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THE PHARMACOLOGY OF LOCAL ANESTHETICS
REGIONAL ANESTHESIA
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THE PHARMACOLOGY OF LOCAL ANESTHETICS John E. Tetzlaff, MD
The pharmacology of local anesthetics is an integration of the basic physiology of excitable cells and the mechanism by which local anesthetics are capable of interrupting conduction of neural messages. The common characteristics of the molecules with local anesthetic action have been identified and can explain the properties of the agents. These same chemical characteristics also explain toxicity of these agents and differences that exist between local anesthetics with similar structure. BASIC NERVE CELL PHYSIOLOGY
The function of excitable tissue is based on the presence of a cell with a lipid membrane, axoplasm, membrane-integrated, ion-specific channels, and ion gradients maintained by energy-dependent enzymes. Potassium moves freely through the membrane, whereas sodium moves in a semipermeable manner, controlled by gates on the sodium channels. Sodium is restricted to the extracellular space, except when specific ion channels are open. Potassium selectively accumulates inside the nerve cell to preserve electrical neutrality. In an unexcited state, the electrical potential inside the cell is negative in reference to the outside of the cell and very close to the potential that would be determined by potassium alone. This is the resting potential of the nerve cell membrane. During conduction of an impulse (action potential), sodium channels open and sodium ions move into the cell, depolarizing the cell. The gate that opens and closes these channels is present on the axoplasmic side of the From the Department of General Anesthesiology, The Cleveland Clinic Foundation, Cleveland, Ohio
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nerve cell membrane. In the open state, this channel is susceptible to the action of local anesthetic molecules that cause it to remain inactive and prevent subsequent depolarization. This is the basis for conduction blockade. From isolated nerve cell studies, sodium channel function can be evaluated. When the membrane is rapidly depolarized from the resting state ( - 70 mV) to - 20 mV, there is a rapid increase in sodium channel permeability. The greater the depolarization, up to +20 mV, the greater the sodium permeability. Beyond +20 mV, there is no greater increase in sodium conductance. This verifies that there are a finite number of sodium channels in the membrane. Like the neuromuscular junction, neural conductance has considerable redundancy. Even with 80% to 90% of sodium channel blocked, nerve impulse conduction continues, although at a slower rate. PHYSIOLOGY OF CONDUCTION BLOCKADE
Conduction block is the reversible interruption of conduction within a neural structure by a local anesthetic agent. Conduction block occurs when local anesthetic molecules occupy enough sodium channels within an axon to interrupt activity." Each membrane has a peak sodium current that is 5 to 6 times greater than necessary to initiate an action potential; this is the safety factor of conductance. Local anesthetics reduce this safety factor by progressively interrupting sodium channel excitability, and when it reaches zero, conductance The binding in these channels is semispecific, but no distinct receptor has been identified. The bond is weak in the case of closed channels and strongest and most rapid in the case of open sodium channels. This leads to the phenomenon "use-dependent" or "frequency-dependent" block. The sodium channel is triggered to its open (activated) state by depolarization, and then to its closed (inactivated) state by repolarization. Local anesthetics have significantly higher affinity for the open sodium channel. The more often a nerve is stimulated, the higher percentage of the time its sodium channels are activated, and hence, more susceptible to conduction block. In general, local anesthetics have a higher potency for nerves with a higher frequency of stimulation. Impulse extinction50is the probability that an arriving impulse will stop at a given area of a nerve. Impulse extinction is related to local anesthetic dose delivered and local anesthetic concentration, both at injection and at arrival inside the nerve. It is also related to the length of a nerve that is exposed to the local anesthetic and by the presence or absence of myelination. Myelination decreases the length of nerve necessary to be exposed to local anesthetic, as only the nodes of Ranvier in the myelinated nerves need to be exposed to local anesthetic in order for block to occur. If one node is blocked, conduction will be interrupted less than 30% of the time. For two adjacent nodes, this increases to
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greater than 70%, and for three consecutive nodes, it is 100% likely that conduction block will occur. This also explains why smaller, myelinated fibers are easier to block than larger fibers, with other variables being constant. In unmyelinated nerves a full circumference, as well as length of the nerve, must be bathed by local anesthetic. Variability in the onset of conduction block in different fibers within the same neural structure is referred to as temporal 0nset.2~Temporal onset is related to fiber size, spatial relationships within the nerve fiber, and concentration of injected local anesthetic. Fiber type is a factor because of the relationship of fiber size to conduction blo~k.2~ The larger the fiber, the slower the block and the higher concentration of the agent necessary to achieve the same frequency of impulse extinction. Fiber types are divided into three categories, designated A, B, and C. The A fiber type is subdivided into four subcategories: alpha, beta, gamma, and delta. The A-alpha fibers are the largest in the body and conduct motor impulses. The A-beta fibers innervate some muscle and predominately conduct light touch and pressure. The A-gamma fibers innervate muscle spindles for joint proprioception. The A-delta fibers are the smallest of the A fiber type and conduct pain and temperature sensation and signal tissue damage. The B fibers are all preganglionic, sympathetic nerve fibers, smaller than the entire A group, and are the easiest to block in the body. All of the fibers of the A and the B group are myelinated. The C group are the smallest fibers, are unmyelinated, and conduct pain, temperature, and postganglionic autonomic function.
STRUCTURE OF THE LOCAL ANESTHETIC MOLECULE
The components of a local anesthetic molecule that create the conditions for reversible conduction block have been identified.14Local anesthetics that are clinically useful have an aromatic (hydrophobic) ring structure connected to a tertiary amine (hydrophilic) by a short alkyl, intermediate chain that contains an amide or ester bond. Hence, all of these molecules are amines and would be called amino-amide or aminoester. This is shortened to amide or ester as a classification of the two main local anesthetic groups.
The Aromatic Group
The aromatic side of the local anesthetic molecule provides most of the lipophilic properties of the molecule. Because the nerve cell membrane is a lipid environment, this part of the molecule is mainly involved in passage through the nerve cell membrane, and is directly related to potency.47,56 The size of the aromatic group restricts the movement of the tertiary amine to an axis perpendicular to the aromatic group. This
facilitates the alignment of the tertiary amine with the sodium channel on the axoplasmic side of the membrane.
The Hydrophilic Group
The hydrophilic group is the side of the molecule that accepts protons and is most involved in occupation of the sodium channel. For most clinically useful local anesthetics, this is a tertiary amine group, which is prepared commercially as a hydrochloride salt. Affinity for an ionic structure within the axoplasmic opening of the sodium channel is the chemical basis for sodium channel blockade?
The Intermediate Chain and Amide/Ester Bond
The length of the intermediate bond is a determinant of local anesthetic activity. When the length is between 3 and 7 carbon-equivalents, local anesthetic action can occur.= When less or more, local anesthetic action rapidly disappears. This implies that there must be a critical length of separation of the aromatic group from the tertiary amine for sodium channel block to occur. The amide or ester bond makes creation of the molecule more simple, as two diverse sides of the molecule are brought together by a chemical reaction which creates the bond. This also allows for the reversible action of clinically useful local anesthetics, as metabolism can begin with interruption of this bond. Potency of the local anesthetic increases as the lipid coefficient of these hydrophilic bonds increases.
BIOCHEMISTRY OF LOCAL ANESTHETIC MOLECULES
All of the local anesthetics are weak bases, with pKa between 7.7 and 9.1. They accept a proton to a cationic form at pH below their pKa. The nonionic form is poorly soluble in water. The local anesthetic solutions are generally prepared as hydrochloride salts of the cation with a pH of 5.0 to 6.0 unless they are commercially prepared with epinephrine.= In that case, the pH is much lower (2.0-3.0) to preserve the activity of the epinephrine. The pharmacologic activity of local anesthetic molecules is determined by several of their physiochemical properties. These include lipid solubility, protein binding, and the pKa of each local anesthetic molecule.14 These properties can be used to explain the clinical behavior of these agents-onset, potency, duration, and toxicity. Each of these properties will be explained in some detail.
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Lipid Solubility
Lipid solubility determines the potency of local anesthetic molec u l e ~ ?The ~ hydrophobic nature of the nerve cell membrane explains this relationship between lipid solubility and potency. Local anesthetic molecules are highly lipophilic and easily penetrate nerve cell membranes; more molecules become intracellular, resulting in more blockade. Graphs of the potency of local anesthetics against the oil/water partition coefficients demonstrate the clear relationship between potency and lipid ~olubility.’~ Studies involving exposed, intact nerves demonstrate the relationship between the minimal effective concentration required to interrupt conduction block and lipid solubility.35Clinically, this phenomenon is confirmed by comparison of agents. Adding an aliphatic group to the tertiary amine of mepivacaine (1-4 carbons) creates bupivacaine, which is more lipid soluble and incrementally more potent. This is also observed in the addition of a 4-carbon group to procaine, creating tetracaine, which is similarly more lipid soluble and potent. Experimental addition of ionic groups to existing local anesthetic molecules eliminates the local anesthetic activity by decreasing their lipid solubility. Protein Binding
The protein binding potential determines the duration of action of a local anesthetic m~lecule.’~ Agents with greater protein binding remain associated with the neural membrane for a longer time interval. Increased protein binding results in longer duration of local anesthetic action. Agents that are poorly protein bound, such as procaine, are weakly associated with the nerve cell membrane, and duration of local anesthetic blockade can be extremely short. Those which are highly protein bound, such as bupivacaine, are tightly associated with the nerve cell membrane and have a long duration of action.
PKa The pKa determines the speed of onset of conduction b10ck.l~The pKa of a local anesthetic molecule is that pH at which 50% of the agent exists in the cationic and basic forms. The base is the form with the majority of lipid solubility. Onset is related to the concentration of the base on the extracellular side of the nerve cell membrane. Because the pKa of most local anesthetic agents is higher than physiologic (7.7-9.0), and because local anesthetic solutions are prepared at a pH of 5.0 to 6.0, the majority of the molecules exist in the cationic form. Onset requires buffering of the injected solution to physiologic pH to establish a sigmficant concentration of the base. The higher the pKa, the higher the percentage of cationic form, and hence, the lower the concentration of the base and the slower speed of onset of the local anesthetic agent.
