Physiology and Pharmacology of Local Anesthetic Agentst By Benjamin G. Covino, Ph.D., M.D.tt Local anesthetic drugs may be defined as phar- part to the selectively permeable characteristics of macological agents which are capable of producing the membrane. The resting membrane is fully perme- a loss of sensation in a circumscribed area of the able to potassium ions but only slightly permeable body. This localized form of anesthesia is due to an to sodium ions, which accounts for the low intra- inhibition of excitation at nerve endings or to a cellular concentration of sodium. The high intra- blockade of the conduction process in peripheral cellular concentration of potassium is maintained by nervous tissue. Regional anesthesia originated in the attractive forces of the negative charges, mainly 1884 when Koller described the topical anesthetic on proteins, within the cell, which counterbalances properties of cocaine, an alkaloid that had been iso- the tendency of potassium ions to diffuse out of the lated from the leaves of the Erythroxylin coca bush. cell by passive movement along a concentration gra- Procaine, which was synthesized by Einhorn in 1905, dient and across a freely permeable membrane. was the first injectable agent of clinical value for the During the period of nerve inactivity, a negative production of local anesthesia. Following the intro- electrical potential (resting potential) of approxi- duction of procaine, numerous compounds of sim- mately -90 mv exists across the cell membrane. ilar chemical structure were developed. Tetracaine Thus, at rest, the nerve cell behaves as a potassium and chloroprocaine are the procaine-like agents electrode which would react to intra or extracellular which have persisted to this day as clinically useful changes in potassium but not sodium concentra- local anesthetic drugs. tions. Excitation of a nerve results in an increase in In 1943, Lofgren synthesized lidocaine, which rep- the permeability of the cell membrane to sodium resented a new chemical class of local anesthetic ions. The initial flux of sodium ions from the extra- compounds. Whereas the procaine-like drugs are cellular space to the interior of the nerve cell results ester derivatives of para-aminobenzoic acid, lido- in a depolorization of the cell membrane from the caine, is an amide derivative of diethylamino acetic resting potential level to the threshold or firing level acid. Since the advent of lidocaine, many other of approximately - 50 to - 60 mv. At this point, a amide substances, such as mepivacaine, prilocaine, maximum increase in the permeability of the cell bupivacaine, and etidocaine, have been introduced membrane to sodium ions occurs and an explosively into clinical practice as local anesthetic agents each rapid influx of sodium ions into the axoplasm fol- with its own pharmacological profile. lows. At the end of depolarization or at the peak of Mechanism of Local Anesthesia the action potential, the nerve membrane is essen- Local anesthetic agents exert their primary phar- tially transformed from a potassium electrode to a macological action by interfering with the excitation- sodium electrode with a positive membrane poten- conduction process of peripheral nerve fibers and tial of + 40 mv. nerve endings. The electrophysiological properties At the conclusion of the depolarization phase, the of the nerve membrane are dependent on: (a) the permeability of the cell membrane to sodium ions concentration of electrolytes in nerve cytoplasm and again decreases and high potassium permeability is extracellular fluid; and (b) the permeability of the cell restored. Potassium moves out of the cell, resulting membrane to various ions - particularly, sodium in repolarization of the membrane until such time and potassium. The ionic composition of the cy- as the original electrochemical equilibrium and rest- toplasm and extracellular fluid differ markedly. The ing potential is re-achieved. The flux of sodium ions intracellular concentration of potassium is approx- into the cell during depolarization and potassium imately 110 to 170 meq/liter. In extracellular fluid the ions out of the cell during repolarization is a passive situation is reversed. The concentration of sodium phenomenon, since each ion is moving down its is approximately 140 meq/liter, chloride is 110 meq/ concentration gradient. Under normal conditions liter, and potassium is 5 meq/liter. This ionic asym- this entire process of depolarization and repolari- metry on either