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    Sodium (Na) channels are membrane-bound proteins that are composed of one large α subunit, through which Na ions pass, and one or two smaller β subunits. Voltage-gated Na channels exist in (at least) three states—resting (nonconducting), open (conducting), and inactivated (nonconducting). Local anesthetics bind a specific region of the α subunit and inhibit voltage-gated Na channels, preventing channel activation and the Na influx associated with membrane depolarization.
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    Sensitivity of nerve fibers to inhibition by local anesthetics is determined by axonal diameter, myelination, and other anatomic and physiological factors.
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    Potency correlates with octanol solubility, which in turn reflects 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 measurement of local anesthetic potency that is analogous to the minimum alveolar concentration of inhalation anesthetics.
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    Onset of action depends on many factors, including lipid solubility and the relative concentration of the nonionized lipid-soluble form (B) and the ionized water-soluble form (BH+), expressed by the pKa. The pKa is the pH at which the fraction of ionized and nonionized drug is equal. Less potent, less lipid-soluble agents generally have a faster onset than more potent, more lipid-soluble agents.
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    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.
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    In regional anesthesia local anesthetics are typically injected or applied very close to their intended site of action; thus their pharmacokinetic profiles are much more important determinants of elimination and toxicity than of their desired clinical effect.
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    The rate of systemic absorption is related to the vascularity of the site of injection: intravenous (or intraarterial) > tracheal > intercostal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.
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    Ester local anesthetics are predominantly metabolized by pseudocholinesterase. Amide local anesthetics are metabolized (N-dealkylation and hydroxylation) by microsomal P-450 enzymes in the liver.
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    The central nervous system is vulnerable to local anesthetic toxicity and is the site of premonitory signs of rising blood concentrations in awake patients.
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    Major cardiovascular toxicity usually requires about three times the local anesthetic concentration in blood as that required to produce seizures.
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    Unintentional 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.
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    True hypersensitivity reactions to local anesthetic agents—as distinct from systemic toxicity caused by excessive plasma concentration—are uncommon. Esters appear more likely to induce a true allergic reaction (due to IgG or IgE antibodies) especially if they are derivatives (eg, procaine or benzocaine) of p-aminobenzoic acid, a known allergen.

Local and regional anesthesia and analgesia techniques depend on a group of drugs—local anesthetics—that transiently inhibit sensory, motor, or autonomic nerve function, or a combination of these functions, when the drugs are injected or applied near neural tissue. This chapter presents the mechanism of action, ...

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