Chapter 8 Local Anesthetics
Structure activity relationships
2. What is the basic structure of local anesthetics?
3. Why are local anesthetics marketed as hydrochloride salts?
4. What are two differences between ester and amide local anesthetics that make classifying local anesthetics important?
5. Name four ester local anesthetics.
6. Name seven amide local anesthetics.
7. What is an easy way to remember whether a local anesthetic is an ester or an amine?
Mechanism of action
8. What is the mechanism of action of local anesthetics?
9. Where is the major site of local anesthetic effect?
10. How is the effect of a local anesthetic on the nerve terminated?
11. How is the resting membrane potential and the threshold potential altered in nerves that have been infiltrated by local anesthetic?
12. What is the temporal progression of the interruption of the transmission of neural impulses between the autonomic nervous system, motor system, and sensory system after the infiltration of a mixed nerve with local anesthetic?
13. What is frequency-dependent blockade? How does frequency-dependent blockade relate to the activity of local anesthetics?
Classification of nerves and sensitivity to local anesthetics
14. What three characteristics are nerve fibers classified by? What are the three main nerve fiber types?
15. Which types of nerve fibers are myelinated? What is the function of myelin and how does it affect the action of local anesthetics?
16. How many consecutive nodes of Ranvier must be blocked for the effective blockade of the nerve impulse by local anesthetic?
17. Which two nerve fiber types primarily function to conduct sharp and dull pain impulses? Which of these two nerve fibers is more readily blocked by local anesthetic?
18. Which two nerve fiber types primarily function to conduct impulses that result in large motor and small motor activity?
19. What is meant by differential block? Name an anesthetic that has had limited use because of its poor sensory selectivity.
20. How do local anesthetics diffuse through nerve fibers when deposited around a nerve? Which nerve fibers are blocked first as a result?
Spread of anesthesia and peripheral nerve blockade
21. How are the nerve fibers arranged from the mantle to the core in a peripheral nerve with respect to the innervation of proximal and distal structures? How does this correlate with the temporal progression of local anesthetic-induced blockade of proximal and distal structures?
22. What very fundamental difference exists between the local anesthetics and most systemically administered drugs?
Pharmacokinetics
23. Is the pKa of local anesthetics more than or less than 7.4?
24. At physiologic pH, does most local anesthetic exist in the ionized or nonionized form? What form must the local anesthetic be in to cross nerve cell membranes?
25. Does local tissue acidosis create an environment for higher or lower quality local anesthesia? Why?
26. What is the primary determinant of local anesthetic potency?
27. After a local anesthetic has been absorbed from the tissues, what are the primary determinants of local anesthetic peak plasma concentrations?
28. How are ester local anesthetics cleared?
29. How are the amide local anesthetics metabolized?
30. What percent of local anesthetic undergoes renal excretion unchanged?
31. What are two organs that influence the potential for local anesthetic systemic toxicity?
32. What accounts for chloroprocaine’s relatively low systemic toxicity?
33. Patients with atypical plasma cholinesterase are at an increased risk for what complication with regard to local anesthetics?
34. What disease states may influence the rate of clearance of lidocaine from the plasma?
35. How extensive is renal excretion of the parent local anesthetic compound?
36. How does the addition of epinephrine or phenylephrine to a local anesthetic solution prepared for injection affect its systemic absorption?
37. How does the addition of epinephrine or phenylephrine to a local anesthetic solution prepared for injection affect its duration of action?
38. How does the addition of epinephrine or phenylephrine to a local anesthetic solution prepared for injection affect its potential for systemic toxicity?
39. How does the addition of epinephrine or phenylephrine to a local anesthetic solution prepared for injection affect the rate of onset of anesthesia?
40. How does the addition of epinephrine or phenylephrine to a local anesthetic solution prepared for injection affect local bleeding?
41. What are some potential negative effects of the addition of epinephrine to a local anesthetic solution prepared for injection?
42. Name some situations in which the addition of epinephrine to a local anesthetic solution prepared for injection may not be recommended.
Side effects
43. What are some potential negative side effects associated with the administration of local anesthetics?
44. What is the most common cause of local anesthetic systemic toxicity?
45. What are the factors that influence the magnitude of the systemic absorption of local anesthetic from the tissue injection site?
46. From highest to lowest, what is the relative order of peak plasma concentrations of local anesthetic associated with the following regional anesthetic procedures: brachial plexus, caudal, intercostal, epidural, sciatic/femoral?
