LOCAL ANESTHETICS

LOCAL ANESTHETICSLOCAL ANESTHETICS

A.Ghaleb,MDA.Ghaleb,MD

LOCAL ANESTHETICSLOCAL ANESTHETICS

• The electrical potential inside the cell is negative The electrical potential inside the cell is negative and close to the potential that would be and close to the potential that would be determined by potassium alone. determined by potassium alone.

• This is the resting potentialThis is the resting potential (-70 mV). During the (-70 mV). During the transmission of an action potential, sodium moves transmission of an action potential, sodium moves into the cell through open sodium channels, into the cell through open sodium channels, depolarizing the cell.depolarizing the cell.

• Local anesthetics are compounds with the ability Local anesthetics are compounds with the ability to interrupt the transmission of the action potential to interrupt the transmission of the action potential in excitable membranes. They bind to specific in excitable membranes. They bind to specific receptors on the Na+ channels and their action at receptors on the Na+ channels and their action at clinically recommended doses is reversible. clinically recommended doses is reversible.

Historical perspectiveHistorical perspective

• The natives of Peru chewed coca leaves and The natives of Peru chewed coca leaves and knew about their cerebral-stimulating knew about their cerebral-stimulating effects. The leaves of effects. The leaves of erythroxylon cocaerythroxylon coca were taken to Europe where Niemann were taken to Europe where Niemann isolated cocaine in Germany in 1860.isolated cocaine in Germany in 1860.

• Koller in 1884 is credited with the Koller in 1884 is credited with the introduction of cocaine as a topical introduction of cocaine as a topical ophthalmic local anesthetic in Austria.ophthalmic local anesthetic in Austria.

• Cardiovascular side effects as well as Cardiovascular side effects as well as potential for dependency and abuse were potential for dependency and abuse were soon recognized, which led to the search for soon recognized, which led to the search for a better local anesthetic. a better local anesthetic.


• 1850’s invention of the syringe and hypodermic hollow 1850’s invention of the syringe and hypodermic hollow needleneedle

• 1884 Halsted, blocks the brachial plexus with a solution of 1884 Halsted, blocks the brachial plexus with a solution of cocaine under direct vision (surgical exposure).cocaine under direct vision (surgical exposure).

• 1897 Braun in Germany relates cocaine toxicity with 1897 Braun in Germany relates cocaine toxicity with systemic absorption and advocates the use of epinephrine.systemic absorption and advocates the use of epinephrine.

• 1898 Bier performs the first planned spinal anesthesia.1898 Bier performs the first planned spinal anesthesia.• 1911 Hirschel performs the first percutaneous axillary block1911 Hirschel performs the first percutaneous axillary block• 1911 Kulenkampff performs the first percutaneous 1911 Kulenkampff performs the first percutaneous

supraclavicular blocksupraclavicular block• Date of introduction in clinical practice of some local Date of introduction in clinical practice of some local

anesthetics:anesthetics:


• 1905 procaine; 1932 tetracaine; 1905 procaine; 1932 tetracaine; 1947 lidocaine; 1955 chloroprocaine 1947 lidocaine; 1955 chloroprocaine (last ester type local anesthetic (last ester type local anesthetic introduced that is still in clinical use); introduced that is still in clinical use); 1957 mepivacaine; 1963 1957 mepivacaine; 1963 bupivacaine; 1997 ropivacaine; 1999 bupivacaine; 1997 ropivacaine; 1999 levobupivacaine.levobupivacaine.

Chemical structureChemical structure

• weak bases with a pka above 7.4 and poorly weak bases with a pka above 7.4 and poorly soluble in water.soluble in water.

• Commercially available as acidic solutions (pH 4-Commercially available as acidic solutions (pH 4-7) of hydrochloride salts, which are hydrosoluble. 7) of hydrochloride salts, which are hydrosoluble.

• A typical local anesthetic is composed of two A typical local anesthetic is composed of two portions linked together by a chemical chain. One portions linked together by a chemical chain. One portion consists of a benzene ring (lipid soluble portion consists of a benzene ring (lipid soluble “hydrophobic”) and the other is an amine group “hydrophobic”) and the other is an amine group that is ionizable and water-soluble (hydrophilic). that is ionizable and water-soluble (hydrophilic).

• The chemical chain can be either ester type (-The chemical chain can be either ester type (-CO-) or amide type (-HNC-) defining two different CO-) or amide type (-HNC-) defining two different groups of local anesthetics, esters and amides.groups of local anesthetics, esters and amides.

• The injected local anesthetic volume spreads initially by The injected local anesthetic volume spreads initially by mass movement.mass movement.

• This first step determines how much local anesthetic This first step determines how much local anesthetic effectively reaches the nerve.effectively reaches the nerve.

• Moves across “points of least resistance”, which do not Moves across “points of least resistance”, which do not necessarily lead into the desired nerve(s), stressing the necessarily lead into the desired nerve(s), stressing the need to bring the needle in proximity to the target nerve(s).need to bring the needle in proximity to the target nerve(s).

• The local anesthetic solution diffuses through tissues; each The local anesthetic solution diffuses through tissues; each layer of them acting as a physical barrier and in the process layer of them acting as a physical barrier and in the process part of the solution gets absorbed into the circulation.part of the solution gets absorbed into the circulation.

• Finally a small percentage of the anesthetic reaches the Finally a small percentage of the anesthetic reaches the target nerve membrane at which point the different target nerve membrane at which point the different physicochemical properties of the individual anesthetic will physicochemical properties of the individual anesthetic will dictate the speed, duration and nature of the interaction dictate the speed, duration and nature of the interaction with the receptors.with the receptors.