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Alteration of the pH of the injected local anesthetic can also influence the onset of local anesthetic action. Because the concentration of the nonionic form of the molecule determines onset, and because the solution is prepared in an acid medium that results in a huge preponderance of the ionic form, any factor that increases the concentration of the nonionic form results in accelerated onset. Preparation of the agent as a hydrocarbonate salt as opposed to a hydrochloride salt greatly increases the concentration of carbon dioxide in the solution? This results in rapid diffusion of CO, into the nerve cell, which has the effect of acidifying the intracellular environment and increasing the pH of the extracellular environment. This will pull local anesthetic into the cell by favoring the cationic form intracellularly and shifting the equilibrium toward the base extracellularly. This should accelerate the onset of local anesthetic action, and numerous clinical studies confirm this.l 7, 13, 38, 57 An analogous action occurs with addition of sodium bicarbonate to the local anesthetic solution prior to injection, increasing the pH to near-physiologic, greatly increasing the proportion of the base at the time of injection. Clinical studies also confirm this theoretical observation?, lo, 39, 58
Toxicity Toxicity of local anesthetics is related to the potency of the local anesthetic, as toxicity is determined by elements of conduction block that occur within central nervous system (CNS) str~ctures.'~ It is related also to the total dose delivered, the rate of plasma uptake, protein binding, and the site of injection. The site of injection influences the rate of plasma uptake by the vascularity of the tissues. The more vascular the site of injection, the more readily uptake can occur, and the more sudden and intense central nervous system toxic effects will be. Both the rate of change and the absolute level of local anesthetic influence CNS toxicity, with more rapid accumulation being more toxic. This is borne out by the clinical experience in which intercostal blocks are associated with the highest clinical blood levels of local anesthetics, and subarachnoid injection of local anesthetic is associated with the lowest blood levels. Agents that raise the seizure threshold, such as benzodiazepines, can prevent seizure activity or decrease the risk of CNS excitation evolving to seizure activity.I7 The CNS toxic effects of local anesthetics in the clinical setting are directly related to lipid solubility. Although the agents that are highly lipid soluble may be more potent as local anesthetics, the therapeutic to toxic ratio is narrower and the degree of safety in using the agents is less. The toxic form of the local anesthetic is the nonionic, unbound fraction in the blood that is available to penetrate the blood-brain barrier. The more protein bound the agent, the slower the time course to symptoms, and the narrower the gap between the first milder symptoms of
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CNS toxicity, and the more dangerous massive reaction to CNS local anesthetic exposure. To counteract the intrinsic vasodilatory properties of local anesthetics, a frequent choice is the addition of an exogenous vasoconstrictor~3 The most common additions include epinephrine, ephedrine, and phenylephrine. Addition of epinephrine results in lower peak plasma levels and a slower time course to the peak level, which reduces the CNS toxicity potential. With the less lipophilic agents, this decreased vascular uptake can prolong the duration of the local anesthetic; however, there are toxic effects associated with exogenously added vasoconstrictors, including hypertension, tachycardia, cardiac arrhythmia, and myocardial ischemia. Cardiac Toxicity of Local Anesthetics
All local anesthetics have a direct depressant effect on the cardiovascular system in a dose-related fa~hi0n.I~ Specific cardiovascular depression with agents that are highly lipid soluble, such as bupivacaine and etidocaine, is not only related to their increased lipid solubility, but to sodium channel block within the cardiac conduction system. Bupivacaine has a fast-in, slow-out kinetic pattern at the sodium channel, resulting in accumulation of bupivacaine in the conduction system that increases as heart rate increases.&When the primary conducting system is blocked, there is increased activity in reentrant pathways that predisposes the heart to ventricular arrythmia. When the result is ventricular tachycardia or fibrillation, this arrhythmia can be refractory to treatment. Local anesthetic-induced cardiac toxicity is potentiated by hypoxia, hypercarbia, and a ~ i d o s i s The . ~ ~ cardiac toxicity of bupivacaine is further accentuated during pregnancy, probably mediated by progesterone and the adverse physiologic effects of pregnancy on venous return during resuscitation.54 Methemoglobinemia
Prilocaine and benzocaine can cause the oxidation of the ferric form 28 When of hemoglobin to the ferrous form, creating methem~globin.'~, the amount exceeds 4 g/dL, visible cyanosis can occur. In most cases, this cyanosis is benign, but in cases where oxygen transport is an important issue or when symptoms of tissue hypoxia occur, treatment with methylene blue is rapidly successful in reversing cyanosis. Direct Tissue Toxicity of Local Anesthetics
All local anesthetic molecules at some concentration are directly cytotoxic to nerve cells." In addition to the cytotoxicity of the agents
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themselves, various buffers and preservatives have been found to be cytotoxic.@I The potential for intraneural injection is present with all injected local anesthetics. In these cases, it is not the concentration, but rather hydrostatic pressure that causes neural injury. Allergy True allergy to local anesthetics is rare.* The majority of local anesthetic allergies are associated with the ester agents.26 This is related to metabolism of these agents to para-amino-benzoic acid (PABA) and the ubiquitous presence of PABA throughout the pharmaceutical and cosmetic industries. Allergy to amide local anesthetics is rare. A few cases have been found to be related to methylparaben, which is added as a preservative to multidose vials of lidocaine.15 Use of local anesthetics without the use of monitoring can contribute to the problem of incorrect diagnosis of allergy. When the local anesthetic is used with epinephrine, intravascular injection of epinephrine is a possibility. In the absence of monitoring, the distinction from allergy could be difficult.26 During a dental anesthetic, for example, a local anesthetic with concentrated epinephrine is injected into the maxillary area, a compact, highly vascular site. This creates the possibility of pressurized intravascular injection of epinephrine. Shortly after injection, flushing, palpitation, and malaise is reported. The symptoms are related to adrenergic effects of epinephrine, as opposed to allergy, which is symptomatic because of histamine-mediated hypotension. The increased heart rate is present in both, but the extreme palpitation and hypertension are adrenergic, whereas the tachycardia of allergy is associated with vasodilatation and hypotension.
SPECIFIC AGENTS Esters Procaine Procaine is a short-acting amino ester local anesthetic with pKa of 8.9. Commercially prepared solutions have a pH of 5.5 to 6.0, slow onset, and a very short blood half-life owing to rapid hydrolysis by plasma cholinesterase.59 The plasma half-life is believed to be approximately 20 seconds. Hence, there is very little toxicity associated with this agent. Due to extremely limited protein binding, it has a short duration of action. The toxic dose is believed to be in the range of 1000 mg, but reports of toxicity associated with procaine are extremely rare. Clinical uses of procaine at the present time are extremely limited. It is effective for skin infiltration in limited areas. It is used in combination with tetracaine for spinal anesthesia in certain circumstances.
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2-Chloroprocaine
2-Chloroprocaine is a rapid-onset, short-duration local anesthetic with a pKa of 9.0, prepared in solution with a pH of 2.5 to 4.0. It is characterized by rapid onset despite a high pKa due to its extremely low toxicity, allowing for high concentrations to be used clinically. It has a short plasma half-life, and reports of CNS toxicity are uncommon.” The toxic dose is in a range of 800 to 1000 mg or more with epinephrine, and it is believed to be the least toxic in the CNS or cardiovascular systems of all agents in current use. Epidural anesthesia is the most common application for 2-chloroprocaine. It has the most rapid termination of action of current local anesthetics used in the epidural space with a time to 2-segment regression of 30 minutes. 2-Chloroprocaine is also used in peripheral blocks with a 45 to 60 minute duration of action or compounded with other long-acting agents for prolonged duration. The potential advantage of compounding with other agents is that the rapid onset of chloroprocaine can be combined with the long duration of the more lipophilic agents; however, the pH of chloroprocaine causes the clinical duration of bupivacaine to be considerably shortened.12 Several controversies have been associated with chloroprocaine. Serious neurologic deficits have occurred after massive subarachnoid injec** 49, 51 tion of chloroprocaine during attempted epidural ane~thesia.~~, Initially, the agent itself was believed to be causative; however, subsequent evaluation suggested that the antioxidant bisulfite produced the neural damage.4l The neural damage has not been reported since the reformulation of chloroprocaine, without bisulfite. The second controversy is more recent. Ambulatory patients having epidural anesthesia with chloroprocaine have developed severe lumbar muscle spasm during recovery. The most likely cause is the next preservative used in the formulation of chloroprocaine: ethylenediamine tetraacetic acid (EDTA), which causes muscle spasm by interfering with calcium regulation of skeletal muscle relaxation-contraction.26The present solution is prepared with no preservative, and back spasms have not been reported with this reformulation. Tetracaine
Tetracaine is an ester local anesthetic with a pKa of 8.6 prepared in a liquid form with a pH between 4.5 and 6.5. It has a slow onset, very short plasma half-life,48and long duration of action. Systemic toxicity is reported to be considerably higher than with procaine and 2-chloroprocaine. Reports of toxicity are uncommon, and clinical studies with high doses of tetracaine do not identify toxicity unless intravascular injection occurs. The plasma half-life is 2.5 to 4 minutes. The toxic dose is believed to be in the 2 mg/ kg range, or 120 total m The most common clinical application of tetracaine is for spinal anest esia. It is also compounded with other agents with a faster onset and shorter duration to prolong
8‘
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peripheral block or epidural anesthesia. In addition, it is used by ophthalmologists for topical anesthesia of the eye and by endoscopists for topical anesthesia of mucous membranes, including the airway. The potential for rapid uptake of tetracaine from mucous membranes must be considered as a risk for toxicity. Many of the early reports of toxicity with tetracaine were related to rapid vascular absorbance from mucous membranes. When applied to the larynx, anesthesia of the airway will persist for a very long duration, and airway reflexes will be absent. Cocaine