47. Which two organ systems are most likely to be affected by excessive plasma concentrations of local anesthetic?
48. What are the initial and subsequent manifestations of central nervous system toxicity due to increasingly excessive plasma concentrations of local anesthetic?
49. What is a possible pathophysiologic mechanism for seizures that result from excessive plasma concentrations of local anesthetic?
50. What are some potential adverse effects of local anesthetic-induced seizures?
51. How should local anesthetic-induced seizures be treated?
52. What is the indication for and disadvantage of the administration of neuromuscular blocking drugs for the treatment of seizures?
53. Is the cardiovascular system more or less susceptible to local anesthetic toxicity than the central nervous system?
54. What are two mechanisms by which local anesthetics produce hypotension?
55. What is the mechanism by which local anesthetics exert their cardiotoxic effects? How is this manifested on the electrocardiogram?
56. How is the relative cardiotoxicity between local anesthetic agents compared? What is the relative cardiotoxicity between lidocaine, bupivacaine, and ropivacaine?
57. How does bupivacaine differ from lidocaine with respect to their cardiotoxic effects, and what underlying electrophysiologic differences exist between lidocaine and bupivacaine that might contribute to their differing clinical toxicities?
58. What is the maximum recommended concentration of bupivacaine to be administered for obstetric epidural anesthesia? Why?
59. What relatively simple and apparently effective therapy for treatment of systemic local anesthetic toxicity has been recently introduced into clinical practice? What appears to be its predominant mechanism of action?
60. The administration of which local anesthetics have been associated with methemoglobinemia? What is the mechanism by which this occurs? How can it be treated?
61. What is the nature of the neurotoxicity that has been reported in association with the use of chloroprocaine? What is the mechanism by which this occurs?
63. What is the mechanism by which local anesthetics have resulted in cauda equina syndrome?
64. What changes have been recommended with respect to the dose of lidocaine used for spinal anesthesia?
65. What changes in practice have occurred with respect to the relative use of lidocaine for spinal anesthesia?
66. What is the allergenic potential of local anesthetics? What are the potential causes of an allergic reaction associated with administration of local anesthetics?
67. Does cross-sensitivity exist between the classes of local anesthetics?
Clinical uses
Answers*
Structure activity relationships
2. Local anesthetics consist of a lipophilic end and a hydrophilic end connected by a hydrocarbon chain. The lipophilic end is an aromatic ring, and the hydrophilic end is a tertiary amine and proton acceptor. The bond that links the hydrocarbon chain to the lipophilic end of the structure is either an ester (—CO—) or an amide (—HNC—). The local anesthetic is thus classified as either an ester or an amide local anesthetic. (131, Figure 11-2)
3. Local anesthetics are bases that are poorly water-soluble. For this reason they are marketed as hydrochloride salts. The resulting solution is generally slightly acidic with a pH of about 6. (133)
4. The metabolism and possibly the potential to produce allergic reactions differ between ester and amide local anesthetics, making this classification of local anesthetics important. (131)
5. The ester local anesthetics include procaine, chloroprocaine, cocaine, and tetracaine. (132, Figure 11-3)
6. The amide local anesthetics include lidocaine, mepivacaine, bupivacaine, levobupivacaine, etidocaine, prilocaine, and ropivacaine. (132, Figure 11-3)
7. As a general rule, ester local anesthetics will have only one “i” in their generic name, while the amides will have two. (132, Figure 11-3)
Mechanism of action
8. Local anesthetics act by producing a conduction blockade of neural impulses in the affected nerve. This is accomplished through the prevention of the passage of sodium ions through ion-selective sodium channels in the nerve membranes. The inability of sodium ions to pass through their ion selective channels results in slowing of the rate of depolarization. As a result, the threshold potential is not reached and an action potential is not propagated. (131)
9. Local anesthetics are thought to exert their predominant action on the nerve by binding to a specific receptor on the sodium ion channel. The location of the binding site appears to be within the inner vestibule of the sodium channel. (131)
10. The conduction blockade produced by a local anesthetic is normally completely reversible (i.e., reversal of the blockade is spontaneous, predictable, and complete). (130)
11. Neither the resting membrane potential nor the threshold potential is appreciably altered by local anesthetics. (131)
12. The temporal progression of the interruption of the transmission of impulses is autonomic, sensory, and then motor nerve blockade. This yields a temporal progression of autonomic nervous system blockade, then sensory nervous system blockade, followed by skeletal muscle paralysis. (135)
