Local Anesthetics

Atypical plasma cholinesterase has been shown to significanlty reduce the rate of which of the following A. Bupivacaine B. Lidocaine C. Procaine D. Ropivacaine

. Procaine - The metabolism of local anesthetics differs according to their chemical structure as either amides or esters. Plasma cholinesterase catalyzes the hydrolysis of ester local anesthetics. - The hydrolysis occurs through the action of cholinesterase in plasma, red blood cells, and the liver. - The plasma half-lives of procaine and chloroprocaine are shorter than 1 minute. The rapid rate of clearance of these drugs significantly reduces the potential of toxicity. -Conversely, hydrolysis of tetracaine is slower and it has limited clinical use -. Saturated, inhibited, or genetically atypical plasma cholinesterase can significantly prolong the plasma half-life of ester local anesthetics. - This would have little effect on duration of the ester agent because absorption away from the site of injection would occur as usual; however, this effect could theoretically increase the chance for systemic toxicity. - For example, atypical plasma cholinesterase has been shown to significantly reduce the rate of procaine metabolism.. - Metabolism of the amide local anesthetics occurs primarily in the liver predominantly by microsomal cytochrome P-450 enzymes CYP1A2 and CYP3A4

Which of the following are ways to reduce the indicence of LAST (SATA) A. Use of midazolam B. US guided regional anesthesia C. Lower local anesthetic dose D. Bolus doses

A, B, & C - This safety improvement is attributed to the widespread adoption of enhanced safety measures, namely ultrasound guided regional anesthesia, aspirating before injection, incremental injection, lower local anesthetic doses and use of a test dose - Added safety measures included performing the blocks with the patients either awake or sedated with meaningful contact maintained to allow early identification of LAST, and the use of midazolam, which may have increased the potential seizure threshold.

The functional unit of peripheral nerves A. Axon B. Axolemma C. Schwann cells D. Axoplasm

A. Axon - The axon, an extension of a centrally located neuron, is the functional unit of peripheral nerves. - A cell membrane, or axolemma, and intracellular contents, or axoplasm, are the major components of the axon. - Schwann cells, whose functions are support and insulation, surround each axon. - In unmyelinated nerves single Schwann cells cover several axons. - Conversely, in larger nerves the Schwann cell sheath covers only one axon and has several concentric layers of myelin.

Which of the following is the treatment of methhemoglobinemia A. Methylene blue B. 20% lipid emulsions C. Epinephrine D. Sodium Bicarbonate

A. - Benzocaine and benzocaine-containing mixtures are widely used for topical anesthesia. The FDA has issued multiple safety bulletins warning of benzocaine-induced methemoglobinemia.129 In a 2006 communication the FDA reported 247 cases of methemoglobinemia from benzocaine sprays including three deaths. Since then the number of cases has continued to rise. - The development of methemoglobinemia does not seem to be dose related. - Symptoms appear within minutes up to 2 hours after benzocaine use. - The cases were primarily in teething children less than 2 years old. Benzocaine gels and liquids are marketed under the names Anbesol, Hurricaine, Orajel, Baby Orajel, Orabase, and some store brands. - Benzocaine should not be used in children under 2 years old. - Prilocaine can produce methemoglobinemia because of one of its metabolites o-toluidine, which oxidizes hemoglobin to methemoglobin. The tendency of prilocaine to produce methemoglobin is dose related. - Current recommendations are that prilocaine should not be used in children younger than 6 months old, in pregnant women, or in patients taking other oxidizing drugs.The dose should be limited to 2.5 mg/kg. - The treatment for elevated methemoglobin is methylene blue, which is initiated at a rate of 1 to 2 mg/kg intravenously over 3 to 10 minutes. - If the methemoglobin level is greater than 50% or the clinical condition worsens, then the higher dose of methylene blue 2 mg/kg can be given initially. The dose can be repeated if symptoms fail to improve or high methemoglobin levels persist. - A level of methemoglobin greater than 70% may require transfusion or dialysis. Recognition is critical because a delay in treatment can lead to cardiopulmonary compromise, neurologic sequelae, and even death.

Which of the following is false regarding local anesthetic systemic toxicity (LAST) A. The voltage-gated sodium, potassium and calcium channels in excitable tissues of the central nervous and cardiac system are stimulated B. Normal functioning of the central nervous system involves both excitatory and inhibitory neurons with the inhibitory neurons being blocked first C. A toxic level of local anesthetic results in decreased contractility and several arrhythmias, the first of which is commonly bradycardia. D. Blockade of the cardiac ion channels will affect initiation and propagation of the contraction, and repolarization.

A. - Local anesthetic systemic toxicity (LAST) is a serious but rare consequence of regional anesthesia. It most commonly results from an inadvertent vascular injection or absorption of large amounts of drug from certain nerve blocks requiring large volume injections. - It can also occasionally result from continuous infusion and accumulation of drug and metabolites over many days. The subsequent high systemic blood levels lead to LAST. - When inadvertent systemic delivery or rapid absorption of large quantities of local anesthetic occurs, the voltage-gated sodium, potassium and calcium channels in excitable tissues of the central nervous and cardiac system are depressed. Normal functioning of the central nervous system involves both excitatory and inhibitory neurons. - As LAST progresses, the inhibitory neurons are blocked first. This lack of inhibition on the excitatory neuron is thought to be the mechanism of the observed seizure. - The functioning of the heart depends on mechanisms similar to that of the neuron. Blockade of the cardiac ion channels will affect initiation and propagation of the contraction, and repolarization. - A toxic level of local anesthetic results in decreased contractility and several arrhythmias, the first of which is commonly bradycardia. Ventricular fibrillation is the most serious of the arrhythmias.

Which LA drug class is associated with a higher risk for allergic reaction A. Ester-type B. Amide-type

A. - Local anesthetics can, however, produce allergic, hypersensitivity, and anaphylactic reactions. The use of ester local anesthetics is associated with a greater incidence of allergic reactions than the use of amides. - This is likely because esters are derivatives of and metabolized to para-aminobenzoic acid (PABA), which is an allergenic compound. - Allergy to local anesthetics may be caused by methylparaben, paraben, or metabisulfite used as preservatives. - In 1984 the FDA mandated removal of methylparaben from single-dose local anesthetic cartridges commonly used in dentistry which greatly reduced allergic reactions. - Sulfites are antioxidants used to stabilize epinephrine in local anesthetic solutions. They are not typically used when the local anesthetic does not contain epinephrine. - Sulfites have been involved in nonIgE-mediated hypersensitivity reactions, particularly in patients with asthma. Because testing is very inconsistent, it is difficult to know the role sulfites may play in reactions attributed to a local anesthetic preparation. - Preservative-free solutions are available but not commonly used. - Cross-reactivity among the ester-type local anesthetics is high. - Allergy to the amides remains extremely rare. - Cross-reactivity within the amides as a class is extremely rare and between esters and amides is absent. - A thorough history of allergy may be difficult because many patients call all local anesthetic drugs "Novacaine." - They may not be aware of the specific agent administered. Clinicians use amides when possible because the incidence of allergy is extremely low, and they are not cross-reactive with other amides or esters. If a true allergy is suspected, referral to an allergist for skin testing and incremental dose challenges is necessary.

What is the resting membrane potential of a resting peripheral nerve A. -70 mV to -90 mV B. -50 mV to -80 mV C. -40 mV to -60 mV D. -800 mV to -100 mV

A. - Measurement with an electrode placed in the axoplasm of a resting peripheral nerve demonstrates a negative membrane potential of −70 mV to −90 mV. - This voltage difference across the neuronal membrane at steady state is called the resting membrane potential - An ionic imbalance between the axoplasm and the extracellular fluid causes the electrical potential. - Several physiologic mechanisms create the ionic gradient; the primary one is an active, energy-dependent process executed by a sodium-potassium pump (Na+-K+/ATPase) located in the axolemma.

Which of the following LA does not cause vasoconstriction A.Procaine B. Ropivacaine C. Lidocaine D. Cocaine

A. All local anesthetics except cocaine, ropivacaine, and lidocaine produce relaxation of vascular smooth muscle. - The resultant vasodilation increases blood flow to the tissue in which the drug is deposited. This results in an increase in the drug's absorption, which limits its duration of action and increases the probability of toxic effects. - It is interesting to note that ropivacaine and lidocaine are the only parenterally administered local anesthetics with mild vasoconstrictive properties. - Cocaine also has vasoconstrictive properties because of its ability to block reuptake of norepinephrine. It is used only topically. -All local anesthetics are not affected equally when epinephrine is added to the solution. There is a definite benefit in extending the duration of analgesic effects with both short- and intermediate-acting agents. -The prolongation of the duration with long-acting drugs is less well defined..

Which of the following is the most common presentation sign of LA toxicity A. CNS B. CNS & CV C. CV D. None of the aboe

A. CNS

Which of the following is not a characteristic of an ester LA A. Longer acting because they are more lipophilic and protein bound and require transport to the liver for metabolism B. Metabolism is catalyzed by plasma and tissue cholinesterase via hydrolysis C. Have a higher allergy potential D. Tend to be shorter acting due to ready metabolism;

A. Esters - Ester metabolism is catalyzed by plasma and tissue cholinesterase via hydrolysis; occurs throughout the body and is rapid. - Although local anesthetic allergy is uncommon, esters have a higher allergy potential, and if patients exhibit an allergy to any ester drug, all other esters should be avoided. - Ester drugs tend to be shorter acting due to ready metabolism; tetracaine is the longest acting ester.

According to the guarded receptor or modulated receptor hypothesis of local anesthetic action, which functional states of the Na channels does the local anesthetic bind A. Resting B. Open C. Inactive

A. & B. - Local anesthetics preferentially bind to both the open or inactivated states and not to the closed state. - This is referred to as the guarded receptor or modulated receptor hypothesis of local anesthetic action. - The open or inactive state may increase the affinity for binding the physical access of the drug to the receptor, or both. - In addition, it has long been noted that local anesthetics work faster as the Nav is repetitively depolarized. - This is termed as use-dependent or phasic block. The more frequently the channel is depolarized, the more time it is available in the open and inactive states and thus available to local anesthetic blockade

What determines the duration og action of an LA (SATA) A. Lipophilicity B. Protein binding C. Size of the molecules D. Ionization

A. & B. - The duration of action of local anesthetics demonstrates a relationship to protein binding and lipid solubility. - In theory, drugs that have a high affinity for protein and lipids attach more firmly to these substances in the vicinity of the Nav channel receptor. This means that the drug remains in the channel and surrounding areas for a longer time producing prolonged conduction blockade. - It appears therefore that there is a correlation between the degree of protein binding and duration of the local anesthetic. - The addition of larger chemical radicals to the amide or aromatic end of the drugs results in greater protein binding. - The duration is directly proportional to plasma protein binding, presumably because the local anesthetic receptor on the neural membrane is also composed of protein. - It has been posited that local anesthetics that have increased protein-binding properties (e.g., ropivacaine 94%, bupivacaine 97%) produce longer-duration anesthesia as a consequence of more efficient binding of the anesthetic to the Nav channel. - For example, bupivacaine is more than 90% bound to plasma protein; however, its homologue, mepivacaine, is only 65% bound. - The duration of action of bupivacaine is significantly longer than for mepivacaine. - Local anesthetics are weak bases and bind mainly to α1-acid glycoprotein (AAG). Secondary binding to albumin also occurs.

Which of the following LA is included in the EMLA cream (SATA) A. Lidocaine B. Benzocaine C. Tetracaine D. Prilocaine

A. & D. - Eutectic mixture of local anesthetics (EMLA) is a mixture of lidocaine and prilocaine that is applied to the skin as either a cream or patch. - A eutectic mixture of chemicals has a lower melting point and solidifies at a lower temperature when combined. - Pharmacokinetic studies indicate that satisfactory dermal analgesia is achieved 1 hour after application with an occlusive dressing; maximal analgesia occurs 2 to 3 hours after application. - When EMLA is applied to areas of abnormal skin (e.g., where psoriasis or eczema is present), absorption is faster, plasma levels are higher, and the duration of anesthesia is shorter. - Systemic absorption of lidocaine and prilocaine is dependent on the duration and surface area of application. - Toxicity is more likely to occur in infants and small children than in adults.

Identify the A fibers based on their function A. Provide motor function, touch, and pressure sensation B. Innervate muscle spindles and are responsible for reflexes. C. Responsible for motor functions and proprioception. D. Provide pain and temperature sensation.