Cocaine is an ester local anesthetic with a pKa of 8.5 and a pH in commercial preparation that is extremely variable.= It is most commonly prepared as a liquid alkaloid to decrease abuse potential. It is a slowonset, short-duration local anesthetic that has the unique characteristic of being a vasoconstrictor. Toxicity is related to local anesthetic properties as well as interference with the reuptake of catecholamines, resulting in hypertension, tachycardia, arrhythmia, and myocardial ischemia. An idiopathic response can lead to acute coronary vasospasm in young patients with no prior history of coronary artery disease, and has resulted in myocardial infarction. Because of the combination of anesthesia and intense vasoconctriction, cocaine is ideally suited to procedures where shrinkage of mucous membranes and decreased bleeding are important, such as preparation for nasal intubation or intranasal surgery. Potentiation of catecholamine-induced arryhthmia can occur with other anesthetic agents, such as halothane, theophylline, or antidepressants. There are no other clinical uses for cocaine currently. Benzocaine
Benzocaine is an ester local anesthetic with a pKa of 3.5 and pH in preparation between 4.5 and 6.0. It has a slow onset, short duration, and moderate toxicity. Benzocaine is a secondary amine, in contrast to all the other clinically used local anesthetics, which are tertiary amines. This limits the ability of the agent to pass through neural membranes. As a consequence, its clinical use is limited to topical anesthesia. The estimated toxic dose is in the 200 to 300 mg range. Excessive use of benzocaine in pediatric cases is associated with methemoglobinemia.2s Amides
Lidocaine
Lidocaine is the most commonly used local anesthetic in the United States.14It has a pKa of 7.7, and in commercial preparations, the pH is between 5.0 to 6.0 without epinephrine. With epinephrine, the pH is in the 2.0 to 2.5 range. It has a rapid onset of action with intermediate
, ,'
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duration. Its toxicity is intermediate with metabolism occurring in the liver. The redistribution half-life is 8 to 9 minutes, and the elimination half-life is 45 to 60 minutes. The estimated adult toxic dose with lidocaine is 500 mg (or 7 mg/kg) without epinephrine, and higher when used with epinephrine. Lidocaine is associated with good topical anesthesia when used in Topical application results in a high level the 1%to 4% con~entration.2~ of vascular absorbance. The total dose must be limited and delivered over a time interval as long as possible to avoid toxicity. Lidocaine is the most common choice for intravenous regional anesthesia ( N U )at 0.5% concentration with a duration of 45 to 60 minutes. Lidocaine is used in 5% concentration combined with 7.5% glucose for hyperbaric spinal anesthesia with 45 to 90 minutes' duration. Used at 1.5% to 2.0% in plain solutions, it provides an isobaric spinal anesthetic with a slightly longer duration. Epinephrine will prolong the duration of lidocaine spinal anesthesia. Lidocaine is used for epidural anesthesia and analgesia in the 1.5% to 2% concentration. At the 1.5% concentration the motor block may be somewhat marginal, but at 2.0% dense motor block should be present in most patients. The time to 2-segment regression is in the 60 to 80 minute range. Peripheral conduction block can be performed with 1.0% to 1.5% lidocaine. The duration of action is typically 1 to 3 hours and is prolonged with the use of epinephrine. Lidocaine is the only local anesthetic with extensive use parenterally. It is used as an antiarrhythmic and to supress noxious reflexes, such as coughing,62 sympathetic ~tirnulation,~~ or increases in intracranial pressure associated with endotracheal intubation or suctioning.61 Controversy associated with lidocaine mainly resides in its use in obstetric anesthesia. In the late 1970s, S ~ a n l o nreported ~~ exaggerated neurologic depression of the fetus after epidural lidocaine for cesarean section. Subsequently, work suggested the changes found in this system of scoring are very subtle, not clinically significant, and not reproducible from investigator to investigator'; however, because of the low pKa of the agent and the propensity for ion trapping, lidocaine is not believed to be indicated in large doses for epidural anesthesia in mothers who have fetuses with any signs of fetal distress. This is because the fetal pH is already one tenth of a pH unit lower than the mother in the normal state, and any hypoxia or fetal stress may be associated with an even lower fetal pH and a higher propensity for ion trapping6 and hence higher toxicity of lidocaine in the newborn. More recently, controversy has arisen regarding transient neurologic symptoms (TNS) occurring after lidocaine use for spinal anesthesia. Mepivacaine
Mepivacaine is an amide local anesthetic with a pKa of 7.6 and a pH of 5.5 in solution. It has a rapid onset, intermediate duration, and intermediate toxicity. Onset can be accelerated by alkalinization with bicarbonate. Textbooks suggest mepivacaine toxicity is higher than that
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of lidocaine, but the clinical experience suggests the Fetal metabolism of mepivacaine is limited by hepatic immaturity, and mepivacaine is not believed to be indicated for use in obstetrics.8The toxic dose is 400 mg without epinephrine and 500 to 600 mg with the use of epinephrine, but the basis for this is anecdotal, and in many of the clinical studies the dose is considerably larger without reported toxicity when used with epinephrine. Clinical uses for mepivacaine include infiltration at the 1%concentration, which is associated with a 1.5 to 3 hour duration. Epidural anesthesia with 2% mepivacaine has a rapid onset with dense motor and sensory block, even in the larger nerve roots. The time to 2-segment regression is approximately 70 to 90 minutes. Redosing for longer procedures does not cause tachyphylaxis, and cumulative toxicity is low. Spinal anesthesia at the 4% concentration was used historically with a duration of 60 to 90 minutes. Controversy with lidocaine spinal anesthesia has renewed the interest in this application. Peripheral conduction block is performed at the 1% to 1.5% range with predictably good sensory and motor block with a duration of 2 to 3 hours. Bupivacaine
Bupivacaine is an amide local anesthetic with a pKa of 8.1 and a commercial preparation pH of 4.5 to 5.5. It has a slow onset, long duration of action, and high toxicity potential." The toxic dose is 2.5 to 3 mg/kg. Effects of alkalinization with bicarbonate are equivocal and are limited to pH 6.8 and below by precipitation. Infiltration of 0.25% bupivacaine produces sensory anesthesia with a duration of action of 2 to 4 hours or greater. Epidural analgesia and anesthesia are performed between a 0.25% and 0.75% concentration with very slow onset, and 2- to 5- hour interval to 2-segment regression. There is considerable variability in the quality of motor block achieved, with complete block at the highest doses and almost no motor block below 0.1%. At very low concentration, analgesia can be achieved with most motor function retained. Bupivacaine can be compounded with other agents to increase the speed of onset while retaining long duration of action; however, the addition of chloroprocaine to bupivacaine considerably decreases the duration.I2 Spinal anesthesia is performed at the 0.75% concentration combined with 8.75% dextrose for hyperbaric spinal anesthesia, and also is performed with plain bupivacaine in concentrations ranging from 0.125% to 0.75% with satisfactory results. It should be noted that this agent is not approved in the United States by the Food and Drug Administration for isobaric spinal anesthesia, but is often used in clinical practice. Bupivacaine is used at the 0.5% to 0.75% concentration for major conduction block. Epinephrine does not affect the duration of the block but decreases plasma uptake, and may help to identify intravascular injection. The use of bupivacaine for major
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conduction block is associated with long duration anesthesia, occasionally extending as long as 24 hours. Considerable controversy surrounds the use of bupivacaine. Early reports of sudden cardiac arrest with bupivacaine are associated with considerable morbidity and mortality.16,37 The mortality is probably related to the high protein binding and lipid solubility of the agent. Cardiovascular collapse is caused by the specific accumulation in the conduction system of the heart, activating re-entrant pathways and causing intractable ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation. These arrhythmias are refractory to treatment. Some success has been obtained with prolonged cardiopulmonary resuscitation, bretyllium,32and cardiopulmonary By consensus, the 0.75% concentration is not used in obstetrics. It is clear that the toxicity associated with bupivacaine is magrufied by respiratory acidosis, hypoxia, and in the parturient because of the physiology of pregnancy and direct effects of proge~terone.~~ Etidocaine
Etidocaine is an amide local anesthetic with a pKa of 7.7, a pH of 4.5, and similar clinical profile to bupivacaine. The toxic dose is believed to be in the 300 to 400 mg range, the higher range with epinephrine. Etidocaine can be used for infiltration anesthesia at 0.5%, peripheral nerve block at 0.5% to 1%with duration from 3 to 12 hours, and epidural anesthesia at 1%to 1.5% with duration of 3 to 5 hours. Profound motor block is sometimes associated with a limited sensory block, and this may make the agent less ideally suited to surgical epidural anesthesia than bupivacaine with the similar toxicity profile.44 Prilocaine
Prilocaine is an amide local anesthetic with a pKa of 7.7 and pH solution of 4.5. It has a rapid onset, intermediate duration, and low toxicity. Its toxic dose is 600 mg with or without epinephrine; however, metabolism to o-toluidine is associated with methemoglobinemia, which usually is not clinically significant but is clinically distressing until differentiation from oxygen desaturation can be e~tab1ished.l~ Clinical uses include infiltration at the 0.5% to 1%range with a duration of 1 to 2 hours. IVRA at 0.5% concentration results in 45 to 60 minutes' duration. Peripheral nerve block is performed at 1.5% to 2% with an expected duration of 2 to 3 hours. Epidural anesthesia at the 2% to 3% concentration results in 1 to 3 hours of expected duration. Dibucaine
Dibucaine is an amino amide local anesthetic with a pKa of 8.4and pH of 4.5 to 5.0. It has intermediate onset, very long duration, consider-
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able potency, and very high toxicity, with two types of clinical application. There is some use of dibucaine for spinal anesthesia, although very rarely in the United States. Dibucaine is also used for the laboratory assessment of the activity of cholinesterase in the serum. Ropivacaine