13. According to the modulated receptor model, sodium ion channels alternate between several conformational states, and local anesthetics bind to these different conformational states with different affinities. During excitation, the sodium channel moves from a resting-closed state to an activated-open state, with passage of sodium ions and consequent depolarization. After depolarization, the channel assumes an inactivated-closed conformational state. Local anesthetics bind to the activated and inactivated states more readily than the resting state, attenuating conformational change. Drug dissociation from the inactivated conformational state is slower than from the resting state. Thus, repeated depolarization produces more effective anesthetic binding. The electrophysiologic consequence of this effect is progressive enhancement of conduction blockade with repetitive stimulation, an effect referred to as use-dependent or frequency-dependent block. For this reason, selective conduction blockade of nerve fibers by local anesthetics may in part be related to the characteristic frequency of activity of the nerve. (132-133)
Classification of nerves and sensitivity to local anesthetics
14. Fiber diameter, the presence or absence of myelin, and function are the three characteristics by which nerve fibers are classified. A, B, and C are the three main types of nerve fibers. (133, 135, Table 11-2)
15. The A and B nerve fiber types are myelinated. Myelin is composed of plasma membranes of specialized Schwann cells that wrap around the axon during axonal growth. Myelin functions to insulate the axolemma, or nerve cell membrane, from the surrounding conducting media. It also forces the depolarizing current to flow through periodic interruptions in the myelin sheath called the nodes of Ranvier. The sodium channels that are instrumental in nerve pulse propagation and conduction are concentrated at these nodes of Ranvier. Myelin increases the speed of nerve conduction and makes the nerve membrane more susceptible to local anesthetic-induced conduction blockade. (133, 135, Table 11-2)
16. In general, three consecutive nodes of Ranvier must be exposed to adequate concentrations of local anesthetic for the effective blockade of nerve impulses to occur. (135)
17. The nerve fiber type A-δ, which is myelinated, conducts sharp or fast/first pain impulses. The nerve fiber type C, which is unmyelinated, conducts dull burning pain impulses. The large diameter type A-δ fiber appears to be more sensitive to blockade than the smaller diameter type C fiber. This lends support to the theory that myelination of nerves has a greater influence than nerve fiber diameter on the conduction blockade produced by local anesthetics. In clinical practice, however, the relatively high concentrations of local anesthetic that are generally achieved will overcome this difference. (135, Table 11-2)
18. The nerve fiber types A-α and A-β, which are both myelinated, conduct motor nerve impulses. The nerve fiber type A-α conducts large motor nerve impulses, and the nerve fiber type A-β conducts small motor nerve impulses. (135, Table 11-2)
19. Differential block refers to the relative block of sensory versus motor function. For equivalent analgesia or anesthesia, etidocaine tends to produce more profound motor block than most commonly used local anesthetics, making it an unfavorable choice, particularly for use in labor or postoperative pain management. (135)
20. Local anesthetics diffuse along a concentration gradient from the outer surface, or mantle, of the nerve toward the center, or core, of the nerve. As a result, the nerve fibers located in the mantle of the nerve are blocked before those in the core of the nerve. (135, Figure 11-5)
Spread of anesthesia and peripheral nerve blockade
21. In a peripheral nerve, the nerve fibers in the mantle generally innervate more proximal anatomic structures. The distal anatomic structures are more frequently innervated by nerve fibers near the core of the nerve. This physiologic orientation of nerve fibers in a peripheral nerve explains the observed initial proximal analgesia with subsequent progressive distal spread as local anesthetics diffuse to reach more central core nerve fibers. (135, Figure 11-5)
22. In contrast to most systemically administered drugs, the local anesthetics are deposited at the target site, and systemic absorption and circulation serve to attenuate or curtail their effect rather than distribute them to their site of action. (135)
Pharmacokinetics
23. The pKa of most local anesthetics is greater than 7.4 (benzocaine is a notable exception with a pKa of approximately 3.5). This means that the pH at which the cationic form and nonionized form will be equivalent is greater than 7.4 for almost all of the clinically used anesthetics. (133, Table 11-1)
24. Most local anesthetic molecules exist in the ionized, hydrophilic form at physiologic pH. However, local anesthetics must be in the nonionized, lipid-soluble form to cross the lipophilic nerve cell membranes. (131, 133, Table 11-1)