side of the cell membrane is due in zation occurs within 1 msec. The depolarization phase occupies approximately 30 percent of the en- tire action potential, whereas repolarization ac- tThe Niels B. Jorgensen Memorial lecture presented at the An- nual Scientific meeting of the American Dental Society of counts for the remaining 70 percent. Anesthesiology, April 1981, Chicago, Illinois. Dr. Covino's Following return of the membrane to the resting presentation was also sponsored by the Niels B. Jorgensen potential level, a very slight excess of sodium ions Memorial Library, Loma Linda University. is present within the cell and a very slight excess of ttProfessor, Department of Anaesthesia Harvard Medical School potassium ions exists outside of the nerve cell. Res- Chairman, Department of Anesthesia toration of the normal ionic gradient across the Brigham and Women's Hospital nerve membrane requires the expenditure of energy Boston, Massachusetts 02115 for the active transport of sodium ions from the 98 ANESTIHESIA PROGRESS inside to the outside of the nerve cell against a con- agents such as benzocaine and benzyl alcohol act by centration gradient. This active transport of sodium penetrating the nerve membrane, causing membrane ions is made possible by the function of the so-called expansion and a resultant decrease in the diameter "sodium pump." The energy required to drive the of the sodium channel.3 sodium pump is derived from the oxidative metab- In summary, the mechanism of action of local an- olism of adenosine triphosphate. This metabolic esthetic agents is related to the following sequence pump, which actively extrudes intracellular sodium of events: (a) binding of local anesthetic molecules ions, also is believed responsible, in part, for the to receptor sites in the nerve membrane; (b) reduc- transport of potassium ions from the extracellular tion in sodium permeability; (c) decrease in the rate space to the interior of the nerve cell, since potas- of depolarization; (d) failure to achieve threshold sium ions also must move against a concentration potential level; (e) lack of development of a prop- gradient in order to restore the normal K/K, ratio agated action potential; and () conduction blockade. across the cell membrane. Potassium will return to Active Form of Local Anesthetic Agents the interior of the cell until the electrostatic attrac- Most of the clinically useful local anesthetic prep- tion of the intracellular negative charges balances the arations are available in the form of solutions of a chemical concentration gradient. salt, e.g., lidocaine is usually prepared as an 0.5 - Electrophysiological studies have failed to show 2.0 percent solution of lidocaine hydrochloride. In any alteration in the membrane resting potential of solution, the salts of these local anesthetic coin- isolated nerves following exposure to varying con- pounds exist as uncharged molecules (B) and as pos- centrations of different local anesthetic agents such itively charged cations (BH+). The relative propor- as procaine or lidocaine.' In addition, little or no tion between the uncharged base (B) and charged change in the threshold potential occurs following cation (BH +) depends on the pK;, of the specific application of local anesthetic agents to an isolated chemical compound and the pH of the solution, i.e., nerve. The predominant change occurs during the pH = pKa- log (BH+/B). Since pK, is constant for depolarization phase of the action potential. A de- any specific compound, the relative proportion of crease in the maximum rate of rise of the action free base and charged cation will be dependent es- potential of the isolated lumbar spinal ganglion of sentially on the pH of the local anesthetic solution the frog from a control value of 190 v/sec to 120 v/ (BH + B + H +). As the pH of the solution is decreased sec has been observed after 15 minutes exposure to and the H + concentration increased, the e(quilibrium a solution of 0.005 percent (0.2 mmolar) lidocaine.' will shift towards the charged cationic form and rel- This decrease in the rate of depolarization is not atively more cation will be present than free base. accompanied by any significant change in the rate of Conversely, as the pH is increased and the H+ con- repolarization. When depolarization is not sufficient centration decreased, the equilibrium will shift to- to reduce the membrane potential of an individual wards the free base form and relatively more of the fiber to the threshold