section epub:type=”chapter” id=”c0120″ role=”doc-chapter”> Local anesthetics are extensively used during anesthesia and postoperative care. The basic physiology of nerve conduction, pharmacology of local anesthetics, and identification and treatment of complications that may arise from local anesthetic use is important for the perianesthesia nurse to understand. This knowledge allows the perianesthesia nurse to provide comprehensive and safe care to patients. amides; bupivacaine; chloroprocaine; cocaine; esters; levobupivacaine; lidocaine; liposomal bupivacaine; local anesthetics; local anesthetic systemic toxicity; mepivacaine; procaine; ropivacaine; tetracaine Local anesthetics are used to render a portion of the body insensate to painful stimuli through reversible nerve conduction blockade. Erythroxylum coca, the source of cocaine, was used in antiquity. In 1855, cocaine was isolated from the coca bean and rapidly found a place in modern medicine. In 1884, Carl Koller demonstrated its ability to anesthetize the eye, and William Halsted used cocaine for infiltration and nerve blocks. Cocaine had two major problems: toxicity and physical dependence. Procaine was introduced in 1905 as the first ester local anesthetic suitable for injection. In 1948, Löfgren introduced lidocaine, the first clinically useful amide local anesthetic.1,2 The use of local anesthetics for anesthesia and/or postoperative analgesia continues to evolve. Advances in pharmacology and technology have increased the use of local anesthetics. They are an integral part of a multimodal approach to pain management. The basic physiology of nerve conduction, pharmacology of local anesthetics, and identification and treatment of complications that may arise from local anesthetic use is important for the perianesthesia nurse to understand. Definitions Conduction Block Anesthesia Local anesthetic injected in the immediate vicinity of a major nerve plexus (brachial plexus, lumbar plexus, and neuraxial anesthesia). Field Block Anesthesia Local anesthetic injected, in a fanlike manner, into tissue surrounding an incision, laceration, or puncture site. Infiltration Anesthesia Local anesthetic injected at an incision or puncture site. Intravenous Anesthesia (i.e., Bier Block) Lidocaine is injected into the vein of an exsanguinated arm or leg with an inflated tourniquet, resulting in extremity anesthesia. Neuraxial Blockade A generic term that encompasses both spinal and epidural anesthesia. Peripheral Nerve Block Local anesthetic deposited in the immediate vicinity of an individual (specified) nerve to produce anesthesia. Topical Anesthesia Local anesthetic applied to the skin or mucous membranes (pharyngeal cavity or urethra). Systemic absorption from the mucous membranes is rapid. Excessive dosing can lead to local anesthetic toxicity.3–5 Neurons convey information to and from the central nervous system (CNS). Sensory information is transmitted from the periphery by afferent neurons to the CNS. Motor impulses are transmitted by efferent neurons from the CNS to the periphery. Individual neurons contain a cell body, dendrites, and axons. Dendrites are multiple extensions of the cell body that transmit information toward the cell body. An axon is a single extension that transmits information away from the cell body. Axons are enveloped in a cell membrane known as the axolemma. Endoneurium is the connective tissue that envelops individual nerve fibers. Several nerve fibers form fascicles and are in turn covered with perineurium. Several fascicles covered with perineurium are bundled together and covered by connective tissue to form the epineurium that encompasses the entire nerve (Fig. 24.1).4–6 Three transverse sections of peripheral nerve are marked A through C. A) Cell shows labels (top to bottom) as follows: Epineurium, endoneurium, and perineurium. B) Cell shows labels (top to bottom) as follows: Nucleus of Schwann cell, nerve fiber, and myelin sheath. C) Cell shows labels (top to bottom) as follows: Nerve fiber, nucleus of Schwann cell, and Schwann cell sheath. Local anesthetics work at the level of the sodium channel to prevent action potentials from occurring and not by altering resting or threshold potential. Local anesthetic molecules are stereospecific and bind within the sodium channel or near its opening. Local anesthetic molecules have a greater affinity for receptors during their open or inactive state. When local anesthetic molecules bind with the sodium channel, it prevents a conformational change, slowing the influx of sodium and nerve depolarization. Eventually the minimum blocking concentration of the local anesthetic prevents an action potential from being achieved, blocking nerve electrical conduction and causing numbness (Fig. 24.2).4,6–8 Four states of voltage-gated channel are marked A through D. A) Voltage-gated sodium channel at resting state shows