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  • Image not available.Most local anesthetics block voltage-gated sodium channels from inside the cell, preventing subsequent channel activation and interfering with the large transient sodium influx associated with membrane depolarization. Impulse conduction slows, the rate of rise and the magnitude of the action potential decrease, and the threshold for excitation is raised progressively until an action potential can no longer be generated and impulse propagation is abolished.
  • Image not available.Not all nerve fibers are equally affected by local anesthetics. Sensitivity to blockade is determined by axonal diameter, degree of myelination, and various other anatomic and physiological factors.
  • Image not available.Potency correlates with lipid solubility, that is, the ability of the local anesthetic molecule to penetrate membranes, a hydrophobic environment.
  • Image not available.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. Local anesthetics with a pKa closest to physiological pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset.
  • Image not available.Duration of action is generally correlated with lipid solubility. Highly lipid-soluble local anesthetics have a longer duration of action, presumably because they are less likely to be cleared by blood flow.
  • Image not available.Because local anesthetics are typically injected or applied very close to their intended site of action their pharmacokinetic profiles are generally more important determinants of elimination and toxicity than is their desired clinical effect.
  • Image not available.The rate of systemic absorption is proportionate to the vascularity of the site of injection: intravenous > tracheal > intercostal > caudal > paracervical > epidural > brachial plexus > sciatic > subcutaneous.
  • Image not available.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.
  • Image not available.The central nervous system is the site of premonitory signs of overdose in awake patients. Early symptoms are circumoral numbness, tongue paresthesia, and dizziness. Sensory complaints may include tinnitus and blurred vision. Excitatory signs (eg, restlessness, agitation, nervousness, paranoia) often precede central nervous system depression (eg, slurred speech, drowsiness, unconsciousness). Muscle twitching heralds the onset of tonic–clonic seizures.
  • Image not available.Major cardiovascular toxicity usually requires about three times the concentration of blood that produces seizures. Cardiac arrhythmia or circulatory collapse is therefore the usual presenting sign of local anesthetic overdose during general anesthesia.
  • Image not available.Unintentional intravascular injection of bupivacaine during regional anesthesia produces severe cardiotoxic reactions, including hypotension, atrioventricular heart block, idioventricular rhythms, and life-threatening arrhythmias such as ventricular tachycardia and fibrillation.
  • Image not available.True hypersensitivity reactions to local anesthetic agents—as distinct from systemic toxicity caused by excessive plasma concentration—are quite uncommon. Esters are more likely to induce an allergic reaction because they are derivatives of p-aminobenzoic acid, a known allergen.

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Local and regional anesthesia techniques depend on a group of drugs—local anesthetics—that produces transient loss of sensory, motor, and autonomic function when the drugs are injected or applied in proximity to neural tissue. This chapter presents the mechanism of action, structure–activity relationships, and clinical ...

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