Local Anesthetics

Michael M. Bottros

Lara Wiley Crock

Simon Haroutounian

Physicochemical Properties of Local Anesthetics

“Cocaine and its salts have a marked anesthetizing effect when brought in contact with the skin and mucous membrane in concentrated solution; this property suggests its occasional use as a local anesthetic, especially in connection with afflictions of the mucous membrane.” Cocaine and its potential clinical use as a local anesthetic were described by Sigmund Freud in his 1884 paper “Uber Coca.” Almost as an afterthought, he describes cocaine’s potential use as a local anesthetic in the very last paragraph¹: “Indeed, the anesthetizing properties of cocaine should make it suitable for a good many further applications.” A friend of Freud, Carl Koller, utilized this property of cocaine for ophthalmologic procedures. Thus, Koller is credited with demonstrating the first local anesthetic in modern clinical practice.¹ Although still somewhat controversial as to when cocaine was first used as a spinal anesthetic, Corning² described what he believed was an extradural block using cocaine in 1885, and Bier³ described a spinal anesthetic effect with cocaine in 1898. Clinically useful due to its properties as both a local anesthetic and vasoconstrictor, cocaine has undesirable side effects that limit its routine use.⁴ Other local anesthetics were developed based on the chemical structure of cocaine, and the clinical application of local anesthetics became widespread in modern medicine. The use of local anesthetics has continued to increase in clinical practice, as there is increased interest in the use of regional techniques for surgery as well as in the treatment of chronic pain.

MOLECULAR STRUCTURE

The chemical structure of cocaine was determined by Richard Willståtter in 1898, allowing for the development of the synthetic analogs of cocaine.⁵ All currently available local anesthetics have an amine group (usually a tertiary amine) and an aromatic ring. With the exception of benzocaine, these two groups are separated by an intermediate ester or amide linkage (Fig. 82.1). They are classified by their chemical bond as either amino esters (e.g., include cocaine, procaine, chloroprocaine, tetracaine) or amino amides (e.g., lidocaine, prilocaine, bupivacaine, mepivacaine). Esters and amides have distinct properties as a result of their molecular structure. The amino amide bond is more resistant to enzymatic cleavage; therefore, amide local anesthetics are more stable when compared to ester local anesthetics. Amides and esters are metabolized in distinct ways—amides by the liver microsomes and esters by plasma esterases. Chirality, acid-base balance, lipid solubility, and protein binding can all affect the activity of local anesthetics.

FIGURE 82.1 Local anesthetic structure. Similarities and differences between ester and amide local anesthetics.

CHIRALITY

Stereoisomers have identical sets of atoms that are configured in the same positions with different spatial arrangements. Furthermore, enantiomers are pairs of stereoisomers that appear as nonsuperimposable mirror images, commonly referred to as chiral. More than one-third of synthetic drugs are structurally defined as chiral.⁶ Commonly used local anesthetics with the exception of lidocaine are chiral. The body responds to chiral molecules differently because stereoisomers may have different receptor binding properties.

An example of a chiral local anesthetic is bupivacaine, a potent and long-acting local anesthetic with the unfortunate potential for cardiovascular and central nervous system (CNS) toxicity. Bupivacaine is manufactured as a racemic mixture of 50% Rbupivacaine and 50% S-bupivacaine. S- and R-enantiomers have been shown to have unique pharmacodynamic properties (e.g., potency and potential for systemic toxicity). R-enantiomers, like R-bupivacaine, have greater potency for blockade of both neuronal and cardiac sodium (Na⁺) channels. R-bupivacaine is 1.5 times more potent when compared to S-bupivacaine (also known as levobupivacaine) when the Na⁺ channel is in an inactive state.⁶ Because of the potential systemic toxicity and higher potency, R-enantiomers are more powerful local anesthetics with
a narrower therapeutic index. S-enantiomers on the other hand, have a lower binding potential for cardiac Na⁺ channels and may be safer.⁷ Ropivacaine (a pure S-enantiomer propyl homolog of S-bupivacaine) was developed in response to the need for a long-acting amino amide local anesthetic such as bupivacaine, with a greater margin of safety.⁸ It has been shown in both animal and human studies to have similar clinical efficacy compared to bupivacaine but with 30% to 40% less cardiotoxicity.⁹^,¹⁰^,¹¹^,¹²