Structure-activity Structure-activity relationshiprelationship • Lipid solubilityLipid solubility • Determines both the potency and the duration of Determines both the potency and the duration of

action of the local anesthetics by binding the drug action of the local anesthetics by binding the drug close to the site of action and thereby decreasing the close to the site of action and thereby decreasing the rate of metabolism by plasma esterase and liver rate of metabolism by plasma esterase and liver enzymes.enzymes.

• In addition the local anesthetic receptor site on Na+ In addition the local anesthetic receptor site on Na+ channels is thought to be hydrophobic, so its affinity channels is thought to be hydrophobic, so its affinity for hydrophobic drugs is greater. for hydrophobic drugs is greater.

• Hydrophobicity also increases toxicity, so the Hydrophobicity also increases toxicity, so the therapeutic index actually is decreased for more therapeutic index actually is decreased for more hydrophobic drugs.hydrophobic drugs.

Structure-activity Structure-activity relationshiprelationship • Protein bindingProtein binding • Related to duration of action. Related to duration of action. • In the body, local anesthetics are bound in large part to plasma and In the body, local anesthetics are bound in large part to plasma and

tissue proteins. The bound portion is not pharmacologically active. tissue proteins. The bound portion is not pharmacologically active. The most important binding proteins in plasma are albumin and The most important binding proteins in plasma are albumin and alpha-1-acid glycoprotein (AAG)alpha-1-acid glycoprotein (AAG)

• The fraction of drug bound to protein in plasma correlates with the The fraction of drug bound to protein in plasma correlates with the duration of action of local anesthetics: duration of action of local anesthetics: bupivacaine > ropivacaine bupivacaine > ropivacaine > mepivacaine > lidocaine > procaine and 2-chloroprocaine.> mepivacaine > lidocaine > procaine and 2-chloroprocaine.

• This suggests that the bond between the local anesthetic molecule This suggests that the bond between the local anesthetic molecule and the sodium channel receptor protein may be similar to that of and the sodium channel receptor protein may be similar to that of local anesthetic binding to plasma protein (similar amino acid local anesthetic binding to plasma protein (similar amino acid sequences). sequences).

• Drugs as lidocaine, tetracaine and bupivacaine have been Drugs as lidocaine, tetracaine and bupivacaine have been incorporated into liposomes to prolong the duration of action and incorporated into liposomes to prolong the duration of action and decrease toxicity. Liposomes are vesicles with two layers of decrease toxicity. Liposomes are vesicles with two layers of phospholipids, which slow down the release of the drug effectively phospholipids, which slow down the release of the drug effectively prolonging the duration of actionprolonging the duration of action

Structure-activity Structure-activity relationshiprelationship• Protein bindingProtein binding • This suggests that the bond between the local This suggests that the bond between the local

anesthetic molecule and the sodium channel anesthetic molecule and the sodium channel receptor protein may be similar to that of local receptor protein may be similar to that of local anesthetic binding to plasma protein (similar anesthetic binding to plasma protein (similar amino acid sequences). amino acid sequences).

• Drugs as lidocaine, tetracaine and bupivacaine Drugs as lidocaine, tetracaine and bupivacaine have been incorporated into liposomes to prolong have been incorporated into liposomes to prolong the duration of action and decrease toxicity. the duration of action and decrease toxicity. Liposomes are vesicles with two layers of Liposomes are vesicles with two layers of phospholipids, which slow down the release of the phospholipids, which slow down the release of the drug effectively prolonging the duration of actiondrug effectively prolonging the duration of action

Structure-activity Structure-activity relationshiprelationship • The pkaThe pka of the local anesthetic determines the ratio of the of the local anesthetic determines the ratio of the

ionized (cationic) and the uncharged (base) form of the drug. ionized (cationic) and the uncharged (base) form of the drug. • The pka for local anesthetics ranges from 7.6 to 9.2. The pka for local anesthetics ranges from 7.6 to 9.2. • By definition the pka is the pH at which 50% of the drug is By definition the pka is the pH at which 50% of the drug is

ionized and 50% is present as a base.ionized and 50% is present as a base.• The pka generally correlates with the speed of onsetThe pka generally correlates with the speed of onset of most of most

local anesthetics. The closer the pka to the physiologic pH local anesthetics. The closer the pka to the physiologic pH the faster the onset (e.g., lidocaine with a pka of 7.7 is 25% the faster the onset (e.g., lidocaine with a pka of 7.7 is 25% non-ionized at ph 7.4 and has a more rapid onset of action non-ionized at ph 7.4 and has a more rapid onset of action than bupivacaine with a pka of 8.1 which is only 15% non-than bupivacaine with a pka of 8.1 which is only 15% non-ionized). ionized).

• One important exception is 2-chloroprocaine with a pka of One important exception is 2-chloroprocaine with a pka of 9.0 and very short onset of action. This fast onset could be 9.0 and very short onset of action. This fast onset could be related to its low toxicity, which allows for high related to its low toxicity, which allows for high concentrations to be used clinically. It is also claimed to have concentrations to be used clinically. It is also claimed to have also better “tissue penetrability”. also better “tissue penetrability”.

Mechanism of action and sodium Mechanism of action and sodium

channelschannels

• The non-charged hydrophobic fraction (B) crosses the The non-charged hydrophobic fraction (B) crosses the lipidic nerve membrane and initiates the events that lipidic nerve membrane and initiates the events that lead to blocking of sodium channels.lead to blocking of sodium channels.

• Once inside a new equilibrium, dictated by the Once inside a new equilibrium, dictated by the compound pka and the intracellular pH, is reached compound pka and the intracellular pH, is reached between the non-charged and charged (BH+) between the non-charged and charged (BH+) fractions. fractions.

• Because of the relative more acidic intracellular Because of the relative more acidic intracellular environment, the relative proportion of charged environment, the relative proportion of charged fraction increases. This fraction interacts with the Na+ fraction increases. This fraction interacts with the Na+ channel. channel.

• Local anesthetics do not ordinarily affect the Local anesthetics do not ordinarily affect the membrane resting potential.membrane resting potential.

