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Neural blockade by local anesthetics
Life §ciences Vol . 20, pp . 915-920, 1977 . Printed in the U .S .A.
Pergamon Press
1IINIREVIEW NEURAL BLOCKADE BY LOCAL ANESTHETICS Rudolph H . de Jong, M.D . Anesthesia Research Center (RN-10) Univ . Washington School of Medicine Seattle, WA
98195
The bimolecular phospholipid membrane that separates axoplasm from extracellular fluid holds the key to nerve excitability : and so to local anesthesia . Local anesthetics block impul se propagation by preventing membrane depolarization . They do this by occluding the sodium pores (probably by plugging the channel's internal axoplasmic mouth) . The poslüvely charged local anesthetic cation binds to oppositely charged anionic channel components, whereas the uncharged lipid soluble anesthetic base furnishes the carrier species that penetrates the membrane . Dissolved in water, local anesthetic salt crystals dissociate to yield anesthetic cation and base whose proportions are governed by the drug's fixed p1C and the tissue's variable pH . The more acid the surroundings, tfle more cation and the less base coexist . The cation/base concentration ratio is critical to optimal blockade . Too little base, and few anesthetic molecules manage to reach the neural target ; too little cation, and few sodium channels will be plugged . Drugs called Local Anesthetics are used widely to selectively numb ("anesthetize") a body part . Other drugs (e .g ., phenol, alcohol) or techniques (e .g ., cooling, compression) exist that exert a similar selective numbing action : it is the reversibility of their effect that differentiates local anesthetics from other agents having similar action . And it is the ease of application and predictability of results that favors drug-induced local anesthesia over alternate physical methods . As our knowledge of the elusive transmembrane ionic channels leaped forward, so has our understanding of the mechanisms by which local anesthetics block 4jam A se propagation in nerves . The cardinal features of local anesthesia are perhaps best brought out by contracting them with those of general anesthesia . General anesthesia results when certain agents are introduced into the bloodstream; either directly, as by intravenous injection or, more circuitously, by uptake from the lungs . Though the target organ Of general anesthetics is the central nervous system, their presence in the circulation inevitably affects other organ systems as well . Local anesthetics, conversely, are deposited in immediate proximity to their target neural structures . Because they do not depend on the circulation for transport, they do not affect distant organ systems ; local anesthetics, as their name implies, act locally .
915
91 6
Local Anesthetics
Vol . 20, No . 6, 1977
Conduction Blockade Local anesthetics halt impulse traffic along an axon in a reversible manner and without damaging the neural membrane . Even so, striking changes in neural function herald the onset of blockade . Local anesthetics progressively lower the amplitude of the compound action potential, reduce its rate of rise, elevate the firing threshold, slow the velocity of impulse conduction and lengthen the refractory period . These changes progress until the ever smaller local currents drop below the ever rising firing threshold: the nerve is rendered inexcitable or, as we usually call it, is blocked (1) . There is overwhelming evidence that local anesthetics impede sodium ion access to the axon interior, probably by directly or indirectly occluding the transmembrane sodium channels (2) . With sodium entrance denied, depolarization cannot take place, the axon thus remains polarized . A local anesthetic block is a non-depolarization block, resembling in same respects the action of curare at the neuromuscular junction . The insulating properties of myelin limit local anesthetic access to the nerve membrane ; everywhere, that is, except at the nodes. Since so little membrane is exposed, a relatively greater density (i .e ., higher concentration) of local anesthetic is required to produce conduction block in myelinated than in nonmyelinated fibers . Further, as impulses can skip over one or two consecutive blocked (i .e ., inexcitable) nodes, it follows that at least 5 or 6 mm of nerve needs to be bathed in the anesthetic solution (3) . In fact, taking irregular diffusion into whole nerve into account, a minimum of perhaps 8 to 10 mm of nerve must be covered by anesthetic solution to ensure thorough blockade (4) . Membrane Site of Action There is little question that local anesthetics block impulse conduction by interfering with the very process fundamental to generation of the action potential : that is, the transient rise in membrane permeability to sodium