25. Local tissue acidosis is associated with a lower quality anesthesia. This is presumed to be due to an increase in the ionized fraction of the drug in an acidotic environment, with less of the neutral form available to penetrate the cell membrane. (133, Figure 11-4)
26. The primary determinant of the potency of a local anesthetic is its lipid solubility. (133)
27. The rate of systemic uptake and the rate of clearance of the drug are the two primary determinants of peak plasma concentrations of a local anesthetic after its absorption from tissue sites. (136)
28. Ester local anesthetics are cleared by hydrolysis by pseudocholinesterase enzymes in the plasma. (136)
29. Amide local anesthetics undergo degradation in the liver by hepatic microsomal enzymes. (136)
30. Less than 5% of the injected dose of local anesthetic undergoes renal excretion unchanged. The low water solubility of local anesthetics limits their renal excretion. (136)
31. The lungs and the liver both influence the potential for local anesthetic systemic toxicity. The extent to which the lungs extract local anesthetics from the circulation—so-called first-pass pulmonary extraction—influences systemic toxicity by preventing the rapid accumulation of local anesthetics in the plasma. The liver also influences local anesthetic systemic toxicity, especially for the amide local anesthetics that depend upon the liver for metabolism. (136)
32. The relatively rapid hydrolysis by plasma cholinesterase makes chloroprocaine less likely to produce sustained plasma concentrations. (136)
33. Patients with atypical plasma cholinesterase enzyme may be at increased risk for developing excessive plasma concentrations of ester local anesthetics. Ester local anesthetics rely on plasma hydrolysis for their metabolism, which may be limited or absent in these patients. (136)
34. Lidocaine, an amide local anesthetic, is cleared by hepatic metabolism. The clearance of lidocaine from the plasma parallels hepatic blood flow. Liver disease or decreases in hepatic blood flow as can occur with congestive heart failure or general anesthesia can decrease the rate of metabolism of lidocaine. (136)
35. The low water solubility of the local anesthetics usually limits renal excretion of the parent compound to less than 5% of the administered dose. (136)
36. The addition of epinephrine or phenylephrine to a local anesthetic solution produces a local tissue vasoconstriction. This results in a slowing of the rate of systemic absorption of the local anesthetic. (136)
37. The addition of epinephrine or phenylephrine to a local anesthetic solution produces local tissue vasoconstriction. This results in a prolonged duration of action of the local anesthetic by keeping the anesthetic in contact with the nerve fibers for a longer period of time. (136)
38. The addition of epinephrine or phenylephrine to a local anesthetic solution causes a slower rate of systemic absorption and a prolonged duration of action. This increases the likelihood that the rate of metabolism will match the rate of absorption, resulting in a decrease in the possibility of systemic toxicity. Inclusion of epinephrine may also decrease the potential for toxicity by serving as a marker for misplaced intravascular injection, whereby the elevation of heart rate can serve as a warning of such misplacement, alerting the clinician to halt injection and thus prevent the administration of additional anesthetic. (136)
39. The addition of epinephrine or phenylephrine to a local anesthetic solution has little effect on the rate of onset of anesthesia. (136)
40. The addition of epinephrine or phenylephrine to a local anesthetic solution decreases bleeding in the area infiltrated due to its vasoconstrictive properties. (136)
41. The systemic absorption of epinephrine from the local anesthetic solution may contribute to cardiac dysrhythmias or accentuate hypertension in vulnerable patients. (136)
42. The addition of epinephrine to a local anesthetic solution may not be recommended in patients with unstable angina, cardiac dysrhythmias, uncontrolled hypertension, or uteroplacental insufficiency. The addition of epinephrine to a local anesthetic solution is not recommended for intravenous anesthesia or for peripheral nerve block anesthesia in areas that may lack collateral blood flow, such as the digits (though the soundness of this latter proscription has been recently questioned). (136)
Side effects
43. Potential negative side effects associated with the administration of local anesthetics include systemic toxicity, neurotoxicity, and allergic reactions. (136)
44. Local anesthetic systemic toxicity occurs as a result of excessive plasma concentrations of a local anesthetic drug. The most common cause of local anesthetic systemic toxicity is accidental intravascular injection of local anesthetic solution during the performance of a nerve block. (136)
45. The magnitude of the systemic absorption of local anesthetic from the tissue injection site is influenced by the pharmacologic profile of the local anesthetic, the total dose injected, the vascularity of the injection site, and the inclusion of a vasoconstrictor in the local anesthetic solution. (136)