potential level, a propagated local anesthetic agent will exist in the free base form. action potential fails to develop. Both the uncharged base form (B) and the charged Since the depolarization phase is related to an in- cationic form (BH+) of local anesthetic agents are flux of sodium ions across the cell membrane, the involved in the process of conduction block.45 The action of local anesthetic agents on sodium perme- base diffuses more easily through the nerve sheath ability has been investigated. Direct measurements and so is required for optimal penetration which is of sodium and potassium conductance by voltage reflected clinically in onset of anesthesia. Following clamp techniques have shown that local anesthetic diffusion through the epineurium, equilibriumn reoc- agents block neural sodium currents.2 Lidocaine curs between B and BH + and the charged cation causes a complete inhibition of sodium conduct- actually binds to the receptor site in the nerve mem- ance, but only a 5 percent decrease in potassium brane. Therefore, the cationic form is ultimately re- conductance. In addition, tetrodotoxin, the puffer sponsible for the suppression of electrophvsiolog- fish poison which possesses potent local anesthetic ical events in peripheral nerve which is reflecte(d activity, completely inhibits sodium conductance clinically in the profoundness of anesthesia. and conduction in nerves at a concentration of Pharmacological Basis of Local Anesthesia 30 nM with no discernible effect on potassium Chemical compounds that demonstrate local an1- conductance. esthetic activity usuallv possess the following chem- Local anesthetic agents are believed to act at the ical arrangement: sodium channel of the nerve membrane. However, Aromatic portion Intermnediate chainl the specific receptor location varies according to the Amine portion type of local anesthetic agent. The coniventionial The agents of clinical importance can be catego- agents, such as lidocaine and procaine, are believed rized into two distinct chemical groups. Local ani- to bind at receptor sites located on the inner surifce esthetics with an ester link between the aromiiatic por- of the nerve membrane. Biotoxins, such as tetro- tion and the intermediate chain are referred to as dotoxin and saxitoxin, act at receptor sites located amino-esters and include procaine, chloroprocainie, on the external surface of the membrane. Finallv, and tetracaine (Table 1). Local anestlhetics witlh ani

JULY-AU(;UST 1981 99 TABLE 1 TABLE 2 Chemical Structure and Primary Anesthetic Use of Relationship of Physical Chemical Properties Ester and Amide-type of Local Anesthetics to Local Anesthetic Activity

AGENT CHEMICAL CONFIGURATO0N PRIMARY ANESTHETIC USE Relative Approxi- Approxi- In Vivo mate A.roma c Intermediate Amine mate Lipophilic Chain Hydrophilic Agent Potency Lipid Duration Protein A. Esters Solubility (Min) Binding PROCAINE H2N e CGOCH2CH1 ~wCzHs Infiltration C2H5 LOW POTENCY - SHORT DURATION C:l Procaine 1 < 1 60-90 5 CHLOROPROCAINE COCH2CH2 Obstetrical HpH :-N,P Epidural : 'C2H5 INTERMEDIATE POTENCY/DURATION TETRACAINE L_N,CH3 Spinal Mepivacaine 2 1 120-240 75 -30CH3

B. Amades Prilocaine 2 1.5 100-240 55 CHC Lidocaine 2 4 90-200 65 Infiltration NEPIVACAINE NHC- Peripheral nerve block Swgical epidural HIGH POTENCY - LONG DURATION Bupivacaine 8 30 180-600 95 C4H9 Tetracaine 8 80 180-600 85 Peripheral nerve blocks BUPIVACAINE OCH30 I NHCO Surgical and Obstetrical epidural Etidocaine 6 140 180-600 94

,C2H5CHg nerve. On the other hand, the partition coefficient InSltration LIDOCAINE Qi3 -N Peripheral nerve blocks 013 NHCOCH2 Surgical epidural of bupivacaine, tetracaine and etidocaine vary from -C Obstotrical spinal approximately 30 to 140, indicating an extremely high degree of lipid solubility for these agents. These CH3 N Infiltration drugs produce conduction blockade in an isolated PRILOCAINE :NHCOCH -N-C3H7 Peripheral nerve blocks Surgical apidural nerve at very low concentrations such that their in- 1CH trinsic anesthetic potency is approximately 20 times greater than that of procaine.fi The relationship of ETIDOCAINE INHOCHQ -N Peripheral nerve blocks Surgical opidumal lipid solubility to intrinsic anesthetic potency is con- 3 sistent with the biochemical composition of the nerve membrane. Chemical analysis of the axolemma amide link between the aromatic end and interme- ofthe first stellar nerve ofthe giant squid has revealed diate chain are referred to as amino-amides and in- that approximately 