ions . Much more difficult to answer is how local anesthetics alter the membrane's configuration so as to stem the invasion by sodium ions . The place to look, evidently, is at or near the sodium channel ; for it is the voltage-dependent gating function that is somehow impeded by local anesthetic molecules (2,5) . An external site of membrane attachment of local anesthetics, based mainly on their rapid action, has long been postulated . More recent evidence, however, increasingly points to the sodium channel's internal (axoplasmic) mouth as the more likely site of local anesthetic action (6, 7) . That local anesthetics are effective too when applied externally must therefore be attributed to their rapid diffusion through:the membrane (8) . In fact, non-diffusable local anesthetic cation is virtually inactive when applied externally, yet produces rapid block when perfused internally through an axon (9) . In that regard alone, local anesthetics differ fundamentally from marine toxins such as tetrodotoxin (TTX) which plug the sodium channel by occluding the pore's external entrance (10) . (The reader should note that local anesthetics do not block the passage of sodium ion per se, but rather the ionic traffic through the sodium channels . Nerve bathed in a sodium-substitute solution is blocked just as readily by local anesthetics as it would be in a sodium-containing medium (11) .) Whereas the exact locus of a local anesthetic's channel-blocking action is uncertain as yet, its attachment to phospholipid membrane components is well
Local Anesthetics
Vol . 20, No . 6, 1977
91 7
documented . This in turn is linked to the important function of phospholipids in excitability artificial membrane lacking phospholipid in inexcitable . The negatively charged phosphate tails of the phospholipid molecule in particular are essential to excitability . Local anesthetics, having two positively charged ends, attach to (and so bridge) two phosphate groups, one molecule thereby stabilizing two anionic phosphate tails (12) . The electrostatically stable complex so formed firmly glues the gating structures together, so preventing their opening (1) . While electrostatic bonding amply suffices to explain how conventional local anesthetics work, the hypothesis falls a bit short of the mark where agents such as benzocaine are concerned . The latter, by virtue of a low pR (see below), exists essentially only in the unionized (base) form at physiofogic pH . To account for benzocaine blockade, the lipid-soluble base is thought to cause membrane swelling of a scope sufficient to pinch the sodium channels shut by external compression (1,2) . Lateral compression certainly seems to take a back seat to cationic plugging, for benzocaine is but a marginal blocking agent . pH Effec ts The pure synthetic local anesthetic is a weakly basic amine -- soluble in liquids, but poorly soluble and unstable in water . Salts of the local anesthet ic base, conversely, are readily soluble in water and stable in solution . The usual local anesthetic solution contains a salt (commonly the hydrochloride) of the local anesthetic base . in this aqueous solution the positively charged quaternary amine species of the local anesthetic (the cation ) is in dissociation equilibrium with the uncharged local anesthetic base according to : R--HH+ cation
$
R=-N + H+ base
it is apparent from this dissociation reaction that the relative concentrations of cation and base vary with the hydrogen ion concentration of the solution . When the pH of the solution equals the local anesthetic's pR (negative logarithm of the dissociation constant), equal amounts of cation aand base coexist in the solution . Since the p1C of most local anesthetics ranges between 7 .5 and 9 (Table) the solution contains considerably more anesthetic cation than base at tissue pH . The proportion of the concentrations of cation and base in solution is derived from the equation log[cation] a log [base]
pxa
- pH
where [cation] and [base] denote "concentrations" of the local anesthetic cation and base respectively . The cation (i .e ., the positively charged quarternary amine) is the species that binds to anionic receptors on the nerve membrane and plugs the sodium channels, so rendering the nerve inexcitable . Clearly, one needs the local anesthetic cation to block inpluse conduction . The concentration of local anesthetic base, conversely, determines drug penetration, and thereby the quantity of local anesthetic to reach the nerve membrane . The proportion of base in increased by raising the pH of the solution : alkalinizing a local anesthetic solution accordingly enhances drug penetrance . Whereas an acidified solution is less effective clinically than the same solution at body pH as fewer local anesthetic molecules reach the neural target .
