Local anesthetics are frequently applied directly on or near their target via techniques of regional anesthesia. Thus, plasma levels rarely bear a relationship to their desired effects; however, these plasma levels are critical for systemic toxicity. The pharmacokinetics describing the blood concentration after administration of a drug are illustrated in Figure 12.1. Clearance of amide-type local anesthetics depends on liver function and may be limited in any disease state that reduces hepatic blood flow. An increase of α-1-acid glycoprotein and other plasma proteins (e.g. due to cancer) can lead to more rapid delivery of the drug to the liver and therefore lead to faster clearance. Ester-type drugs are hydrolyzed by plasma pseudocholinesterase. Thus, patients with genetically abnormal pseudocholinesterase are at increased risk for toxic side effects, since metabolism is slower. However, to a limited degree, the liver also extracts and metabolizes ester-type compounds. An increase of apparent volume of distribution may occur in older and more adipose patients. The lung has also been implicated as a site of local anesthetic metabolism, providing a dose-dependent first-pass uptake effect. Renal disease has little effect on these pharmacokinetics.

Fig. 12.1 Plasma levels, and therefore the likelihood of systemic toxicity, depend on the location of injection. It should also be noted that significant individual variations are observed both in the pharmacokinetics and the pharmacodynamics, including the ‘toxic plasma level’.

Pharmacodynamics, or the relative potency and efficacy of the medication, depends on the mode of application, e.g. peripheral nerve blockade, spinal, or epidural injection.

Table 12.1 summarizes some pharmacokinetic and -dynamic parameters for amide- and ester-type local anesthetics.

Table 12.1 Pharmacokinetic and -dynamic properties of several amide- and ester-type local anesthetics

Transport to the ion channel

Most local anesthetics are weak bases that are converted to their uncharged lipid-soluble form to pass through the phospholipid membrane into the cell as shown in Figure 12.2. However, once inside they are converted to the charged form to block the sodium channel. The Henderson-Hasselbalch equation relates the pH to the pKa and the relative concentrations of uncharged base (B) and charged base (BH⁺). Given the reaction:

Fig. 12.2 Local anesthetics are weak bases that preferentially travel into the cell in their uncharged, lipid-soluble form. Once inside, they enter the pore of the channel in the pharmacologically active protonated form.

The pH determines the ratio of B and BH⁺:

By definition, the pKa is the pH at which 50% of the local anesthetic is uncharged ([B]=[BH⁺]). As shown in Figure 12.3, the pKa range for commonly used local anesthetics lies in a narrow band.

Fig. 12.3 Commonly used local anesthetics and their pKa values.

For amide local anesthetics, the pKa generally correlates with the speed of onset. In general, it is thought that the closer the pKa is to the pH in the tissue surrounding the nerve, the faster the onset, as there are more local anesthetic molecules available in the neutral (uncharged) form. The neutral form is largely responsible for traversing the membrane. However, lipid solubility also plays an important factor.

Modulation of pH by carbonation

The addition of bicarbonate has also been used to increase the pH of local anesthetic solutions, thus increasing the concentration of nonionized lipophilic free base. This will theoretically increase the rate of diffusion of the drug and its speed of onset. Figure 12.4 illustrates this concept using lidocaine. Clinically, the addition of 1 mEq of sodium bicarbonate to each 10 mL of commercially prepared 1.5% lidocaine solution produces a significantly faster onset of anesthesia and more rapid spread of sensory block.⁵

Fig. 12.4 The pH of a solution containing local anesthetics (e.g., lidocaine) can be manipulated by adding bicarbonate. This changes the proportion of uncharged, lipid-soluble drug and can have a pronounced effect on the speed of onset of the block.

Most local anesthetics are bases that are poorly soluble in water, but that can be dissolved in hydrophobic organic solvents. Therefore, most local anesthetics are marketed in the form of hydrochloride salts.

Table 12.2 lists several common local anesthetics with their pKa values and their usual pH in storage.

Table 12.2 pKa and pH of commonly used local anesthetics

Drug	pKa	pH of solution in vial
2-chloroprocaine	9.1	2.5–4
Procaine	8.9	5.5–6
Tetracaine	8.4	4.5–6.5
Cocaine	8.5	variable
Lidocaine	7.9	5.6 (without epi)
		3.5–5.5 (with epi)
Levobupivacaine	8.1	4.0–6.5 (without epi)
Bupivacaine	8.1	4.5–5.5 (without epi)
		3.5–5.5 (with epi)
Mepivacaine	7.7	5.5

epi, epinephrine.