A. A beta fiber- provide motor function, touch, and pressure sensation B. A gamma fiber- innervate muscle spindles and are responsible for reflexes. C. A alpha fibers- responsible for motor functions and proprioception. D. A delta fibers- provide pain and temperature sensation.

These fibers are the largest in diameter (12 µm to 20 µm) and the most heavily myelinated; they have the fastest conduction velocity of all the fibers A. A fiber B. B fiber C. C fiber D. D fiber

A. A fiber - Essential to the understanding of differential block is the concept that the diameter and myelination of nerve fibers influence the sensitivity to local anesthetics. - For simplicity nerve fibers are separated into three groups—A, B, and C—on the basis of diameter. -The A fibers are further divided into four subgroups known as alpha, beta, gamma, and delta fibers. - The alpha fibers are the largest in diameter (12 µm to 20 µm) and the most heavily myelinated; they have the fastest conduction velocity of all the fibers, including B and C fibers. - Alpha fibers are responsible for motor functions and proprioception. - The A beta (5 µm to 12 µm) and A gamma fibers (3 µm to 6 µm) have conduction velocities second only to A alpha fibers. - The A beta fibers provide motor function, touch, and pressure sensation; - the A gamma fibers innervate muscle spindles and are responsible for reflexes. - The A delta fibers provide pain and temperature sensation. These fibers have a smaller diameter (1 µm to 5 µm) and slower conduction velocity than other A fibers. The beta, gamma, and delta fibers are all myelinated to a similar extent.

Which subunit does LA bind to in the sodium receptor A. A subunit B. B subunit

A. A subunit - The sodium channel is a dynamic transmembrane protein consisting of the large sodium-conducting pore (α subunit) and varying numbers of adjacent smaller β subunits. Nine distinct functional subtypes of voltage-gated Na+ channels are recognized, corresponding to nine genes for their pore-forming α subunits. These have different tissue distributions in the adult and are differentially regulated at the cellular level by receptor-coupled cell signaling systems.15 Different isoforms of voltage-gated Na+ channels, based on biophysical and pharmacologic studies, can provide distinct targets for interventions in various pain syndromes.16 The large polypeptide that forms the α subunit is further divided into four subunits (DI to DIV) (Fig. 10-5). H is the α subunit that allows ion conduction and binds to local anesthetics. However, β subunits may modulate local anesthetic binding to the α subunit. Binding affinities of local anesthetics to the sodium ion channels are stereospecific and depend on the conformational state of the sodium channel (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Identify which mechanistic action that contributes to the lipid resuscitation (lipid sink, metabolic effect, membrane effect, cytoprotection, inotropic effect, pharmacokinetic effect A. Activation of serine/threonine kinase (Akt) cascade leading to inhibition of GSK-3, which is glycogen synthase kinase B. Capture of local anesthetic in the blood C. Promotion of calcium entry via voltage-dependent calcium channels D. Increased fatty acid uptake by mitochondria E. Accelerated shunting F. Interference with local anesthetic binding of sodium channels

A. Cytoprotective B. Lipid sink C. Inotropic effect D. Metabolic effect E. Pharmacokinetic effect F. Membrane effect - Lipid emulsion therapy for LAST is the newest and most promising therapy that has emerged. Both laboratory and clinical use has shown it to be instrumental in facilitating successful recovery. - The exact mechanisms for the beneficial effects is not clear. The mechanisms of action of lipid infusion can be broadly separated into intracellular (metabolic, signaling), intravascular (partitioning, sink), and membrane (channel) effects. 0 Six mechanistic actions may contribute to lipid resuscitation including: (1) capture of local anesthetic in the blood (lipid sink); (2) increased fatty acid uptake by mitochondria (metabolic effect); (3) interference with local anesthetic binding of sodium channels (membrane effect); (4) activation of serine/threonine kinase (Akt) cascade leading to inhibition of GSK-3, which is glycogen synthase kinase (cytoprotection); (5) promotion of calcium entry via voltage-dependent calcium channels (ionotropic/inotropic effect); and (6) accelerated shunting (pharmacokinetic effects) - Lipid emulsion is also recommended in pregnant patients.115 It is also being used for a variety of drug overdoses in emergency situations

Identify the layer of connective tissue in a peripheral nerve A. A delicate connective tissue composed of longitudinally arranged collagen, surrounds and embeds the axons in the fasciculi B. Consists of layers of flattened, overlapping cells, binds a group of fascicles together C. Composed of areolar connective tissue that functionally holds the fascicles together to form a peripheral nerve

A. Endonerium B. Perinerium C. Epinerium - Peripheral nerves have structures containing bundles of axons called fasciculi. Three layers of connective tissue—the endoneurium, perineurium, and epineurium—also are components of a peripheral nerve. - The endoneurium, which is a delicate connective tissue composed of longitudinally arranged collagen, surrounds and embeds the axons in the fasciculi. - The perineurium, which consists of layers of flattened, overlapping cells, binds a group of fascicles together. - The epineurium, which surrounds the perineurium, is composed of areolar connective tissue that functionally holds the fascicles together to form a peripheral nerve. - These layers of connective tissue are important because they serve as barriers through which local anesthetics must diffuse if they are to exert their pharmacologic action

Which of the following should not be observed in patient with LAST A. Epinephrine 1mg every 2-3 minutes during resuscitation B. Avoidance of propofol in CVS unstable patient C. Drawing blood levels of LA plasma concentration D. Transfer to a clinical area with appropriate monitoring, equipment, and staff for > 12 hr monitoring.

A. Epinephrine 1mg every 2-3 minutes during resuscitation Treatment Maintain and secure the airway; 100% oxygen. • Timing of lipid infusion in LAST is controversial. The most conservative approach, waiting until after ACLS has proven unsuccessful, is unreasonable because early treatment can prevent cardiovascular collapse. Infusing lipid at the earliest sign of LAST can result in unnecessary treatment because only a fraction of patients will progress to severe toxicity. The most reasonable approach is to implement lipid therapy on the basis of clinical severity and rate of progression of LAST. • There is laboratory evidence that epinephrine can impair resuscitation from LAST and reduce the efficacy of lipid rescue. Therefore it is recommended to avoid high doses of epinephrine and use smaller doses, for example, 1 mcg/kg for treating hypotension. • Propofol should not be used when there are signs of cardiovascular instability. Propofol is a cardiovascular depressant with lipid content too low to provide benefit. Its use is discouraged when there is a risk of progression to cardiovascular collapse. • Consider drawing blood to measure LA plasma concentration if there is no delay to definitive treatment. • Transfer to a clinical area with appropriate monitoring, equipment, and staff for > 12 hr monitoring. • Regular clinical review to exclude pancreatitis, including serial amylase or lipase for 2 days. • Report cases and use of ILE to www.lipidrescue.org.

Based on the principles of use-dependent or phasic block, in what manner can a local anesthetic work faster A. Increase Na .channel depolarization B. Decrease Na channel depolarization C. Either scenario will produce a fast response D. None of the above

A. Increase Nav depolarization - Local anesthetics work faster as the Nav is repetitively depolarized. - This is termed as use-dependent or phasic block. The more frequently the channel is depolarized, the more time it is available in the open and inactive states and thus available to local anesthetic blockade

Liposomes, cyclodextrins, and biopolymers are used to _______ the duration of action and ______ the toxicity of LA A. Increase; decrease B. Increase; increase C. decrease; increase D. decrease; decrease

A. Increase; decrease - Various formulation and drug delivery system including liposomes, cyclodextrins, and biopolymers are studied to prolong the duration and to limit the toxicity of local anesthetics. The goal is to upload higher amount of local anesthetic into the molecule and to have a consistent release of local anesthetic in the tissues.5 Liposomes, hydrophobic-based polymer particles such as Poly(lactic-co-glycolic acid) microspheres and solid polymers such as Poly(sebacic-co-ricinoleic acid) P(SA:RA) and their combination with synthetic and natural local anesthetic are examples of delivery systems currently in development or in clinical use. - Drugs such as lidocaine, tetracaine, and bupivacaine have been incorporated into liposomes to prolong the duration of action and decrease toxicity.7 Bupivacaine extended release liposome injection was recently approved by U.S. Food and Drug Administration (FDA) for local infiltration anesthesia for hemorrhoidectomy and bunionectomy.8-10 Bupivacaine extended release liposome injection consists of microscopic, spherical, and multivesicular liposomes and each liposome particle is composed of a honeycomb-like structure of numerous internal aqueous chambers. Lipid membranes separate these aqueous chambers, and the chambers contain encapsulated bupivacaine. Bupivacaine is released from the liposome particles by a complex mechanism over an extended period (up to 96 hours). (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

___________ sensitivity to LA may be present during pregnancy A. Increased B. Decreased

A. Increased - Increased sensitivity (more rapid onset of conduction blockade) may be present during pregnancy.22 Alterations in protein-binding characteristics of bupivacaine may result in increased concentrations of pharmacologically active unbound drug in the parturient's plasma.23 Nevertheless, progesterone, which binds to the same α1-acid glycoprotein as bupivacaine, does not influence protein binding of this local anesthetic.23 This evidence suggests that bupivacaine and progesterone bind to discrete but separate sites on protein molecules. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Which of the following is the action of LA A. Inhibits the passage of sodium ions B. Alter resting transmembrane potential C. Alter threshold potential

A. Inhibits the passage of sodium ions - Local anesthetics bind to specific sites in voltage-gated Na+ channels. They block Na+ current, thereby reducing excitability of neuronal, cardiac or central nervous system tissue.13 Local anesthetics prevent transmission of nerve impulses (conduction blockade) by inhibiting passage of sodium ions through ion-selective sodium channels in nerve membranes.14 The sodium channel itself is a specific receptor for local anesthetic molecules. Failure of sodium ion channel permeability to increase slows the rate of depolarization such that threshold potential is not reached and thus an action potential is not propagated (Fig. 10-4). Local anesthetics do not alter the resting transmembrane potential or threshold potential. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

What determines the potency of an LA A. Lipophilicity B. Protein binding C. Size of the molecules D. Ionization

A. Lipophilicity - There is a strong relationship between the lipid solubility of local anesthetics and their potency. - This finding is understandable considering that the axolemma and myelin sheath are composed primarily of lipids - Lipid-soluble drugs pass more readily through the nerve membrane. - Larger, more lipid-soluble local anesthetics are relatively water insoluble, highly protein bound, and less readily washed out from nerves and surrounding tissues. - They bind to Nav channels with a higher affinity than agents with lower lipid solubility. - Increased lipid solubility correlates with increased protein binding, increased potency, longer duration of action, and a higher tendency for severe cardiac toxicity. - It follows that fewer molecules or lower concentrations of these drugs are required for the production of blockade than if nonlipid-soluble anesthetics are used. - Changes in either the aromatic or amine moieties of the local anesthetic molecule can affect the lipid-water partition coefficient. - In the amide series, for example, the addition of a butyl group to the amine end of mepivacaine leads to the formation of bupivacaine. - Bupivacaine is twenty-sixfold as lipid soluble and fourfold as potent as mepivacaine. - In the case of the esters the addition of a butyl group to the aromatic end of procaine produces tetracaine, which is considerably more lipid soluble and potent than procaine - Vascular and tissue distribution properties of the drug may also affect the potency of the drug.

Identify the functional state of the sodium channel (resting/ closed, open, inactive) A. A conformational change in the proteins that compose the channel occurs after a nerve is stimulated reversal of the membrane potential occurs until the threshold potential is reached B. The membrane is at its resting potential C. The return of the Na+ channel to an impermeable state, prevents initiation of an action potential

A. Open state B. Resting/ closed state C. Inactive state - Local anesthetics work by reversibly binding to the voltage-gated sodium channels (Nav). - Sodium channels have three functional states: resting (closed), open, and inactive. - The resting state exists when the membrane is at its resting potential. - When a nerve is stimulated reversal of the membrane potential occurs until the threshold potential is reached. When this happens a conformational change in the proteins that compose the channel occurs, resulting in the open state. - An inactive state, characterized by the return of the Na+ channel to an impermeable state, follows the open state. - This state, which prevents the initiation of an action potential, lasts until the restoration of the resting membrane potential. - This three-state concept describes the changes in the Nav that occur during depolarization and repolarization.