Ropivacaine is the newest addition to the clinical local anesthetic options. Ropivacaine has a pKa of 8.2 and the pH in commercial preparations is 5.5 to 6.0. Ropivacaine is a chemical analog of mepivacaine and bupivacaine. It was designed to retain the favorable properties of bupivacaine while decreasing the cardiac toxicity?0 The idea came from the observed similarity between the chemical structures of bupivacaine and mepivacaine, except for the substitution on the hydrophilic side, which was a methyl group for mepivacaine and a butyl group (4 carbons) for bupivacaine. Severe cardiovascular toxicity is rare with mepivacaine and much more common with b ~ p i v a c a i n e By . ~ ~decreasing the substitution by one carbon (isopropyl), the favorable properties of bupivacaine are retained and the cardiac toxicity decreased toward that of mepivacaine. The clinical experience, so far, suggests that it is equally potent with bupivacaine, although at this time it has been used at a concentration slightly higher than that of bupivacaineP In animal models, the selective cardiac toxicity of ropivacaine appears to be intermediate between that of mepivacaine and bupivacaine.*O The quality of clinical block with ropivacaine appears to be very similar in onset, duration, and quality to that of bupivacaine. At lower concentrations there may be even less motor block than with bupivacaine at comparable analge~ia.6~ Le vobupivacaine
Levobupivacaine is the pure S-enantiomer of bupivacaine. Preclinical trials suggest levobupivacaine has a potency similar to bupivacaine while exhibiting significantly less central nervous system and cardiac toxicity. References 1. Abboud TK, Kim KC, Noueihed R, et al: Epidural bupivacaine, chloroprocaine, or lidocaine for caesarean section: Maternal and neonatal effects. Anesth Analg 62914919, 1983 2. Benlabed M, Jullien P, Guelmi K, et al: Alkalinization of 0.5%lidocaine for intravenous regional anesthesia. Reg Anesth 15:59-60, 1990 3. Bokesch PM, Raymond SA, Strichartz GR Dependence of lidocaine potency on pH and pC02. Anesth Analg 669-17, 1987 4. Bromage PB: Allergy to local anaesthetics. Anaesthesia 30239-2441975 5. Bromage PR, Gertal M Improved brachial plexus blockade with bupivacaine hydrochloride and carbonated lidocaine. Anesthesiology 36479437, 1972
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6. Brown WUJ, Bell GC, Alper M H Acidosis, local anesthetics, and the newborn. Obstet Gynecol4827-30, 1976 7. Brown DT, Morison DH, Covino BG, et al: Comparison of carbonated bupivacaine and bupivicaine hydrochloride for extradural anesthesia. Br J Anaesth 52419422,1980 8. Brown WUJ, Bell GC, Lurie AO, et al: Newborn blood levels of lidocaine and mepivacaine in the first postnatal day following maternal epidural anesthesia. Anesthesiology 42698-707, 1975 9. Butterworth JF, Strichartz G R Molecular mechanisms of local anesthesia: A review. Anesthesiology 72:711-734, 1990 10. Capogna G, Celleno D, Tagariello V The effect of pH adjustment of 2% mepivacaine on epidural anesthesia. Reg Anesth 14121-123, 1989 11. Cohen SE, Thurlow A: Comparison of a chloroprocaine-bupivacaine mixture with chloroprocaine and bupivacaine used individually for obstetric epidural analgesia. Anesthesiology 51:288-292, 1979 12. Corke BC, Carlson CG, Dettbarn W-D: The influence of 2-chloroprocaine on the subsequent analgesic potency of bupivacaine. Anesthesiology 60:25-27, 1984 13. Cousins MJ, Bromage PR A comparison of the hydrochloride and carbonated salts of lignocaine for caudal analgesia in out-patients. Br J Anaesth 43:1149-1154, 1971 14. Covino BG: Pharmacology of local anesthetic agents. Br J Anaesth 58:701-716, 1986 15. Crampton R S Methylparaben in lidocaine. JAMA 205:803, 1968 16. Davis NL, de Tong RH: Successful resuscitation following massive bupivacaine overdose. Anesth Analg 61:624, 1982 17. de Jong RH, Heavner JE: Local anesthetics seizure prevention: Diazepam versus pentobarbital. Anesthesiology 36:449457, 1972 18. DiFazio CA, Carron H, Grosslight KR, et al: Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 65:76&764, 1986 19. Flanagan HL, Datta S, Lambert DH, et al: Effect of pregnancy on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 66:123-126,1987 20. Feldman HS, Arthur GR, Pitkanen M, et al: Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog. Anesth Analg 73:373-384, 1991 21. Fibuch EE, Opper SE: Back pain following epidurally administered nesacaine-MPF. Anesth Analg 69:113-115, 1989 22. Fink B R The long and the short of conduction block. Anesth Analg 68:551-555, 1989 23. Fleming JA, Byck R, Barash PG: Pharmacology and therapeutic applications of cocaine. Anesthesiology 73518-531, 1990 24. Galindo A, Witcher T Mixtures of local anesthetics: Bupivacaine-chloroprocaine.Anesth Analg 59:683-685, 1980 25. Geddes I C Local anaesthetics. Lava1 Medical 42:787-793, 1971 26. Giovannitti JA, Bennett C R Assessment of allergy to local anesthetics. J Am Dent ASSOC 98:701-706, 1979 27. Gissen AJ, Covino BG, Gregus J: Differential sensitivities of mammalian nerve fibers to local anesthetic agents. Anesthesiology 53:467-474, 1980 28. Grum DF, Rice l W y Methemoglobinemia from topical benzocaine. Clev Clin J Med 57357-359, 1990 29. Hamill JF,. Bedford RF, Weaver DC, et al: Lidocaine before endotracheal intubation: Intravenous or laryngotracheal? Anesthesiology 55:578, 1981 30. Hickey R, Hoffman J, Ramamurthy S: A comparison of ropivacaine 0.5% and bupivacaine 0.5% for brachial plexus block. Anesthesiology 74639442, 1991 31. Kane RE: Neurologic deficits following epidural or spinal anesthesia. Anesth Analg 60:150-161, 1981 32. Kasten GW, Martin ST Bupivicaine cardiovascular toxicity: Comparison of treatment with bretylium and lidocaine. Anesth Analg 64911-916, 1985 33. Kozody R: Catecholamines and neuraxial anesthesia. Can J Anaesth 37836838, 1990 34. Kuhnert BR, Kuhnert PM, Philipson EH, et al: The half-life of 2-chloroprocaine. Anesth Analg 65:273-278, 1986 35. Langerman L, Bansinath M, Grant G The partition coefficient as a predictor of local
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anesthetic potency for spinal anesthesia: Evaluation of five local anesthetics in a mouse model. Anesth Analg 79:490-494, 1994 36. Long WB, Rosenblum S, Grady IP: Successful resuscitation of bupivacaine-induced cardiac arrest using cardiopulmonary bypass. Anesth Analg 69:403-406, 1989 37. Mallampati SR, Liu PL, Knapp RM: Convulsions and ventricular tachycardia from bupivacaine with epinephrine: Successful resuscitation. Anesth Analg 63:856, 1984 38. McClure JJ, Scott DB: Comparison of bupivacaine hydrochloride and carbonated bupivacaine in brachial plexus block by the interscalene technique. Br J Anaesth 53:52> 526, 1981 39. McMorland GH, Douglas MJ, Jeffery WK, et al: Effect pH-Adjustment of bupivacaine on onset and duration of epidural analgesia in parturients. Can J Anaesth 33:537-541, 1986 40. Moller R, Covino BG: Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of tetracaine and ropivacaine: A new amide local anesthetic. Anesthesiology 72322-329, 1990 41. Moore DC: Chloroprocaine not absolved of neurotoxicity. Anesth Analg 63:538-546, 1984 42. Moore DC, Bridenbaugh LD, Thompson GE, et al: Bupivacaine: A review of 11,080 cases. Anesth Analg 5742-53, 1978 43. Moore DC, Spierdijk J, vanKleef JD,et a1 Chloroprocaine neurotoxicity: Four additional cases. Anesth Analg 61:155-158, 1982 44. Morishima HO, Pedersen H, Finster M, et al: Etidocaine toxicity in the adult, newborn, and fetal sheep. Anesthesiology 58342-346, 1983 45. Myers RR, Kalichman MW, Reisner LS, et al:Neurotoxicity of local anesthetics: Altered perineural permeability, edema, and nerve fiber injury. Anesthesiology 6429-35, 1986 46. Nath S, Haggmark S, Johansson G, et a1 Differential depressant and electrophysiologic cardiotoxicity of local anesthetics: An experimental study with special reference to lidocaine and bupivicaine. Anesth Analg 65:126>1270, 1986 47. Piccinini F, Chiarra A, Villani F: The active form of local anesthetic drugs. Experientia 28140-141, 1972 48. Porush I, Shimamura A, Takahashi L D Determination of tetracaine in blood. J PharmaC O ~Sci 541809-1810, 1965 49. Ravindran RS, Bond VK, Tasch MD, et al: Prolonged neural blockade following regional analgesia with 2-chloroprocaine. Anesth Analg 59:447-451, 1980 50. Raymond SA, Steffensen SC, Gugino LD, et al: The role of length of nerve exposed to local anesthetics in impulse blocking action. Anesth Analg 68:56>570, 1989 51. Reisner LS, Hochman BN, Plumer MH: Persistent neurologic deficit and adhesive arachnoiditis following intrathecal 2-chloroprocaine injection. Anesth Analg 59:452454, 1980 52. Rosen MA, Thigpen JW, Shnider SM, et al: Bupivacaine-induced cardiotoxicity in hypoxic acidotic sheep. Anesth Analg 64:1089-1096, 1985 53. Scanlon JW, Brown WLJJ, Weiss JB, et al: Neurobehavioral responses of newborn infants after maternal epidural anesthesia. Anesthesiology 40:121-128, 1974 54. Snatos AC, Pedersen H, Harmon TW, et al: Does pregnancy alter the systemic toxicity of local anesthetics? Anesthesiology 70991-995, 1989 55. Stoelting RK: Circulatory changes during direct laryngoscopy and tracheal intubation: Influence of duration of laryngoscopy with or without prior lidocaine. Anesthesiology 47381-384, 1977 56. Strichartz G Molecular mechanism of nerve block by local anesthetics. Anesthesiology 45:42141, 1976 57. Sukhani R, Winnie AP: Clinical pharmacokinetics of carbonated local anesthetics. Anesth Analg 66739-745’1987 58. Tetzlaff JE, Yoon HJ, OHara J, et al: Alkalinization of mepivacaine accelerates onset of interscalene block for shoulder surgery. Reg Anesth 15:242-244, 1990 59. Thompson DS, Seifen AB, Ferrari AA, et al: Reappraisal of procaine as a short-abing anesthetic adjuvant. Am J Surg 1383798404,1979 60. Wang BC, Hillman DE, Spielholz NI, et al:Chronic neurological defiats and nesacaine-
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CE: An effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 63445-447, 1984 61. Yano M, Nishiyama H, Yokota H, et al: Effect of lidocaine on ICP response to endotrah e a l sudioning. Anesthesiology 64:651, 1986 62. Yukioka H, Yoshimoto N, Nishimura K, et al: Intravenous lidocaine as a suppressant of coughing during tracheal intubation. Anesth Analg 64:1189-1192, 1985 63. Zaric D, Axelsson K, Nydahl P-A, et al: Sensory and motor blocakade during epidural analgesia with I%, 0.75%, and 0.5% ropivacaine: A double blind study. Anesth Analg 72~509-515, 1991
Address reprint requests to John E. Tetzlaff, MD Department of General Anesthesiology, E31 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 e-mail: [email protected]
088943537/00 $15.00
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THE PHARMACOLOGY OF LOCAL ANESTHETICS John E. Tetzlaff, MD
The pharmacology of local anesthetics is an integration of the basic physiology of excitable cells and the mechanism by which local anesthetics are capable of interrupting conduction of neural messages. The common characteristics of the molecules with local anesthetic action have been identified and can explain the properties of the agents. These same chemical characteristics also explain toxicity of these agents and differences that exist between local anesthetics with similar structure. BASIC NERVE CELL PHYSIOLOGY