ACID-BASE BALANCE

The pH and acid dissociation constant (pK_a) of local anesthetics have a large effect on their onset of action. The pK_a of a specific drug is the pH at which the lipid-soluble neutral form and the charged hydrophilic form are in equilibrium. Most local anesthetics have a pK_a value close to but higher than physiologic pH, making them weak bases. At physiologic pH, local anesthetics exist in a positively charged conjugated acid and an unprotonated neutral form. When unprotonated, the local anesthetic can more easily cross into the cell through the lipid bilayer to reach its receptor binding site. At physiologic pH of 7.4, a drug with a lower pK_a will more readily cross the cell lipid membrane (higher percentage will be in the uncharged, lipophilic form). Thus, the pK_a of a local anesthetic generally correlates with its onset. The pH inside the cell is lower, which shifts the equilibrium toward a higher ratio of positively charged local anesthetic molecules. It is the charged form that binds to the pore of the voltage-gated Na⁺ channel, causing the anesthetic effects.

Tissue that has been damaged or is infected often produces an acidic extracellular microenvironment, thus increasing the percentage of charged local anesthetic outside the cells. The positively charged local anesthetic cannot easily cross the lipid bilayer and reach the intracellular binding site. For this reason, local anesthetics are not as effective in providing adequate analgesia to infected or damaged tissue.

Just as an acidic extracellular environment can prevent adequate analgesia from reaching the intended target, an acidic intracellular environment can prolong the effect of a local anesthetic. For example, the administration of an accidental overdose of local anesthetic can result in CNS toxicity. At lower toxic doses, central inhibitory neuronal pathways are blocked. This neuronal disinhibition can result in a tonic-clonic seizure, leading to a lactic acidosis in the CNS. As the CNS becomes more acidic, the local anesthetic is essentially trapped inside the cell due to its ionization, exacerbating its CNS toxicity.

LIPOPHILIC-HYDROPHILIC BALANCE

The lipid solubility, or lipophilic nature of a local anesthetic, influences its ability to pass through a lipid bilayer and thus its potency and duration of action. More lipophilic local anesthetics can not only permeate neurons more readily but also result in sequestration of the local anesthetic in lipid-soluble perineural compartments such as the myelin sheath where they are sequestered. The accumulation of local anesthetics in lipid-soluble neuronal components creates a depot of local anesthetics, resulting in a slow release from these lipophilic compartments. Consequently, although the lipophilic local anesthetics may cross membranes more readily, these drugs often have a lower onset of action and prolonged duration of action.¹³^,¹⁴ Increased lipophilicity often translates to greater potency due to drug ability to cross lipid membranes and a greater affinity to bind Na⁺ channels.¹⁴^,¹⁵

Local Anesthetic Pharmacology

PHARMACODYNAMICS

Hodgkin and Huxley used a giant squid axon to determine that electrical signals in the nerves are initiated by voltage-dependent activation of inward sodium currents.¹⁶^,¹⁷ In 1970, Fraizer used squid giant axons and quaternary compounds to demonstrate that local anesthetics need to penetrate into the cell to inhibit depolarization and action potentials.¹⁸ It was later discovered that local anesthetics work by binding to and blocking voltage-gated sodium channels (Fig. 82.2). Voltage-gated sodium channels exist in three conformational states: open, closed, and inactivated. Without a stimulus, the channel is in its closed state. In response to a change in membrane potential, the voltage-gated sodium channel will open. After a few milliseconds, an intracellular loop (P) (see Fig. 82.2) will fold inward and occlude the channel pore. This renders the sodium channel inactive, and the channel will temporarily not respond to further changes in membrane potential. Local anesthetics can gain access and bind to the intracellular binding site preferably when the channel is in an open state.¹⁹