Mechanism of action and sodium Mechanism of action and sodium channelschannels

• The Na+ channel is a protein structure that The Na+ channel is a protein structure that communicates the extracellular of the nerve with its communicates the extracellular of the nerve with its axoplasm and consists of four repeating alpha subunits, axoplasm and consists of four repeating alpha subunits, a beta-1 and beta-2 subunits. The alpha subunits are a beta-1 and beta-2 subunits. The alpha subunits are involved in ion movement and local anesthetic activity. involved in ion movement and local anesthetic activity.

• It is generally accepted that local anesthetics main It is generally accepted that local anesthetics main action involves interaction with specific binding sites action involves interaction with specific binding sites within the Na+ channel. within the Na+ channel.

• The voltage–dependence of channel opening is The voltage–dependence of channel opening is hypothesized to reflect conformational changes in hypothesized to reflect conformational changes in response to changes in transmembrane potential. The response to changes in transmembrane potential. The voltage sensors or gates are located in the S4 helix; the voltage sensors or gates are located in the S4 helix; the S4 helices are both hydrophobic and positively charged. S4 helices are both hydrophobic and positively charged.

Mechanism of action and sodium Mechanism of action and sodium channelschannels

• The Na+ channels seem to exist in three different states, The Na+ channels seem to exist in three different states, closed, open and inactive.closed, open and inactive.

• With depolarization the protein molecules of the channel With depolarization the protein molecules of the channel undergo conformational changes from the closed (resting) undergo conformational changes from the closed (resting) state to the ion-permeable state or open state. state to the ion-permeable state or open state.

• The channel goes then through a transitional inactive state The channel goes then through a transitional inactive state where the proteins leave the channel still closed and ion-where the proteins leave the channel still closed and ion-impermeable. impermeable.

• With repolarization the proteins revert to their resting With repolarization the proteins revert to their resting configuration. Local anesthetics configuration. Local anesthetics may also block may also block in some in some degreedegree calcium calcium andand potassium potassium channelschannels as well asas well as N- N-methyl-D-aspartate (NMDA) methyl-D-aspartate (NMDA) receptors.receptors.

• Other drugs like tricyclic antidepressants (amitriptyline), Other drugs like tricyclic antidepressants (amitriptyline), meperidine, volatile anesthetics and ketamine also have meperidine, volatile anesthetics and ketamine also have sodium channel-blocking properties sodium channel-blocking properties

Frequency and voltage dependence of Frequency and voltage dependence of

local anesthetic actionlocal anesthetic action

• A resting nerve is much less sensitive to local A resting nerve is much less sensitive to local anesthetic than one that is being stimulated. anesthetic than one that is being stimulated.

• The degree of block also depends on the nerve The degree of block also depends on the nerve resting membrane potential, a more positive resting membrane potential, a more positive membrane potential causes a greater degree membrane potential causes a greater degree of block. of block.

• These frequency and voltage dependent These frequency and voltage dependent effects occur because the local anesthetic in effects occur because the local anesthetic in its charged form gain access to its biding site its charged form gain access to its biding site within the channel only when the Na+ channel within the channel only when the Na+ channel is in an open state is in an open state

Pregnancy and local Pregnancy and local anestheticsanesthetics • Increased sensitivity (more rapid onset, more Increased sensitivity (more rapid onset, more

profound block) may be present during pregnancy.profound block) may be present during pregnancy.• Also alterations in protein binding of bupivacaine Also alterations in protein binding of bupivacaine

may result in increased concentrations of active may result in increased concentrations of active unbound drug in the pregnant patient. unbound drug in the pregnant patient.

• During pregnancy, placental transfer is more active During pregnancy, placental transfer is more active for lipid soluble local anesthetics, whereas higher for lipid soluble local anesthetics, whereas higher protein binding becomes an obstacle to such transfer. protein binding becomes an obstacle to such transfer. In any case, agents with a pka closer to physiologic In any case, agents with a pka closer to physiologic pH have a higher placental transfer. For example the pH have a higher placental transfer. For example the umbilical vein/maternal vein ratio for mepivacaine is umbilical vein/maternal vein ratio for mepivacaine is 0.8 (pka 7.6) while for bupivacaine is 0.3 (pka 8.1).0.8 (pka 7.6) while for bupivacaine is 0.3 (pka 8.1).

Pregnancy and local Pregnancy and local anestheticsanesthetics

• In the presence of fetal acidosis, local In the presence of fetal acidosis, local anesthetics cross the placenta and anesthetics cross the placenta and become ionized in higher proportion become ionized in higher proportion than at normal pH. As ionized than at normal pH. As ionized substances they cannot cross back to substances they cannot cross back to the maternal circulation (“ion trapping”). the maternal circulation (“ion trapping”). 2-chloroprocaine with its very short 2-chloroprocaine with its very short maternal and fetal half-lives is maternal and fetal half-lives is theoretically an ideal local anesthetic in theoretically an ideal local anesthetic in the presence of fetal acidosis.the presence of fetal acidosis.

Fiber size and pattern of Fiber size and pattern of

blockadeblockade • As a general rule small nerve fibers are more As a general rule small nerve fibers are more

susceptible to local anestheticssusceptible to local anesthetics• However other factors like myelinazation and relative However other factors like myelinazation and relative

position of the fibers (mantle and core) within a nerve position of the fibers (mantle and core) within a nerve also play a role.also play a role.

• The smallest nerve fibers are nonmyelinated and are The smallest nerve fibers are nonmyelinated and are blocked more readily than larger myelinated fibers. blocked more readily than larger myelinated fibers.

• However myelinated fibers are blocked before However myelinated fibers are blocked before nonmyelinated fibers of the same diameter. nonmyelinated fibers of the same diameter.