46. The relative order from highest to lowest of peak plasma concentrations of local anesthetic associated with regional anesthesia is intercostal nerve block, caudal block, epidural, brachial plexus, and sciatic/femoral. (136, Figure 11-6)
47. The central nervous system and cardiovascular system are most likely to be affected by excessive plasma concentrations of local anesthetic. (136)
48. The initial manifestations of central nervous system toxicity due to excessive plasma concentrations of local anesthetic include circumoral numbness, facial tingling, restlessness, vertigo, tinnitus, and slurred speech. With progressively increasing concentrations of local anesthetic in the plasma, symptoms may progress to manifestations of central nervous system excitation, such as facial and extremity muscular twitching and tremors. Finally, tonic-clonic seizures, apnea, and death can follow. However, deviations from this classic progression are common. (137)
49. Local anesthetic drugs in excessive plasma concentrations sufficient to cause seizures are believed to initially depress inhibitory pathways in the cerebral cortex. This allows for the unopposed action of excitatory pathways in the central nervous system, which manifests as seizures. As the concentration of local anesthetic in the plasma increases, there is subsequent inhibition of both excitatory and inhibitory pathways in the brain. Ultimately this leads to generalized global central nervous system depression. (137)
50. Potential adverse effects of local anesthetic-induced seizures are arterial hypoxemia, metabolic acidosis, and pulmonary aspiration of gastric contents. The mainstay of treatment of local anesthetic-induced seizures, as with all seizures, is aimed toward supporting the patient while attempting to abort the seizure with anticonvulsant drugs. Supplemental oxygen should be administered. The patient’s airway may need to be secured with a cuffed endotracheal tube if there is a need to facilitate adequate ventilation and delivery of oxygen to the lungs, and to protect the airway from the aspiration of gastric contents. (137)
51. Anticonvulsant drugs that can be used to stop local anesthetic-induced seizures include diazepam and propofol. Diazepam is the preferred agent, though propofol is generally more readily accessible for immediate administration. However, propofol should be used cautiously in small doses as seizures may portend cardiovascular toxicity that might be augmented by propofol’s cardiovascular depression. (137)
52. The administration of paralyzing doses of a rapidly acting neuromuscular blocking drug may be necessary to facilitate intubation of the trachea during a seizure. The administration of a neuromuscular blocking drug with prolonged paralytic effects during a seizure may be indicated when benzodiazepines and barbiturates have not been effective in stopping the seizure activity. However, while the neuromuscular block aborts the peripheral seizure activity, it does not alter the abnormal cerebral electrical activity, and therefore does not negate the need to adequately control underlying seizure activity with anticonvulsants. (137)
53. The cardiovascular system is generally less susceptible to local anesthetic toxicity than the central nervous system. That is, the dose of local anesthetic required to produce central nervous system toxicity is less than the dose of local anesthetic required to result in cardiotoxicity. (138)
54. Two mechanisms by which local anesthetics produce hypotension include the relaxation of peripheral vascular smooth muscle and direct myocardial depression. (138)
55. Local anesthetics exert their cardiotoxic effects primarily through the blockade of sodium ion channels in the myocardium. This blockade results in an increase in the conduction time throughout the heart, manifested as a prolongation of the P-R interval and widening of the QRS complex. Local anesthetics also produce a dose-dependent negative inotropic effect. Clinically, these may result in a decreased cardiac output. With extremely elevated serum levels of local anesthetic, bradycardia and sinus arrest can result. (138)
56. The relative cardiotoxicity of local anesthetic agents is made through a comparison of the dose (or serum concentration) required to produce cardiovascular collapse relative to central nervous system toxicity. Through the evaluation of these ratios, it has been determined that bupivacaine is roughly twice as cardiotoxic as lidocaine and that levobupivacaine and ropivacaine are intermediate. (138)
57. Bupivacaine is more cardiotoxic than lidocaine per dose administered to achieve a given anesthetic effect. When electrophysiological differences between anesthetics are compared, lidocaine is found to enter the sodium ion channel quickly and to leave quickly. In contrast, recovery from bupivacaine blockade during diastole is relatively prolonged, making it far more potent with respect to depressing the maximum upstroke velocity of the cardiac action potential (Vmax) in ventricular cardiac muscle. As a result, bupivacaine has been labeled a “fast-in, slow-out” local anesthetic. This characteristic likely creates conditions favorable for unidirectional block and reentry. Other mechanisms may contribute to bupivacaine’s cardiotoxicity, including disruption of atrioventricular nodal conduction, depression of myocardial contractility, and indirect effects mediated by the central nervous system. (140)