Molecular mechanism of sodium channel blockade

Although LAs may also interfere with other channels, their interaction with sodium channels is clinically most relevant.

The generation and propagation of impulses in nerve axons to carry afferent (sensory) and efferent (motor, sympathetic) information requires the flow of specific ionic currents through channels in the plasma membrane. These channels open and close depending on the electrical potential of the cell membrane. The major determinant of the depolarization of nerve fibers is the specific influx of Na⁺ ions through sodium channels located in nerve axons. Local anesthetic agents reversibly bind to and block sodium channels, thereby preventing the initiation or propagation of the electrical impulses required for nerve conduction. It now appears that although the uncharged form of a local anesthetic is more likely to cross into the cell membrane as mentioned above, either form may bind to the Na⁺ channel. The local anesthetic blocks the channel by binding to the receptor from inside the cell. A well-established technique in electrophysiology, the patch-clamp technique (Figure 12.5, illustrating the ‘whole-cell’ mode of this technique), was instrumental in explaining the basic molecular mechanism of Na⁺ channel blockade caused by LAs. Most LA enter the channel from cell cytoplasm when the channel has been activated to the ‘open’ state. Upon blocking the flow of sodium ions, the channel enters the ‘inactivated’ state. LA bind tightly to and stabilize the inactivated state.

Fig. 12.5 Whole-cell patch-clamp technique. With this method, the tip of the patch electrode (glass pipette) is brought into contact with the cell surface. The cell membrane is then ruptured by applying brief suction. This allows free exchange between the solution inside the glass pipette and the cytoplasm. The electrode that is inside the glass pipette is connected to the patch clamp device, which measures the current flow through the cell membrane during depolarization.

Use-dependent block (additional block when stimulating at a high frequency)

Local anesthetics such as lidocaine and bupivacaine exhibit a phenomenon called use dependency.^6,⁷ This means that if a neuronal cell is stimulated at a low frequency of 0.03 Hz (e.g., once every 30 sec) at a given concentration, a certain amount of inhibition of Na⁺ current will ensue and establish a steady state block. This block is called a tonic block and is thought to be equivalent to the regional/local block performed in the operating room when there is no high-frequency stimulation by pain fibers (before surgery). If, however, under the same conditions (same concentration of drug) the frequency is increased (e.g., 5 Hz, or once every 200 msec), an additional block will occur, and a new steady state will result. This interesting feature is called use-dependent block. It is seen with all local anesthetics, and is particularly prominent with amitriptyline, which also has local anesthetic properties, and has been commonly used orally for neuropathic pain. However, due to a very narrow therapeutic ratio, amitriptyline has no clinical use as a local anesthetic. It is thought that bupivacaine and amitriptyline have a higher affinity to the LA binding site than, for example, lidocaine, and therefore at higher stimulation frequencies there is not enough time for the drug to dissociate from the binding site and leave the channel.⁸ The concept of use-dependent block is illustrated in Figure 12.6, depicting amitriptyline versus bupivacaine, as the former also has significant local anesthetic properties.

Fig. 12.6 Use-dependent block of bupivacaine versus amitriptyline. Initially, a steady-state tonic block is achieved with amitriptyline and bupivacaine at a concentration of 3 μM; this inhibition of Na⁺ current is considered to be the baseline. With stimulation at a frequency of 5 Hz, an additional ≈10% Na⁺ current block is achieved with bupivacaine, compared to ≈ 40% with amitriptyline.

Clinical relevance of use-dependent block

With the currently available, and also some of the experimental local anesthetics, relatively little tonic block can be found at low concentrations.⁹ This suggests that discharge at a high rate from stimulated sensory/pain fibers could be blocked, while leaving other nerve fibers (motor) undisturbed. Therefore, this property may make it possible to selectively block the ‘firing’ of high-frequency action potentials produced by pain fibers while leaving the ‘normal’ action potential transmission intact.

For the same reason, drugs inducing a high degree of use-dependent block, when given at higher concentrations, should prolong the duration of a complete block. In other words, a drug with a high degree of use-dependent blockade could give a differential block, i.e. a selective block of specific (pain-transmitting) nerve fiber groups ¹⁰ at lower concentrations, and a prolonged complete block at higher concentrations (similar to bupivacaine, but to a much greater extent). Preclinical in vivo¹¹ and clinical studies¹² appear to confirm the role of use-dependent block in anesthesia/analgesia.