Which of the following condition has the least amount of effect to the clearance of an LA A. Renal Failure B. Heart Failure C. Liver disease D. Hypovolemia

A. Renal Failure - Hepatic clearance is a function of the hepatic extraction ratio and hepatic blood flow and is the primary factor that determines the rate of elimination of amide local anesthetics. - The hepatic extraction ratio is dependent on the ratio of free to protein-bound drug and represents the activity level specific to the liver for removing a drug from plasma. - This ratio indicates the percentage of drug removed with each pass through the liver. The clearance of drugs that have higher hepatic extraction ratios depends on adequate hepatic blood flow. - Hepatic enzyme activity is important when drugs with lower ratios such as bupivacaine are used - Pathologic conditions that influence hepatic function may prolong the elimination half-life of these drugs by a reduction in hepatic blood flow, enzyme activity, or both. - For example, lidocaine has a plasma half-life of 1.6 hours; however, in severe hepatic disease, its half-life is 4.9 hours. - This probably results from both an enzymatic and a perfusion effect. - Flow-limited clearance is affected by upper abdominal and laparoscopic surgery, inhalation anesthetics, hypovolemia, and congestive heart failure. - Heart failure significantly reduces the rate of elimination of lidocaine because of a concomitant reduction in hepatic blood flow. - Clinically, hepatic dysfunction does not necessitate a reduction of dose for a single injection nerve block. Doses of amides used in continuous infusions or repeat blocks should be reduced 10% to 50%. - Only 1% to 5% of the injected dose of local anesthetic is accounted for by unchanged renal and hepatic excretion. - However, the inactive, more water-soluble metabolites of local anesthetics appear in the urine. Although renal dysfunction affects the clearance far less than hepatic failure, it can result in the accumulation of potentially toxic metabolites. - It may also affect protein binding to both AAG and albumin. Some authors have suggested a 10% to 20% reduction in patients with severe renal disease.

The major determinant ion responsible for action potential A. Sodium B. Potassium C. Calcium D. Chloride

A. Sodium - When an electrical impulse is applied to a resting nerve, the membrane potential is reversed because of the intracellular movement of Na+. - This occurs because of the higher concentration of Na+ outside the cell, and the stimulation-induced increase in membrane permeability to this ion. - The sudden influx of Na+ that occurs in response to stimulation overrides the efflux of K+ directed at maintaining the resting membrane potential. - Once the process has reversed the membrane potential to 20 mV, an outward electrochemical gradient develops; this gradient resists the concentration-dependent, inward diffusion of Na+. - This state of equilibrium causes the Na+ channels to close. Shortly after Na+ enters the cell, K+ channels begin to open, and the ion rapidly diffuses out of the neuron according to its concentration gradient. - The active removal of intracellular Na+ by the Na+-K+ pump and the passive diffusion of K+ outward restore the resting membrane potential. During repolarization, three Na+ ions leave the cell for each two K+ ions that enter -The sequence of events that results in an action potential results from the passage of ions through pores or "channels" located in the axolemma. - These channels, which are composed of globular proteins, have transmural orientation to the phospholipid molecules that constitute the axolemma. - Although K+ and calcium (Ca2+) channels are important, the Na+ channels are the most significant and best understood with respect to the initiation and propagation of the action potential.

Which of the following is where LA has the most affinity to A. Sodium channels B. Potassium channels C. Calcium channels D. G protein coupled receptors

A. Sodium channels - In addition to sodium ion channels, local anesthetics block voltage-dependent potassium ion channels. Compared with sodium ion channels, local anesthetics exhibit a much lower affinity for potassium channels. However, blockade of potassium ion channels might explain broadening of the action potential in the presence of local anesthetics. Considering the structural similarity between voltage-dependent calcium ion channels and sodium ion channels, it is not surprising that calcium ion currents (L-type is most sensitive) may also be blocked by local anesthetics.20 Although local anesthetics are considered principally ion channel blockers, there is evidence that these drugs may also act on G protein-coupled receptors (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Which side is the hydrophilic group A. Tertiary amine B. Unsaturated aromatic ring C. Hydrocarbon chain

A. Tertiary amine - Local anesthetics consist of a lipophilic and a hydrophilic portion separated by a connecting hydrocarbon chain (Fig. 10-1). The hydrophilic group is usually a tertiary amine, such as diethylamine, whereas the lipophilic portion is usually an unsaturated aromatic ring, such as paraaminobenzoic acid. The lipophilic portion is essential for anesthetic activity, and therapeutically useful local anesthetics require a delicate balance between lipid solubility and water solubility. In almost all instances, an ester(-CO-) or an amide (-NHC-) bond links the hydrocarbon chain to the lipophilic aromatic ring. The nature of this bond is the basis for classifying drugs that produce conduction blockade of nerve impulses as ester local anesthetics or amide local anesthetics (Fig. 10-2). The important differences between ester and amide local anesthetics relate to the site of metabolism and the potential to produce allergic reactions. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

What linearly determines the peak plasma concentration of an LA A. Total dose B. Volume C. Concentration D. Dilution

A. Total dose - The total dose of local anesthetic, rather than the volume or concentration, linearly determines the peak plasma concentration. - For example, 400 mg of lidocaine yields the same peak plasma concentration regardless of whether 40 mL of a 1% or 80 mL of a 0.5% is injected.

Local anesthetic molecules can gain access to receptors only when sodium channels are in A. activated-open B. inactivated-closed C. rested-closed

A. activated-open - Sodium ion channels tend to recover from local anesthetic-induced conduction blockade between action potentials. Additional conduction blockade is developed each time sodium channels open during an action potential (frequency-dependent blockade). Local anesthetic molecules can gain access to receptors only when sodium channels are in activated-open states and local anesthetic binds more strongly to inactivated state. For this reason, selective conduction blockade of nerve fibers by local anesthetics may be related to the nerve's characteristic frequencies of activity as well as to its anatomic properties such as diameter. Indeed, a resting nerve is less sensitive to local anesthetic-induced conduction blockade than is a nerve that has been repetitively stimulated. The pharmacologic effects of other drugs, including anticonvulsants and barbiturates in addition to local anesthetics, may reflect frequency-dependent blockade. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Which of the following is not a racemic mixture A. Mepivacaine B. Ropivacaine C. Levobupicavaine D. Bupivacaine

B & C - The pipecoloxylidide local anesthetics (mepivacaine, bupivacaine, ropivacaine, levobupivacaine) are chiral drugs because their molecules possess an asymmetric carbon atom (see Fig. 10-2). As such, these drugs may have a left- (S) or right- (R) handed configuration. Mepivacaine and bupivacaine are available for clinical use as racemic mixtures (50:50 mixture) of the enantiomers. The enantiomers of a chiral drug may vary in their pharmacokinetics, pharmacodynamics, and toxicity.1 These differences in pharmacologic activity reflect the fact that individual enantiomers bind to receptors or enzymes that are chiral amino acids with stereoselective properties. The S enantiomers of bupivacaine and mepivacaine appear to be less toxic than the commercially available racemic mixtures of these local anesthetics.2 In contrast to mepivacaine and bupivacaine, ropivacaine and levobupivacaine have been developed as a pure S enantiomers.3 These S enantiomers are considered to produce less neurotoxicity and cardiotoxicity than racemic mixtures or the R enantiomers of local anesthetics, perhaps reflecting decreased potency at sodium ion channel.4 (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Which of the following statement is false regarding LA and ion trapping A. The acidosis resulting from hypoxia may increase the ionized fraction of local anesthetic within the cerebral circulation, thereby decreasing the ability of the anesthetic to cross the blood-brain barrier, leave the brain, and reenter the systemic circulation. This phenomenon may prolong and enhance the central nervous system toxicity of local anesthetics. B. Local anesthetic accumulation in the fetal circulation is decreased by the fact that fetal pH is higher than maternal pH, which may result in high fetal levels of local anesthetics. C. Local anesthetics injected into acidotic, infected tissues are rendered ineffective because of the loss of lipid solubility. D. Carbonation of local anesthetics speeds the onset and intensity of action of neural blockade. E. Commercially available local anesthetics are prepared in a slightly acidic formulation that improves the stability of the drug by increasing the concentration of the ionized, water-soluble form of the drug. Addition of sodium bicarbonate to the local anesthetic mixture increases the pH of the solution, thereby increasing the concentration of the nonionized, lipid-soluble form of the drug.

B. - Local anesthetics are basic drugs. As discussed previously, they have both water- and lipid-soluble properties. Factors that raise the pH of their environment increase their lipid solubility, and conversely, lower pH environments, result in increased water solubility. These changes to pH result in altered proportions of lipid- and water-soluble fractions of the drugs, which may have clinical consequences. At times the term used for this phenomenon is ion trapping. Ion trapping results from changes in pH in relationship to the pKa of the agent. - In the event of local anesthetic overdose, associated respiratory depression may occur resulting in hypoxia and acidosis. The acidosis resulting from hypoxia may increase the ionized fraction of local anesthetic within the cerebral circulation, thereby decreasing the ability of the anesthetic to cross the blood-brain barrier, leave the brain, and reenter the systemic circulation. This phenomenon may prolong and enhance the central nervous system toxicity of local anesthetics. - Local anesthetic accumulation in the fetal circulation is enhanced by the fact that fetal pH is lower than maternal pH, which may result in high fetal levels of local anesthetics. • Local anesthetics injected into acidotic, infected tissues are rendered ineffective because of the loss of lipid solubility. The lipid solubility of local anesthetics is diminished in an acidotic environment because of an increased concentration of the ionized, water-soluble form of the drug. The loss of lipid solubility prevents absorption into the nerve, thereby preventing access to the site of action. • Carbonation of local anesthetics speeds the onset and intensity of action of neural blockade. Carbon dioxide readily diffuses into the nerve, lowering the pH within the nerve. The lipid-soluble form of local anesthetic, after passing through the neuronal membrane, receives protons from the intraneuronal environment and ionizes. An increase in the ionized fraction within the neuron produces a higher concentration of the active form of the anesthetic available at the sodium channel, the site of action. This practice has been largely abandoned in modern clinical practice. • Commercially available local anesthetics are prepared in a slightly acidic formulation that improves the stability of the drug by increasing the concentration of the ionized, water-soluble form of the drug. Addition of sodium bicarbonate to the local anesthetic mixture increases the pH of the solution, thereby increasing the concentration of the nonionized, lipid-soluble form of the drug. Improving the lipid solubility of the local anesthetic improves diffusion of the local anesthetic through the neuronal membrane, leading to a more rapid onset of action. This seems to be most effective in epidural blocks and least effective in peripheral blocks.

Which of the following is not included in the tumescent local anesthesia (TLA) for liposuction A. Epinephrine B. Hyaluronidase C. Sodium Bicarbonate D. Lidocaine

B. - Tumescent local anesthesia (TLA) involves the use of lidocaine, sodium bicarbonate, and epinephrine diluted in normal saline to provide anesthesia for liposuction. - The term tumescent refers to the physical appearance of tissues after the instillation of large volumes. Very low concentrations (0.05-0.1%) of lidocaine, mixed with epinephrine are used. - Common preparations involve the dilution of 500 to 1000 mg to 1000 mL of normal saline. Epinephrine (0.5 mg to 1 mg), and sodium bicarbonate are added to the preparation. - The volume of tumescent anesthesia solution used is determined by the achievement of palpable tumescence (uniform swelling) of the surgical field. - The maximum dose of lidocaine in TLA can approach 35 to 55 mg/kg. Peak serum levels occur 12 hours postinfiltration, and complete elimination is usually within 36 hours. - Strict adherence to liposuction guidelines has minimized adverse reactions from this technique.