• In general autonomic fibers, small nonmyelinated C In general autonomic fibers, small nonmyelinated C fibers (mediating pain), and small myelinated A delta fibers (mediating pain), and small myelinated A delta fibers (mediating pain and temperature) are blocked fibers (mediating pain and temperature) are blocked before A gamma, A beta and A alpha fibers (carrying before A gamma, A beta and A alpha fibers (carrying postural, touch, pressure and motor information).postural, touch, pressure and motor information).

Fiber size and pattern of Fiber size and pattern of blockadeblockade

• In large nerve trunks motor fibers are usually In large nerve trunks motor fibers are usually located in the outer portion of the bundle and are located in the outer portion of the bundle and are more accessible to local anesthetic. Thus motor more accessible to local anesthetic. Thus motor fibers may be blocked before sensory fibers in large fibers may be blocked before sensory fibers in large mixed nerves.mixed nerves.

• In addition the frequency-dependence of local In addition the frequency-dependence of local anesthetic action favors block of small sensory anesthetic action favors block of small sensory fibers. They generate long action potential (5 ms) at fibers. They generate long action potential (5 ms) at high frequency, whereas motor fibers generate high frequency, whereas motor fibers generate short action potentials (0.5 ms) at lower frequency. short action potentials (0.5 ms) at lower frequency. These characteristics of sensory fibers in general, These characteristics of sensory fibers in general, and of pain fibers in particular, favor frequency-and of pain fibers in particular, favor frequency-dependent block.dependent block.

Modulating local anesthetic actionModulating local anesthetic actionpH adjustmentpH adjustment

• Local anesthetics pass through the nerve membrane in a non-Local anesthetics pass through the nerve membrane in a non-ionized hydrophobic (lipid soluble) base form. ionized hydrophobic (lipid soluble) base form.

• In the axoplasm they equilibrate into an ionic form that is In the axoplasm they equilibrate into an ionic form that is active within the sodium channel. The rate-limiting step in this active within the sodium channel. The rate-limiting step in this cascade is penetration of the local anesthetic through the cascade is penetration of the local anesthetic through the nerve membrane. nerve membrane.

• All available local anesthetics contain very little drug in the All available local anesthetics contain very little drug in the non-ionized state. This fraction depends on the pka of the non-ionized state. This fraction depends on the pka of the drug and the ph of the solution. drug and the ph of the solution.

• Changes in ph can produce a shortening of the onset time, Changes in ph can produce a shortening of the onset time, being the limiting factor for ph adjustment the solubility of the being the limiting factor for ph adjustment the solubility of the base form of the drug (precipitation).base form of the drug (precipitation).

• DiFazio et al (Anesth Analg 1986:65; 760-64) demonstrated DiFazio et al (Anesth Analg 1986:65; 760-64) demonstrated more than 50% decrease in onset of epidural anesthesia when more than 50% decrease in onset of epidural anesthesia when the pH of commercially available lidocaine with epinephrine the pH of commercially available lidocaine with epinephrine was raised from 4.5 to 7.2 by the addition of bicarbonate.was raised from 4.5 to 7.2 by the addition of bicarbonate.


• Hilgier (Reg Anesth 1985:10; 59-61) reported a marked Hilgier (Reg Anesth 1985:10; 59-61) reported a marked improvement in the onset time for brachial plexus improvement in the onset time for brachial plexus anesthesia when bupivacaine with epinephrine (pH 3.9) was anesthesia when bupivacaine with epinephrine (pH 3.9) was alkalinized to pH 6.4 before injection. alkalinized to pH 6.4 before injection.

• However, when only small changes in pH can be achieved However, when only small changes in pH can be achieved because of the limited solubility of the base, only small because of the limited solubility of the base, only small decreases in onset time will occur, as when plain decreases in onset time will occur, as when plain bupivacaine is alkalinized. For each local anesthetic there is bupivacaine is alkalinized. For each local anesthetic there is a ph at which the amount of base in solution is maximal (a a ph at which the amount of base in solution is maximal (a saturated solution). saturated solution).

• Chloroprocaine plus 1 mL of sodium bicarbonate for 30 mL Chloroprocaine plus 1 mL of sodium bicarbonate for 30 mL of solution raises the pH to 6.8. Adding 1 mL of sodium of solution raises the pH to 6.8. Adding 1 mL of sodium bicarbonate per 10 mL of lidocaine or mepivacaine raises bicarbonate per 10 mL of lidocaine or mepivacaine raises the pH of the solution to 7.2 and adding 0.1 mL of the pH of the solution to 7.2 and adding 0.1 mL of bicarbonate per 10 mL of bupivacaine raises the pH of the bicarbonate per 10 mL of bupivacaine raises the pH of the solution to 6.4solution to 6.4


• CarbonationCarbonation

• Another approach to shortening onset time Another approach to shortening onset time has been the use of carbonated local has been the use of carbonated local anesthetic solutions. The solution contains anesthetic solutions. The solution contains large amounts of carbon dioxide, which large amounts of carbon dioxide, which readily diffuses into the axoplasm of the readily diffuses into the axoplasm of the nerve lowering the ph and favoring the nerve lowering the ph and favoring the formation of the cationic active form of the formation of the cationic active form of the local anesthetic. Carbonated solutions are local anesthetic. Carbonated solutions are not available in the United States not available in the United States

LOCAL ANESTHETICS LOCAL ANESTHETICS

ADDITIVESADDITIVES • VasoconstrictorsVasoconstrictors to prolong the anesthetic effect and to prolong the anesthetic effect and

to decrease absorption. to decrease absorption. • Epinephrine is also used to detect intravascular injection Epinephrine is also used to detect intravascular injection

(test dose). (test dose). • Vasoconstrictors may also improve the quality and Vasoconstrictors may also improve the quality and

density of the block especially with spinal and epidural density of the block especially with spinal and epidural anesthesia. This has been demonstrated with anesthesia. This has been demonstrated with tetracaine, lidocaine and bupivacaine. The mechanism tetracaine, lidocaine and bupivacaine. The mechanism is unclear.is unclear.