Local anesthetics work by preventing action potential propagation in axons through their inhibitory action on sodium channels.²⁰ These voltage-gated sodium channels contain a main β-subunit, where the local anesthetics bind and one or more α-subunits.¹⁶^,¹⁹ Local anesthetics reversibly bind to the β-subunit from inside the cell and inactivate voltage-gated sodium channels, thus preventing channel activation and inhibiting sodium influx, preventing depolarization of the nerve cell membrane (Fig. 82.2). When a local anesthetic binds to the open state of a sodium channel, it stabilizes the inactive state of the channel and prevents further activation. Local anesthetics increase the threshold for electrical excitation in nerves, slow propagation of the impulse, reduce the rate of rise of the action potential, and eventually block conduction.²¹

PHARMACOKINETICS

The pharmacokinetic properties of local anesthetics (i.e., absorption, distribution, metabolism/biotransformation, and excretion), patient factors (i.e., age, overall health, and the functional state of eliminating organs), and clinical circumstances must be combined in order to predict the pharmacokinetic profile of a local anesthetic in a particular patient.

FIGURE 82.2 Diagram of a voltage-gated sodium channel structure and the site of action of local anesthetics. Local anesthetics exist in an equilibrium as a neutral base (LA) and as a charged form (LAH+). The uncharged form (LA) more easily passes through the lipid bilayer to the interior of the cell. Inside the cell, it can be protonated again (LAH+), thus allowing it to bind to, and inhibit (close), the voltage-gated sodium channel. (Adapted from Drasner K. Local anesthetics. In: Katzung B, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012:452.)

Absorption

The plasma concentration following systemic absorption of a local anesthetic is highly dependent on the site of administration, the dose, and the physicochemical properties of the drug. The more vascular an injection site, the higher the systemic absorption of the local anesthetic. The highest systemic absorption occurs with intravenous administration. The systemic absorption of local anesthetics after regional anesthesia occurs at decreasing rate after tracheal, intercostal, caudal, paracervical, thoracic/lumbar epidural, brachial plexus, and sciatic nerve blocks and is the lowest with subcutaneous infiltration (Fig. 82.3).²²^,²³ For example, similar plasma concentrations of lidocaine are achieved after 300 mg delivered as an intercostal nerve block, 500 mg via an epidural block, and 1,000 mg subcutaneously.²⁴ All local anesthetics produce some level of vasoactivity, with most producing vasodilatation. However, the vasoactivity of local anesthetics is dependent on the drug, the dose, as well as the organ targeted.²⁴ Vasodilatation increases absorption of the local anesthetic into the systemic circulation. Enhanced absorption reduces the local anesthetic duration and increases the concentration of the drug in the blood. Cocaine is the only local anesthetic that consistently produces vasoconstriction (following initial vasodilatation). The addition of epinephrine to some local anesthetic nerve blocks can reduce absorption by causing vasoconstriction, thus prolonging the nerve block. The extent of this prolongation appears to vary with the site of the nerve block and the vasoconstrictor agent used. For example, 5 µg/mL of epinephrine, added to lidocaine, reduced the peak plasma concentration of subcutaneously infiltrated lidocaine by 50% but only by 20% to 30% when added to intercostal, epidural, and brachial plexus lidocaine blocks.²⁴ See “Vasoconstrictor Effect” section for further information.

Distribution

Once local anesthetics are absorbed in the blood, they readily cross into all tissues. Organs and tissues and organs with high levels of perfusion (such as the heart and brain) will have higher levels of local anesthetics. Local anesthetics (in their unionized form) are lipophilic and therefore readily cross the blood brain barrier. Depression of the CNS by local anesthetics causes initial sedation. Local anesthetics raise the seizure threshold by decreasing the excitability of cortical neurons in epileptic patients. However, at toxic plasma (and brain) levels, local anesthetics cause seizures.²⁵

FIGURE 82.3 Degree of systemic absorption based on local anesthetic injection site. The highest systemic absorption occurs with intravenous administration, decreasing after tracheal, intercostal, caudal, paracervical, thoracic/lumbar epidural, brachial plexus, and sciatic nerve blocks and is the lowest with subcutaneous infiltration. (Based on Drasner K. Local anesthetics. In: Katzung B, Masters SB, Trevor AJ, eds. Basic & Clinical Pharmacology. 12th ed. New York: McGraw-Hill; 2012:452-453.)