90 percent of the axolemma con- clude lidocaine, mepivacaine, prilocaine, bupiva- sisted of lipids.7 Therefore, local anesthetic agents caine and etidocaine (Table 1). The basic difference which are highly lipid soluble penetrate the nerve between the ester and amide compounds resides in membrane more easily, which is reflected biologi- (a) the manner in which they are metabolized and cally in increased potency. (b) their allergic potential. The ester agents are hy- The protein-binding characteristics of local anes- drolyzed in plasma by pseudocholinesterase, whereas thetic agents primarily influence the duration of ac- the amide compounds undergo enzymatic degrada- tion (Table 2). Agents such as procaine are poorlv tion in the liver. Para-aminobenzoic acid is one of bound to proteins and basically possess a relatively the metabolites formed from the hydrolysis of ester- short duration of action. Conversely, tetracaine, type compounds. This substance is capable of in- bupivacaine and etidocaine are highly bound to pro- ducing allergic-type reactions in a small percentage teins and display the longest duration of anesthesia.6 of the general population. The amide, lidocaine-like, The relationship between protein-binding of local drugs are not metabolized to para-aminobenzoic anesthetic agents and their duration of action is again acid and reports of allergic phenomena with these consistent with the basic structure of the nerve mem- agents are extremely rare. brane.7 Proteins account for approximately 10 per- The anesthetic profile of a chemical compound is cent of the nerve membrane. Therefore, agents dependent on its (a) lipid solubilitv, (b) protein-bind- which penetrate the axolemma and attach more ing, (c) pK;,, (d) non-nervous tissue diffusibilitv, anid firmly to the membrane proteins will tend to possess (e) intrinsic vasodilator activitv. Lipid solubilitv ap- a prolonged duration of anesthetic activitv. pears to be a primary determinant of intrinsic an- The pK., of a chemical compound mav be defined esthetic potency (Table 2). The lipid solubilitv of as the pH at which its ionized (BH+) and nonionized procaine, as determined by partition coefficient mea- (B) forms are in complete equilibrium. As previouslv surements, is less than one and this drug is least indicated, the uncharged base form (B) of a local potent in suppressing conduction in an isolated anesthetic agent is primarilv responsible for diffusion 100 ANESTIIESIA PROGRESS across the nerve sheath. The onset of anesthesia is the vascular system. The degree of vascular absorp- directly related to the rate of epineural diffusion tion is related to the blood flow through the area which, in turn, is correlated with the amount of drug in which the drug is deposited. All local anesthetic in the base form. The percentage of a specific local drugs, except cocaine, are vasodilator in nature. anesthetic drug which is present in the base form However, the degree of vasodilation produced bv when injected into tissue whose pH is 7.4 is inversely the various agents does differ. In vitro studies have proportional to the pK, of that agent. For example, shown that the intrinsic anesthetic potency of lido- lidocaine, which has a pK,1 of 7.74, is 65 percent caine is significantly greater than that of mepivacaine, ionized and 35 percent nonionized at a tissue pH of while their durations of action are similar. However, 7.4. On the other hand, tetracaine, with a pK1 of 8.6, in vivo, mepivacaine is similar in potency and pro- is 95 percent ionized and only 5 percent nonionized duces a longer duration of anesthesia than lidocaine. at a tissue pH of 7.4. Both in vitro and in vivo studies These differences between in vitro and in vivo results have confirmed that local anesthetic drugs such as are attributable to the greater vasodilator activity of lidocaine, whose pK, is closer to tissue pH, have a lidocaine which results in greater vascular absorption more rapid onset time than agents with a high pKa,, such that less lidocaine is available for nerve block- such as tetracaine (Table 3).s ade. In summary, chemical alterations within an ho- TABLE 3 mologous group produce quantitative changes in Relationship of pKa to Percent Base Form and physico-chemical properties, such as lipid solubility Time for 50 Percent Conduction Block in and protein-binding, which can alter the anesthetic Isolated Nerve properties of the compounds. Within the ester se- ries, the addition of a butyl group to the aromatic Agent Chemical