• Epinephrine may simply increase the amount of local Epinephrine may simply increase the amount of local anesthetic available by reducing absorption. It could anesthetic available by reducing absorption. It could have also some anesthetic effect by means of its alpha have also some anesthetic effect by means of its alpha 2-agonist actions. 2-agonist actions.

• Subarachnoid epinephrine potentially delays the time Subarachnoid epinephrine potentially delays the time for urination, which may delay discharge. for urination, which may delay discharge.

• Epinephrine used other than intrathecally is absorbed systemically and Epinephrine used other than intrathecally is absorbed systemically and may produce adverse cardiovascular effects. may produce adverse cardiovascular effects.

• In small doses the beta-adrenergic effects predominate with increased In small doses the beta-adrenergic effects predominate with increased cardiac output and heart rate. Dose larger than 0.25 mg (250 ug) may cardiac output and heart rate. Dose larger than 0.25 mg (250 ug) may be associated with arrhythmias or other undesirable cardiac effects.be associated with arrhythmias or other undesirable cardiac effects.

• Lately concerns have been raised about potential neural ischemia Lately concerns have been raised about potential neural ischemia caused by epinephrine acting on epineural vessels and vaso nervorum. caused by epinephrine acting on epineural vessels and vaso nervorum. This potential risk has to be balanced against lower risk of systemic This potential risk has to be balanced against lower risk of systemic toxicity, marker for intravascular injection and prolongation of action. toxicity, marker for intravascular injection and prolongation of action.

• Neal in 2003 Neal in 2003 adding 5 ug/mL (1:200,000 dilution) prolongs the duration of lidocaine for adding 5 ug/mL (1:200,000 dilution) prolongs the duration of lidocaine for

peripheral nerve blocks from 186 minutes to 264 minutes.peripheral nerve blocks from 186 minutes to 264 minutes. Adding only 2.5 ug/mL (1:400,000 dilution) prolongs the block to 240 Adding only 2.5 ug/mL (1:400,000 dilution) prolongs the block to 240

minutes (almost the same prolongation) without apparent effect on minutes (almost the same prolongation) without apparent effect on nerve blood flow.nerve blood flow.

Patients with micro angiopathy (e.g., diabetics) who could be at increase Patients with micro angiopathy (e.g., diabetics) who could be at increase risk for neural ischemia secondary to vasoconstriction potentially could risk for neural ischemia secondary to vasoconstriction potentially could benefit from the use of more diluted epinephrine (1:400,000).benefit from the use of more diluted epinephrine (1:400,000).

LOCAL ANESTHETICS LOCAL ANESTHETICS ADDITIVESADDITIVES

• OpioidsOpioids

• The addition of short-acting opioids such as The addition of short-acting opioids such as fentanyl and sufentanil to spinal anesthetics fentanyl and sufentanil to spinal anesthetics appears to intensify the block and prolong the appears to intensify the block and prolong the duration of anesthesia similar to epinephrine duration of anesthesia similar to epinephrine without affecting urination. They also prolong without affecting urination. They also prolong analgesia beyond the duration of local analgesia beyond the duration of local anesthetics. When used epidurally they anesthetics. When used epidurally they usually produced pruritus. Their usefulness in usually produced pruritus. Their usefulness in peripheral nerve blocks is not clear peripheral nerve blocks is not clear

LOCAL ANESTHETICS LOCAL ANESTHETICS ADDITIVESADDITIVES

• ClonidineClonidine• Alpha 2-agonists have analgesic effects when injected on nerves Alpha 2-agonists have analgesic effects when injected on nerves

or in the subarachnoid space. Side effects (hypotension, or in the subarachnoid space. Side effects (hypotension, bradycardia) limit its use but small doses (50-75 ucg) have bradycardia) limit its use but small doses (50-75 ucg) have shown to significantly prolong analgesia in spinal, epidural, shown to significantly prolong analgesia in spinal, epidural, intravenous regional, and peripheral nerve blocks both when intravenous regional, and peripheral nerve blocks both when injected with the local anesthetics and when given orally.injected with the local anesthetics and when given orally.

• HyaluronidaseHyaluronidase• It breaks down collagen bonds potentially facilitating the spread It breaks down collagen bonds potentially facilitating the spread

of local anesthetic through tissue planes. The evidence however of local anesthetic through tissue planes. The evidence however shows at least in the epidural space to decrease the quality of shows at least in the epidural space to decrease the quality of anesthesia. Its use seems limited to retrobulbar blocks.anesthesia. Its use seems limited to retrobulbar blocks.

• DextranDextran• Dextran and other high-molecular-weight compounds have been Dextran and other high-molecular-weight compounds have been

advocated to increase the duration of local anesthetics. The advocated to increase the duration of local anesthetics. The evidence is lacking.evidence is lacking.

METABOLISM OF LOCAL METABOLISM OF LOCAL

ANESTHETICSANESTHETICS • Ester local anestheticsEster local anesthetics• They are hydrolyzed at the ester linkage by plasma They are hydrolyzed at the ester linkage by plasma

pseudocholinesterase (also hydrolyses acetylcholine and pseudocholinesterase (also hydrolyses acetylcholine and succinylcholine). The hydrolysis of 2-chloroprocaine is about succinylcholine). The hydrolysis of 2-chloroprocaine is about four times faster than procaine, which in turn is hydrolyzed four times faster than procaine, which in turn is hydrolyzed about four times faster than tetracaine. In individuals with about four times faster than tetracaine. In individuals with atypical plasma pseudocholinesterase the half-life of these atypical plasma pseudocholinesterase the half-life of these drugs is prolonged and potentially could lead to plasma drugs is prolonged and potentially could lead to plasma accumulation.accumulation.