The function of excitable tissue is based on the presence of a cell with a lipid membrane, axoplasm, membrane-integrated, ion-specific channels, and ion gradients maintained by energy-dependent enzymes. Potassium moves freely through the membrane, whereas sodium moves in a semipermeable manner, controlled by gates on the sodium channels. Sodium is restricted to the extracellular space, except when specific ion channels are open. Potassium selectively accumulates inside the nerve cell to preserve electrical neutrality. In an unexcited state, the electrical potential inside the cell is negative in reference to the outside of the cell and very close to the potential that would be determined by potassium alone. This is the resting potential of the nerve cell membrane. During conduction of an impulse (action potential), sodium channels open and sodium ions move into the cell, depolarizing the cell. The gate that opens and closes these channels is present on the axoplasmic side of the From the Department of General Anesthesiology, The Cleveland Clinic Foundation, Cleveland, Ohio
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nerve cell membrane. In the open state, this channel is susceptible to the action of local anesthetic molecules that cause it to remain inactive and prevent subsequent depolarization. This is the basis for conduction blockade. From isolated nerve cell studies, sodium channel function can be evaluated. When the membrane is rapidly depolarized from the resting state ( - 70 mV) to - 20 mV, there is a rapid increase in sodium channel permeability. The greater the depolarization, up to +20 mV, the greater the sodium permeability. Beyond +20 mV, there is no greater increase in sodium conductance. This verifies that there are a finite number of sodium channels in the membrane. Like the neuromuscular junction, neural conductance has considerable redundancy. Even with 80% to 90% of sodium channel blocked, nerve impulse conduction continues, although at a slower rate. PHYSIOLOGY OF CONDUCTION BLOCKADE
Conduction block is the reversible interruption of conduction within a neural structure by a local anesthetic agent. Conduction block occurs when local anesthetic molecules occupy enough sodium channels within an axon to interrupt activity." Each membrane has a peak sodium current that is 5 to 6 times greater than necessary to initiate an action potential; this is the safety factor of conductance. Local anesthetics reduce this safety factor by progressively interrupting sodium channel excitability, and when it reaches zero, conductance The binding in these channels is semispecific, but no distinct receptor has been identified. The bond is weak in the case of closed channels and strongest and most rapid in the case of open sodium channels. This leads to the phenomenon "use-dependent" or "frequency-dependent" block. The sodium channel is triggered to its open (activated) state by depolarization, and then to its closed (inactivated) state by repolarization. Local anesthetics have significantly higher affinity for the open sodium channel. The more often a nerve is stimulated, the higher percentage of the time its sodium channels are activated, and hence, more susceptible to conduction block. In general, local anesthetics have a higher potency for nerves with a higher frequency of stimulation. Impulse extinction50is the probability that an arriving impulse will stop at a given area of a nerve. Impulse extinction is related to local anesthetic dose delivered and local anesthetic concentration, both at injection and at arrival inside the nerve. It is also related to the length of a nerve that is exposed to the local anesthetic and by the presence or absence of myelination. Myelination decreases the length of nerve necessary to be exposed to local anesthetic, as only the nodes of Ranvier in the myelinated nerves need to be exposed to local anesthetic in order for block to occur. If one node is blocked, conduction will be interrupted less than 30% of the time. For two adjacent nodes, this increases to
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greater than 70%, and for three consecutive nodes, it is 100% likely that conduction block will occur. This also explains why smaller, myelinated fibers are easier to block than larger fibers, with other variables being constant. In unmyelinated nerves a full circumference, as well as length of the nerve, must be bathed by local anesthetic. Variability in the onset of conduction block in different fibers within the same neural structure is referred to as temporal 0nset.2~Temporal onset is related to fiber size, spatial relationships within the nerve fiber, and concentration of injected local anesthetic. Fiber type is a factor because of the relationship of fiber size to conduction blo~k.2~ The larger the fiber, the slower the block and the higher concentration of the agent necessary to achieve the same frequency of impulse extinction. Fiber types are divided into three categories, designated A, B, and C. The A fiber type is subdivided into four subcategories: alpha, beta, gamma, and delta. The A-alpha fibers are the largest in the body and conduct motor impulses. The A-beta fibers innervate some muscle and predominately conduct light touch and pressure. The A-gamma fibers innervate muscle spindles for joint proprioception. The A-delta fibers are the smallest of the A fiber type and conduct pain and temperature sensation and signal tissue damage. The B fibers are all preganglionic, sympathetic nerve fibers, smaller than the entire A group, and are the easiest to block in the body. All of the fibers of the A and the B group are myelinated. The C group are the smallest fibers, are unmyelinated, and conduct pain, temperature, and postganglionic autonomic function.
STRUCTURE OF THE LOCAL ANESTHETIC MOLECULE
The components of a local anesthetic molecule that create the conditions for reversible conduction block have been identified.14Local anesthetics that are clinically useful have an aromatic (hydrophobic) ring structure connected to a tertiary amine (hydrophilic) by a short alkyl, intermediate chain that contains an amide or ester bond. Hence, all of these molecules are amines and would be called amino-amide or aminoester. This is shortened to amide or ester as a classification of the two main local anesthetic groups.
The Aromatic Group
The aromatic side of the local anesthetic molecule provides most of the lipophilic properties of the molecule. Because the nerve cell membrane is a lipid environment, this part of the molecule is mainly involved in passage through the nerve cell membrane, and is directly related to potency.47,56 The size of the aromatic group restricts the movement of the tertiary amine to an axis perpendicular to the aromatic group. This
facilitates the alignment of the tertiary amine with the sodium channel on the axoplasmic side of the membrane.
The Hydrophilic Group
The hydrophilic group is the side of the molecule that accepts protons and is most involved in occupation of the sodium channel. For most clinically useful local anesthetics, this is a tertiary amine group, which is prepared commercially as a hydrochloride salt. Affinity for an ionic structure within the axoplasmic opening of the sodium channel is the chemical basis for sodium channel blockade?
The Intermediate Chain and Amide/Ester Bond
The length of the intermediate bond is a determinant of local anesthetic activity. When the length is between 3 and 7 carbon-equivalents, local anesthetic action can occur.= When less or more, local anesthetic action rapidly disappears. This implies that there must be a critical length of separation of the aromatic group from the tertiary amine for sodium channel block to occur. The amide or ester bond makes creation of the molecule more simple, as two diverse sides of the molecule are brought together by a chemical reaction which creates the bond. This also allows for the reversible action of clinically useful local anesthetics, as metabolism can begin with interruption of this bond. Potency of the local anesthetic increases as the lipid coefficient of these hydrophilic bonds increases.
BIOCHEMISTRY OF LOCAL ANESTHETIC MOLECULES
All of the local anesthetics are weak bases, with pKa between 7.7 and 9.1. They accept a proton to a cationic form at pH below their pKa. The nonionic form is poorly soluble in water. The local anesthetic solutions are generally prepared as hydrochloride salts of the cation with a pH of 5.0 to 6.0 unless they are commercially prepared with epinephrine.= In that case, the pH is much lower (2.0-3.0) to preserve the activity of the epinephrine. The pharmacologic activity of local anesthetic molecules is determined by several of their physiochemical properties. These include lipid solubility, protein binding, and the pKa of each local anesthetic molecule.14 These properties can be used to explain the clinical behavior of these agents-onset, potency, duration, and toxicity. Each of these properties will be explained in some detail.
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Lipid Solubility
Lipid solubility determines the potency of local anesthetic molec u l e ~ ?The ~ hydrophobic nature of the nerve cell membrane explains this relationship between lipid solubility and potency. Local anesthetic molecules are highly lipophilic and easily penetrate nerve cell membranes; more molecules become intracellular, resulting in more blockade. Graphs of the potency of local anesthetics against the oil/water partition coefficients demonstrate the clear relationship between potency and lipid ~olubility.’~ Studies involving exposed, intact nerves demonstrate the relationship between the minimal effective concentration required to interrupt conduction block and lipid solubility.35Clinically, this phenomenon is confirmed by comparison of agents. Adding an aliphatic group to the tertiary amine of mepivacaine (1-4 carbons) creates bupivacaine, which is more lipid soluble and incrementally more potent. This is also observed in the addition of a 4-carbon group to procaine, creating tetracaine, which is similarly more lipid soluble and potent. Experimental addition of ionic groups to existing local anesthetic molecules eliminates the local anesthetic activity by decreasing their lipid solubility. Protein Binding
The protein binding potential determines the duration of action of a local anesthetic m~lecule.’~ Agents with greater protein binding remain associated with the neural membrane for a longer time interval. Increased protein binding results in longer duration of local anesthetic action. Agents that are poorly protein bound, such as procaine, are weakly associated with the nerve cell membrane, and duration of local anesthetic blockade can be extremely short. Those which are highly protein bound, such as bupivacaine, are tightly associated with the nerve cell membrane and have a long duration of action.
PKa The pKa determines the speed of onset of conduction b10ck.l~The pKa of a local anesthetic molecule is that pH at which 50% of the agent exists in the cationic and basic forms. The base is the form with the majority of lipid solubility. Onset is related to the concentration of the base on the extracellular side of the nerve cell membrane. Because the pKa of most local anesthetic agents is higher than physiologic (7.7-9.0), and because local anesthetic solutions are prepared at a pH of 5.0 to 6.0, the majority of the molecules exist in the cationic form. Onset requires buffering of the injected solution to physiologic pH to establish a sigmficant concentration of the base. The higher the pKa, the higher the percentage of cationic form, and hence, the lower the concentration of the base and the slower speed of onset of the local anesthetic agent.