Class pK, A Base Onset end of the procaine molecule increases lipid solu- at pH 7.4 (Min) bility and protein-binding and results in a com- Prilocaine Amino-amide 7.7 35 2-4 pound, tetracaine, which has a greater intrinsic an- esthetic potency and longer duration of anesthetic Lidocaine Amino-amide 7.7 35 2-4 activity. In the amide series, the addition of a butyl Etidocaine Amino-amide 7.7 35 2-4 group to the amine end of mepivacaine transforms Bupivacaine Amino-amide 8.1 20 5-8 this agent into a compound, bupivacaine, which is Tetracaine more lipid soluble, more highly protein-bound, Amino-ester 8.6 5 10-15 and, biologically, possesses a greater intrinsic po- Procaine Amino-ester 8.9 2 14-18 tency and longer duration of action. In the case of lidocaine, substitution of a propyl for an ethyl group In an isolated nerve, onset time is a function of at the amine end, and the addition of an ethyl group the rate of diffusion of a compound through the to the alpha carbon in the intermediate chain yields epineurium which, in turn, is related to percentage etidocaine, which is more lipid soluble, more highlv of drug in the base form. However, in vivo, a local protein-bound, and, biologically, a local anesthetic anesthetic must diffuse initiallv through non-nerve agent of greater potency and longer duration. connective tissue barriers. Differences do exist be- On the basis of differences in anesthetic potency tween the rate of non-nervous tissue diffusion for and duration of action, it is possible to classifv the various agents. For example, procaine and chloro- clinically useful injectable local anesthetic com- procaine have similar pK,'s of 9.1 and similar onset pounds into three categories: times for conduction blockade in an isolated nerve. Group I - Agents of low anesthetic potency and However, in vivo, the onset of anesthesia for chlo- short duration of action: e.g., procaine and chlo- roprocaine is significantly shorter than that of pro- roprocaine. caine, which is indicative of a more rapid rate of Group II - Agents of intermediate anesthetic po- non-nervous tissue diffusibility. Similarly, in the tency and duration of action: e.g., lidocaine, me- amide series, lidocaine and prilocaine possess the pivacaine, and prilocaine. same pK,1 and onset of action in isolated nerves, Group III - Agents of high anesthetic potency whereas lidocaine has a slightly faster onset of anes- and long duration of action: e.g., tetracaine, bupi- thesia in vivo. The factors that determine diffusibilitv vacaine, and etidocaine. through non-nervous tissue are unclear. Physiological Disposition of Local Anesthetic Agents Finally, intrinsic vasodilator activity of different The vascular absorption, tissue distribution, me- local anesthetic agents will influence their apparent tabolism and excretion of local anesthetic agents are potency and duration of action in vivo. The degree of particular importance in terms of their potential and duration of nerve block is related to the amount toxicity. Absorption varies as a function of site of of local anesthetic drug which diffuses to the recep- injection, dosage, addition of a vasoconstrictor tor site at the nerve membrane. Following injection agent, and the specific agent emploved.9 In general, of a local anesthetic agent, some of the drug will be the greater the vascular supply of the tissue (e.g., taken up by the nerve and some will be aI)sorbed by muscle mucous membranes), the greater the absorp-

JULY-AUGUST 1981 101 tion without a vasoconstrictor. For intra-oral in- The metabolism of local anesthetic agents varies jections, the infiltration of two cartridges (1.8 ml) of according to their chemical classification. The ester lidocaine 20 mg/ml or 76 mg will produce a peak or procaine-like agents undergo hydrolysis in plasma blood level of 0.5-2 ,ug/ml within 20-30 minutes. An by plasma cholinesterases. Chloroprocaine shows equal dose applied topically in the uncharged base the most rapid rate of hydrolysis (4.7 ,umole/ml/hr) form can reach higher levels within 5 minutes ap- compared to procaine (1.1 ,umole/ml/hr) and tetra- proaching intravenous administration. An inferior caine (0.3pmole/ml/hr).16Less than 2 percent of un- alveolar block, with reduced vascularity at the site changed procaine is excreted, while approximately of injection, will have the lowest blood level and be 90 percent of para-aminobenzoic acid, which is the least influenced by a vasoconstrictor. The blood primary metabolite of procaine, appears in urine. level