91 8
Local Anesthetics
Vol. 20, No . 6, 1977
TABLE DISSOCIATION CONSTANTS OF SCHE LOCAL ANESTHETICS (1) Agent
2% 3.5
Benzocaine
Mepivacaine
7 .6
Lidocaine
7 .9
Etidocaine
7 .7
Prilocaine
7 .9
Tetracaine
8 .2
Bupivacaine
8 .1
Cocaine
8 .7
Dibucaine
8 .8 8 .9
Procaine Hexylcaine
9 .3
One immediate corollary of dissociation is the common observation that local anesthetics "don't work well" when injected into an infected area, as when attempting to lance an abscess. While lots of cations are formed, they are stuckt for, being electrically charged, cations cannot migrate to the neural target without assistance from the uncharged anesthetic base . . . and that species is in short supply . Another consequence of dissociation is the reduced anesthetic potency that certain acid stabilizers impart . For instance, ccemercial local anesthetic solutions containing epinephrine commonly are buffered to a lower pH than the standard solution so as to minimize vasoconstrictor oxidation . These acid solutions seem to be less effective than the nearly neutral standard local anesthetic solution (13) . New Horizons A neat approach to providing effective proportions of local anesthetic base and cation derives from a clever chemical trick. By juggling inter-atomic distances, one can synthesize a molecule with a tendency to curl its amino-alkyl tail around and onto itself, so forming a six-membered ring structure. Such cyclization of an uncharged molecule yields a quaternary amine with the usual impulseblocking properties of local anesthetic cations (14) . Attractive here is that cyclization is independent of pH . Thus one can inject a solution composed of predominately anesthetic base and let it diffuse into the nerve . Once in the nerve, cyclization takes place, the anesthetically active cation is formed and block ensues . Making this class of drugs all the more attractive is that the cation (being charged) cannot easily diffuse outward . The anesthetic drug thus is trapped, and very long-lasting anesthesia is the result . The aforementioned marine toxins (represented by TTR), which plug the sodium channel's external pore entrance, form another potential seed stock for a new and different family of local anesthetics. As these potent blocking agents attach to the membrane's external surface, they do not need to change back to the unionized species -- necessary to traverse the lipid membrane an route to the sodium channel's axoplasmic mouth -- as conventional local anesthetics must do . Marine toxins, accordingly, are rapid acting extr®ely potent agents, and
Vol . 20, No . 6, 1977
Locai Anesthetics
919
blockade is virtually pH-independent . While still far too toxic for human application, suitable derivatives say well fill the bill eventually . REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 .
R. H . DE JONG, Local Anesthetics , Chas . C . Thomas, Springfield (1976) . G . STRICHARTZ, Anesthesiology 45 in press (1976) . G . A . CONDOURIS, R . H . GOEBEL, and T . BRADY, J . Pharmacol . M512 . Ther . 196 723-736 (1976) . D . N . FRANZ and R . S . PERRY, _J . Physiol . _ 236 193-210 (1974) . J . M . RITCHIE, Br . J . Anaesth . 47 191-198 (1975) . X . R. COURTNEY, J. _ Pharma Col . . Ther . 195 225-236 (1975) . B . G . COVINO and H . G . VASSALLA, Local Anesthetics : Mechanisms of Action and Clinical Use, Grune a Stratton, New York (1976) . D . T . FRAZISR, T . NARAHASHI, and N . YAMADA, _J . Pharmacol . Exp . Thar . 171 45-51 (1970) . T . NARAHASHI, D . T . FRAZIER, and N . YAMADA, J . Pharmacol . Exp . Ther . 17 1 32-44 (1970) . B . HILLE, K . COURTNEY, and R . DUNK, Molecular Mechanisms of Anesthesia (ed . B . R. Fink ; pp . 13-20), Raven Press, New York (1975)_ G . A . CONDOURIS, _J . Pharmacol . Exp . Thar . 141 253-259 (1963) . S . NCLAUGHLIN, Molecular Mechanisms of Anesthesia (ed . B . R . Fink ; pp . 193220), Raven Press, New York (1975) . R . H . DBE JONG and S . C . CULL, Anesthesiology 24 801-808 (1963) . S . B . ROSS and S . B . A. Â1ERMAN, J . Pharmacol . EXP . Ther . 18 2 351-361 (972).