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Alteration of the pH of the injected local anesthetic can also influence the onset of local anesthetic action. Because the concentration of the nonionic form of the molecule determines onset, and because the solution is prepared in an acid medium that results in a huge preponderance of the ionic form, any factor that increases the concentration of the nonionic form results in accelerated onset. Preparation of the agent as a hydrocarbonate salt as opposed to a hydrochloride salt greatly increases the concentration of carbon dioxide in the solution? This results in rapid diffusion of CO, into the nerve cell, which has the effect of acidifying the intracellular environment and increasing the pH of the extracellular environment. This will pull local anesthetic into the cell by favoring the cationic form intracellularly and shifting the equilibrium toward the base extracellularly. This should accelerate the onset of local anesthetic action, and numerous clinical studies confirm this.l 7, 13, 38, 57 An analogous action occurs with addition of sodium bicarbonate to the local anesthetic solution prior to injection, increasing the pH to near-physiologic, greatly increasing the proportion of the base at the time of injection. Clinical studies also confirm this theoretical observation?, lo, 39, 58
Toxicity Toxicity of local anesthetics is related to the potency of the local anesthetic, as toxicity is determined by elements of conduction block that occur within central nervous system (CNS) str~ctures.'~ It is related also to the total dose delivered, the rate of plasma uptake, protein binding, and the site of injection. The site of injection influences the rate of plasma uptake by the vascularity of the tissues. The more vascular the site of injection, the more readily uptake can occur, and the more sudden and intense central nervous system toxic effects will be. Both the rate of change and the absolute level of local anesthetic influence CNS toxicity, with more rapid accumulation being more toxic. This is borne out by the clinical experience in which intercostal blocks are associated with the highest clinical blood levels of local anesthetics, and subarachnoid injection of local anesthetic is associated with the lowest blood levels. Agents that raise the seizure threshold, such as benzodiazepines, can prevent seizure activity or decrease the risk of CNS excitation evolving to seizure activity.I7 The CNS toxic effects of local anesthetics in the clinical setting are directly related to lipid solubility. Although the agents that are highly lipid soluble may be more potent as local anesthetics, the therapeutic to toxic ratio is narrower and the degree of safety in using the agents is less. The toxic form of the local anesthetic is the nonionic, unbound fraction in the blood that is available to penetrate the blood-brain barrier. The more protein bound the agent, the slower the time course to symptoms, and the narrower the gap between the first milder symptoms of
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CNS toxicity, and the more dangerous massive reaction to CNS local anesthetic exposure. To counteract the intrinsic vasodilatory properties of local anesthetics, a frequent choice is the addition of an exogenous vasoconstrictor~3 The most common additions include epinephrine, ephedrine, and phenylephrine. Addition of epinephrine results in lower peak plasma levels and a slower time course to the peak level, which reduces the CNS toxicity potential. With the less lipophilic agents, this decreased vascular uptake can prolong the duration of the local anesthetic; however, there are toxic effects associated with exogenously added vasoconstrictors, including hypertension, tachycardia, cardiac arrhythmia, and myocardial ischemia. Cardiac Toxicity of Local Anesthetics
All local anesthetics have a direct depressant effect on the cardiovascular system in a dose-related fa~hi0n.I~ Specific cardiovascular depression with agents that are highly lipid soluble, such as bupivacaine and etidocaine, is not only related to their increased lipid solubility, but to sodium channel block within the cardiac conduction system. Bupivacaine has a fast-in, slow-out kinetic pattern at the sodium channel, resulting in accumulation of bupivacaine in the conduction system that increases as heart rate increases.&When the primary conducting system is blocked, there is increased activity in reentrant pathways that predisposes the heart to ventricular arrythmia. When the result is ventricular tachycardia or fibrillation, this arrhythmia can be refractory to treatment. Local anesthetic-induced cardiac toxicity is potentiated by hypoxia, hypercarbia, and a ~ i d o s i s The . ~ ~ cardiac toxicity of bupivacaine is further accentuated during pregnancy, probably mediated by progesterone and the adverse physiologic effects of pregnancy on venous return during resuscitation.54 Methemoglobinemia
Prilocaine and benzocaine can cause the oxidation of the ferric form 28 When of hemoglobin to the ferrous form, creating methem~globin.'~, the amount exceeds 4 g/dL, visible cyanosis can occur. In most cases, this cyanosis is benign, but in cases where oxygen transport is an important issue or when symptoms of tissue hypoxia occur, treatment with methylene blue is rapidly successful in reversing cyanosis. Direct Tissue Toxicity of Local Anesthetics
All local anesthetic molecules at some concentration are directly cytotoxic to nerve cells." In addition to the cytotoxicity of the agents
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themselves, various buffers and preservatives have been found to be cytotoxic.@I The potential for intraneural injection is present with all injected local anesthetics. In these cases, it is not the concentration, but rather hydrostatic pressure that causes neural injury. Allergy True allergy to local anesthetics is rare.* The majority of local anesthetic allergies are associated with the ester agents.26 This is related to metabolism of these agents to para-amino-benzoic acid (PABA) and the ubiquitous presence of PABA throughout the pharmaceutical and cosmetic industries. Allergy to amide local anesthetics is rare. A few cases have been found to be related to methylparaben, which is added as a preservative to multidose vials of lidocaine.15 Use of local anesthetics without the use of monitoring can contribute to the problem of incorrect diagnosis of allergy. When the local anesthetic is used with epinephrine, intravascular injection of epinephrine is a possibility. In the absence of monitoring, the distinction from allergy could be difficult.26 During a dental anesthetic, for example, a local anesthetic with concentrated epinephrine is injected into the maxillary area, a compact, highly vascular site. This creates the possibility of pressurized intravascular injection of epinephrine. Shortly after injection, flushing, palpitation, and malaise is reported. The symptoms are related to adrenergic effects of epinephrine, as opposed to allergy, which is symptomatic because of histamine-mediated hypotension. The increased heart rate is present in both, but the extreme palpitation and hypertension are adrenergic, whereas the tachycardia of allergy is associated with vasodilatation and hypotension.
SPECIFIC AGENTS Esters Procaine Procaine is a short-acting amino ester local anesthetic with pKa of 8.9. Commercially prepared solutions have a pH of 5.5 to 6.0, slow onset, and a very short blood half-life owing to rapid hydrolysis by plasma cholinesterase.59 The plasma half-life is believed to be approximately 20 seconds. Hence, there is very little toxicity associated with this agent. Due to extremely limited protein binding, it has a short duration of action. The toxic dose is believed to be in the range of 1000 mg, but reports of toxicity associated with procaine are extremely rare. Clinical uses of procaine at the present time are extremely limited. It is effective for skin infiltration in limited areas. It is used in combination with tetracaine for spinal anesthesia in certain circumstances.
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2-Chloroprocaine
2-Chloroprocaine is a rapid-onset, short-duration local anesthetic with a pKa of 9.0, prepared in solution with a pH of 2.5 to 4.0. It is characterized by rapid onset despite a high pKa due to its extremely low toxicity, allowing for high concentrations to be used clinically. It has a short plasma half-life, and reports of CNS toxicity are uncommon.” The toxic dose is in a range of 800 to 1000 mg or more with epinephrine, and it is believed to be the least toxic in the CNS or cardiovascular systems of all agents in current use. Epidural anesthesia is the most common application for 2-chloroprocaine. It has the most rapid termination of action of current local anesthetics used in the epidural space with a time to 2-segment regression of 30 minutes. 2-Chloroprocaine is also used in peripheral blocks with a 45 to 60 minute duration of action or compounded with other long-acting agents for prolonged duration. The potential advantage of compounding with other agents is that the rapid onset of chloroprocaine can be combined with the long duration of the more lipophilic agents; however, the pH of chloroprocaine causes the clinical duration of bupivacaine to be considerably shortened.12 Several controversies have been associated with chloroprocaine. Serious neurologic deficits have occurred after massive subarachnoid injec** 49, 51 tion of chloroprocaine during attempted epidural ane~thesia.~~, Initially, the agent itself was believed to be causative; however, subsequent evaluation suggested that the antioxidant bisulfite produced the neural damage.4l The neural damage has not been reported since the reformulation of chloroprocaine, without bisulfite. The second controversy is more recent. Ambulatory patients having epidural anesthesia with chloroprocaine have developed severe lumbar muscle spasm during recovery. The most likely cause is the next preservative used in the formulation of chloroprocaine: ethylenediamine tetraacetic acid (EDTA), which causes muscle spasm by interfering with calcium regulation of skeletal muscle relaxation-contraction.26The present solution is prepared with no preservative, and back spasms have not been reported with this reformulation. Tetracaine
Tetracaine is an ester local anesthetic with a pKa of 8.6 prepared in a liquid form with a pH between 4.5 and 6.5. It has a slow onset, very short plasma half-life,48and long duration of action. Systemic toxicity is reported to be considerably higher than with procaine and 2-chloroprocaine. Reports of toxicity are uncommon, and clinical studies with high doses of tetracaine do not identify toxicity unless intravascular injection occurs. The plasma half-life is 2.5 to 4 minutes. The toxic dose is believed to be in the 2 mg/ kg range, or 120 total m The most common clinical application of tetracaine is for spinal anest esia. It is also compounded with other agents with a faster onset and shorter duration to prolong