• The hydrolysis of all ester anesthetics leads to the The hydrolysis of all ester anesthetics leads to the formation of para-aminobenzoic acid (PABA), which is formation of para-aminobenzoic acid (PABA), which is associated with a low potential for allergic reactions. associated with a low potential for allergic reactions. Allergic reactions may also develop from the use of multiple Allergic reactions may also develop from the use of multiple dose vials of amide local anesthetics that contain PABA as a dose vials of amide local anesthetics that contain PABA as a preservative.preservative.

METABOLISM OF LOCAL METABOLISM OF LOCAL ANESTHETICSANESTHETICS

• Amide local anestheticsAmide local anesthetics• They are transported into the liver before their biotransformation. They are transported into the liver before their biotransformation.

The two major factors controlling the clearance of amide local The two major factors controlling the clearance of amide local anesthetics by the liver are: hepatic blood flow and hepatic function.anesthetics by the liver are: hepatic blood flow and hepatic function.

• The metabolism of local anesthetics as well as that of many other The metabolism of local anesthetics as well as that of many other drugs occurs in the liver by the cytochrome P-450 enzymes. Because drugs occurs in the liver by the cytochrome P-450 enzymes. Because the liver has a large capacity for metabolizing drugs it is unlikely that the liver has a large capacity for metabolizing drugs it is unlikely that drug interaction would affect the metabolism of local anesthetics.drug interaction would affect the metabolism of local anesthetics.

• Drugs such as general anesthetics, norepinephrine, cimetidine, Drugs such as general anesthetics, norepinephrine, cimetidine, propranolol and calcium channel blockers (e.g., diltiazem) can propranolol and calcium channel blockers (e.g., diltiazem) can decrease hepatic blood flow and increase the elimination half-life of decrease hepatic blood flow and increase the elimination half-life of amides. Similarly decreases in hepatic function caused by a lowering amides. Similarly decreases in hepatic function caused by a lowering of body temperature, immaturity of the hepatic enzyme system in of body temperature, immaturity of the hepatic enzyme system in the fetus, or liver damage (e.g., cirrhosis) lead to a decreased rate of the fetus, or liver damage (e.g., cirrhosis) lead to a decreased rate of hepatic metabolism of the amides. Renal clearance of unchanged hepatic metabolism of the amides. Renal clearance of unchanged local anesthetics is a minor route of elimination (lidocaine is only 3% local anesthetics is a minor route of elimination (lidocaine is only 3% to 5% recovered unchanged in the urine of adults while for to 5% recovered unchanged in the urine of adults while for bupivacaine is 10% to 16%).bupivacaine is 10% to 16%).

LOCAL ANESTHETIC LOCAL ANESTHETIC TOXICITYTOXICITY • Systemic local anesthesia toxicity is related to plasma levels. Systemic local anesthesia toxicity is related to plasma levels.

Plasma concentration depends on:Plasma concentration depends on:• The total dose The total dose • The net absorption, which depends on: vasoactivity of the drug, The net absorption, which depends on: vasoactivity of the drug,

site vascularity and use of a vasoconstrictor. site vascularity and use of a vasoconstrictor. • Biotransformation and elimination of the drug from the circulationBiotransformation and elimination of the drug from the circulation

• Peak local anesthetic blood levels are directly related to the dose Peak local anesthetic blood levels are directly related to the dose administered at any given site. Generally the administration of a administered at any given site. Generally the administration of a 100-mg dose of lidocaine in the epidural or caudal space results in 100-mg dose of lidocaine in the epidural or caudal space results in approximately a 1 ucg/mL peak blood level in an average adult. approximately a 1 ucg/mL peak blood level in an average adult. The same dose injected into less vascular areas (e.g., brachial The same dose injected into less vascular areas (e.g., brachial plexus axillary approach or subcutaneous infiltration) produces a plexus axillary approach or subcutaneous infiltration) produces a peak blood level of app 0.5 ucg/mL. The same dose injected peak blood level of app 0.5 ucg/mL. The same dose injected intercostal produces a 1.5 ucg/mL plasma level.intercostal produces a 1.5 ucg/mL plasma level.

LOCAL ANESTHETIC LOCAL ANESTHETIC TOXICITYTOXICITY • Systemic local anesthesia toxicity Systemic local anesthesia toxicity • Peak blood levels may also be affected by the rate of Peak blood levels may also be affected by the rate of

biotransformation and elimination. In general this is biotransformation and elimination. In general this is the case only for very actively metabolized drugs such the case only for very actively metabolized drugs such as 2-chloroprocaine, which has a plasma half-life of as 2-chloroprocaine, which has a plasma half-life of about 45 seconds to1 minute.about 45 seconds to1 minute.

• For amide local anesthetics like lidocaine peak plasma For amide local anesthetics like lidocaine peak plasma level after regional anesthesia primarily result from level after regional anesthesia primarily result from absorption. Lidocaine biotransformation half-life is absorption. Lidocaine biotransformation half-life is approximately 90 minutes. Local anesthetics interfere approximately 90 minutes. Local anesthetics interfere with the functions of all organs in which transmission with the functions of all organs in which transmission of impulses occurs, among others the CNS and of impulses occurs, among others the CNS and cardiovascular systems.cardiovascular systems.