EFFECTS OF LOCAL ANESTHETICS OTHER THAN NA⁺ CHANNEL BLOCKADE

Local anesthetics also have been shown to inhibit K⁺ channels, Ca²⁺channels, nicotinic acetylcholine-activated conductance, the substance P receptor, and even the G protein modulation of certain channels. These alternative actions may contribute to local anesthesia and to some aspects of toxicity.

Inhibition of current flow through other ion channels

Voltage-gated and voltage-independent K⁺ channels were found to be blocked by relatively low concentrations of local anesthetics. The respective affinity varies among the different subtypes. Similarly, Ca²⁺channels are also blocked by local anesthetics. The exact role and contribution to the desired effect and upon the potential side effects of local anesthetics is not known.

Inhibition of signaling through G protein-coupled receptors

Local anesthetics have may have significant effects in several settings other than local and regional anesthesia or antiarrhythmia. Some of these effects occur at concentrations that are much lower than those required for Na⁺ channel blockade. For example, the half-maximal inhibitory concentration (IC₅₀) of lidocaine at the neuronal Na⁺ channel is approximately 50–100 mM (depending on the specific channel subtype and study preparation), whereas the compound inhibits signaling through M₁ muscarinic receptors (expressed recombinantly in Xenopus laevis oocytes) with an IC₅₀ of 20 nM, that is, 1000- to 5000- fold lower. This greatly increased sensitivity of other targets implies that at relatively low LA concentrations (such as attained in blood during epidural anesthesia or analgesia or during intravenous LA infusion) other significant pharmacologic effects may be present.¹³

Interactions of LAs with neutrophil signaling

Polymorphonucleocytes (PMNs) do not express Na⁺channels, and LA effects on these cells therefore are not caused by Na⁺channel blockade. LA effects on these cells are also not affected by experimental Na⁺ channel blockers such as tetrodotoxin or veratridine. Overactive inflammatory responses that destroy rather than protect are critical in the development of a number of perioperative disease states, such as postoperative pain, adult respiratory distress syndrome (ARDS), systemic inflammatory response syndrome, and multiorgan failure. Perioperative modulation of such responses is therefore relevant to the practice of anesthesiology and interventional spine medicine, and LAs may play significant roles in this regard.¹³

Leukotriene B₄, formed in inflammatory cells such as PMNs and monocytes, is a potent stimulator of PMN activity and therefore has an important role in inflammation.¹⁴ It induces margination at endothelial cells, degranulation, diapedesis, and superoxide generation and acts synergistically with prostaglandin E₂ to enhance vascular permeability. Therefore, renewed interest has been created following the discovery that LAs block leukotriene release.¹⁵

Effects of local anesthetics on polymorphonucleocyte adhesion

Excessive adhesion of PMNs to endothelium may induce endothelial injury, which is mediated by several adhesion molecules. One of the most important for firm adhesion of PMN to endothelium and subsequent transmigration (diapedesis) is CD11b–CD18, a member of the integrin family. This receptor is expressed constitutively on the surface of nonactivated PMN, but expression increases markedly after inflammatory stimulation. Binding of activated PMN to endothelial cells by CD11b–CD18 increases intracellular peroxide levels in the endothelial cells, in which reactive oxygen species can have detrimental effects. Monoclonal antibodies against CD11b–CD18 protect in vitro against endothelial cell injury. In vitro studies have shown a reduction of TNF-α-induced upregulation of CD11b–CD18 surface expression on PMN after ropivacaine or lidocaine treatment. This may contribute to the beneficial in vivo effects of ropivacaine on ulcerative colitis at tissue concentrations (100–300 mM) obtained after rectal LA administration.¹³

Effects of local anesthetics on PMN priming

The priming process can be described as a potentiated response of PMNs after previous exposure to priming agents, such as TNF-α, platelet-activating factor, IL-8, lipopolysaccharide, or granulocyte-macrophage colony stimulating factor. Priming is a key regulatory mechanism of PMN function and seems to play a pivotal role in the ‘overstimulation’ of inflammatory pathways, which then induces tissue damage rather than protection of the host.

It is possible that inhibition of priming contributes to the antiinflammatory actions of LAs, and in particular suppresses the deleterious effects of the uncontrolled, overactive response of inflammatory cells to a stimulating agent. This might explain how LAs can decrease tissue damage without significantly inhibiting PMN functions required for host defense. In summary, LAs do not scavenge the reactive oxygen species generated, but rather inhibit the ability of PMNs to produce them.¹³

SUMMARY OF LOCAL ANESTHETIC AGENTS

General considerations

Clinically used local anesthetics may be classified as amino esters (procaine, chloroprocaine, tetracaine, and cocaine) or amino amides (lidocaine, mepivacaine, prilocaine, bupivacaine, ropivacaine, levobupivacaine) as shown in Table 12.1 (Fig. 12.7).