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peripheral block or epidural anesthesia. In addition, it is used by ophthalmologists for topical anesthesia of the eye and by endoscopists for topical anesthesia of mucous membranes, including the airway. The potential for rapid uptake of tetracaine from mucous membranes must be considered as a risk for toxicity. Many of the early reports of toxicity with tetracaine were related to rapid vascular absorbance from mucous membranes. When applied to the larynx, anesthesia of the airway will persist for a very long duration, and airway reflexes will be absent. Cocaine
Cocaine is an ester local anesthetic with a pKa of 8.5 and a pH in commercial preparation that is extremely variable.= It is most commonly prepared as a liquid alkaloid to decrease abuse potential. It is a slowonset, short-duration local anesthetic that has the unique characteristic of being a vasoconstrictor. Toxicity is related to local anesthetic properties as well as interference with the reuptake of catecholamines, resulting in hypertension, tachycardia, arrhythmia, and myocardial ischemia. An idiopathic response can lead to acute coronary vasospasm in young patients with no prior history of coronary artery disease, and has resulted in myocardial infarction. Because of the combination of anesthesia and intense vasoconctriction, cocaine is ideally suited to procedures where shrinkage of mucous membranes and decreased bleeding are important, such as preparation for nasal intubation or intranasal surgery. Potentiation of catecholamine-induced arryhthmia can occur with other anesthetic agents, such as halothane, theophylline, or antidepressants. There are no other clinical uses for cocaine currently. Benzocaine
Benzocaine is an ester local anesthetic with a pKa of 3.5 and pH in preparation between 4.5 and 6.0. It has a slow onset, short duration, and moderate toxicity. Benzocaine is a secondary amine, in contrast to all the other clinically used local anesthetics, which are tertiary amines. This limits the ability of the agent to pass through neural membranes. As a consequence, its clinical use is limited to topical anesthesia. The estimated toxic dose is in the 200 to 300 mg range. Excessive use of benzocaine in pediatric cases is associated with methemoglobinemia.2s Amides
Lidocaine
Lidocaine is the most commonly used local anesthetic in the United States.14It has a pKa of 7.7, and in commercial preparations, the pH is between 5.0 to 6.0 without epinephrine. With epinephrine, the pH is in the 2.0 to 2.5 range. It has a rapid onset of action with intermediate
, ,'
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duration. Its toxicity is intermediate with metabolism occurring in the liver. The redistribution half-life is 8 to 9 minutes, and the elimination half-life is 45 to 60 minutes. The estimated adult toxic dose with lidocaine is 500 mg (or 7 mg/kg) without epinephrine, and higher when used with epinephrine. Lidocaine is associated with good topical anesthesia when used in Topical application results in a high level the 1%to 4% con~entration.2~ of vascular absorbance. The total dose must be limited and delivered over a time interval as long as possible to avoid toxicity. Lidocaine is the most common choice for intravenous regional anesthesia ( N U )at 0.5% concentration with a duration of 45 to 60 minutes. Lidocaine is used in 5% concentration combined with 7.5% glucose for hyperbaric spinal anesthesia with 45 to 90 minutes' duration. Used at 1.5% to 2.0% in plain solutions, it provides an isobaric spinal anesthetic with a slightly longer duration. Epinephrine will prolong the duration of lidocaine spinal anesthesia. Lidocaine is used for epidural anesthesia and analgesia in the 1.5% to 2% concentration. At the 1.5% concentration the motor block may be somewhat marginal, but at 2.0% dense motor block should be present in most patients. The time to 2-segment regression is in the 60 to 80 minute range. Peripheral conduction block can be performed with 1.0% to 1.5% lidocaine. The duration of action is typically 1 to 3 hours and is prolonged with the use of epinephrine. Lidocaine is the only local anesthetic with extensive use parenterally. It is used as an antiarrhythmic and to supress noxious reflexes, such as coughing,62 sympathetic ~tirnulation,~~ or increases in intracranial pressure associated with endotracheal intubation or suctioning.61 Controversy associated with lidocaine mainly resides in its use in obstetric anesthesia. In the late 1970s, S ~ a n l o nreported ~~ exaggerated neurologic depression of the fetus after epidural lidocaine for cesarean section. Subsequently, work suggested the changes found in this system of scoring are very subtle, not clinically significant, and not reproducible from investigator to investigator'; however, because of the low pKa of the agent and the propensity for ion trapping, lidocaine is not believed to be indicated in large doses for epidural anesthesia in mothers who have fetuses with any signs of fetal distress. This is because the fetal pH is already one tenth of a pH unit lower than the mother in the normal state, and any hypoxia or fetal stress may be associated with an even lower fetal pH and a higher propensity for ion trapping6 and hence higher toxicity of lidocaine in the newborn. More recently, controversy has arisen regarding transient neurologic symptoms (TNS) occurring after lidocaine use for spinal anesthesia. Mepivacaine
Mepivacaine is an amide local anesthetic with a pKa of 7.6 and a pH of 5.5 in solution. It has a rapid onset, intermediate duration, and intermediate toxicity. Onset can be accelerated by alkalinization with bicarbonate. Textbooks suggest mepivacaine toxicity is higher than that
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of lidocaine, but the clinical experience suggests the Fetal metabolism of mepivacaine is limited by hepatic immaturity, and mepivacaine is not believed to be indicated for use in obstetrics.8The toxic dose is 400 mg without epinephrine and 500 to 600 mg with the use of epinephrine, but the basis for this is anecdotal, and in many of the clinical studies the dose is considerably larger without reported toxicity when used with epinephrine. Clinical uses for mepivacaine include infiltration at the 1%concentration, which is associated with a 1.5 to 3 hour duration. Epidural anesthesia with 2% mepivacaine has a rapid onset with dense motor and sensory block, even in the larger nerve roots. The time to 2-segment regression is approximately 70 to 90 minutes. Redosing for longer procedures does not cause tachyphylaxis, and cumulative toxicity is low. Spinal anesthesia at the 4% concentration was used historically with a duration of 60 to 90 minutes. Controversy with lidocaine spinal anesthesia has renewed the interest in this application. Peripheral conduction block is performed at the 1% to 1.5% range with predictably good sensory and motor block with a duration of 2 to 3 hours. Bupivacaine
Bupivacaine is an amide local anesthetic with a pKa of 8.1 and a commercial preparation pH of 4.5 to 5.5. It has a slow onset, long duration of action, and high toxicity potential." The toxic dose is 2.5 to 3 mg/kg. Effects of alkalinization with bicarbonate are equivocal and are limited to pH 6.8 and below by precipitation. Infiltration of 0.25% bupivacaine produces sensory anesthesia with a duration of action of 2 to 4 hours or greater. Epidural analgesia and anesthesia are performed between a 0.25% and 0.75% concentration with very slow onset, and 2- to 5- hour interval to 2-segment regression. There is considerable variability in the quality of motor block achieved, with complete block at the highest doses and almost no motor block below 0.1%. At very low concentration, analgesia can be achieved with most motor function retained. Bupivacaine can be compounded with other agents to increase the speed of onset while retaining long duration of action; however, the addition of chloroprocaine to bupivacaine considerably decreases the duration.I2 Spinal anesthesia is performed at the 0.75% concentration combined with 8.75% dextrose for hyperbaric spinal anesthesia, and also is performed with plain bupivacaine in concentrations ranging from 0.125% to 0.75% with satisfactory results. It should be noted that this agent is not approved in the United States by the Food and Drug Administration for isobaric spinal anesthesia, but is often used in clinical practice. Bupivacaine is used at the 0.5% to 0.75% concentration for major conduction block. Epinephrine does not affect the duration of the block but decreases plasma uptake, and may help to identify intravascular injection. The use of bupivacaine for major
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conduction block is associated with long duration anesthesia, occasionally extending as long as 24 hours. Considerable controversy surrounds the use of bupivacaine. Early reports of sudden cardiac arrest with bupivacaine are associated with considerable morbidity and mortality.16,37 The mortality is probably related to the high protein binding and lipid solubility of the agent. Cardiovascular collapse is caused by the specific accumulation in the conduction system of the heart, activating re-entrant pathways and causing intractable ventricular arrhythmia, including ventricular tachycardia and ventricular fibrillation. These arrhythmias are refractory to treatment. Some success has been obtained with prolonged cardiopulmonary resuscitation, bretyllium,32and cardiopulmonary By consensus, the 0.75% concentration is not used in obstetrics. It is clear that the toxicity associated with bupivacaine is magrufied by respiratory acidosis, hypoxia, and in the parturient because of the physiology of pregnancy and direct effects of proge~terone.~~ Etidocaine
Etidocaine is an amide local anesthetic with a pKa of 7.7, a pH of 4.5, and similar clinical profile to bupivacaine. The toxic dose is believed to be in the 300 to 400 mg range, the higher range with epinephrine. Etidocaine can be used for infiltration anesthesia at 0.5%, peripheral nerve block at 0.5% to 1%with duration from 3 to 12 hours, and epidural anesthesia at 1%to 1.5% with duration of 3 to 5 hours. Profound motor block is sometimes associated with a limited sensory block, and this may make the agent less ideally suited to surgical epidural anesthesia than bupivacaine with the similar toxicity profile.44 Prilocaine
Prilocaine is an amide local anesthetic with a pKa of 7.7 and pH solution of 4.5. It has a rapid onset, intermediate duration, and low toxicity. Its toxic dose is 600 mg with or without epinephrine; however, metabolism to o-toluidine is associated with methemoglobinemia, which usually is not clinically significant but is clinically distressing until differentiation from oxygen desaturation can be e~tab1ished.l~ Clinical uses include infiltration at the 0.5% to 1%range with a duration of 1 to 2 hours. IVRA at 0.5% concentration results in 45 to 60 minutes' duration. Peripheral nerve block is performed at 1.5% to 2% with an expected duration of 2 to 3 hours. Epidural anesthesia at the 2% to 3% concentration results in 1 to 3 hours of expected duration. Dibucaine
Dibucaine is an amino amide local anesthetic with a pKa of 8.4and pH of 4.5 to 5.0. It has intermediate onset, very long duration, consider-