LOCAL ANESTHETIC LOCAL ANESTHETIC TOXICITYTOXICITY • Central nervous systemCentral nervous system • Toxic levels are usually produced by inadvertent Toxic levels are usually produced by inadvertent

intravascular injection.intravascular injection.• It can also result from the slow absorption following It can also result from the slow absorption following

peripheral injection. peripheral injection. • A sequence of symptoms can include:A sequence of symptoms can include:• Numbness of the tongue Numbness of the tongue • Lightheadedness Lightheadedness • Tinnitus Tinnitus • Restlessness Restlessness • Tachycardia Tachycardia • Convulsions Convulsions • Respiratory arrestRespiratory arrest

LOCAL ANESTHETIC LOCAL ANESTHETIC TOXICITYTOXICITY • Cardiovascular systemCardiovascular system

– The cardiovascular manifestations usually follow the The cardiovascular manifestations usually follow the CNS effects (therapeutic index). CNS effects (therapeutic index). The exception is The exception is bupivacainebupivacaine, which can produce cardiac toxicity at , which can produce cardiac toxicity at subconvulsant concentrations.subconvulsant concentrations.

– Rhythm and conduction are rarely affected by Rhythm and conduction are rarely affected by lidocaine, mepivacaine and tetracaine but lidocaine, mepivacaine and tetracaine but bupivacaine and etidocaine can produce bupivacaine and etidocaine can produce ventricular arrhythmias.ventricular arrhythmias.

– EKG shows a prolongation of PR and widening of the EKG shows a prolongation of PR and widening of the QRSQRS

– Higher incidence in pregnancyHigher incidence in pregnancy– CV toxicity is increased under hypoxia and acidosis.CV toxicity is increased under hypoxia and acidosis.

Treatment of systemic Treatment of systemic toxicitytoxicity • ABC (Airway, Breathing and Circulation) is the ABC (Airway, Breathing and Circulation) is the

mainstay of treatment. mainstay of treatment. • Administration of O2 by mask or bag and mask is Administration of O2 by mask or bag and mask is

often all that is necessary to treat seizures. If seizures often all that is necessary to treat seizures. If seizures interfere with ventilation benzodiazepines, thiopental interfere with ventilation benzodiazepines, thiopental or propofol can be used. The use of succinylcholine or propofol can be used. The use of succinylcholine effectively facilitates ventilation and by abolishing effectively facilitates ventilation and by abolishing muscular activity decreases the severity of acidosis. muscular activity decreases the severity of acidosis. However neuronal seizure activity is not inhibited and However neuronal seizure activity is not inhibited and thus cerebral metabolism and oxygen requirements thus cerebral metabolism and oxygen requirements remain increased. remain increased.

• ..

Treatment of systemic Treatment of systemic toxicitytoxicity• Little information is available regarding the treatment of Little information is available regarding the treatment of

cardiovascular toxicity of local anesthetics in humans. cardiovascular toxicity of local anesthetics in humans. Animal data suggest that (1) high doses of epinephrine may Animal data suggest that (1) high doses of epinephrine may be necessary to support heart rate and blood pressure; (2) be necessary to support heart rate and blood pressure; (2) atropine may be useful for bradycardia; (3) DC atropine may be useful for bradycardia; (3) DC cardioversion is often successful; and (4) ventricular cardioversion is often successful; and (4) ventricular arrhythmias are probably better treated with amiodarone arrhythmias are probably better treated with amiodarone than with lidocaine. Amiodarone is used as for ACLS, 150 than with lidocaine. Amiodarone is used as for ACLS, 150 mg over 10 min, followed by 1 mg/min for 6 hrs then 0.5 mg over 10 min, followed by 1 mg/min for 6 hrs then 0.5 mg/min. Supplementary infusion of 150 mg as necessary up mg/min. Supplementary infusion of 150 mg as necessary up to 2 g. For pulseless VT or VF, initial administration is 300 to 2 g. For pulseless VT or VF, initial administration is 300 mg rapid infusion in 20-30 mL of saline or dextrose in mg rapid infusion in 20-30 mL of saline or dextrose in water. Vasopressin (40 U IV, single dose, one time only) is water. Vasopressin (40 U IV, single dose, one time only) is more frequently used now before epinephrine (1 mg IV more frequently used now before epinephrine (1 mg IV every 3-5 minutes). every 3-5 minutes). The best treatment for toxic The best treatment for toxic reactions is preventionreactions is prevention

Maximum doseMaximum dose

• Regional anesthesiologists perform peripheral nerve blocks with Regional anesthesiologists perform peripheral nerve blocks with an amount of local anesthetic that usually exceeds the maximum an amount of local anesthetic that usually exceeds the maximum recommended doses. recommended doses.

• The common recommendations for maximum doses as suggested The common recommendations for maximum doses as suggested by the literature “are not evidence based” (14) and have proven by the literature “are not evidence based” (14) and have proven to be “poor approximation of safety” (15). to be “poor approximation of safety” (15).

• Many practitioners have called to review these guidelines to better Many practitioners have called to review these guidelines to better reflect the reality of clinical practice. The American Society of reflect the reality of clinical practice. The American Society of Regional Anesthesia convened a “Conference in Local Anesthetic Regional Anesthesia convened a “Conference in Local Anesthetic Toxicity” with a panel of experts in 2001 to discuss the subject. Toxicity” with a panel of experts in 2001 to discuss the subject. Many papers related to that conference have been published.Many papers related to that conference have been published.

• In a review article by Rosenberg et al (14) the authors propose In a review article by Rosenberg et al (14) the authors propose that the safe ranges should be block specific and related to that the safe ranges should be block specific and related to patient’s age (e.g., epidural), organ dysfunction (especially for patient’s age (e.g., epidural), organ dysfunction (especially for repeated doses) and pregnancy. They suggest also adding repeated doses) and pregnancy. They suggest also adding epinephrine 2.5 to 5 µg/ml when not contraindicated. epinephrine 2.5 to 5 µg/ml when not contraindicated.

