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The successful use of regional anesthesia requires knowledge of the pharmacologic properties of the various local anesthetics, as well as technical skill in performance of the nerve block. Local anesthetic requirements vary considerably and depend on factors such as the type of block, the surgical procedure, and the physiologic status of the patient.
Commonly used aminoester local anesthetics include procaine, chloroprocaine, tetracaine, and cocaine. Commonly used aminoamides include lidocaine, mepivacaine, prilocaine, bupivacaine (racemic and its levo enantiomer), ropivacaine, and etidocaine. The ester and amide local anesthetics differ in their chemical stability, locus of biotransformation, and allergic potential. Amides are extremely stable, whereas esters are relatively unstable in solution. The aminoesters are hydrolyzed in plasma by cholinesterase enzymes, whereas the amide compounds undergo enzymatic degradation in the liver. Two exceptions to this trend include cocaine, an ester that is metabolized predominantly by hepatic carboxylesterase, and articaine, an amide local anesthetic widely used in dentistry that is inactivated by plasma carboxyesterase-induced cleavage of a methyl ester on the aromatic ring.
p-Aminobenzoic acid is one of the metabolites of ester-type compounds that can induce allergic-type reactions in a small percentage of patients. The aminoamides are not metabolized to p-aminobenzoic acid, and reports of allergic reactions to these agents are extremely rare.
The clinically important properties of the various local anesthetics include potency, speed of onset, duration of anesthetic action, and differential sensory/motor blockade. As previously indicated, the profile of the individual drugs is determined by their physicochemical characteristics ( Table 14-2 ).
Hydrophobicity appears to be a primary determinant of intrinsic anesthetic potency[5] [28] [29] [30] because the anesthetic molecule must penetrate the nerve membrane and bind at a partially hydrophobic site on the Na+ channel. Clinically, however, the correlation between hydrophobicity and anesthetic potency is not as precise as in an isolated nerve. For example, etidocaine is more potent than bupivacaine in an isolated nerve, but it is actually less potent than bupivacaine in vivo.[31] [32] [33] Differences between in vitro and in vivo potency may be related to a number of factors, including local anesthetic charge and hydrophobicity (which influence partitioning into and transverse diffusion across biologic membranes) and vasodilator or vasoconstrictor properties (which influence the initial rate of vascular uptake from injection sites into the central circulation).
The onset of conduction block in isolated nerves is related to the physicochemical properties of the individual drugs. In vivo latency is also dependent on the dose or concentration of local anesthetic used. For example, 0.25% bupivacaine possesses a rather slow onset of action, but increasing the concentration to 0.75% results in a significant acceleration of anesthetic effect.[33] Chloroprocaine demonstrates a rapid onset of action in humans despite the fact that its pKa is approximately 9; its proportion of charged molecules is high (97%), and thus its onset of action in isolated nerves is relatively slow.[34] However, the low systemic toxicity of this drug allows its use in high concentrations (e.g., 3%). Therefore, the rapid onset of chloroprocaine in vivo may be related simply to mass diffusion as a result of the large number of molecules placed in the vicinity of peripheral nerves. In humans, 1.5% lidocaine produces a more rapid onset of epidural anesthesia than 1.5% chloroprocaine does[35] ; however, 3% chloroprocaine results in more rapid onset than 2% lidocaine does.
The duration of action of the various local anesthetics differs markedly. Procaine and chloroprocaine have a short duration of action. Lidocaine, mepivacaine, and prilocaine produce a moderate duration of anesthesia, whereas tetracaine, bupivacaine, and etidocaine have the longest durations. For example, with procaine the duration of brachial plexus blockade is 30 to 60 minutes, whereas up to approximately 10 hours of anesthesia has been reported for brachial plexus blockade induced by bupivacaine or etidocaine.[36]
In humans, the duration of anesthesia is markedly influenced by the peripheral vascular effects of the local anesthetic. Many local anesthetics have a biphasic effect on vascular smooth muscle: at low concentrations they tend to cause vasoconstriction, whereas at larger, clinically administered concentrations, they cause vasodilation.[37] [38] However, differences exist in the degree of vasodilator activity of the various drugs. For example, lidocaine is a more potent vasodilator than mepivacaine or prilocaine. Although little difference in the rate of recovery from conduction block is apparent between these agents in an isolated nerve, in vivo, the anesthesia produced by lidocaine is of shorter duration than that produced by mepivacaine or prilocaine. In the spinal cord, the pial vessels are dilated by bupivacaine but constricted by ropivacaine, thus suggesting a stereoselective effect on vascular tone independent of nerve block per se.[39]
Effects of local anesthetics on vascular tone and regional blood flow are complex and vary according to concentration, time, and the particular vascular bed near the site of application, among other factors. As a practical example, the topical local anesthetic formulation EMLA (eutectic mixture of the local anesthetics lidocaine and prilocaine) vasoconstricts cutaneous vessels initially and throughout most of the first hour of application, but vasodilation is observed after 2 or more hours of application.
Another important clinical consideration is the ability of local anesthetics to cause differential inhibition of sensory and motor activity. Bupivacaine became popular in the 1980s for epidural blockade because it was better than previously available drugs in producing adequate antinociception without profound inhibition of motor activity, particularly when dilute solutions are used. Bupivacaine and etidocaine provide an interesting contrast in their differential sensory- and motor-blocking activity, although they are both potent, long-acting anesthetics.[40] Bupivacaine is widely used epidurally for obstetric analgesia and postoperative pain management because it can provide acceptable analgesia with only mild muscle weakness, particularly when used for infusions in concentrations of 0.125% or less (also see Chapter 43 Chapter 44 Chapter 45 and Chapter 58 ). When given by epidural bolus dosing, bupivacaine produces more effective sensory than motor blockade over a concentration range from 0.25% to 0.75%, whereas etidocaine produces almost equal effective sensory and motor blockade over this concentration range.
Traditional texts often state that small-diameter axons, such as C fibers, are more susceptible to local anesthetic blockade than larger-diameter fibers are. However, when careful measurements are made of single-impulse annihilation in individual nerve fibers, exactly the opposite differential susceptibility is seen (see earlier).[41] [42] Repetitive stimulation, such as occurs during propagation of trains of impulses, produces a further, phasic inhibition of excitability, but it is unclear how this inhibition will effect a functionally selective failure of impulses. The length of drug-exposed nerve in the intrathecal space, imposed by anatomic restrictions, can perhaps explain clinically documented differential spinal or epidural blockade [43] because longer drug-exposed regions yield block by lower concentrations of local anesthetic.[44] However, this reasoning does not explain the functionally differential loss from peripheral nerve block. Other factors may include actual spread of the drug along the nerve[45] or its selective ability to inhibit Na+ channels over K+ channels,[46] which in itself can produce a differential block because these channels are present in very different proportions in different types of nerves.[47] Because of these confounding factors, clinicians should be discouraged from making conclusions about fiber-type involvement in chronic pain syndromes based on the dose or concentration needed for pain relief in diagnostic nerve blockade.[48]
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