phospholipid bilayer with channel closed. Text above the bilayer read, Out. Text above the bilayer read, In. B) Activation takes place. Channel is open. Sodium ion travels from outside to inside the bilayer. C) L A is attached to one side of gate. D) Inactivation takes place. Inactive state shows a sphere inactivating the gate. Peripheral nerves are divided into three classifications based on diameter, myelination, and conduction velocity. Type A and B peripheral nerve fibers are myelinated, whereas C fibers are not. Type A fibers have the fastest conduction velocities followed by B and C fibers. Type A fibers are further divided into alpha (α), beta (β), gamma (γ), and delta (δ) fibers. Type A-α fibers have the fastest conduction velocities and are considered motor neurons (produce efferent transmission). Type A-β fibers are slower than A-α fibers, similar to A-γ fibers in conduction velocity, and are considered sensory neurons (produce afferent transmission), which detect touch, pressure, and proprioception. Type A-γ fibers have a similar conduction speed to A-β fibers and are considered motor neurons (produce efferent transmission) to muscle spindles and are also responsible for reflexes. Type A-δ fibers have the slowest conduction velocity of the all of the A fibers and are considered sensory neurons (produce efferent transmission) for sharp pain (also known as fast pain, such as an incision or pinprick) and temperature. Type B fibers have a slower conduction velocity than A fibers and are what is known as preganglionic sympathetic neurons (produce efferent transmission). Type C fibers are unmyelinated, have the slowest conduction velocity, and are postganglionic sympathetic neurons (produce efferent transmission). Type C fibers transmit slow pain (generalized ache or burning sensation) and temperature (Table 24.1).3,4,6,8 From Brown C. Anesthesia, moderated sedation/analgesia. In: Schick L, Windle PE, eds. Perianesthesia nursing core curriculum: preprocedure, phase I and phase II PACU nursing. 4th ed. St. Louis, MO: Elsevier; 2021. Classification of peripheral nerves is important in determining the sequence of local anesthetic blockade. Type B fibers are the most sensitive. Dilation of cutaneous blood vessels is often the first sign of local anesthetic onset. Type C fibers and A-δ are the next sensitive. They result in the inability to feel cool sensations such as an alcohol wipe. Next in sensitivity are the A-γ, A-β, and A-α fibers, which result in the loss of sensation, pressure, proprioception, and finally motor paralysis. Local anesthetic concentration must be adequate to block nerve fibers. It takes approximately twice the concentration of local anesthetic to block motor fibers as it does to block sensory fibers. Sympathetic fibers require the least amount of local anesthesia. The order of blockade onset is B fibers > C fibers = A-δ fibers > A-γ fibers > A-β fibers > A-α fibers. Recovery from local anesthetic happens in the opposite manner. It should be noted, however, that recovery usually occurs unevenly—that is, the patient may recover some motor and sensory functions simultaneously in different blocked areas. Different regional blocks may also exhibit different recovery patterns. The typical physiologic sequence of nerve blockade onset and some of the symptoms an individual may feel during the onset of nerve blockade is shown in Box 24.1.3,4,6,8 A local anesthetic molecule contains a lipophilic group, an intermediate bond, and a hydrophilic group. Classification is dependent on the intermediate bond, which is either an ester (–CO–) or an amide (–HNC–). The lipophilic (attracted to fat) and hydrophilic (attracted to water) portions of the molecular structure are crucial to its ability to cross tissue barriers and reach their site of action. The intermediate bond, either an ester or an amide, determines the type of local anesthetic, affecting metabolism and potential for allergic reactions.4 Commonly administered amides and esters are noted in Box 24.2. Some differences between esters and amides are noted in Table 24.2. From Nagelhout JJ, Elisha S. Nurse Anesthesia. 6th ed. St. Louis, MO: Elsevier; 2018. Pharmacokinetics is the study of a medication’s absorption, distribution, metabolism, and excretion.6 Local anesthetics differ from most other drugs (with regards to action) since they function at the local tissue level instead of being injected intravenously (IV). Once they are systemically absorbed into the bloodstream, they wear off. Systemic absorption can also lead to toxicity if too large a dose is given or if it is accidentally injected intravascularly. Fig. 24.3 depicts the fate of a local anesthetic once it is injected into a tissue. Flow chart shows a syringe injected into skin. A reversible reaction reads, L A positive converts to L A and H positive. Text reads, Anesthetic. Three reversible arrows lead to nonspecific