Pergamon Press
1IINIREVIEW NEURAL BLOCKADE BY LOCAL ANESTHETICS Rudolph H . de Jong, M.D . Anesthesia Research Center (RN-10) Univ . Washington School of Medicine Seattle, WA
98195
The bimolecular phospholipid membrane that separates axoplasm from extracellular fluid holds the key to nerve excitability : and so to local anesthesia . Local anesthetics block impul se propagation by preventing membrane depolarization . They do this by occluding the sodium pores (probably by plugging the channel's internal axoplasmic mouth) . The poslüvely charged local anesthetic cation binds to oppositely charged anionic channel components, whereas the uncharged lipid soluble anesthetic base furnishes the carrier species that penetrates the membrane . Dissolved in water, local anesthetic salt crystals dissociate to yield anesthetic cation and base whose proportions are governed by the drug's fixed p1C and the tissue's variable pH . The more acid the surroundings, tfle more cation and the less base coexist . The cation/base concentration ratio is critical to optimal blockade . Too little base, and few anesthetic molecules manage to reach the neural target ; too little cation, and few sodium channels will be plugged . Drugs called Local Anesthetics are used widely to selectively numb ("anesthetize") a body part . Other drugs (e .g ., phenol, alcohol) or techniques (e .g ., cooling, compression) exist that exert a similar selective numbing action : it is the reversibility of their effect that differentiates local anesthetics from other agents having similar action . And it is the ease of application and predictability of results that favors drug-induced local anesthesia over alternate physical methods . As our knowledge of the elusive transmembrane ionic channels leaped forward, so has our understanding of the mechanisms by which local anesthetics block 4jam A se propagation in nerves . The cardinal features of local anesthesia are perhaps best brought out by contracting them with those of general anesthesia . General anesthesia results when certain agents are introduced into the bloodstream; either directly, as by intravenous injection or, more circuitously, by uptake from the lungs . Though the target organ Of general anesthetics is the central nervous system, their presence in the circulation inevitably affects other organ systems as well . Local anesthetics, conversely, are deposited in immediate proximity to their target neural structures . Because they do not depend on the circulation for transport, they do not affect distant organ systems ; local anesthetics, as their name implies, act locally .
915
91 6
Local Anesthetics
Vol . 20, No . 6, 1977
Conduction Blockade Local anesthetics halt impulse traffic along an axon in a reversible manner and without damaging the neural membrane . Even so, striking changes in neural function herald the onset of blockade . Local anesthetics progressively lower the amplitude of the compound action potential, reduce its rate of rise, elevate the firing threshold, slow the velocity of impulse conduction and lengthen the refractory period . These changes progress until the ever smaller local currents drop below the ever rising firing threshold: the nerve is rendered inexcitable or, as we usually call it, is blocked (1) . There is overwhelming evidence that local anesthetics impede sodium ion access to the axon interior, probably by directly or indirectly occluding the transmembrane sodium channels (2) . With sodium entrance denied, depolarization cannot take place, the axon thus remains polarized . A local anesthetic block is a non-depolarization block, resembling in same respects the action of curare at the neuromuscular junction . The insulating properties of myelin limit local anesthetic access to the nerve membrane ; everywhere, that is, except at the nodes. Since so little membrane is exposed, a relatively greater density (i .e ., higher concentration) of local anesthetic is required to produce conduction block in myelinated than in nonmyelinated fibers . Further, as impulses can skip over one or two consecutive blocked (i .e ., inexcitable) nodes, it follows that at least 5 or 6 mm of nerve needs to be bathed in the anesthetic solution (3) . In fact, taking irregular diffusion into whole nerve into account, a minimum of perhaps 8 to 10 mm of nerve must be covered by anesthetic solution to ensure thorough blockade (4) . Membrane Site of Action There is little question that local anesthetics block impulse conduction by interfering with the very process fundamental to generation of the action potential : that is, the transient rise in membrane permeability to sodium ions . Much more difficult to answer is how local anesthetics alter the membrane's