Fig. 12.7 Biochemical synthesis of ester and amide bonds.

Ester and amide local anesthetics differ in their chemical stability, metabolism, and allergic potential. Amides are extremely stable, whereas esters are relatively unstable in solution. Esters are hydrolyzed in plasma by the cholinesterase enzymes, whereas the amide compounds undergo enzymatic degradation in the liver. Cocaine is an exception to this as it is metabolized predominantly by the liver. The metabolites of esters include p-aminobenzoic acid (PABA), which can rarely induce allergic-type reactions. Allergies to amides are extremely rare. Tables 12.3–12.8 list usual doses of local anesthetics based on the type of block. A brief synopsis of commonly used local anesthetics follows below.

Table 12.3 Maximum recommended doses of local anesthetics^a

Table 12.4 Tissue infiltration

Drug	Volume for 70 kg person (mL)	Usual duration (min)
Chloroprocaine 1–2% plain	70–35	15–30
Chloroprocaine 1–2% with epinephrine^a (1:200 000–1:400 000)	105–53	30–60
Prilocaine 0.5–1% plain	100–50	30–90
Prilocaine 0.5–1% with epinephrine^a (1:200 000–1:400 000)	112–56	60–120
Lidocaine 0.5–1% plain	70–35	30–60
Lidocaine 0.5–1% with epinephrine^a (1:200 000–1:400 000)	100–50	60–120
Mepivacaine 0.5–1% plain	70–35	45–90
Mepivacaine 0.5–1% with epinephrine^a (1:200 000–1:400 000)	100–50	60–120
Bupivacaine 0.25–0.5% plain	56–28	120–180
Bupivacaine 0.25–0.5% with epinephrine^a (1:200 000–1:400 000)	70–35	150–240
Levobupivacaine 0.25–0.5%	70–35	120–180
Levobupivacaine 0.25–0.5% with epinephrine^a (1:200 000–1:400 000)	84–42	150–240
Ropivacaine 0.2–0.5%	105–42	90–150

Note: do not exceed maximum dosage listed in Table 12.3.

a Caution: Maximal adult recommended dose of epinephrine –250 mcg per dose; for children –3 mcg/kg per dose.

Table 12.5A Minor nerve blocks (single nerve such as ulnar or radial, blocks below the knee)

Drug	Volume (mL)	Usual duration (min)
Lidocaine 1–2% plain	5–10	60–120
Lidocaine 1–2% with epinephrine^a (1:200 000–1:400 000)	5–10	120–180
Chloroprocaine 2–3% plain	5–10	15–30
Chloroprocaine 2–3% with epinephrine^a (1:200 000–1:400 000)	5–10	30–60
Prilocaine 1–2% plain	5–10	60–120
Prilocaine 1–2% with epinephrine^a (1:200 000–1:400 000)	5–10	120–180
Mepivacaine 1–1.5% plain	5–10	60–120
Mepivacaine 1–1.5% with epinephrine^a (1:200 000–1:400 000)	5–10	120–360
Bupivacaine 0.25–0.5% plain	5–10	180–480
Bupivacaine 0.25–0.5% with epinephrine^a (1:200 000–1:400 000)	5–10	240–960
Levobupivacaine 0.25–0.5% plain	5–10	180–480
Levobupivacaine 0.25–0.5% with epinephrine^a (1:200 000–1:400 000)	5–10	240–960
Ropivacaine 0.2–0.5%	5–10	120–480

Note: most minor nerve blocks are performed without the addition of epinephrine. Epinephrine is contraindicated in blocks of the digits or penis because tissue ischemia may result. Also, do not exceed maximum dosage listed when blocking several nerves.

a Caution: Maximal adult recommended dose of epinephrine −250 mcg per dose; for children − 3 mcg/kg per dose.