tissue binding, bloodstream uptake and removal, and nerve blockade. Bloodstream uptake and removal leads to liver hepatic metabolism or plasma hydrolysis and a reversible arrow, which further leads to systemic tissue distribution. Liver hepatic metabolism or plasma hydrolysis leads to renal excretion. Potency and duration of action of a local anesthetic are closely correlated to lipid solubility. In general, the more lipid soluble the local anesthetic, the more potent it is and the longer its duration of action. Potent local anesthetics readily bind with proteins and neural tissue leading to their longer duration of action and toxicity potential. Bupivacaine, ropivacaine, and tetracaine are the most potent. Lidocaine, mepivacaine, and prilocaine exhibit moderate potency. Procaine and chloroprocaine are the least potent.4,7–9 Absorption of local anesthetics is dependent on site of injection, dose, vasoconstrictor, pharmacologic profile, and individual physiologic factors.3,4,10 Vascularity of tissue has a direct effect on systemic absorption. If a tissue has more blood flow, the local anesthetic will have an increased uptake into the vascular system which may lead to toxicity. Absorption of local anesthetic varies by route of administration. Absorption rates from highest to lowest are as follows: IV, tracheal, intercostal, caudal, epidural, brachial plexus, sciatic, and subcutaneous.3,10,11 Total dose is also a significant factor. The greater the dose, the greater the systemic absorption.6 Attention to the total dose is important to avoid toxicity. Epinephrine produces local vasoconstriction and can be added to the local anesthetic to decrease systemic absorption, prolong duration of action, and reduce toxicity. The ability of epinephrine to decrease systemic absorption varies by local anesthetic and injection site. The addition of epinephrine for peripheral nerve blocks and epidurals increases duration of action and decreases blood levels of lidocaine, mepivacaine, and bupivacaine by 10% to 30%, but does not alter duration or blood levels for ropivacaine. Attention should be placed on the total dose of epinephrine to avoid deleterious effects.4,6 All local anesthetics, with the exception of cocaine and ropivacaine, cause a degree of vasodilation. Vasodilation results in increased blood flow to the area of injection and absorption. A final factor in determining the absorption rate of local anesthetics is individual physiologic conditions. Extremes of age are a factor because newborns have immature hepatic function, and the elderly have decreased hepatic enzyme function and blood flow, resulting in increased blood concentrations. During pregnancy, doses of local anesthetic should be decreased by one third because of hyperdynamic circulation and hormonal changes that can result in toxicity. Renal, hepatic, and cardiovascular disease can also affect local anesthetic pharmacokinetics.4,6,12 Uptake of local anesthetics results in their distribution to various tissues. The initial rapid disappearance phase (α) includes uptake into highly perfused tissue (brain, lung, liver, kidney, and heart). The lungs act as a large reservoir and decrease initial blood concentrations. The slow phase of disappearance (β) includes distribution to the gut and muscle. Muscle provides a large reservoir for local anesthetics.4,6,12 During pregnancy, amide local anesthetic molecules can be transferred across the placenta and accumulate in an acidotic environment; this is known as ion trapping.3,4 Metabolism depends on classification: amide or ester. Amides are metabolized primarily in the liver through the cytochrome P-450 system. Extremes of age and diseases that affect liver perfusion and enzyme activity alter hepatic elimination of amides. Individual amides exhibit different clearance rates (prilocaine > lidocaine > mepivacaine > bupivacaine > ropivacaine). Esters undergo rapid hydrolysis in the blood, which limits toxicity. Plasma cholinesterase is the primary enzyme responsible.4 Caution should be used in patients with an acquired or genetic pseudocholinesterase deficiency, which can decrease metabolism and lead to potentially toxic blood concentrations.4,13 Metabolism of some ester local anesthetics results in the production of p-aminobenzoic acid (PABA), a known allergen. It is this byproduct of metabolism that makes ester local anesthetics more likely than amides to result in an allergic reaction.4,12 Maximum doses are general guidelines derived from animal studies in an attempt to identify median effective and toxic doses. Health care providers should take into account the site of injection, the addition or absence of epinephrine, and individual medical conditions such as age; renal, hepatic, and cardiac disease; and pregnancy.4 Refer to Table 24.3 for maximum doses of local anesthetics. IRVA, Intravenous regional anesthesia; PABA, p-aminobenzoic acid.