configuration so as to stem the invasion by sodium ions . The place to look, evidently, is at or near the sodium channel ; for it is the voltage-dependent gating function that is somehow impeded by local anesthetic molecules (2,5) . An external site of membrane attachment of local anesthetics, based mainly on their rapid action, has long been postulated . More recent evidence, however, increasingly points to the sodium channel's internal (axoplasmic) mouth as the more likely site of local anesthetic action (6, 7) . That local anesthetics are effective too when applied externally must therefore be attributed to their rapid diffusion through:the membrane (8) . In fact, non-diffusable local anesthetic cation is virtually inactive when applied externally, yet produces rapid block when perfused internally through an axon (9) . In that regard alone, local anesthetics differ fundamentally from marine toxins such as tetrodotoxin (TTX) which plug the sodium channel by occluding the pore's external entrance (10) . (The reader should note that local anesthetics do not block the passage of sodium ion per se, but rather the ionic traffic through the sodium channels . Nerve bathed in a sodium-substitute solution is blocked just as readily by local anesthetics as it would be in a sodium-containing medium (11) .) Whereas the exact locus of a local anesthetic's channel-blocking action is uncertain as yet, its attachment to phospholipid membrane components is well
Local Anesthetics
Vol . 20, No . 6, 1977
91 7
documented . This in turn is linked to the important function of phospholipids in excitability artificial membrane lacking phospholipid in inexcitable . The negatively charged phosphate tails of the phospholipid molecule in particular are essential to excitability . Local anesthetics, having two positively charged ends, attach to (and so bridge) two phosphate groups, one molecule thereby stabilizing two anionic phosphate tails (12) . The electrostatically stable complex so formed firmly glues the gating structures together, so preventing their opening (1) . While electrostatic bonding amply suffices to explain how conventional local anesthetics work, the hypothesis falls a bit short of the mark where agents such as benzocaine are concerned . The latter, by virtue of a low pR (see below), exists essentially only in the unionized (base) form at physiofogic pH . To account for benzocaine blockade, the lipid-soluble base is thought to cause membrane swelling of a scope sufficient to pinch the sodium channels shut by external compression (1,2) . Lateral compression certainly seems to take a back seat to cationic plugging, for benzocaine is but a marginal blocking agent . pH Effec ts The pure synthetic local anesthetic is a weakly basic amine -- soluble in liquids, but poorly soluble and unstable in water . Salts of the local anesthet ic base, conversely, are readily soluble in water and stable in solution . The usual local anesthetic solution contains a salt (commonly the hydrochloride) of the local anesthetic base . in this aqueous solution the positively charged quaternary amine species of the local anesthetic (the cation ) is in dissociation equilibrium with the uncharged local anesthetic base according to : R--HH+ cation
$
R=-N + H+ base
it is apparent from this dissociation reaction that the relative concentrations of cation and base vary with the hydrogen ion concentration of the solution . When the pH of the solution equals the local anesthetic's pR (negative logarithm of the dissociation constant), equal amounts of cation aand base coexist in the solution . Since the p1C of most local anesthetics ranges between 7 .5 and 9 (Table) the solution contains considerably more anesthetic cation than base at tissue pH . The proportion of the concentrations of cation and base in solution is derived from the equation log[cation] a log [base]
pxa
- pH
where [cation] and [base] denote "concentrations" of the local anesthetic cation and base respectively . The cation (i .e ., the positively charged quarternary amine) is the species that binds to anionic receptors on the nerve membrane and plugs the sodium channels, so rendering the nerve inexcitable . Clearly, one needs the local anesthetic cation to block inpluse conduction . The concentration of local anesthetic base, conversely, determines drug penetration, and thereby the quantity of local anesthetic to reach the nerve membrane . The proportion of base in increased by raising the pH of the solution : alkalinizing a local anesthetic solution accordingly enhances drug penetrance . Whereas an acidified solution is less effective clinically than the same solution at body pH as fewer local anesthetic molecules reach the neural target .