of local anesthetic agents is related to the total On the other hand, only 33 percent of diethylami- dose of drug administered rather than the specific noethanol, the other major metabolite of procaine, volume or concentration of solution employed.9 A is excreted unchanged. linear relationship tends to exist between the injected The amide, or lidocaine-like, agents undergo en- amount of drug and the peak anesthetic blood level. zymatic degradation primarily in the liver. Prilocaine Addition of a vasoconstrictor agent to local an- undergoes the most rapid rate of hepatic metabo- esthetic solutions decreases the rate of absorption lism. Lidocaine, mepivacaine, and etidocaine are in- of certain agents. 5 ,ug/ml of epinephrine (1:200,000) ternrediate in terms or rate of degradation, while reduces the peak blood levels of lidocaine and me- bupivacaine is metabolized most slowly. Some deg- pivacaine by approximately 30 percent, irrespective radation of the amide-type compounds may occur of the site of administration.6 Epinephrine will de- in non-hepatic tissue as indicated by the formation crease the peak blood levels of prilocaine, bupiva- of certain metabolites following the incubation of caine, and etidocaine achieved after peripheral nerve prilocaine with kidney slices. The metabolism of the blocks, but has little influence on the absorption of amide-type agents is more complex than that of the these drugs following lumbar epidural administra- ester drugs. The complete metabolism for all the tion.9'10 Phenylephrine, and norepinephrine can also amide compounds has not been elucidated. Lido- reduce local anesthetic absorption, but not as effec- caine, which has been studied most extensively, tively as epinephrine." undergoes primarily oxidative deethylation to mon- The rate and degree of vascular absorption varies oethylglycinexylidide, followed by a subsequent hy- between various agents. Lidocaine is absorbed more drolysis to hydroxyxylidine.17 Less than 5 percent of rapidly than prilocaine, while bupivacaine is ab- unchanged amide-type drugs is excreted into the ur- sorbed more rapidly than etidocaine.12 The lower ine. The major portion of an injected dose appears blood levels of prilocaine probably reflects its tend- in the form of various metabolites. For example, 73 ency to produce less vasodilation than lidocaine or percent of lidocaine can be accounted for in human mepivacaine. The lower peak blood levels of eti- urine by hydroxyxylidine. The renal clearance of the docaine compared to bupivacaine may be related to amide agents is inversely related to their protein- the greater lipid solubility and uptake by peripheral binding capacity. Prilocaine, which has a lower fat of etiodcaine. protein-binding capacity than lido-caine, has a sub- Following absorption from the injection site, lo- stantially higher clearance value than lidocaine. Renal cal anesthetic agents distribute throughout total clearance also is inversely proportional to the pH body water. An initial rapid disappearance from of urine, suggesting urinary excretion by nonionic blood (alpha phase) occurs which is related to uptake diffusion. 18 by rapidly equilibrating tissues, i.e., tissues with a Systemic Toxicity of Local Anesthetic Agents high vascular perfusion. A secondary, slower dis- The toxicity of local anesthetic agents mainly in- appearance rate (beta phase) reflects distribution to volves the central nervous system and cardiovascular slowly perfused tissues and metabolism and excre- system. tion of the compound. The disappearance rate of a) CNS effects: Local anesthetic agents readily prilocaine is significantly more rapid than that of cross the blood-brain barrier and toxic levels can lidocaine or mepivacaine.13The rate of tissue redis- produce signs of CNS excitation and depression. The tribution for these latter two agents is similar. Sim- initial symptoms of local anesthetic toxicity in man ilarly, the alpha and beta half-lives of etidocaine are consist of a generalized feeling of lightheadedness significantly shorter than those of bupivacaine, which and dizziness, followed by auditory and visual dis- indicates a more rapid rate of tissue redistribution turbances, such as difficulty in focusing and tinnitus. for etidocaine.'4 Although all tissues will take up lo- Drowsiness, disorientation, and a temporary lack of cal anesthetics, the highest concentrations are found consciousness may also occur. Slurred speech, shiv- in the more highly perfused organs, such as lung and ering, muscle twitching, and tremors of the face and kidney. 15 The greatest percentage of an injected dose extremities appear to be the immediate precursors of a local anesthetic agent distributes to skeletal of a generalized convulsive state. A further increase muscle due to the large mass of this tissue in the in the dose of local anesthetic agents during the ex- body. citation period, results in cessation of convulsive