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able potency, and very high toxicity, with two types of clinical application. There is some use of dibucaine for spinal anesthesia, although very rarely in the United States. Dibucaine is also used for the laboratory assessment of the activity of cholinesterase in the serum. Ropivacaine
Ropivacaine is the newest addition to the clinical local anesthetic options. Ropivacaine has a pKa of 8.2 and the pH in commercial preparations is 5.5 to 6.0. Ropivacaine is a chemical analog of mepivacaine and bupivacaine. It was designed to retain the favorable properties of bupivacaine while decreasing the cardiac toxicity?0 The idea came from the observed similarity between the chemical structures of bupivacaine and mepivacaine, except for the substitution on the hydrophilic side, which was a methyl group for mepivacaine and a butyl group (4 carbons) for bupivacaine. Severe cardiovascular toxicity is rare with mepivacaine and much more common with b ~ p i v a c a i n e By . ~ ~decreasing the substitution by one carbon (isopropyl), the favorable properties of bupivacaine are retained and the cardiac toxicity decreased toward that of mepivacaine. The clinical experience, so far, suggests that it is equally potent with bupivacaine, although at this time it has been used at a concentration slightly higher than that of bupivacaineP In animal models, the selective cardiac toxicity of ropivacaine appears to be intermediate between that of mepivacaine and bupivacaine.*O The quality of clinical block with ropivacaine appears to be very similar in onset, duration, and quality to that of bupivacaine. At lower concentrations there may be even less motor block than with bupivacaine at comparable analge~ia.6~ Le vobupivacaine
Levobupivacaine is the pure S-enantiomer of bupivacaine. Preclinical trials suggest levobupivacaine has a potency similar to bupivacaine while exhibiting significantly less central nervous system and cardiac toxicity. References 1. Abboud TK, Kim KC, Noueihed R, et al: Epidural bupivacaine, chloroprocaine, or lidocaine for caesarean section: Maternal and neonatal effects. Anesth Analg 62914919, 1983 2. Benlabed M, Jullien P, Guelmi K, et al: Alkalinization of 0.5%lidocaine for intravenous regional anesthesia. Reg Anesth 15:59-60, 1990 3. Bokesch PM, Raymond SA, Strichartz GR Dependence of lidocaine potency on pH and pC02. Anesth Analg 669-17, 1987 4. Bromage PB: Allergy to local anaesthetics. Anaesthesia 30239-2441975 5. Bromage PR, Gertal M Improved brachial plexus blockade with bupivacaine hydrochloride and carbonated lidocaine. Anesthesiology 36479437, 1972
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6. Brown WUJ, Bell GC, Alper M H Acidosis, local anesthetics, and the newborn. Obstet Gynecol4827-30, 1976 7. Brown DT, Morison DH, Covino BG, et al: Comparison of carbonated bupivacaine and bupivicaine hydrochloride for extradural anesthesia. Br J Anaesth 52419422,1980 8. Brown WUJ, Bell GC, Lurie AO, et al: Newborn blood levels of lidocaine and mepivacaine in the first postnatal day following maternal epidural anesthesia. Anesthesiology 42698-707, 1975 9. Butterworth JF, Strichartz G R Molecular mechanisms of local anesthesia: A review. Anesthesiology 72:711-734, 1990 10. Capogna G, Celleno D, Tagariello V The effect of pH adjustment of 2% mepivacaine on epidural anesthesia. Reg Anesth 14121-123, 1989 11. Cohen SE, Thurlow A: Comparison of a chloroprocaine-bupivacaine mixture with chloroprocaine and bupivacaine used individually for obstetric epidural analgesia. Anesthesiology 51:288-292, 1979 12. Corke BC, Carlson CG, Dettbarn W-D: The influence of 2-chloroprocaine on the subsequent analgesic potency of bupivacaine. Anesthesiology 60:25-27, 1984 13. Cousins MJ, Bromage PR A comparison of the hydrochloride and carbonated salts of lignocaine for caudal analgesia in out-patients. Br J Anaesth 43:1149-1154, 1971 14. Covino BG: Pharmacology of local anesthetic agents. Br J Anaesth 58:701-716, 1986 15. Crampton R S Methylparaben in lidocaine. JAMA 205:803, 1968 16. Davis NL, de Tong RH: Successful resuscitation following massive bupivacaine overdose. Anesth Analg 61:624, 1982 17. de Jong RH, Heavner JE: Local anesthetics seizure prevention: Diazepam versus pentobarbital. Anesthesiology 36:449457, 1972 18. DiFazio CA, Carron H, Grosslight KR, et al: Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 65:76&764, 1986 19. Flanagan HL, Datta S, Lambert DH, et al: Effect of pregnancy on bupivacaine-induced conduction blockade in the isolated rabbit vagus nerve. Anesth Analg 66:123-126,1987 20. Feldman HS, Arthur GR, Pitkanen M, et al: Treatment of acute systemic toxicity after the rapid intravenous injection of ropivacaine and bupivacaine in the conscious dog. Anesth Analg 73:373-384, 1991 21. Fibuch EE, Opper SE: Back pain following epidurally administered nesacaine-MPF. Anesth Analg 69:113-115, 1989 22. Fink B R The long and the short of conduction block. Anesth Analg 68:551-555, 1989 23. Fleming JA, Byck R, Barash PG: Pharmacology and therapeutic applications of cocaine. Anesthesiology 73518-531, 1990 24. Galindo A, Witcher T Mixtures of local anesthetics: Bupivacaine-chloroprocaine.Anesth Analg 59:683-685, 1980 25. Geddes I C Local anaesthetics. Lava1 Medical 42:787-793, 1971 26. Giovannitti JA, Bennett C R Assessment of allergy to local anesthetics. J Am Dent ASSOC 98:701-706, 1979 27. Gissen AJ, Covino BG, Gregus J: Differential sensitivities of mammalian nerve fibers to local anesthetic agents. Anesthesiology 53:467-474, 1980 28. Grum DF, Rice l W y Methemoglobinemia from topical benzocaine. Clev Clin J Med 57357-359, 1990 29. Hamill JF,. Bedford RF, Weaver DC, et al: Lidocaine before endotracheal intubation: Intravenous or laryngotracheal? Anesthesiology 55:578, 1981 30. Hickey R, Hoffman J, Ramamurthy S: A comparison of ropivacaine 0.5% and bupivacaine 0.5% for brachial plexus block. Anesthesiology 74639442, 1991 31. Kane RE: Neurologic deficits following epidural or spinal anesthesia. Anesth Analg 60:150-161, 1981 32. Kasten GW, Martin ST Bupivicaine cardiovascular toxicity: Comparison of treatment with bretylium and lidocaine. Anesth Analg 64911-916, 1985 33. Kozody R: Catecholamines and neuraxial anesthesia. Can J Anaesth 37836838, 1990 34. Kuhnert BR, Kuhnert PM, Philipson EH, et al: The half-life of 2-chloroprocaine. Anesth Analg 65:273-278, 1986 35. Langerman L, Bansinath M, Grant G The partition coefficient as a predictor of local
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anesthetic potency for spinal anesthesia: Evaluation of five local anesthetics in a mouse model. Anesth Analg 79:490-494, 1994 36. Long WB, Rosenblum S, Grady IP: Successful resuscitation of bupivacaine-induced cardiac arrest using cardiopulmonary bypass. Anesth Analg 69:403-406, 1989 37. Mallampati SR, Liu PL, Knapp RM: Convulsions and ventricular tachycardia from bupivacaine with epinephrine: Successful resuscitation. Anesth Analg 63:856, 1984 38. McClure JJ, Scott DB: Comparison of bupivacaine hydrochloride and carbonated bupivacaine in brachial plexus block by the interscalene technique. Br J Anaesth 53:52> 526, 1981 39. McMorland GH, Douglas MJ, Jeffery WK, et al: Effect pH-Adjustment of bupivacaine on onset and duration of epidural analgesia in parturients. Can J Anaesth 33:537-541, 1986 40. Moller R, Covino BG: Cardiac electrophysiologic properties of bupivacaine and lidocaine compared with those of tetracaine and ropivacaine: A new amide local anesthetic. Anesthesiology 72322-329, 1990 41. Moore DC: Chloroprocaine not absolved of neurotoxicity. Anesth Analg 63:538-546, 1984 42. Moore DC, Bridenbaugh LD, Thompson GE, et al: Bupivacaine: A review of 11,080 cases. Anesth Analg 5742-53, 1978 43. Moore DC, Spierdijk J, vanKleef JD,et a1 Chloroprocaine neurotoxicity: Four additional cases. Anesth Analg 61:155-158, 1982 44. Morishima HO, Pedersen H, Finster M, et al: Etidocaine toxicity in the adult, newborn, and fetal sheep. Anesthesiology 58342-346, 1983 45. Myers RR, Kalichman MW, Reisner LS, et al:Neurotoxicity of local anesthetics: Altered perineural permeability, edema, and nerve fiber injury. Anesthesiology 6429-35, 1986 46. Nath S, Haggmark S, Johansson G, et a1 Differential depressant and electrophysiologic cardiotoxicity of local anesthetics: An experimental study with special reference to lidocaine and bupivicaine. Anesth Analg 65:126>1270, 1986 47. Piccinini F, Chiarra A, Villani F: The active form of local anesthetic drugs. Experientia 28140-141, 1972 48. Porush I, Shimamura A, Takahashi L D Determination of tetracaine in blood. J PharmaC O ~Sci 541809-1810, 1965 49. Ravindran RS, Bond VK, Tasch MD, et al: Prolonged neural blockade following regional analgesia with 2-chloroprocaine. Anesth Analg 59:447-451, 1980 50. Raymond SA, Steffensen SC, Gugino LD, et al: The role of length of nerve exposed to local anesthetics in impulse blocking action. Anesth Analg 68:56>570, 1989 51. Reisner LS, Hochman BN, Plumer MH: Persistent neurologic deficit and adhesive arachnoiditis following intrathecal 2-chloroprocaine injection. Anesth Analg 59:452454, 1980 52. Rosen MA, Thigpen JW, Shnider SM, et al: Bupivacaine-induced cardiotoxicity in hypoxic acidotic sheep. Anesth Analg 64:1089-1096, 1985 53. Scanlon JW, Brown WLJJ, Weiss JB, et al: Neurobehavioral responses of newborn infants after maternal epidural anesthesia. Anesthesiology 40:121-128, 1974 54. Snatos AC, Pedersen H, Harmon TW, et al: Does pregnancy alter the systemic toxicity of local anesthetics? Anesthesiology 70991-995, 1989 55. Stoelting RK: Circulatory changes during direct laryngoscopy and tracheal intubation: Influence of duration of laryngoscopy with or without prior lidocaine. Anesthesiology 47381-384, 1977 56. Strichartz G Molecular mechanism of nerve block by local anesthetics. Anesthesiology 45:42141, 1976 57. Sukhani R, Winnie AP: Clinical pharmacokinetics of carbonated local anesthetics. Anesth Analg 66739-745’1987 58. Tetzlaff JE, Yoon HJ, OHara J, et al: Alkalinization of mepivacaine accelerates onset of interscalene block for shoulder surgery. Reg Anesth 15:242-244, 1990 59. Thompson DS, Seifen AB, Ferrari AA, et al: Reappraisal of procaine as a short-abing anesthetic adjuvant. Am J Surg 1383798404,1979 60. Wang BC, Hillman DE, Spielholz NI, et al:Chronic neurological defiats and nesacaine-
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CE: An effect of the anesthetic, 2-chloroprocaine, or the antioxidant, sodium bisulfite? Anesth Analg 63445-447, 1984 61. Yano M, Nishiyama H, Yokota H, et al: Effect of lidocaine on ICP response to endotrah e a l sudioning. Anesthesiology 64:651, 1986 62. Yukioka H, Yoshimoto N, Nishimura K, et al: Intravenous lidocaine as a suppressant of coughing during tracheal intubation. Anesth Analg 64:1189-1192, 1985 63. Zaric D, Axelsson K, Nydahl P-A, et al: Sensory and motor blocakade during epidural analgesia with I%, 0.75%, and 0.5% ropivacaine: A double blind study. Anesth Analg 72~509-515, 1991
Address reprint requests to John E. Tetzlaff, MD Department of General Anesthesiology, E31 The Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland, OH 44195 e-mail: [email protected]