Biotransformation and Excretion

The primary site of amino amide local anesthetic metabolism is in the liver through hepatic carboxylesterases and cytochrome P450 enzyme. An exception is prilocaine, which is metabolized in both the liver and lungs. Ester local anesthetics, with the exception of cocaine, are hydrolyzed by plasma cholinesterases and tissue esterases.²⁵^,²⁶ The metabolites of both amino ester and amino amide local anesthetics are primarily excreted by the kidneys. Urine concentrations of ester local anesthetics are small due to their metabolism in plasma. Only 2% of procaine is found in urine, whereas 90% is found as its para-aminobenzoate metabolite, para-aminobenzoic acid (PABA).²⁷

The rates of hydrolysis of local anesthetics inversely determine their degree of toxicity. A slowly hydrolyzed ester local anesthetic such as tetracaine is more toxic than chloroprocaine, which is hydrolyzed much faster.

Effects of Disease States on Local Anesthetic Pharmacokinetics

Because amide local anesthetics are metabolized primarily in the liver, hepatic perfusion and liver function can affect the rate of amide local anesthetic metabolism. Reduced hepatic function results in a reduced plasma clearance of and prolongation of the elimination half-life of intravenous lidocaine. This does not significantly affect the duration of action but predisposes a patient to the toxic effects.²⁸ Renal disease has little effect on the pharmacokinetic parameters such as volume of distribution at steady state and total body clearance of intravenous lidocaine.²⁸ In contrast, patients with cardiac failure had reduced volume of distribution and plasma clearance of intravenous lidocaine.²⁸ Metabolism byproducts of amide local anesthetics can have clinical effects if allowed to accumulate in the blood. Sedation due to high doses of lidocaine is due to the formation of the metabolites glycine xylidide and monoethylglycinexylidide. Despite ester local anesthetics, biotransformation by plasma cholinesterases, and tissue esterase, at normal doses, there appears to be little effect in patients with pseudocholinesterase deficiency.

Regional Administration of Local Anesthetics for Pain Relief

DIFFERENTIAL BLOCKADE

As sodium channels are expresses in both sensory and motor nerve fibers, the regional administration of local anesthetics can result in blocking conduction along both types of fibers. Therefore, along the desired analgesic effect on sensory fibers, other, less desired effects are often observed. Differential blockade is the gradual and sequential inactivation of differing nerve fiber types when exposed to local anesthetics. A number of factors contribute to this phenomenon:

Local anesthetic concentration: Higher concentrations can produce both motor and sensory block, whereas low concentrations produce only sensory block.
Nerve fiber size: Small diameter axons are more susceptible to block than large diameter fibers. Sensory nerve fibers are classified as A, B, and C. Type A fibers include afferent fibers responsible for proprioception (Aα), thermal sensation (Aδ), and mechanosensation (Aβ). Type B fibers are mainly visceral sensory fibers and preganglionic
autonomic fibers. Type C fibers are postganglionic autonomic efferents as well as sensory afferents responsible for the transmission of pain and heat signals. Type A fibers are thickest, and type C fibers are thinnest.
Degree of nerve fiber myelination: Because local anesthetics exert their effect at the node of Ranvier, myelinated fibers are more sensitive to local anesthetic effects than nonmyelinated ones.
Circumferential location of fibers: In nerve bundles, fibers that are located circumferentially are affected first by local anesthetics. In large nerve trunks, motor nerves are usually located circumferentially and may be affected before the sensory fibers. In the extremities, proximal sensory fibers are located more circumferentially than distal sensory fibers. Thus, loss of sensation may spread from the proximal to distal part of the limb.