24: Local Anesthetics
Abstract
Keywords
Nerve physiology and conduction
Nerve fiber type and local anesthetic effects
Fiber Type
Myelin
Function
A-α
+++
Motor (efferent: to skeletal muscle)
A-β
++
Touch, pressure, proprioception (afferent: from skin)
A-γ
++
Motor (efferent: to muscle spindles)
A-δ
++
Pain (sharp, fast) and temperature (efferent: from skin)
B
+
Preganglionic sympathetic (efferent: to vascular smooth muscle)
C
None
Pain (dull, slow) and temperature (afferent from skin); postganglionic sympathetic (efferent: to vascular smooth muscle)
Local anesthetic pharmacology
Chemistry and Stereoisomerism
Esters
Amides
Ester metabolism is catalyzed by plasma and tissue cholinesterase via hydrolysis; occurs throughout the body and is rapid.
Amides are metabolized in the liver by CYP1A2 and CYP3A4, and thus a significant blood level may develop with rapid absorption.
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.
Allergy to amides is extremely rare; there is no cross-allergy among the amide class or between the ester and amide agents.
Ester drugs tend to be shorter acting due to ready metabolism; tetracaine is the longest acting ester.
Amides are longer acting because they are more lipophilic and protein bound and require transport to the liver for metabolism.
Pharmacokinetics
Maximum Doses
Local Anesthetic
Uses and Doses
Onset and Duration
Discussion
Esters
Procaine (Novocain)
Topical: 10%–20%
Infiltration: 0.25%–0.5%
Nerve block: 1%–2%
Maximum dose: 5–6 mg/kg plain (400 mg); 8.5 mg/kg with epinephrine (600 mg)
Onset: Slow for infiltration and nerve block; fast for spinal block
Duration: 30 min plain; 60 min with epinephrine
Introduced in 1905
Limitations include short duration, low potency, and poor stability
Undergoes rapid hydrolysis to PABA; less than 50% excreted unchanged in the urine
Not commonly used for surgical anesthesia in the operating room
Chloroprocaine (Nesacaine)
Infiltration: 1%
Nerve block: 1%–2%
Epidural block: 2%–3%
Maximum dose: 11 mg/kg plain (800 mg); 15 mg/kg with epinephrine (1000 mg)
Onset: Fast (6–12 min)
Duration: 30 min plain; 60 min with epinephrine
Not topically active
Short-duration ester manufactured in preservative-free and preservative-containing solution (sodium bisulfate and methylparaben)
Not administered for spinals due to the risk of neurotoxicity
Preservative-free solutions should be used for epidurals
Twelvefold more potent than procaine
One of the safest local anesthetics in regard to systemic toxicity
Hydrolyzed to inactive metabolites and excreted in the urine
Cocaine
Topical: 4%–20%
Onset: Fast
Moderate-duration ester
Maximum dose: 3 mg/kg
Duration: 10–55 min
Vasoconstrictor and used topically only
Inhibits reuptake of norepinephrine and dopamine; may cause constriction of coronary arteries
Limitations include toxicity, sympathetic stimulation, and abuse potential
Partially metabolized in the liver and by ester hydrolysis
Tetracaine (Pontocaine)
Topical: 0.5%–1%
Infiltration: 0.1%–0.25%
Maximum dose: 1.5 mg/kg plain (100 mg); 2.5 mg/kg with epinephrine (200 mg)
Onset: Slow
Duration: (Topical) 55 min; (Spinal) 1–1.5 hours plain; (Spinal) 2–3 hours with epinephrine
Potent, long-acting ester developed in 1930
May be used topically