Table 12.5B Major nerve blocks (several nerves or a plexus)

Drug	Volume (mL)	Usual duration (min)
Lidocaine 1–2% plain	50–30	60–180
Lidocaine 1–2% with epinephrine^a (1:200 000–1:400 000)	50–30	120–240
Prilocaine 1–2% plain	50–30	60–180
Prilocaine 1–2% with epinephrine^a (1:200 000–1:400 000)	50–30	120–300
Mepivacaine 1–1.5% plain	50–30	60–180
Mepivacaine 1–1.5% with epinephrine^a (1:200 000–1:400 000)	50–30	180–300
Bupivacaine 0.25–0.5% plain	40–20	180–720
Bupivacaine 0.25–0.5% with epinephrine^a (1:200 000–1:400 000)	50–30	360–1440
Levobupivacaine 0.25–0.5% plain	50–30	Same numbers as for bupivacaine
Levobupivacaine 0.25–0.5% with epinephrine^a (1:200 000–1:400 000)	50–30
Ropivacaine 0.5–0.75% plain or with epinephrine^a (1:200 000–1:400 000)	50–30	360–720

Note: do not exceed maximum dosage listed in Table 12.3.

a Caution: Maximal adult recommended dose of epinephrine − 250 mcg per dose; for children − 3 mcg/kg per dose.

Table 12.6 Epidural anesthesia

Drug	Volume (mL)	Usual duration (min)
Chloroprocaine 2–3% plain or with epinephrine (1:200 000)	30–15	30–60
Lidocaine 1–2% plain	25–15	45–60
Lidocaine 1–2% with epinephrine (1:200 000)	25–15	60–75
Prilocaine 1–3% plain	20–10	45–60
Prilocaine 1–3% with epinephrine (1:200 000)	20–10	60–180
Mepivacaine 1–2% plain	25–15	45–75
Mepivacaine 1–2% with epinephrine (1:200 000)	25–15	60–180
Bupivacaine 0.25–0.75% plain	20–10	90–240
Bupivacaine 0.25–0.75% with epinephrine (1:200 000)	25–10	120–300
Levobupivacaine 0.25–0.75% plain	25–10	Same numbers as for bupivacaine
Levobupivacaine 0.25–0.75% with epinephrine (1:200 000)	30–10
Ropivacaine 0.2–1.0% plain or with epinephrine (1:200 000)	20–10	90–300

Note: do not exceed the maximum recommended dose listed in Table 12.3. Administration in fractionated doses of 3–5 mL is recommended.

Table 12.7 Spinal anesthesia – commonly used agents/doses ^a

Drug	Dose (mg)^b	Usual duration^c (min)
Procaine 5–10%	80–160	30–75
Lidocaine 1–2%	20–100	30–90
Mepivacaine 1.5–4%	20–80	30–90
Bupivacaine 0.5–0.75%	5–18	75–300
Levobupivacaine: same as bupivacaine
Ropivacaine 0.5–1%	8–18	75–300

a While the injected volume of local anesthetic solution (with sufficiently high concentration) is critical in providing successful epidural, plexus, and peripheral nerve blockade, it is the actual local anesthetic dose (mg) that defines effective spinal anesthesia.

b The choice of appropriate local anesthetic dose for spinal anesthesia is influenced by the desired block level (segmental spread) and duration.

c Duration (and spread) is also dependent on baricity of spinally injected local anesthetic solution.

Table 12.8 Miscellaneous blocks

Block	Drug	Volume/dose
Epidural roots	Bupivacaine 0.25%	1–1.5 mL
Facet joint blockade	Bupivacaine 0.25%	2–2.5 mL
Intra-articular facet joint injection	Bupivacaine 0.25%	Less than 1 mL as the joint capacity is limited
Epidural lidocaine and steroid injection	Prednisolone and lidocaine	3 mL of lidocaine 0.5% with 3 mL of methylprednisolone (40 mg/mL)
Peripheral nerve, e.g. occipital nerve	Bupivacaine 0.25–0.5%	2–5 mL
Trigger point	Bupivacaine 0.25–0.5%	1–2 mL
Intravenous regional anesthesia	0.5% lidocaine	30–40 mL
Intravenous lidocaine infusion		5 mg/kg over 45 min
Intrathecal therapy	Lidocaine 2% without preservatives	Start 3 mg/day, increase by 20% per week till analgesia
Intra-articular facet joint injection	Bupivacaine 0.25% Only gold members can continue reading. Log In or Register to continue Share this: Click to share on Twitter (Opens in new window) Click to share on Facebook (Opens in new window) Related Related posts: Inflammatory Basis of Spinal Pain Spondyloarthropathies Medical Rehabilitation – Lumbar Axial Pain Postoperative Rehabilitation Cervical Radicular Pain: Injection Procedures Intradiscal Electrothermal Annuloplasty Stay updated, free articles. Join our Telegram channel Tags: Interventional Spine An Algorithmic Approach Sep 8, 2016 \| Posted by admin in PHYSICAL MEDICINE & REHABILITATION \| Comments Off on Pharmacology of Local Anesthetic Agents Full access? Get Clinical Tree Get Clinical Tree app for offline access Get Clinical Tree app for offline access