58. The maximum recommended concentration of bupivacaine to be administered for epidural anesthesia in obstetrics is 0.5%. This recommendation emerged as a result of numerous fatal cardiotoxic reactions that occurred with the administration of 0.75% bupivacaine in this patient population. (140)
59. Recently, a series of systematic experimentation and clinical events have identified a practical and apparently effective therapy for systemic anesthetic toxicity. Following experiments in rats and dogs, which demonstrated that administration of a lipid emulsion could attenuate bupivacaine cardiotoxicity, numerous clinical cases were reported in which intravenous lipid appears to have been effective in reversing local anesthetic systemic toxicity. The mechanism by which lipid is effective is incompletely understood, but its predominant action is most likely related to its ability to extract bupivacaine (or other lipophilic drugs) from aqueous plasma or tissue targets, thus reducing their effective concentration (“lipid sink”). (138)
60. The administration of prilocaine has been associated with methemoglobinemia in a dose-dependent manner, with significant toxicity generally occurring with doses exceeding 600 mg. Methemoglobinemia results from the accumulation of ortho-toluidine, a metabolite of prilocaine. Ortho-toluidine is an oxidizing compound that oxidizes hemoglobin to methemoglobin, creating methemoglobinemia. Methemoglobinemia that occurs through the administration of prilocaine is spontaneously reversible. Alternatively, methylene blue may be administered intravenously to treat this condition. Methemoglobinemia can also be a significant clinical problem with benzocaine topically administered on mucosal surfaces. (140)
61. The administration of chloroprocaine has been associated with prolonged motor and sensory deficits when administered at recommended doses for epidural anesthesia that appeared to have been inadvertently administered into the subarachnoid space. Early studies suggested that this effect might have occurred due to a combination of the low pH of the anesthetic solution (pH approximately 3.0)and the antioxidant sodium bisulfite, which resulted in the liberation of sulfur dioxide. However, this mechanism has been challenged by more recent studies, which implicate the high doses of chloroprocaine, per se. (139)
62. Transient neurologic symptoms (TNS) is a syndrome of pain/dysesthesia in the lower back, posterior thighs, or buttocks that generally occurs within 24 hours of recovery from a spinal anesthetic. Full recovery from the symptoms most often occurs within 3 days. Importantly, TNS is not associated with sensory loss, motor weakness, or bowel or bladder dysfunction. Risk factors for TNS following spinal anesthesia include the use of lidocaine, lithotomy position during surgery, and outpatient status. Indeed, when these three risk factors are combined, the incidence rate has been found to be 24%. Similar to lithotomy, positioning for knee arthroscopy appears to dramatically increase risk. (139)
63. Cauda equina syndrome represents the clinical manifestation of injury to the nerve roots caudal to the conus. Symptoms may include perineal sensory loss, bowel and bladder dysfunction, and lower extremity motor weakness. In the past, a cluster of cases was reported in association with the use of lidocaine administered through microbore spinal catheters (also referred to as small-bore and defined as smaller than 27 gauge). It is believed that pooling of local anesthetic in the most dependent portion of the subarachnoid space led to high concentrations of local anesthetic around the nerve roots of the cauda equina and subsequent irreversible neurotoxicity. Small-bore catheters for continuous spinal anesthesia are no longer marketed in the United States. However, risk remains because similar neurotoxic injury can occur with repetitive doses of any local anesthetic even if administered through a large-bore (e.g., epidural) catheter. In fact, this mechanism of neurotoxic injury has also been reported with repeat needle injection after a failed single-injection spinal anesthesia. (139)
64. Recent experience suggests that lidocaine has greater potential for direct neurotoxicity than traditionally appreciated. In addition to the aforementioned cases of cauda equina syndrome with small-bore catheters, lidocaine appears to be capable of inducing injury when administered at the high end of the manufacturer’s specified dose range for spinal anesthesia (100 mg). Accordingly, it has been suggested that if this drug is used for spinal anesthesia, the dose should be limited to 75 mg, and the concentration of the anesthetic solution should not exceed 2.5%. However, lidocaine with epinephrine remains an appropriate and popular choice for epidural anesthesia and peripheral blocks. (139)
65. The occurrence of major (cauda equina syndrome) and minor (TNS) sequelae occuring with lidocaine has resulted in near abandonment of this agent for spinal anesthesia.