102 ANESTHESIA PROGRESS activity, respiratory arrest, and a flattening of the and QRS duration), an increase in diastolic threshold brain wave pattern consistent with generalized cen- and decreased automaticity, as reflected by sinus bra- tral nervous system depression. dycardia. Lethal concentrations of lidocaine pro- The signs and symptoms of CNS excitation fol- duce asystole. Hemodynamically, lidocaine doses lowed by depression are related to an inhibition of and blood levels considered non-toxic (2-5 jig/ml) cerebral cortical neurons. An initial selective block- cause no alterations in myocardial contractility, di- ade of inhibitory cortical neurons or synapses allows astolic volume, intraventricular pressure, and cardiac facihtory fibers to function unopposed leading to output.2l Blood levels of 5-10 ,ug/ml result in de- excitation and convulsions. Further increases in dos- creased myocardial contractility, increased diastolic age depress both inhibitory and facilitory pathways volume, decreased intraventricular pressure, and de- causing a generalized state of central nervous system creased cardiac output.2' At these blood levels, li- depression. '9 docaine also produces a decrease in peripheral vas- Local anesthetic toxicity is due usually to an in- cular resistance, due to a direct relaxant effect on the advertent rapid intravenous injection or extravas- smooth muscle of peripheral arterioles. This nega- cular administration of an excessive dose. CNS tox- tive inotropic and peripheral vasodilator action can icity following rapid intravenous administration is cause profound hypotension and circulatory col- related to the intrinsic anesthetic potency of the lapse. All local anesthetic agents show a similar pat- agent.20 Procaine is least potent anesthetically and tern of cardiovascular toxicity. The doses of local least toxic following a rapid intravenous injection. anesthetic agents employed for most regional an- Bupivacaine, tetracaine, and etidocaine are the most esthetic procedures result in peak blood levels potent compounds in terms of intrinsic anesthetic which, generally, are not associated with a cardi- and CNS convulsive activity. Lidocaine, mepiva- odepressant effect. However, inadvertent, rapid, in- caine, and prilocaine are intermediate in anesthetic travenous injection, or administration of an exces- potency and convulsive activity. For example, blood sive dose may cause significant cardiovascular levels in excess of 20 ,ug/ml of procaine are associated alterations. with CNS symptoms in man. Lidocaine, mepiva- c) Allergy: True allergic reactions to local an- caine, and prilocaine demonstrate CNS effects at lev- esthetic agents are rare. Ester derivatives of paraa- els of 5-10 ,ug/ml, while bupivacaine, and etidocaine minobenzoic acid, such as aprocaine and tetracaine, show CNS effects at venous blood levels of 1.5 to are responsible for most of the suspected allergic 4 ,ug/ml. phenomena associated with the use of local anes- The potential toxicity of local anesthetic agents thetic agents. Reports of allergic reactions to amide- administered extravascularly will be influenced by fac- type compounds (i.e., lidocaine and mepivacaine) tors such as rate of absorption, tissue redistribution, have been extremely rare. Multiple dose vials of and metabolism. Prilocaine and lidocaine are similar some amide agents contain a preservative, methyl- in terms of intrinsic anesthetic potency and rapid paraben, which may cause cutaneous signs ofallergic- intravenous toxicity, whereas prilocaine is approxi- type reactions.22 mately 60 percent less toxic than lidocaine following Summary subcutaneous administration due to its slower ab- Local anesthesia provides a safe and efficacious sorption and more rapid clearance. Similarly, eti- method of preventing or relieving pain in circum- docaine and bupivacaine are equitoxic following scribed areas of the body and so is particularly useful rapid intravenous injection, but etidocaine is only in dentistry. These agents inhibit excitation in nerve half as toxic as bupivacaine after