Most commonly used for spinal anesthesia
Cerebral spinal fluid does not contain pseudocholinesterase enzymes and must be absorbed systemically to be metabolized
Metabolized more slowly than other esters
Amides
Lidocaine (Xylocaine)
Topical: 2%–4%
Nerve block: 1%–2%
Epidural: 1%–2%
IRVA: 0.5%
Maximum dose: 4.5 mg/kg plain (300 mg) for other blocks; 7 mg/kg with epinephrine (500 mg); (Topical) 3 mg/kg (less due to rapid absorption); (IRVA) 250 mg
Onset: Fast; (Topical) 2–4 min
Duration: 1–2 hours plain; 2–6 hours with epinephrine for nerve block and infiltration; 1–1.5 hours for spinal or epidural anesthesia
Moderate-duration amide introduced in 1948
One of the most common and versatile local anesthetics in current use; rapid onset, intense analgesia, good penetration, and stable
Not commonly used for spinal anesthesia due to risk of transient neurologic symptoms
Metabolized by oxidative dealkylation in the liver; liver disease may reduce elimination and place the patient at risk for toxicity
Mepivacaine (Carbocaine)
Infiltration: 0.5%–1%
Nerve block: 1%–2%
Maximum dose: 4.5 mg/kg plain (300 mg); 7 mg/kg with epinephrine (500 mg)
Onset: Fast
Duration: 45–90 min plain; 2–6 hours with epinephrine
Moderate-duration amide introduced in 1957
Similar to lidocaine except slightly longer duration, less toxicity, and less localized vasodilation
Ropivacaine (Naropin)
Epidural: 0.1%–0.2% (analgesia); higher concentrations for anesthesia
Nerve block: 0.5%–1%
Maximum dose: 200 mg
Onset: Fast
Duration: 2–6 hours
Rapid-onset, long-duration amide local anesthetic that exhibits many advantages over bupivacaine; introduced in 1996
A single enantiomer with a lower risk of toxicity than bupivacaine, which makes it a primary choice for peripheral nerve blocks and epidurals
Less motor blockade at lower doses than bupivacaine, making it an ideal agent for epidural analgesia
Clearance is higher and elimination half-life is shorter than for bupivacaine
Metabolized by cytochrome P-450 system in the liver; less than 1% is excreted unchanged
Unique in its ability to cause localized vasoconstriction, which eliminates the need to add epinephrine
Bupivacaine (Sensorcaine; Marcaine)
Infiltration: 0.1%–0.25%
Onset: Slow
Potent, long-duration local anesthetic introduced in 1973; widely used but limited by reports of cardiotoxicity
Produces profound sensory analgesia with minimal motor blockade at low doses
Development of less toxic, potent long-acting amides has reduced its use for peripheral nerve blocks and epidurals
Nerve block: 0.25%–0.5%
Duration: 2–4 hours plain; 3–7 hours with epinephrine
Spinal: 0.5%–0.75%
Epidural: 0.125% for analgesia; higher concentrations for anesthesia
Maximum dose: 2.5 mg/kg plain (175 mg); 3 mg/kg with epinephrine (225 mg)
Commonly used for spinal anesthesia
Primarily metabolized in the liver
Levobupivacaine (Chirocaine)
Concentrations used are similar to bupivacaine
Maximum dose: 2.5 mg/kg plain; 3.2 mg/kg with epinephrine (150 mg)
Onset: Slow
Duration: 4–11 hours
Long duration S-enantiomer of bupivacaine; because it is a pure isomer, it exhibits less toxicity than bupivacaine
Exhibits many of the same characteristics of bupivacaine in regard to potency, onset, and duration
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