Which of the following is not a risk reduction technique to prevent LAST A. Use lowest dose B. Avoidance of pharmacologic markers and test doses C. Aspiration of the syringe to inspect for blood D. Use of US guidance for LA injection

B. Risk Reduction (Be Sensible) • Use the lowest dose of LA necessary to achieve the desired extent and duration of block. • Local anesthetic blood levels are influenced by site of injection and dose. Factors that can increase the likelihood of LAST include advanced age, heart failure, ischemic heart disease, conduction abnormalities, metabolic (e.g., mitochondrial) disease, liver disease, low plasma protein concentration, metabolic or respiratory acidosis, and medications that inhibit sodium channels. Patients with severe cardiac dysfunction, particularly very low ejection fraction, are more sensitive to LAST and also more prone to receive "stacked" injections (with resulting elevated LA tissue concentrations) because of slowed circulation time. • Consider using a pharmacologic marker and/or test dose, for example, epinephrine 5 mcg/mL of LA. Know the expected response, onset, duration, and limitations of a "test dose" in identifying intravascular injection. • Aspirate the syringe prior to each injection while observing for blood. • Inject incrementally, observing for signs and querying frequently for symptoms of toxicity between each injection. • Use ultrasound guidance for the local anesthetic injection

TAC mixture have been combined for use on traumatic lacerations. This combination has been as effective as infiltration of local anesthetics for the closure of certain types of laceration. Which of the following is in TAC (SATA) A. Lidocaine B. Cocaine C. Tetracaine D. Prilocaine

B. & C. - Three available agents—tetracaine, epinephrine, and cocaine (TAC)—have been combined for use on traumatic lacerations. - The relative concentration of each component is as follows: tetracaine 1%, epinephrine 1:200, and cocaine 4%. This combination has been as effective as infiltration of local anesthetics for the closure of certain types of laceration. - Tetracaine and cocaine can produce excellent topical anesthesia, and cocaine and epinephrine result in vasoconstriction at the site of application. - TAC is much more expensive to administer than lidocaine. The drug combination in TAC can produce significant toxicity.

What is the maximum cumulative dose of 20% lipid emulsions for LAST A. 5 ml/kg B. 10 ml/kg C. 15 ml/kg D. 20 ml/kg

B. 10 ml/kg Suggestions for Administering Lipid Emulsion Immediately Give an initial intravenous bolus 20% lipid emulsion 1.5 ml/kg over 1 min AND Start an intravenous infusion injection of 20% lipid emulsion at 15 ml/kg per hr After 5 Minutes Give a maximum of two repeat Boluses (same dose) if: • cardiovascular stability has not been restored or • an adequate circulation deteriorates Leave 5 min between boluses A maximum of three bolus can be given (including the initial bolus) AND Continue infusion at same rate, but: Double the rate to 30 ml/kg per hr at any time after 5 min, if: • cardiovascular stability has not been restored or • an adequate circulation deteriorates Continue infusion until stable and adequate circulation restored or maximum dose of lipid emulsion given Do not exceed a maximum cumulative dose of 10 ml/kg

These fibers have diameter (less than 3 µm) and exhibit slower conduction velocity and less myelination. These fibers constitute the preganglionic autonomic nerves. Their function is in the preganglionic autonomic vasomotor A. A fiber B. B fiber C. C fiber D. D fiber

B. B fiber - B fibers have a similar diameter (less than 3 µm) to A delta fibers; however, they exhibit slower conduction velocity and less myelination than the A fibers. These fibers constitute the preganglionic autonomic nerves.

This drug is used as an adjunct to prolong the duration of action of the LA A. Ketorolac B. Clonidine C. Opioid D. Dexamethasone

B. Clonidine - Local anesthetic additives include the α2-adrenergic agonists clonidine and dexmedetomidine, opioids, sodium bicarbonate, ketorolac, dexamethasone, and hyaluronidase. - These are variously added to increase the safety, quality, intensity, duration, and rate of onset of anesthesia, and also reduce blood loss. - α2-Adrenergic agonists such as clonidine and dexmedetomidine have local anesthetic properties and can alter the nerve block characteristics. - The addition of 100 mcg of clonidine to a local anesthetic solution prolongs the duration of the long-acting agents approximately 100 additional minutes with minimal side effects. - The effect is produced by inhibition of the hyperpolarization-activated cation current (Ih current). - This current normally restores nerves from the hyperpolarized state to resting potential. - The effect is more pronounced in C-fibers (sensory) than Aδ (motor). - That makes the effects mostly sensory specific. Cost has limited the routine use of clonidine. - The use of dexmedetomidine for peripheral nerve blockade is currently being investigated and is not approved for use in the United States

The phenomenon where nerves functionally have different sensitivity or rates of effect when exposed to local anesthetics A. Phasic block B. Differential block C. Regional block D. Use-dependent block

B. Differential block - It has been observed that nerves functionally have different sensitivity or rates of effect when exposed to local anesthetics. - For example, in most major nerve blocks loss of autonomic function occurs first, followed in sequence by perception of superficial pain, touch, and temperature, motor function, and proprioception. - This phenomenon is termed differential block. - Seen clinically an excellent example of differential block occurs with the use of bupivacaine. - When administered by epidural for labor pain, this local anesthetic spares motor function and provides adequate analgesia.

Term for bundles of axons A. Axon Bundles B. Fasciculi C. Schwann cells D. Node of Ranvier

B. Fasciculi Peripheral nerves have structures containing bundles of axons called fasciculi

What process does procaine go to develop chloprocaine, which ha vary high hydrolysis rate A. Substitution of butyl to amine B. Halogenation C. Substituting a propyl group for an ethyl group

B. Halogenation - Modifying the chemical structure of a local anesthetic alters its pharmacologic effects. For example, lengthening the connecting hydrocarbon chain or increasing the number of carbon atoms on the tertiary amine or aromatic ring often results in a local anesthetic with a different lipid solubility, potency, rate of metabolism, and duration of action (Table 10-1). Substituting a butyl group for the amine group on the benzene ring of procaine results in tetracaine. Compared with procaine, tetracaine is more lipid soluble, is 10 times more potent, and has a longer duration of action corresponding to a 4- to 5-fold decrease in the rate of metabolism. Halogenation of procaine to chloroprocaine results in a 3- to 4-fold increase in the hydrolysis rate of chloroprocaine by plasma cholinesterase. This rapid hydrolysis rate of chloroprocaine limits the duration of action and systemic toxicity of this local anesthetic. Etidocaine resembles lidocaine, but substituting a propyl group for an ethyl group at the amine end and adding an ethyl group on the alpha carbon of the connecting hydrocarbon chain produces a 50-fold increase in lipid solubility and a 2- to 3-fold increase in the duration of action. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

The spread and depth of spinal and epidural anesthesia in pregnant women is A. Decreased B. Increased C. Changed D. Varies on the LA

B. Increased - The use of local anesthetics in pregnancy deserves some special pharmacokinetic and pharmacodynamic consideration. - Clinical observations and studies both indicate that the spread and depth of spinal and epidural anesthesia are increased in pregnant women. - Spread of neuraxial anesthesia increases during pregnancy as a result of decreases in thoracolumbar cerebral spinal fluid (CSF) volume and increased neural susceptibility to local anesthetic. - At first this was thought to be the result of only mechanical factors produced by a gravid uterus. - For example, mechanical factors result in dilation of epidural veins, which leads to narrowing of the epidural and subarachnoid space, thereby reducing the dose requirement. - However, hormonal changes appear to also play a role because there is a greater segmental spread of local anesthetics administered in the epidural space during the first trimester of pregnancy when little compression is evident. - A relationship appears to exist between the progesterone level in CSF and an increased segmental spread and sensitivity of nerves to these drugs.

Which of the following is not an ester local anesthetic A. Procaine B. Lidocaine C. Cocaine D. Benzocaine

B. Lidocaine - Chemically the major difference among local anesthetics is in their ester or an amide linkage that binds the aromatic ring to the amine group. - This linkage is responsible for the classification of these drugs as either esters or amides. The type of linkage is important clinically because it has implications for metabolism, duration, and allergic potential - An easy method for remembering which chemical class a local anesthetic falls into is that the esters have one letter i in their generic name and the amides have two. - The chemical structures are important in determining the pharmacologic effects of these drugs. - Minor chemical alterations to drugs within these two "bond-related" groups can result in significant changes in drug potency, speed of onset, duration of action, and potential for producing differential block

This LA is implicated with the development of CES and TNS and postoperative pain when given as spinal anesthesia A. Prilocaine B. Lidocaine C. Bupivacaine D. Ropivacaine

B. Lidocaine - Lidocaine has been associated with CES when used for continuous spinal anesthesia, and it is no longer used in this anesthetic technique in the United States. - Single dose spinal administration of lidocaine has also been implicated in TNS, which results in back and lower extremity pain for up to 5 days postoperatively. No permanent problems occur. - Symptoms include a burning, aching, cramplike and radiating pain in the anterior and posterior aspect of the thighs. - Pain radiates to the lower extremities, and lower back pain is common. Other anesthetics have been implicated, but it is much more prevalent following spinal lidocaine. - Surgical positioning may be a factor as well. - The exact mechanism is unclear. - Newer techniques and agents other than lidocaine are being used now and this has diminished this problem as a clinical issue. - Treatment is supportive and should include nonsteroidal antiinflammatory agents when possible.

Which of the following is not considered as pipecoloxylidides A. Mepivacaine B. Lidocaine C. Ropivacaine D. Ropivacaine

B. Lidocaine - Mepivacaine, bupivacaine, and ropivacaine are characterized as pipecoloxylidides (see Fig. 10-2). Mepivacaine has a methyl group on the piperidine nitrogen atom (amine end) of the molecule. Addition of a butyl group to the piperidine nitrogen of mepivacaine results in bupivacaine, which is 35 times more lipid soluble and has a potency and duration of action 3 to 4 times that of mepivacaine. Ropivacaine structurally resembles bupivacaine and mepivacaine, with a propyl group on the piperidine nitrogen atom of the molecule. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Procaine has low potency and has a short duration of action with a slow onset. Which of the following pharmacokinetic properties is true A. High lipophilicity B. Low protein binding C. Basic drug with an even pKa than the body D. Water insoluble

B. Low protein binding

To prevent LAST body weight as a guide for dosing should be applied for A. Obstetrics B. Pediatrics C. Geriatrics D. All of the above

B. Pediatrics - Adaption of suggested safety steps such as the use of test doses, incremental injection with frequent aspiration, and the use of pharmacologic markers such as epinephrine or fentanyl have lowered the incidence of LAST in recent years. - Additional practices that have been suggested to improve safety include limiting the total dose of local anesthetic by restricting the use of 0.75% bupivacaine in obstetrics. - The clinical principle in any regional technique is to use the lowest dose possible (the product of the concentration and volume) to produce a satisfactory block. - The use of generalized maximum recommended doses has been questioned. - Systemic blood levels of the same dose of anesthetic vary greatly depending on the area of blockade, technique, and specific drug. - Blood levels are difficult to predict when dosing on a milligram per kilogram basis. - Body weight as a guide should be used only in pediatric patients. - The use of ultrasound-guided techniques has been evaluated with regards to improved patient safety. - Evidence supports the concept that ultrasound guidance is effective in reducing the incidence of local anesthetic systemic toxicity. - There is also a lower predicted frequency of pneumothorax. Ultrasound guidance does not affect the incidence of peripheral nerve injury associated with regional anesthesia. - There is a reduced incidence and intensity of hemidiaphragmatic paresis with ultrasound-guided supraclavicular blocks.

Local anesthetics are __________ soluble in water A. Highly B. Poorly

B. Poorly - Local anesthetics are poorly soluble in water and therefore are marketed most often as water-soluble hydrochloride salts. These hydrochloride salt solutions are acidic (pH 6), contributing to the stability of the local anesthetic. An acidic pH is also important if epinephrine is present in the local anesthetic solution, because this catecholamine is unstable at an alkaline pH. Sodium bisulfite, which is strongly acidic, may be added to commercially prepared local anesthetic-epinephrine solutions (pH 4) to prevent oxidative decomposition of epinephrine. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Ion that is determinant of the resting membrane potential in the axon A. Sodium B. Potassium C. Calcium D. Chloride

B. Potassium - Although the membrane is relatively permeable to the outward diffusion of K+, an intracellular-to-extracellular K+ ratio of 150 : 5 mmol, or 30:1, exists. - An important contributor to this concentration difference is the impermeability of the membrane to other cotransported ions such as Na+. - In addition, the movement of K+ out of the neuron leaves an excess of intracellular negatively charged organic ions. - The negative charge results in an electrostatic counterforce that limits K+ movement out of the neuron. - Two opposing forces influence K+ movement into and out of the neuron. First, a concentration gradient pushes K+ outward. - Second, an electrostatic gradient, created by the impermeability of the membrane to cations, tends to keep the K+ in the cell. - The net effect of these counterforces is modest movement of K+ out of the cell, and this movement creates an intracellular negative charge. The Nernst equation expresses the charge created by the K+ concentration gradient - Determination of the resting membrane potential is not as simple as the Nernst equation for K+ indicates, because Na+ and chloride (Cl−) ions have a minor role in establishing the intracellular resting potential.