66. Less than 1% of all adverse reactions to local anesthetics are believed to be true allergic reactions. When an allergic reaction to a local anesthetic is suspected to have occurred, full documentation should be made in the chart regarding the dose and route of local anesthetic administered and the reaction that occurred. There are three potential causes of an allergic reaction to administered local anesthetic. In addition to the anesthetic itself, a reaction might result from exposure to one of its metabolites. For example, it has been traditionally taught that ester local anesthetics have a proclivity to induce allergic reactions due to one of its breakdown products, para-aminobenzoic acid, making esters more likely than amides to cause allergic reactions, though some have questioned the validity of this assertion. Allergic reactions may also occur to another component of the anesthetic solution (e.g., the preservative methylparaben, used in some commercial preparations of both amides and esters, appears to have significant antigenic potential). (138)
67. Cross-sensitivity has not been found to exist between the classes of local anesthetics. A patient found to be allergic to ester local anesthetics would not be expected to be allergic to amide local anesthetics.
Clinical uses
68. Tetracaine is primarily used as a spinal anesthetic in current clinical practice, where its long duration of action, particularly if used with a vasoconstrictor, can at times be a useful attribute. (139)
69. Of the available local anesthetics, two have received considerable attention as alternatives to lidocaine for short-duration spinal anesthesia: prilocaine and chloroprocaine. However, while prilocaine has an acceptable profile for short-duration anesthesia, it is not available in the United States in a formulation that would be appropriate to administer intrathecally. Consequently, chloroprocaine appears to be the favored contender for lidocaine’s replacement. The rationale for using chloroprocaine for deliberate intrathecal administration largely rests on the relative dose (i.e., the dose required for spinal anesthesia is an order of magnitude less than those previously associated with injuries occuring with inadvertent intrathecal injection of anesthetic intended for the epidural space). Chloroprocaine rarely, if ever, results in TNS, and it has a duration of action as a spinal anesthetic that is even shorter than lidocaine, making it extremely well suited for short-duration outpatient spinal anesthesia. Although the issue of bisulfite toxicity has not been adequately resolved, chloroprocaine administered intrathecally should be bisulfite-free, and the dose should not exceed 60 mg.
70. Isomers are different compounds that have the same molecular formula. Subsets of isomers that have atoms connected by the same sequence of bonds but that have different spatial orientations are called stereoisomers. Enantiomers are a particular class of stereoisomers that exist as mirror images. The term chiral is derived from the Greek cheir for “hand,” because the forms can be considered nonsuperimposable mirror images. Enantiomers have identical physical properties except for the direction of the rotation of the plane of polarized light. This property is used to classify the enantiomer as dextrorotatory (+) if the rotation is to the right or clockwise and as levorotatory (–) if it is to the left or counterclockwise. A racemic mixture is a mixture of equal parts of enantiomers and is optically inactive because the rotation caused by the molecules of one isomer is cancelled by the opposite rotation of its enantiomer. Chiral compounds can also be classified on the basis of absolute configuration, generally designated as R (rectus) or S (sinister). Enantiomers may differ with respect to specific biologic activity. (140)
71. Ropivacaine and levobupivacaine differ from other local anesthetics because they are chiral compounds rather than racemic mixtures. Both are S(−) enantiomers, and were marketed in response to the cardiotoxic effects of bupivacaine because they appear to cause modestly less myocardial depression and are modestly less arrhythmogenic than bupivacaine. (140-141)
72. EMLA is a topical anesthetic cream that consists of lidocaine 2.5% and 2.5% prilocaine. This mixture has a lower melting point than either component, and it exists as an oil at room temperature that is capable of overcoming the barrier of the skin. EMLA cream is particularly useful in children for relieving pain associated with venipuncture or placement of an intravenous catheter, although it may take up to an hour before adequate topical anesthesia is produced. (141)
