Page 476 - Basic _ Clinical Pharmacology ( PDFDrive )

462 SECTION V Drugs That Act in the Central Nervous System

Sodium LA+H + +
channel LAH
Extracellular

LA

Intracellular
LA+H + LAH +
FIGURE 26–1 Schematic diagram depicting paths of local anesthetic (LA) to receptor sites. Extracellular anesthetic exists in equilib-
rium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved
by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to
the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the
membrane (hydrophobic pathway).

pharmacokinetics of the ester-based local anesthetics have not B. Distribution
been extensively studied owing to their rapid breakdown in 1. Localized—As local anesthetic is usually injected directly at
plasma (elimination half-life < 1 minute). the site of the target organ, distribution within this compartment
plays an essential role with respect to achievement of clinical
A. Absorption effect. For example, anesthetics delivered into the subarachnoid
Systemic absorption of injected local anesthetic from the site of space will be diluted with cerebrospinal fluid (CSF) and the pat-
administration is determined by several factors, including dosage, tern of distribution will be dependent upon a host of factors,
site of injection, drug-tissue binding, local tissue blood flow, use among the most critical being the specific gravity relative to that of
of a vasoconstrictor (eg, epinephrine), and the physicochemical CSF and the patient’s position. Solutions are termed hyperbaric,
properties of the drug itself. Anesthetics that are more lipid soluble isobaric, and hypobaric, and will respectively descend, remain
are generally more potent, have a longer duration of action, and relatively static, or ascend, within the subarachnoid space due
take longer to achieve their clinical effect. Extensive protein bind- to gravity when the patient sits upright. A review and analysis
ing also serves to increase the duration of action. of relevant literature cited 25 factors that have been invoked as
Application of a local anesthetic to a highly vascular area such determinants of spread of local anesthetic in CSF, which can be
as the tracheal mucosa or the tissue surrounding intercostal nerves broadly classified as characteristics of the anesthetic solution, CSF
results in more rapid absorption and thus higher blood levels than constituents, patient characteristics, and techniques of injection.
if the local anesthetic is injected into a poorly perfused tissue such Somewhat similar considerations apply to epidural and peripheral
as subcutaneous fat. When used for major conduction blocks, blocks.
the peak serum levels will vary as a function of the specific site of
injection, with intercostal blocks among the highest, and sciatic 2. Systemic—The peak blood levels achieved during major
and femoral among the lowest (Figure 26–2). When vasocon- conduction anesthesia will be minimally affected by the concen-
strictors are used with local anesthetics, the resultant reduction in tration of anesthetic or the speed of injection. The disposition
blood flow serves to reduce the rate of systemic absorption and of these agents can be well approximated by a two-compartment
thus diminishes peak serum levels. This effect is generally most model. The initial alpha phase reflects rapid distribution in blood
evident with the shorter-acting, less potent, and less lipid-soluble and highly perfused organs (eg, brain, liver, heart, kidney), char-
anesthetics. acterized by a steep exponential decline in concentration. This is

TABLE 26–2 Pharmacokinetic properties of several amide local anesthetics.

Agent t 1/2 Distribution (min) t 1/2 Elimination (h) V dss (L) CL (L/min)
Bupivacaine 28 3.5 72 0.47
Lidocaine 10 1.6 91 0.95
Mepivacaine 7 1.9 84 0.78
Prilocaine 5 1.5 261 2.84
Ropivacaine 23 4.2 47 0.44
CL, clearance; V dss , volume of distribution at steady state per 70 kg body weight.