The phenomenon where action potentials jump from node to node A. Transduction B. Saltatory conduction C. Transcription D. Nerve conduction

B. Saltatory conduction - Action potentials jump from node to node, and this phenomenon is known as saltatory conduction, which significantly facilitates conduction speed along the axon. - Myelinated nerves are larger, conduct impulses faster, and are more difficult to block with local anesthetics than are unmyelinated nerves

Which state does LA to the Sodium channels bind A. activated-open B. inactivated-closed C. rested-closed

B. inactivated-closed - Sodium channels exist in activated-open, inactivated-closed, and rested-closed states during various phases of the action potential.18 Voltage-gated Na+ channels undergo fast and slow inactivation processes and this is critical for membrane excitability. The structural changes associated with the inactivation process are poorly understood.19 In the resting nerve membrane, sodium channels are distributed in equilibrium between the rested-closed and inactivated-closed states. By selectively binding to sodium channels in inactivated-closed states, local anesthetic molecules stabilize these channels in this configuration and prevent their change to the rested-closed and activated-open states in response to nerve impulses. Sodium channels in the inactivated-closed state are not permeable to sodium, and thus conduction of nerve impulses in the form of propagated action potentials cannot occur. It is speculated that local anesthetics bind to specific sites located on the inner portion of sodium channels (internal gate or H gate) as well as obstructing sodium channels near their external openings to maintain these channels in inactivated-closed states.14 This binding appears to be weak and to reflect a relatively poor fit of the local anesthetic molecule with the receptor. This is consistent with the broad variety of chemical structures that exhibit local anesthetic activity on sodium channels (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Which of the following LA comes in a sustained release formulation as a liposome injection A. Ropivacaine B. Lidocaine C. Bupivacaine D. Tetracaine

C. - A sustained-release formulation of the local anesthetic bupivacaine that does not require an indwelling catheter to achieve a long duration of action is available. - Bupivacaine extended-release liposome injection, Exparel, consists of bupivacaine encapsulated in DepoFoam. - It provides continuous and extended postsurgical analgesia for up to 72 hours.153 It is marketed as a 20 mL single use vial, 1.3% (13.3 mg/mL). - The maximum dosage should not exceed 266 mg (20 mL, 1.3% of undiluted drug). - It is indicated for single-dose administration into the surgical site to produce postsurgical analgesia.

Which of the following does not happen when EMLA cream is applied to an abnormal skin such as in psoriasis and eczema A. Faster absorption B. Higher Plasma levels C. Duration is longer D. Duration is shorter

C. - When EMLA is applied to areas of abnormal skin (e.g., where psoriasis or eczema is present), absorption is faster, plasma levels are higher, and the duration of anesthesia is shorter.

Which of the following should not be observed to reduce the risk of Cauna Equina Syndrome A. Initial dosing or redosing of subarachnoid local anesthetic in addition, maldistribution (usually sacral) of local anesthetic spread should be ruled out before redosing single-injection or continuous subarachnoid blocks B. The risks and benefits of neuraxial techniques should be considered in patients known to have moderate-to-severe spinal stenosis, especially if within the vertebral territory of the intended injection (Class II). C. The incidence of TNS after 40 to 50 mg intrathecal 2-chloroprocaine seems to be remarkably high. The number of 2-chloropocaine spinal anesthetics reported in the literature is insufficient to determine the risk for CES or other manifestations of neurotoxicity (Class III). D. Physically and temporally separate disinfectant use from block trays and instruments during neuraxial procedures. Allow the solution to completely dry on skin before needle placement (2-3 min).

C. American Society of Regional Anesthesia Recommendations for Minimizing Cauda Equina Syndrome - These recommendations are intended to encourage optimal patient care but cannot ensure the avoidance of adverse outcomes. As with any practice advisory recommendation these are subject to revision as knowledge advances regarding specific complications. • Initial dosing or redosing of subarachnoid local anesthetic in addition, maldistribution (usually sacral) of local anesthetic spread should be ruled out before redosing single-injection or continuous subarachnoid blocks (Class I). • The risks and benefits of neuraxial techniques should be considered in patients known to have moderate-to-severe spinal stenosis, especially if within the vertebral territory of the intended injection (Class II). • The incidence of TNS after 40 to 50 mg intrathecal 2-chloroprocaine seems to be remarkably low. The number of 2-chloropocaine spinal anesthetics reported in the literature is insufficient to determine the risk for CES or other manifestations of neurotoxicity (Class III). • Physically and temporally separate disinfectant use from block trays and instruments during neuraxial procedures. Allow the solution to completely dry on skin before needle placement (2-3 min). Care should be taken to avoid needle or catheter contamination from chlorhexidine spraying or dripping, or from applicator device disposal, onto aseptic work surfaces (Class II).

Which of the following are clinical clues to the diagnosis of methemoglobinemia A. Hypoxia that does not improve with increased fraction of inspired oxygen (FiO2). B. Abnormal coloration of blood. C. Physiologically inappropriate partial pressure of arterial oxygen (PaO2) on blood gas sample with low pulse oximeter saturation—"saturation gap". D. New-onset cyanosis and/or hypoxia after ingestion of an agent with oxidative properties.

C. Clinical Clues to the Diagnosis of Methemoglobinemia in the Anesthetized Patient 1. Hypoxia that does not improve with increased fraction of inspired oxygen (FiO2). 2. Abnormal coloration of blood. 3. Physiologically appropriate partial pressure of arterial oxygen (PaO2) on blood gas sample with low pulse oximeter saturation—"saturation gap". 4. New-onset cyanosis and/or hypoxia after ingestion of an agent with oxidative properties.

What does carbonation do to the speed of onset and intensity of block A. Increases onset and decreases intensity of block B. Decreases onset and decreases intensity of block C. Increases onset and increases intensity of block D. Decreases onset and increases intensity of block

C. - Local anesthetics have been carbonated to speed onset. In isolated nerve preparations, carbonation gives a more rapid onset and greater intensity of block. - Diffusion of carbon dioxide through the nerve membrane can lower the intracellular pH. When local anesthetics accompany this process, they become more ionized within the neuron; this results in an increase in the concentration of the drug in the ionized form at the intracellular binding site. - Controversy exists concerning whether carbonation improves onset time in the in vivo situation. - Separate double-blind studies of lidocaine and bupivacaine have failed to yield positive results. - This inconsistency may exist because the injected carbon dioxide is rapidly buffered in vivo, so intracellular pH is not greatly affected. - This practice has been largely abandoned in modern clinical practice.

Which of the following si not a characteristic segment of a local anesthetic A. An intermediate ester or amide carbon group separates B. An unsaturated aromatic ring system C. A saturated aromatic ring system D. An amine end

C. - The local anesthetics used clinically for neural blockade are aminoesters or aminoamides and are similar in chemical structure. - In general, these drugs have three characteristic segments: - (1) an intermediate ester or amide carbon group separates - (2) an unsaturated - (aromatic) ring system from (3) an amine end. - The aromatic ring provides lipophilic characteristics, whereas the tertiary/quaternary amine gives hydrophilicity to the molecule. - The amine portion is able to become ionized in physiologic pH and thus hydrophilic.

How long should one observe for potential LAST if a patient received a potentially toxic dose of LA A. 1 hour B. 15 minutes C. 30 minutes D. 3 hours

C. 30 minutes • The timing of LAST presentation is variable. Immediate (less than 60 sec) presentation suggests intravascular injection of local anesthetic (LA) with direct access to the brain, whereas presentation that is delayed 1 to 5 minutes suggests intermittent or partial intravascular injection, delayed circulation time, or delayed tissue absorption. Because LAST can present more than 15 minutes after injection, patients who receive potentially toxic doses of LA should be closely monitored for at least 30 minutes after injection. • Classic descriptions of LAST depict a progression of subjective symptoms of central nervous system (CNS) excitement (e.g., agitation, auditory changes, metallic taste, or abrupt onset of psychiatric symptoms) followed by seizures or CNS depression (e.g., drowsiness, coma, or respiratory arrest). Near the end of this continuum, initial signs of cardiac toxicity (e.g., hypertension, tachycardia, or ventricular arrhythmias) are supplanted by cardiac depression (e.g., bradycardia, conduction block, asystole, decreased contractility). However, there is substantial variation in this classic description, including the following: • Simultaneous presentation of CNS and cardiac toxicity • Cardiac toxicity without prodromal signs and symptoms of CNS toxicity • Thus the practitioner must be vigilant for atypical or unexpected presentation of LAST. • Case reports associate LAST with underlying cardiac, neurologic, pulmonary, renal, hepatic, or metabolic disease. Heightened vigilance is warranted in these patients, particularly if they are at the extremes of age. • The overall variability of LAST signs and symptoms, timing of onset, and association with various disease states suggests that practitioners should maintain a low threshold for considering the diagnosis of LAST in patients with atypical or unexpected presentation of CNS or cardiac signs and symptoms after receiving more than a minimal dose of LA.

These are more readily blocked by local anesthetics than any fiber, even though these fibers are myelinated. A. A-d fibers B. C fibers C. B fibers

C. B fibers - Peripheral nerves are composed of myelinated A and B fibers and unmyelinated C fibers. A minimal length of myelinated nerve fiber must be exposed to an adequate concentration of local anesthetic for conduction blockade of nerve impulses to occur. For example, if only one node of Ranvier is blocked (site of change in sodium permeability), the nerve impulse can jump (skip) across this node and conduction blockade does not occur. For conduction blockade to occur in an A fiber, it is necessary to expose at least two and preferably three successive nodes of Ranvier (approximately 1 cm) to an adequate concentration of local anesthetic. Both types of pain-conducting fibers (myelinated A-δ and unmyelinated C fibers) are blocked by similar concentrations of local anesthetics, despite the differences in the diameters of these fibers. Preganglionic B fibers are more readily blocked by local anesthetics than any fiber, even though these fibers are myelinated. - Differential conduction blockade is illustrated by selective blockade of preganglionic sympathetic nervous system B fibers using low concentrations of local anesthetics. Slightly higher concentrations of local anesthetics interrupt conduction in small C fibers and small- and medium-sized A fibers, with loss of sensation for pain and temperature. Nevertheless, touch, proprioception, and motor function are still present such that the patient will sense pressure but not pain with surgical stimulation. In an anxious patient, however, any sensation may be misinterpreted as failure of the local anesthetic. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

Which of the following LA is most associated to the development of LAST A. Lidocaine B. Cocaine C. Bupivacaine D. Ropivacaine

C. Bupivacaine - With respect to the extent of compromise, the type of local anesthetic plays a role. Shorter-acting lidocaine is less cardiotoxic than the longer-acting and more potent bupivacaine. - Most reported deaths related to LAST involve bupivacaine. The difference between short-acting and longer-acting agents may be related to their physical properties. - The more potent agents are more lipid soluble and protein bound. As such, the duration of blockade of any voltage-gated channel is probably longer and thus the recovery is delayed. - The newer agents ropivacaine and levobupivacaine were developed to address this issue of cardiotoxicity. These agents are accepted as safer; however, care should be taken when using large doses of any local anesthetic.

These fibers conduct pain and temperature impulses and are the smallest of all fibers (0.3 µm to 1.3 µm) and have the slowest speed of conduction. These are the only fibers that are unmyelinated. Functions in the postganglionic vasomotor A. A fiber B. B fiber C. C fiber D. D fiber

C. C fiber - The C fibers, which conduct pain and temperature impulses, are the smallest of all fibers (0.3 µm to 1.3 µm) and have the slowest speed of conduction. These are the only fibers that are unmyelinated. - Subsequent isolated studies on the small, unmyelinated C fibers revealed that they were more resistant to blockade than the larger A delta or B fibers.

Which of the following is a late symptom of LAST A. Seizure B. Tinnitus C. Cardivascular depression D. Unconsciousness

C. Cardiovascular depression - The classic typical clinical presentation of LAST is a progression of subjective symptoms of CNS excitation such as agitation, tinnitus, circumoral numbness, blurred vision, and a metallic taste followed by muscle twitching, unconsciousness, and seizures and with very high drug levels, cardiac and respiratory arrest - The sequence occurs because the inhibitory pathways in the brain are affected first, leaving unopposed excitation. This is sometimes referred to as disinhibition. - As the blood (therefore brain) levels increase, the more resistant excitatory pathways are inhibited, leading to unconsciousness and coma. - This was the presentation in approximately 60% of cases, although the types of CNS symptoms varied greatly. - An atypical presentation was evident in approximately 40% of the patients. This was defined as LAST that is delayed for more than 5 minutes or with isolated cardiovascular symptoms alone. - Most of the atypical presentations were for delayed symptoms.

