aminobenzoic acid, a known allergen.

Local and regional anesthesia and analgesia techniques depend on a ...

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