91 8
Local Anesthetics
Vol. 20, No . 6, 1977
TABLE DISSOCIATION CONSTANTS OF SCHE LOCAL ANESTHETICS (1) Agent
2% 3.5
Benzocaine
Mepivacaine
7 .6
Lidocaine
7 .9
Etidocaine
7 .7
Prilocaine
7 .9
Tetracaine
8 .2
Bupivacaine
8 .1
Cocaine
8 .7
Dibucaine
8 .8 8 .9
Procaine Hexylcaine
9 .3
One immediate corollary of dissociation is the common observation that local anesthetics "don't work well" when injected into an infected area, as when attempting to lance an abscess. While lots of cations are formed, they are stuckt for, being electrically charged, cations cannot migrate to the neural target without assistance from the uncharged anesthetic base . . . and that species is in short supply . Another consequence of dissociation is the reduced anesthetic potency that certain acid stabilizers impart . For instance, ccemercial local anesthetic solutions containing epinephrine commonly are buffered to a lower pH than the standard solution so as to minimize vasoconstrictor oxidation . These acid solutions seem to be less effective than the nearly neutral standard local anesthetic solution (13) . New Horizons A neat approach to providing effective proportions of local anesthetic base and cation derives from a clever chemical trick. By juggling inter-atomic distances, one can synthesize a molecule with a tendency to curl its amino-alkyl tail around and onto itself, so forming a six-membered ring structure. Such cyclization of an uncharged molecule yields a quaternary amine with the usual impulseblocking properties of local anesthetic cations (14) . Attractive here is that cyclization is independent of pH . Thus one can inject a solution composed of predominately anesthetic base and let it diffuse into the nerve . Once in the nerve, cyclization takes place, the anesthetically active cation is formed and block ensues . Making this class of drugs all the more attractive is that the cation (being charged) cannot easily diffuse outward . The anesthetic drug thus is trapped, and very long-lasting anesthesia is the result . The aforementioned marine toxins (represented by TTR), which plug the sodium channel's external pore entrance, form another potential seed stock for a new and different family of local anesthetics. As these potent blocking agents attach to the membrane's external surface, they do not need to change back to the unionized species -- necessary to traverse the lipid membrane an route to the sodium channel's axoplasmic mouth -- as conventional local anesthetics must do . Marine toxins, accordingly, are rapid acting extr®ely potent agents, and
Vol . 20, No . 6, 1977
Locai Anesthetics
919
blockade is virtually pH-independent . While still far too toxic for human application, suitable derivatives say well fill the bill eventually . REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 .
R. H . DE JONG, Local Anesthetics , Chas . C . Thomas, Springfield (1976) . G . STRICHARTZ, Anesthesiology 45 in press (1976) . G . A . CONDOURIS, R . H . GOEBEL, and T . BRADY, J . Pharmacol . M512 . Ther . 196 723-736 (1976) . D . N . FRANZ and R . S . PERRY, _J . Physiol . _ 236 193-210 (1974) . J . M . RITCHIE, Br . J . Anaesth . 47 191-198 (1975) . X . R. COURTNEY, J. _ Pharma Col . . Ther . 195 225-236 (1975) . B . G . COVINO and H . G . VASSALLA, Local Anesthetics : Mechanisms of Action and Clinical Use, Grune a Stratton, New York (1976) . D . T . FRAZISR, T . NARAHASHI, and N . YAMADA, _J . Pharmacol . Exp . Thar . 171 45-51 (1970) . T . NARAHASHI, D . T . FRAZIER, and N . YAMADA, J . Pharmacol . Exp . Ther . 17 1 32-44 (1970) . B . HILLE, K . COURTNEY, and R . DUNK, Molecular Mechanisms of Anesthesia (ed . B . R. Fink ; pp . 13-20), Raven Press, New York (1975)_ G . A . CONDOURIS, _J . Pharmacol . Exp . Thar . 141 253-259 (1963) . S . NCLAUGHLIN, Molecular Mechanisms of Anesthesia (ed . B . R . Fink ; pp . 193220), Raven Press, New York (1975) . R . H . DBE JONG and S . C . CULL, Anesthesiology 24 801-808 (1963) . S . B . ROSS and S . B . A. Â1ERMAN, J . Pharmacol . EXP . Ther . 18 2 351-361 (972).