Gokin et al.²⁹ studied the preferential block of sensory and motor fibers using lidocaine in a rat sciatic nerve model. They found that the order of fiber susceptibility, ranked by concentrations that gave peak tonic fiber blockade of 50% (IC50s), was Aγ > Aδ = Aδ > Aαβ > C. Faster conducting C fibers (conduction velocity >1 m/s) were more susceptible than slower ones. Therefore, this does not strictly follow the “size principle” that smaller axons are always blocked first.

SITE OF INJECTION

Local anesthetics are used in a wide variety of anatomical sites. These can generally be grouped into five categories: neuraxial anesthesia, peripheral nerve blockade, intravenous regional anesthesia, infiltration anesthesia, and topical anesthesia.

Neuraxial Anesthesia

Neuraxial anesthesia was first reported for clinical use in the late 19th century by Augustus Karl Gustav Bier, who used intrathecal cocaine on six patients undergoing lower extremity surgery.³⁰ Since then, neuraxial anesthesia has progressed considerably and has become widely used for surgical anesthesia and pain management in a number of different clinical situations. The term neuraxial anesthesia may be further categorized into spinal, epidural, caudal, or combined spinal-epidural (CSE) anesthesia.

Spinal anesthesia involves the administration of local anesthetics into the intrathecal (or subarachnoid) space. As the conus medullaris typically terminates near lumbar nerves L1 or L2, this technique is performed below the L2 level to avoid damage to the spinal cord. As such, this technique may be indicated when the surgical site involves the lower extremities, perineum, or lower trunk. Examples include total hip/knee arthroplasty or cesarean section surgeries.

FIGURE 82.4 Epidural anesthesia. A catheter exits the epidural needle in the epidural space where local anesthetics may be deposited. (From BruceBlaus /Wikimedia Commons/CC-BY-SA-4.0.)

Epidural anesthesia is categorized by the deposition of local anesthetics via catheter or needle placed into the epidural space, located between the ligamentum flavum and the dura mater (Fig. 82.4). Key differences between epidural and spinal anesthesia include location of drug deposition (epidural vs. intrathecal), onset of action (spinal is generally quicker than epidural), and local anesthetic dose (because of uptake into extraneural fat, blood, and lymphatics, epidural doses are higher than spinal). Epidural catheter analgesia (using low-dose local anesthetics, sometimes with the addition of an opioid) is typically used for truncal or lower extremity postoperative pain relief, such as postthoracotomy or abdominal resection cases.

Caudal epidural anesthesia involves the insertion of a needle through the sacral hiatus in order to gain entrance into the sacral epidural space. Caudal anesthesia is commonly used as a regional technique in neonates and infants for abdominal and pelvic surgeries as it decreases the amount of general anesthetic and intravenous opioids required intraoperatively.³¹^,³²

A CSE technique may be used in clinical scenarios during surgery at or below the umbilicus requiring prolonged and effective analgesia. This typically entails performing an intrathecal block for the surgical procedure itself while an epidural catheter is placed (subsequent to the intrathecal block) and used during surgery when the intrathecal block is deficient or an extended duration of relief is needed for unanticipated longer surgical procedures. Postoperatively, the epidural catheter may be used for pain control.³³

Peripheral Nerve Blockade

Peripheral nerve blockade is the deposition of local anesthetic near a nerve or group of nerves associated with the control of sensation and/or movement of a specific part of the body. This may be performed in lieu of or in addition to general anesthesia for surgery. This may be performed as a single-shot technique to facilitate intraoperative and immediate postoperative anesthesia and analgesia. Alternatively, for a longer duration of postoperative analgesia, one can insert a catheter near the nerve/nerves and provide continuous analgesia by supplying an infusion of local anesthetic. Peripheral nerve blockade may be achieved via blind technique, but most are currently performed with concomitant use of either nerve stimulation or ultrasound to guide needle placement.

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