The minimum concentration of local anesthetic necessary to produce conduction blockade of nerve impulses is termed A. MAC B. MEC C. Cm

C. Cm - The minimum concentration of local anesthetic necessary to produce conduction blockade of nerve impulses is termed the Cm. The Cm is analogous to the minimum alveolar concentration (MAC) for inhaled anesthetics. Nerve fiber diameter influences Cm, with larger nerve fibers requiring higher concentrations of local anesthetic for production of conduction blockade. An increased tissue pH or high frequency of nerve stimulation decreases Cm. Each local anesthetic has a unique Cm, reflecting differing potencies of each drug. The Cm of motor fibers is approximately twice that of sensory fibers; thus, sensory anesthesia may not always be accompanied by skeletal muscle paralysis. Despite an unchanged Cm, less local anesthetic is needed for subarachnoid anesthesia than for epidural anesthesia, reflecting greater access of local anesthetics to unprotected nerves in the subarachnoid space. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

What does the addition of sodium bicarbonate do with LA pharmacokinetics A. Increase potency B. increase duration of action C. Hasten onset of action D. Decrease systemic absorption

C. Hasten onset of action - The addition of sodium bicarbonate to local anesthetics is widely used in epidural anesthesia to speed onset of sensory and motor block. - The effects of the addition of sodium bicarbonate to peripheral blocks is unclear. - In theory the mechanism is that addition of bicarbonate increases the pH of the local anesthetic solution resulting in the presence of more drug in the nonionized state. - Studies done with bupivacaine and lidocaine have indicated that this alteration does facilitate the onset and prolong duration of action. - Other researchers, however, have noted variable effects on onset and duration depending on whether epinephrine was contained in the solution. - The major limitation to the addition of bicarbonate is the precipitation that can occur in the local anesthetic solution. It also should be noted that the amount of bicarbonate that can be added without precipitation depends on whether the epinephrine is commercially or "freshly" mixed.59 Manufacturers acidify local anesthetic solutions to increase solubility and stability (the free base is more susceptible to photodegradation and aldehyde formation), which results in a longer shelf-life. For example, the pH range of plain lidocaine is 6.5 to 6.8, compared with 3.5 to 4.5 for preparations that contain epinephrine. The lower pH is used with epinephrine because of the instability of this compound in alkaline solutions. Another benefit of alkalization is that it may result in less pain or stinging on injection. The mechanism of action for this effect could be more complex than just an increase in pH. It may be that the nociceptive nerve fibers may not be as sensitive to the nonionized form of the drug. It also is possible that the nonionized drug diffuses so rapidly through the tissue and axolemma that a sensory block occurs almost instantaneously.

Na channel receptors have greater affinity to which type or form of the local anesthetics A. Nonionized B. Lipophilic C. Ionized D. Hydrophobic

C. Ionized - Local anesthetics block the propagation of the action potential by binding reversibly to specific receptors within or adjacent to the internal opening of the Nav channel. - Studies have indicated that these receptors, located on the intracellular side of the cell membrane, have a greater affinity for the charged or ionized form of the local anesthetics. - The uncharged or nonionized portion of the local anesthetic must first penetrate the cell membrane entering the axoplasm before they produce their effects.

This is the LA to which all other LA is compared A. Cocainde B. Procaine C. Lidocaine D. Bezocaine

C. Lidocaine - Karl Koller introduced cocaine as the first local anesthetic in 1884, for use in ophthalmology. Halsted recognized the ability of injected cocaine to interrupt nerve impulse conduction, leading to the introduction of peripheral nerve block anesthesia and spinal anesthesia. Cocaine (an ester of benzoic acid) is present in large amounts in the leaves of Erythroxylon coca, a plant growing in the Andes Mountains, where its cerebral-stimulating qualities are well known. Another unique feature of cocaine is its ability to produce localized vasoconstriction, making it useful to shrink the nasal mucosa in rhinolaryngologic procedures and nasotracheal intubation. The first synthetic local anesthetic was the ester derivative procaine, introduced by Einhorn in 1905. Lidocaine was synthesized as an amide local anesthetic by Lofgren in 1943. It produces more rapid, intense, and longer-lasting conduction blockade than procaine. Unlike procaine, lidocaine is effective topically and is a highly efficacious cardiac antidysrhythmic drug. For these reasons, lidocaine is the standard to which all other anesthetics are compared. (Flood) Flood, Pamela, James Rathmell, Steven Shafer. Stoelting's Pharmacology and Physiology in Anesthetic Practice, 5th Edition. Wolters Kluwer Health, 20150204. VitalBook file.

The patient is exhibiting cyanotic skin discoloration as well as tachycardia and lightheadedness after receiving LA. Which of the following conditions is most likely A. LAST B. Allergic reaction C. Methemoglobinemia D. Cauna Equina Syndrome

C. Methemoglobinemia - Methemoglobinemia is a disorder characterized by high concentrations of methemoglobin (MetHb) in the blood, which can lead to tissue hypoxia. - The ferrous form of hemoglobin (Fe2+) is oxidized to the ferric form (Fe3+). - Methemoglobin is an oxidized form of hemoglobin with reduced capacity to carry oxygen, which causes a shift to the left of the oxygen-hemoglobin dissociation curve. - Normal methemoglobin levels are less than 1%. - Decreasing oxygen saturation via pulse oximetry, which is unresponsive to oxygen supplementation, may occur. - Clinical clues to the diagnosis of methemoglobinemia in the anesthetized patient are noted in - It can be diagnosed by CO-oximetry, laboratory testing, or implied by symptoms. - Medications are the most common cause of MetHb in clinical practice, and of these local anesthetics (benzocaine and procaine), antibiotics (dapsone), and nitrites (nitroglycerin/nitric oxide) are the most common.

What is the term that is Between Schwann cells that are periodic segments of nerve that do not contain myelin A. Unmyelinated sheath B. Nuerilemma C. Node of Ranvier D. Axon

C. Node of Ranvier - Between Schwann cells are periodic segments of nerve that do not contain myelin. These areas, known as nodes of Ranvier, are where conduction is propagated. - Voltage-gated sodium channels (Nav) are located in these nonmyelinated segments and are the primary site at which local anesthetics exert their action. - Action potentials jump from node to node, and this phenomenon is known as saltatory conduction, which significantly facilitates conduction speed along the axon. - Myelinated nerves are larger, conduct impulses faster, and are more difficult to block with local anesthetics than are unmyelinated nerves

Which of the following is not an amide A. Prilocaine B. Bupivacaine C. Tetracaine D. Ropivacaine

C. Tetracaine Ester and Amide Local Anesthetics Esters Procaine Chloroprocaine Tetracaine Cocaine Benzocaine Amides Lidocaine Mepivacaine Prilocaine Bupivacaine Ropivacaine Articaine

When lipid emulsions are being given to reverse LAST, which of the following should not be given during ACLS resuscutation A. Epinephrine B. Sodium Bicarbonate C. Vasopressin D. Amiodarone

C. Vasopressin - Prompt recognition and treatment are essential to minimizing adverse outcomes of LAST. Airway management remains the primary intervention because preventing hypoxia and acidosis are essential first steps. - Acidosis may enhance toxicity by ion trapping local anesthetic in the brain. - Seizure suppression is essential to facilitate immediate airway control and prevent or reduce metabolic acidosis. - Benzodiazepines are considered the drugs of choice because they are anticonvulsant without causing significant cardiac depression. - When benzodiazepines are not available, small doses of propofol may be appropriate. - Succinylcholine may be useful to suppress intractable seizure-induced tonic-clonic muscle activity in spite of the lack of CNS effects. - Cardiovascular support is essential to maintaining adequate coronary perfusion. The local anesthetics do not irreversibly damage the cardiac cells. - Avoiding tissue hypoxia is essential in reversing the progression of toxic cardiac events. - Local anesthetic cardiotoxicity, especially with bupivacaine, involves both electrophysiologic disturbances and depression of contractility. - The electrical disturbances appear to occur at lower doses and are more contributory to poor outcomes than contractile depression, but differences among specific local anesthetics exist. - Lipid emulsion therapy is recommended as a standard part of LAST resuscitation. - There is some evidence that it is able to restore spontaneous circulation without the use of vasopressors. - In fact, large doses of vasopressors may decrease the effectiveness of lipid emulsions. - Vasopressors may be required to maintain adequate blood pressure, but they can worsen local anesthetic-induced arrhythmias. - Small doses of epinephrine, less than 1 mcg/kg, are recommended. - Vasopressin should be avoided even though it is now part of Advanced Cardiac Life Support guidelines.

Which A fiber has the smallest diameter (1 µm to 5 µm) and slower conduction velocity than other A fibers. A. Alpha B. Beta C. Gamma D. Delta

D. - The A delta fibers provide pain and temperature sensation. These fibers have a smaller diameter (1 µm to 5 µm) and slower conduction velocity than other A fibers. The beta, gamma, and delta fibers are all myelinated to a similar extent.

Which of the following is false with regards to the use of epinephrine as an intravascular marker A. Intravascular injection of epinephrine 10 to 15 mcg/mL in adults produces a 10-beat or greater heart rate increase, or a 15 or greater mm Hg systolic blood pressure (SBP) increase in the absence of β blockade, active labor, advanced age, or general/neuraxial anesthesia. B. Intravascular injection of epinephrine 0.5 mcg/kg in children produces a 15 or greater mm Hg increase in SBP. C. Appropriate subtoxic doses of local anesthetic can produce subjective symptoms of mild systemic toxicity (e.g., auditory changes, excitation, metallic taste) in unpremedicated patients. D. Midazolam 2mg produces sedation if injected intravascularly in laboring patients.

D. • When injecting potentially toxic doses of local anesthetic, use of an intravascular marker is recommended. Although epinephrine is an imperfect marker and its use is open to physician judgment, its benefits likely outweigh its risks in the majority of patients: • Intravascular injection of epinephrine 10 to 15 mcg/mL in adults produces a 10-beat or greater heart rate increase, or a 15 or greater mm Hg systolic blood pressure (SBP) increase in the absence of β blockade, active labor, advanced age, or general/neuraxial anesthesia. • Intravascular injection of epinephrine 0.5 mcg/kg in children produces a 15 or greater mm Hg increase in SBP. • Appropriate subtoxic doses of local anesthetic can produce subjective symptoms of mild systemic toxicity (e.g., auditory changes, excitation, metallic taste) in unpremedicated patients. • Fentanyl 100 mcg produces sedation if injected intravascularly in laboring patients. • There is no single measure that can prevent LAST in clinical practice. • Use the lowest effective dose of local anesthetic (dose = product of volume × concentration). • Use incremental injection of local anesthetics—administer 3 mL to 5 mL aliquots, pausing 15 to 30 seconds between each injection. • When using a fixed needle approach, for example, landmark paresthesia-seeking or electrical stimulation; time between injections should encompass one circulation time (approximately 30-45 sec); however, this ideal may be balanced against the risk of needle movement between injections. Circulation time may be increased with lower extremity blocks. Use of larger dosing increments would dictate the need for longer intervals to reduce the cumulative dose from stacked injections before an event of LAST. Incremental injection may be less important with ultrasound guidance given that frequent needle movement is often used with the technique. • Aspirate the needle or catheter before each injection, recognizing that there is approximately a 2% false-negative rate for this diagnostic intervention. • Ultrasound guidance may reduce the frequency of intravascular injection, but actual reduction of LAST remains unproven in humans. Individual reports describe LAST despite the use of ultrasound-guided regional anesthesia. The overall effectiveness of ultrasound guidance in reducing the frequency of LAST remains to be determined.

Which of the following statement is false A. Almost all clinically useful local anesthetics are tertiary amines and when injected will exist in both nonionized (lipid soluble) and ionized (water soluble) forms according to their particular pKa and the pH of the tissue or compartment they are in. B.. Local anesthetics must gain access to the interior of the neuron to reach their receptor. This occurs by the diffusion of the lipid soluble nonionized fraction across the cell membrane. C.. Once inside the neuron, a new equilibrium forms between ionized and nonionized fractions. The ionized fraction binds to the receptor on the inside of the Nav. D. Benzocaine is a secondary amine and thus is permanently nonionized or neutral. It penetrates the lipid bilayer and enters the axoplasm to inhibit the Na channels

D. - Almost all clinically useful local anesthetics (except benzocaine) are tertiary amines and when injected will exist in both nonionized (lipid soluble) and ionized (water soluble) forms according to their particular pKa (negative logarithm of the acid ionization constant), and the pH of the tissue or compartment they are in. - Local anesthetics must gain access to the interior of the neuron to reach their receptor. This occurs by the diffusion of the lipid soluble nonionized fraction across the cell membrane. - Once inside the neuron, a new equilibrium forms between ionized and nonionized fractions. The ionized fraction binds to the receptor on the inside of the Nav. - Benzocaine is a secondary amine and thus is permanently nonionized or neutral. It penetrates the lipid bilayer and can directly inhibit the Nav without entering the axoplasm first.