• The fact is that most of the systemic toxicity occurs with The fact is that most of the systemic toxicity occurs with unintentional direct intravascular injection unintentional direct intravascular injection

MethgemoglobinemiaMethgemoglobinemia

• Prilocaine and benzocaine can oxidize the ferric form of the Prilocaine and benzocaine can oxidize the ferric form of the hemoglobin to the ferrous form, creating methemoglobin. hemoglobin to the ferrous form, creating methemoglobin. When this exceeds 4 g/dL cyanosis can occur. Depending When this exceeds 4 g/dL cyanosis can occur. Depending on the degree Methemoglobinemia can lead to tissue on the degree Methemoglobinemia can lead to tissue hypoxia. The oxyHb curve shifts to the left (P50 < 27 hypoxia. The oxyHb curve shifts to the left (P50 < 27 mmHg). MetHb has a larger absorbance than Hb and 02Hb mmHg). MetHb has a larger absorbance than Hb and 02Hb at 940 nm but simulates Hb at 660 nm. Therefore at high at 940 nm but simulates Hb at 660 nm. Therefore at high SaO2 levels (more than 85%) the reading underestimates SaO2 levels (more than 85%) the reading underestimates the true value of it or overestimates the O2Hb. At low SaO2 the true value of it or overestimates the O2Hb. At low SaO2 (<85%) the value is falsely high. In the presence of high (<85%) the value is falsely high. In the presence of high MetHb concentrations the SaO2 approaches 85% MetHb concentrations the SaO2 approaches 85% independent of the actual arterial oxygenation. independent of the actual arterial oxygenation.

• Methemoglobinemia is easily treated by the administration Methemoglobinemia is easily treated by the administration of methylene blue (1-5mg/kg) or less successfully of of methylene blue (1-5mg/kg) or less successfully of ascorbic acid (2 mg/kg).ascorbic acid (2 mg/kg).

•

AllergyAllergy

• True allergy to local anesthetics is rare. It is True allergy to local anesthetics is rare. It is relatively more frequent with esters, which are relatively more frequent with esters, which are metabolized to para-amino-benzoic acid (PABA). metabolized to para-amino-benzoic acid (PABA). PABA is frequently used in the pharmaceutical PABA is frequently used in the pharmaceutical and cosmetic industries. Allergy to amide local and cosmetic industries. Allergy to amide local anesthetics is exceedingly rare. There is no anesthetics is exceedingly rare. There is no cross allergy between esters and amides. cross allergy between esters and amides. However use of methylparaben as a However use of methylparaben as a preservative in multidose vials of lidocaine can preservative in multidose vials of lidocaine can elicit allergy in patients allergic to PABA elicit allergy in patients allergic to PABA

ProcaineProcaine

• EsterEsterpka 8.9pka 8.9slow onsetslow onsetvery short half life (20 sec)very short half life (20 sec)protein binding 5%protein binding 5%

• duration: shortduration: short

2-chloroprocaine2-chloroprocaine

• EsterEsterpka 9.0pka 9.0rapid onsetrapid onsetshort duration (it has 30 minutes 2-segment short duration (it has 30 minutes 2-segment regression in epidural)regression in epidural)

• serious neurological deficits have occurred after serious neurological deficits have occurred after massive intrathecal injection planned for spinal massive intrathecal injection planned for spinal possible associated with the antioxidant bisulfite.possible associated with the antioxidant bisulfite.The next preservative used ethylenediamine The next preservative used ethylenediamine tetraacetic acid (EDTA) was associated with severe tetraacetic acid (EDTA) was associated with severe muscle spasm after epidural in ambulatory patients. muscle spasm after epidural in ambulatory patients. The present solution is prepared without preservative The present solution is prepared without preservative and no back spasms have been reported and no back spasms have been reported

TetracaineTetracaine

• EsterEsterpka 8.6pka 8.6slow onsetslow onsetshort plasma half life (2.5 to 4 min) short plasma half life (2.5 to 4 min) and long duration of action and long duration of action

CocaineCocaine

• esteresterpka 8.5pka 8.5slow onsetslow onsetshort durationshort durationvasoconstrictorvasoconstrictorinterferes with the reuptake of cathecolamines interferes with the reuptake of cathecolamines resulting in hypertension, tachycardia, resulting in hypertension, tachycardia, arrhythmia and myocardial ischemia.arrhythmia and myocardial ischemia.Can potentiate cathecolamine-induced Can potentiate cathecolamine-induced arrhythmia by halothane, theophylline or arrhythmia by halothane, theophylline or antidepressants antidepressants

BenzocaineBenzocaine

• ester (only secondary amine). It limits ester (only secondary amine). It limits its ability to pass through membranes.its ability to pass through membranes.pka 3.5pka 3.5slow onsetslow onsetshort durationshort durationTopical anestheticTopical anestheticexcessive use is associated with excessive use is associated with Methemoglobinemia Methemoglobinemia

• LidocaineLidocaineamideamidepka 7.7pka 7.7intermediate onset and durationintermediate onset and durationhalf-life 45-60 min half-life 45-60 min

• MepivacaineMepivacaineamideamidepka 7.6pka 7.6intermediate onset and duration intermediate onset and duration

• BupivacaineBupivacaineamideamidepka 8.1pka 8.1Slow onset, long durationSlow onset, long durationCardiac arrest associated with Cardiac arrest associated with bupivacaine is difficult to treat bupivacaine is difficult to treat possibly due to its high protein possibly due to its high protein binding and high lipid solubility binding and high lipid solubility

• RopivacaineRopivacaineamideamidepka 8.2pka 8.2chemical analog of mepivacaine and chemical analog of mepivacaine and bupivacainebupivacainePrepared as L enantiomerPrepared as L enantiomerOnset and duration as well as potency Onset and duration as well as potency similar to bupivacaine similar to bupivacaine Cardiac toxicity higher than mepivacaine Cardiac toxicity higher than mepivacaine but lower than bupivacaine but lower than bupivacaine

• LevobupivacaineLevobupivacaineamideamideL enantiomer of bupivacaineL enantiomer of bupivacainesimilar to ropivacainesimilar to ropivacaine

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LOCAL ANESTHETICS