subcutaneous injec- endings and fibers by a decrease in sodium perme- tion. Intravenous chloroprocaine is intrinsically ability which, in turn, depresses the rate and degree more toxic than procaine, but is four times less toxic of membrane depolarization. The clinically useful than procaine following subcutaneous adminsitra- local anesthetic agents can be divided chemically into tion due to its rapid hydrolysis in plasma. the amino-esters, e.g., procaine, chloroprocaine Other factors, such as acid-base status of the pa- and tetracaine, and amino-amides, e.g., lidocaine, tient, will influence local anesthetic toxicity. An in- mepivacaine, prilocaine, bupivacaine and etidocaine. verse relationship exists between pCO2 level and Pharmacologically, these agents can be categoried convulsive threshold of local anesthetic agents. The as agents of low potency and short duration of ac- convulsive threshold of procaine in cats decreases tion, e. g., procaine and chloroprocaine; agents of from approximately 35 mg/kg to 15 mg/kg when the intermediate potency and duration of action, e. g., PCO2 is elevated from 25-40 torr to 65-81 torr.2' lidocaine, mepivacaine and prilocaine; and agents of b) Cardiovascular effects: Local anesthetic agents high potency and long duration, e.g., tetracaine, can produce profound cardiovascular changes by a bupivacaine and etidocaine. direct cardiac and peripheral vascular action and, in- Local anesthetic agents can produce toxic reac- directly, by conduction blockade of autonomnic tions which usually involve the central nervous svs- nerve fibers. Lidocaine concentrations of 5-10pug/ml tem of cardiovascular system. Toxic blood levels, may cause a prolongation of conduction through which are due most often to an inadvertent rapid various portions of the heart (increased P-R interval intravenous injection or the extravascular adminis- JULY-AUG;UST 1981 10)3 tration of an excessive dose, may result in overt convulsions followed by CNS depression and car- diovascular collapse due to a direct negative ino- tropic action on the heart and peripheral vasodilator effect. Intravenous toxicity of local anesthetic agents is directly related to their anesthetic potency, whereas toxicity subsequent to extravascular overdose is re- lated to the disposition characteristics of the various drugs. The judicious use of local anesthesia requires knowledge of the pharmacological properties of the various agents, technical skill in the performance of regional anesthetic procedures, and an evaluation of the patient's clinical status. REFERENCES whEr Q.rny 1. 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Only dental products first stellar nerves of squid Dosidieus gigas. Biochiml Biophvs Acta 193:247, 1969. bearing the Astra name assure 8. Truant AP, Takman B Differential phvsical-cheimical and nleu- ropharmacologic properties of local aniesthetic agenits. Anestl you of the quality you have long Analg 38:478, 1959. 9. Scott DB Jebson PJR Braid DP Ortengen B Frisch P Factors associated with Astra. affecting plasma levels of lignocaine and prilocaine. Br J An- aesth 44:1040, 1972. Astra controls both product qual- 10. Lund PC Bush DF Covino BG Determinants of etidocaine concentration in the blood. Anesthesiology 42:497, 1975. ity and product performance, and 11. Dhuner K-G Lewis DH Effect of local anesthetics and va- soconstrictors uponI regional blood flow. Acta Anestlh Scancl backs both with an unwavering (Suppl) 23:347, 1966. 12. 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Keenaghani JB Boves RN The tisstue distribution, metabolism and excretion of lidocaine in rats, giuinea pigs, dogs anid 1an. J Pharmacol Exp Ther 180:454, 1972. 18. Eriksson E Granberg P-O Stuidies on the renial exceretioni of Citanest and Xvlocainie. Acta Aniestlh Scanid (Supple) 16:790, 1965. 19. Taniaka K Yamaski M Blocking of cortical inhibitory synapses bv intravenouis lidocainie. Natuire 209:207, 1966. 20. Eniglessoni S The influieniee of acid-base chlianges oni central niervouis svstemii toxicity of' local an1aesthetic agen1ts. D)octoral Thesis, University of Uppsala. Swedeni, 1973. 21. Collinsworthi KA Kalmain SM Harrison D)C The cliniical phar- A ZFIflep Astra Pharmaceutical Products, Inc. macologv of lidocaine as ani antiarrhythmiic (rig. Cirecilationi *A £ *UULA Worcester, Massachusetts 01606 50:1217, 1974. 22. Aldrete JA Johnson D)A Evaluation of initracuitcaineouis testinig for investigationi of allergy to local aniesthietic agentts. Aniestlh Analag 49:173, 1970.