Which of the following is not a characteristic of an Amide LA A. Are metabolized in the liver by CYP1A2 and CYP3A4 and thus a significant blood level may develop with rapid absorption. B. Allergy to is extremely rare. C. Longer acting because they are more lipophilic and protein bound and require transport to the liver for metabolism D. Metabolism is catalyzed by plasma and tissue cholinesterase via hydrolysis; occurs throughout the body and is rapid.

D. - Amides are metabolized in the liver by CYP1A2 and CYP3A4 and thus a significant blood level may develop with rapid absorption. - Allergy to amides is extremely rare; there is no cross allergy among the amide class or between the ester and amide agents. - Amides are longer acting because they are more lipophilic and protein bound and require transport to the liver for metabolism

What determines the onset of action of an LA A. Lipophilicity B. Protein binding C. Size of the molecules D. Ionization

D. - How readily they diffuse through the nerve membrane depends on their chemical structure, lipid solubility, and state of ionization. - Of these, ionization is the most important because the charged or ionized form of a drug does not penetrate membranes well. - In other words, the more ionized a local anesthetic, the slower it will penetrate a nerve. -Local anesthetics are bases. The pKa of a drug is the pH at which 50% of the drug is in the charged or ionized, and water soluble form, whereas the remaining half is uncharged or nonionized, and lipid soluble. -A basic drug becomes predominantly ionized if it is placed in an environment with a pH that is significantly less than its pKa. - Therefore drugs that have a greater pKa are ionized to a greater extent at body pH than those with a lower pKa. For example, if lidocaine (pKa 7.74) is placed in plasma (pH 7.4), 65% of the drug is ionized, and 35% remains nonionized. - Similarly, if tetracaine (pKa 8.6) is placed in plasma, 95% of the drug becomes ionized, and 5% remains nonionized.29 - Because their ionization is less, local anesthetics with lower pKa (7.6 to 7.8), such as lidocaine, mepivacaine, and prilocaine tend to have a more rapid onset of action than drugs with a greater pKa (8.1 to 8.6), such as bupivacaine, tetracaine, and procaine. - Chloroprocaine is one exception; it has a high pKa but retains a rapid onset, probably because of the clinical use of high concentrations of the drug, which attenuates the ionization effect. In general, the closer the pKa is to pH 7.4, the more rapid the onset. - Some researchers downplay the role of pKa on onset. -They note that onset is slower the more lipid soluble the drug

Which of the following is not observed during ACLS with LAST A. Attenuation of epinephrine B. Avoidance of Vasopressine C. Avoidance of CCB, BB, and Na channel blockers D. Avoidance of Amiodarone

D. • If cardiac arrest occurs, we recommend standard advance cardiac life support with the following modifications: • If epinephrine is used, small initial doses (10 mcg to 100 mcg boluses in adults) are preferred. Administration should be preceded by initiation of intravenous lipid emulsion therapy. • Vasopressin is not recommended. • Avoid calcium channel blockers, β-adrenergic receptor blockers and sodium channel blockers. • If ventricular arrhythmias develop, amiodarone is preferred; treatment with local anesthetics (lidocaine or procainamide) is not recommended. • If signs and symptoms of LAST occur, prompt and effective airway management is crucial to preventing hypoxia and acidosis, which are known to potentiate LAST. • If seizures occur, they should be rapidly halted with benzodiazepines. If benzodiazepines are not readily available, small doses of propofol are acceptable. Future data may support the early use of lipid emulsion for treating seizures. • Although propofol can stop seizures, large doses further depress cardiac function; propofol should be avoided when there are signs of cardiovascular compromise. If seizures persist despite benzodiazepines, small doses of succinylcholine or similar neuromuscular blocker should be considered to minimize acidosis and hypoxemia. • Lipid emulsion therapy: • Consider administering at the first signs of LAST, after airway management. • Dosing Bolus 1.5 ml/kg over 1 min (100 mL in a 70 kg patient) followed by a continuous infusion at 15 ml/kg per hr. If persistent cardiovascular instability or deterioration after 5 minutes: Repeat the same bolus up to two further times. Double the infusion rate to 30 ml/kg per hr. Continue infusion for 10 min after return of cardiovascular stability Maximum 30 min cumulative dose of 10 ml/kg. • Propofol is not a substitute for lipid emulsion. • Failure to respond to lipid emulsion and vasopressor therapy should prompt institution of cardiopulmonary bypass. Because there can be considerable lag in beginning cardiopulmonary bypass, it is reasonable to notify the closest facility capable of providing it when cardiovascular compromise is first identified during an episode of LAST..

Bupivacaine is high potency and has long duration with a slow onset. Which of the following properties contradicts its pharmacokinetics A. High lipophilicity B. High protein binding C. Basic drug with a higher pKa than the body D. Basic drug with an even pKa than the body

D. Basic drug with an even pKa than the body

Which of the following is the most common CVS sign of LA toxicity A. Vtach/ Vfib B. Hypotension C. Tachycardia D. Bradycardia/ Asystole

D. Bradycardia/ Asystole

The patient started developing bowel and bladder dysfunction with bilater lower extremity weaknes and sensory impairment after LA. Which of the following should be suspected A. LAST B. Allergic reaction C. Methemoglobinemia D. Cauna Equina Syndrome

D. Cauna Equina Syndrome - Cauda equina syndrome (CES) manifests as bowel and bladder dysfunction with various degrees of bilateral lower extremity weakness and sensory impairment. - There are multiple causes for CES, ranging from neural element compression from hematoma, abscess, or herniated intervertebral discs, to poorly understood presentations associated with normal clinical settings. - Known risk factors for anesthetic-related CES are supernormal doses of intrathecal local anesthetic and/or the maldistribution of local anesthetic spread within the intrathecal space. - Cases of CES have been associated with previously undiagnosed spinal stenosis. In theory, a tight spinal canal may lead to pressure-induced spinal cord ischemia, or limit normal local anesthetic distribution within the intrathecal sac thereby exposing the cauda equina to high drug concentrations. - Either of these conditions could promote local anesthetic neurotoxicity and could be exacerbated by additional compromise of the spinal canal, as may occur with nonneutral surgical positioning - Past formulations of chloroprocaine were reported to produce prolonged CES when large doses were given by inadvertent intrathecal injection. - The neurotoxicity was thought to be caused by a combination of large intrathecal doses, low pH, and the preservative sodium metabisulfite. - Controversy remains as to whether transient neurologic symptoms (TNS) after spinal anesthesia are a form of local anesthetic neurotoxicity with the use of preservative free intrathecal 2-chloroprocaine. - Spinal 2-chloroprocaine remains off-label in the United States.

Which of the following is primarily metabolized in the liver A. Procaine B. Lidocaine C. Cocaine D. Chloroprocaine

D. Chloroprocaine - Metabolism of the amide local anesthetics occurs primarily in the liver predominantly by microsomal cytochrome P-450 enzymes CYP1A2 and CYP3A4 - Plasma cholinesterase catalyzes the hydrolysis of ester local anesthetics.

This LA has the ability to block the monoamine transporter in adrenergic neurons. The neuronal transporter is responsible for the termination of the action of catecholamines. This catecholamine reuptake blockade results in significant vasoconstriction A. Prilocaine B. Bupivacaine C. Lidocaine D. Cocaine

D. Cocaine - Cocaine is derived from the coca plant and is the only naturally occurring local anesthetic. - Other unique properties include the ability to block the monoamine transporter in adrenergic neurons. The neuronal transporter is responsible for the termination of the action of catecholamines. - This catecholamine reuptake blockade results in significant vasoconstriction. - This action in the CNS also accounts for cocaine's analeptic actions. - It is used primarily for topical anesthesia of the nose and throat. A maximum of 5 mL of 4% solution or 200 mg should be used. -It is frequently administered with other epinephrine-containing preparations so arrhythmias, hypertension, and tachycardia may occur. - Caution is advised for possible drug interactions in patients taking other catecholamine-enhancing drugs such as tricyclic antidepressants or monoamine oxidase inhibitors.

Which of the following regional block technique is most often associated with LAST A. Axillary B. Interscalene C. Intrapleural D. Epidural

D. Epidural - The most common regional block techniques associated with LAST were epidural (33%), axillary (17%), and interscalene (13%). - Seventy-seven cases followed a single injection and 14 occurred with continuous infusion. - Two cases involved both continuous infusions with a supplementary single injection. - Of the continuous infusion cases, half were pediatric cases. - Fifty-two events were related to bupivacaine (55%), 28 to ropivacaine (30%), 4 to levobupivacaine (4%), and 9 were attributed to other local anesthetics (11%). - The patient characteristics were as follows: 63% female; 16% under 16 years old; 29% older than 60 years; five newborns receiving epidural anesthesia, and 37% of all patients had significant comorbidities such as diabetes, renal failure, or isovaleric acidemia.104 - The timing of the onset of symptoms after a single injection varied from 30 seconds to 60 minutes. - It is usually very rapid. In over half the cases, it happened in less than 50 seconds, and 75% of the cases occurred within 5 minutes of injection. - The onset of symptoms following continuous infusion occurred hours or days after starting the drug.

This drug is used as an adjunct to prolong the duration of action of the LA and prevent systemic toxic effects A. Ketorolac B. Clonidine C. Opioid D. Epinephrine

D. Epinephrine - The addition of a vasoconstrictor (e.g., epinephrine) to local anesthetics can reduce the rate of vascular absorption allowing more of the drug to stay in the local area where it was injected. The availability of the drug for neuronal uptake is increased resulting in a longer and more profound block. - Of importance, the slower rate of absorption also attenuates the peak plasma concentration of the drug, thereby reducing systemic toxicity. - The magnitude of this effect depends on the drug, dose, and concentration of both the local anesthetic and the vasoconstrictor, - in addition to the site of injection. For example, addition of epinephrine to mepivacaine prolongs the time to maximum arterial plasma drug concentration in all situations; however, adding epinephrine to a 2% solution used for an intercostal block has the greatest effect

According to ASRA, which of the following should be the first action when patient is suspected with LAST A. Infuse 20% lipid emulsions B. Administration with benzodiazepine C. Alert nearest facility with CPB capability D. Get help

D. Get help For patients experiencing signs or symptoms of local anesthetic systemic toxicity (LAST), the pharmacologic treatment of LAST is different from other cardiac arrest scenarios. • Get help. • Initial focus: • Airway management: ventilate with 100% oxygen. • Seizure suppression: benzodiazepines are preferred. • Basic and Advanced Cardiac Life Support (BLS/ACLS) will require adjustments of medications and perhaps prolonged effort. • Infuse 20% lipid emulsion (values in parenthesis are for a 70-kg patient). • Bolus 1.5 mL/kg (lean body mass) intravenously over 1 min (≈100 mL). • Continuous infusion at 0.25 mL/kg per min (≈18 mL/min; adjust by roller clamp) • Repeat bolus once or twice for persistent cardiovascular collapse. • Double the infusion rate of 0.5 mL/kg per min if blood pressure remains low. • Continue infusion for at least 10 min after attaining circulatory stability. • Recommended upper limit: approximately 10 mL/kg lipid emulsion over the first 30 min. • Avoid vasopressin, calcium channel blockers, β-blockers, or local anesthetic. • Reduce individual epinephrine doses to less than 1 mcg/kg. • Alert the nearest facility having cardiopulmonary bypass capability. • Avoid propofol in patients having signs of cardiovascular instability. • Post LAST events at www.lipidrescue.org and report use of lipid to www.lipidregistry.org.

