- 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
- 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
- Potency correlates with lipid solubility, that
is, the ability of the local anesthetic molecule to penetrate membranes,
a hydrophobic environment.
- 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.
- 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.
- 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.
- 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.
- Ester local anesthetics are predominantly metabolized
by pseudocholinesterase. Amide local anesthetics are metabolized
(N-dealkylation and hydroxylation) by microsomal P-450 enzymes in the
- 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.
- 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.
- 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
- 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.
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 ...