Which of the following does not affect the efficacy and toxicity of an LA A. Vascularity and blood flow to the area B. Lipid and protein binding C. Addition of vasoconstrictors D. Hydrophilicity and ionization

D. Hydrophilicity and ionization - An important difference to note when describing the pharmacokinetics of local anesthetics is intuitive yet bears discussion. - Unlike most medications, these agents are meant to remain localized in the area of injection or application. - The higher the concentration (number of molecules) of drug injected that remain in the area of the nerve or nerves to be blocked, the faster the onset of action. - If multiple nerves are being blocked, a greater intensity may also be evident. - Therefore systemic absorption away from the deposition site results in the offset and termination of drug effect, rather than the onset as with most other drugs. - Factors that affect absorption, such as the vascularity and blood flow of the injection area, lipid and protein binding, and addition of vasoconstrictors, greatly influence duration of action. - The same local anesthetic dose and concentration injected in different areas of the body, with or without added epinephrine, can result in vastly different durations of action. - Absorption also influences toxicity. The slower a local anesthetic is systemically absorbed, the less likely that high blood levels and therefore central nervous system (CNS) or cardiac toxicity will result. - Drug metabolism and elimination more readily "keep up" with absorption, ensuring that toxic blood levels are avoided..

The after the patient received an epidural anesthesia of bupivacaine, the patient complained of ringing in the ears. Which of the following is the patient potentially experiencing A. Normal variance of LA B. Hypotension due to vasodilation C. Suppression of Vestibulococchlear nerve D. Local anesthesia Systemic Toxicity

D. Local anesthesia Systemic Toxicity Detection (Be Vigilant) • Use standard American Society of Anesthesiologists (ASA) monitors. • Monitor the patient during and after completing the injection, as clinical toxicity can be delayed up to 30 min or longer after tumescent procedures. • Consider LAST in any patient with altered mental status, neurologic symptoms, or cardiovascular instability following a regional anesthetic. • Central nervous system signs (may be subtle or absent): • Excitation (agitation, confusion, muscle twitching, seizure) • Depression (drowsiness, obtundation, coma, apnea) • Nonspecific (metallic taste, circumoral numbness, diplopia, tinnitus, dizziness) • Cardiovascular signs (often the only manifestation of severe LAST): • Initially may be hyperdynamic (hypertension, tachycardia, ventricular arrhythmias), then: • Progressive hypotension • Conduction block, bradycardia, or asystole • Ventricular arrhythmia (ventricular tachycardia, torsades de pointes, ventricular fibrillation) • Sedative hypnotic drugs reduce seizure risk, but even light sedation may abolish the patient's ability to recognize or report symptoms of rising LA concentrations.

Distribution of the LA is intially higher in which of the following A. Gut B. Lungs C. Brain D. Muscles

D. Muscles - The absorption or injection of local anesthetics into the systemic circulation results in rapid distribution throughout the body. Distribution results in a rapid decrease in the plasma concentration as the drug moves into highly perfused tissue. - Rapid distribution into the brain and heart can be a concern because this can lead to systemic toxicity. A secondary, slower disappearance follows, which reflects a combination of distribution into tissues with a more limited blood supply, drug metabolism, and excretion. - Although local anesthetics are distributed throughout the body, their concentration varies in different tissues. Immediately after vascular uptake, more greatly perfused tissues, such as the brain, heart, and lungs, receive more of these drugs than do less perfused tissues. - Once equilibration occurs, the local anesthetic leaves the highly perfused tissue and is deposited in tissue with less perfusion. - As with many drugs, as they redistribute in the body over time, muscle tissue receives the greatest amount of local anesthetic from redistribution. - The distribution process varies significantly with different local anesthetics. - For example, the disappearance rate of prilocaine is more rapid than that of mepivacaine or lidocaine. Ropivacaine also has a shorter half-life than bupivacaine. - Distribution of the ester local anesthetics is similar to the amides; however, their rate of metabolism in plasma is very rapid, resulting in much lower and shorter duration systemic plasma concentrations

Which of the following is not a mechanism of action of hyaluronidase to the LA A. Facilitates diffusion B. Limit acute increase IOP C. Reduce hematoma size D. Prolong duration of action

D. Prolong duration of action - The addition of hyaluronidase to local anesthetics as a spreading factor facilitates the diffusion of the drugs in tissues. - This additive accomplishes this effect via the hydrolysis of hyaluronic acid, which is a glycosaminoglycan found extensively in the interstitial matrix and basement membranes of tissue. - Hyaluronic acid is the main component of interstitial gel, which inhibits the spread of substances through tissue. - It is has long been used in ophthalmic blocks to improve quality, speed onset, limit the acute increase in intraocular pressure with periocular injections, and reduce the incidence of postoperative strabismus. - It has also been suggested that hyaluronidase reduces hematoma size if a needle that is used with the regional technique punctures a major blood vessel. -Other common uses are to facilitate the spread of fluids during hypodermoclysis and radiopaque agents in subcutaneous urography. - The addition of hyaluronidase can result in certain undesirable effects, such as the initiation of allergic reactions, a shortening of the duration of anesthetic action, and an increase in drug toxicity. - A new human recombinant product Hylenex is now available that may improve the safety profile. - Off-label use for cosmetic applications, to reduce edema, epidural adhesions, and chronic lower back pain have led to an increased interest in this agent

Which is the most commonst CNS sign of LA toxicity A. Agitation B. Dizziness C. Loss of consciousness D. Seizure

D. Seizure

True or False: Differential blocks can be explained in exact manner where unmyelinated C fibers being affected the greatest by the local anesthetics

False - It was first believed that nerve fiber diameter was the sole determinant of differential blockade. This assumption came from the results of isolated in vitro studies performed only on myelinated nerves. Subsequent isolated studies on the small, unmyelinated - C fibers revealed that they were more resistant to blockade than the larger A delta or B fibers.8 - This apparent inconsistency can possibly be explained by the concept of conduction safety. This concept refers to the voltage change needed for the propagation of the action potential along the nerve. This voltage change is significantly greater than the action potential threshold and provides a safety factor for impulse conduction. - Safety factor is the ratio between the magnitude of the action potential and the magnitude of the critical membrane potential. - Research has indicated that the margin of safety for transmission is greater in small, slow fibers than in large, fast fibers. - Lastly, differential block may be influenced by the rate of diffusion of local anesthetic molecules across multilayered lipoprotein membranes of the myelin sheath. - For example, the clinical resistance to blockade observed in A fibers may be the result of a slower onset resulting from a greater diffusion barrier. As discussed in more detail later, diffusion can be influenced by such factors as the pKa and the concentration of the local anesthetic, in addition to the pH of the surrounding tissue and nerve fiber..

True or False: There has been association between systemic toxicity and the use of LA for Local wound infiltration

False - Pain can be effectively alleviated with local anesthetics; however, their clinical usefulness is limited by their relatively short duration of action. - Even long-acting local anesthetics such as bupivacaine and ropivacaine have durations less than 8 to 16 hours. - Wound infiltration prior to closing is a common practice for immediate short-term postoperative pain relief. - Direct application of local anesthetic and opiate drugs via continuous infusion indwelling catheters provides long-term analgesia. - Wound catheters are commonly placed in the subcutaneous, fascial, intraarticular, pleural, and periosteal areas. - Local anesthetic systemic toxicity has not been reported. - Problems associated with the use of indwelling catheters are blockage or breakage, migration away from the intended area, and infection. When intraarticular bupivacaine is used in high concentrations for long periods, chondrotoxicity has been reported

True or False The addition of epinephrine decreases the peak plasma level of all local anesthetics

False - The addition of epinephrine does not attenuate the peak plasma level of all local anesthetics; for example, epinephrine significantly reduces the peak plasma concentration of lidocaine and mepivacaine regardless of the site of administration. - On the other hand, epinephrine does not significantly affect the peak plasma level of prilocaine or bupivacaine after epidural anesthesia. - The lack of effect seen with prilocaine may be explained by its slower absorption and rapid tissue redistribution. - In the case of bupivacaine, it may be explained by the significant lipid solubility and uptake in the epidural adipose tissue. - There is some controversy as to whether epinephrine may produce neurotoxicity when added to local anesthetics. - Some clinicians only recommend its use for nerve blocks done without ultrasound guidance or where the needle tip and local anesthetic spread are not adequately visualized as a safety measure to detect intravascular injection. - Studies that have compared vasoconstrictors conclude that epinephrine is superior to drugs such as phenylephrine and norepinephrine in producing vasoconstriction with local anesthetics. - The usual concentration of epinephrine used for this purpose is 1:200,000 or 5 mcg/mL.

Order the following according to the rate of absorption A. Intracaudal B. Intrapleural C. Intercostal D. Subcutaneous E. Epidural F. Brachial Plexus G. Sciatic-Femroal

Greatest absorption to least absorption: 1. B. Intrapleural 2. C. Intercostal 3. A. Intracaudal 4. E. Epidural 5. F. Brachial-Plexus 6. G. Sciatic-Femoral 7. D. Subcutaneous - The speed of absorption and entry of the local anesthetic into the systemic circulation obviously has significant implications for toxicity. - Absorption of drugs generally occurs in the following order of rapidity: interpleural blocks greater than intercostal greater than caudal greater than epidural greater than brachial plexus greater than sciatic-femoral and subcutaneous blocks. - Thus blood levels measured after an interpleural block will be higher with a greater potential for toxicity than with a subcutaneous block.

True or False: Epinephrine does not prolong the duration of blockade to the same extent with all local anesthetics.

True - For example, it prolongs the duration for local infiltration, peripheral nerve block, and epidural anesthesia with procaine, mepivacaine, and lidocaine. - Research indicates that adding epinephrine to lidocaine solutions increases the intensity and duration of block. - The early increase in intensity is not matched with an increase in intraneural lidocaine content at these early times, although the prolonged duration of block by epinephrine appears to correspond to an enlarged lidocaine content in a nerve at later times, as if a very slowly emptying "effector compartment" received a larger share of the dose. - The increase in early analgesia without increased lidocaine content may be explained by a pharmacodynamic action of epinephrine that transiently enhances potency of lidocaine, but also by a pharmacokinetic effect that alters the distribution of the same net content of lidocaine within the nerve. - In the case of prilocaine and bupivacaine, infiltration and peripheral nerve blocks are prolonged with epinephrine, whereas no significant effect occurs with epidural anesthesia. - The rationale for this discrepancy might be that epidural fat significantly absorbs ropivacaine and bupivacaine because of their high lipid solubility. - These drugs are released slowly from the fat deposit, which could prolong the block. - This process overrides the effects of epinephrine on duration of action. In addition, the drug concentration can contribute to the differential effect seen with epinephrine. - For example, epinephrine can prolong epidural blocks with 0.125% or 0.25% bupivacaine when used in patients in labor.50,51 Conversely, epinephrine has less effect with the epidural administration of 0.5% or 0.75% bupivacaine

True or False: Local anesthetics have antimetastatic effects

True - It has been suggested after several small retrospective studies that regional or local anesthesia may improve patient survival and the disease free interval after cancer surgery. - A number of prospective randomized controlled trials are ongoing, which may clarify this possible action. - The potential mechanisms of the antimetastatic effects include both direct and indirect effects of local anesthetics. - Direct effects include interference with tumor promoting pathways, and direct toxic effects on tumors when used for local infiltration. - Indirect effects result from a reduction of the perioperative stress response and the preservation of the immune response.

True or False Aside from voltage ligand receptors, local anesthetics also affect G-protein couple receptors

True - Local anesthetics have additional effects on G-protein-coupled receptors affecting intracellular calcium signaling pathways. - The inflammatory modulating action of local anesthetics may result from interruptions in these pathways. - The antiinflammatory response to local anesthetics also occurs resulting from suppression of polymorphonuclear leukocyte priming, which prevents overactive inflammatory responses without impairing host defenses or suppressing normal inflammation.

True or False: In general when combining different LA, studies indicate a a faster onset can be achieved but duration of the block may be decreased

True - Most current local anesthetics possess either a fast onset but intermediate duration or a slow onset and long duration. Clinicians frequently mix local anesthetics to obtain a more rapid onset and a long duration of action. - The use of intermediate-acting mepivacaine combined with long-acting bupivacaine for an ultrasound-guided interscalene block has been reported. - Onset was not improved compared to bupivacaine alone, but duration was longer than mepivacaine alone. - The duration was shorter than bupivacaine alone. In general, studies indicate a faster onset can be achieved but duration of the block may be decreased. - Some clinicians have suggested that the use of combinations reduces the risk of toxicity; however, drug errors may increase when using more complex dosing schemes. - In addition, the toxicity of local anesthetic combinations appears to be additive. - The authors suggest that the increased use of ultrasound-guided techniques allows for the use of lower doses and more precise deposition of drug, which may diminish the use of combined local anesthetics.