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Local Anesthetic Drugs

Barash, Cullen, and Stoelting's Clinical Anesthesia, 9e — Chapter 22

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1. Historical Background

• Cocaine was the first local anesthetic, isolated by German chemists Albert Niemann and Wilhelm Lossen in 1860. Carl Koller demonstrated its analgesic properties for ophthalmologic use in 1884. Simultaneous reports emerged of CNS and cardiovascular toxicity, and addiction.
• Procaine (Novocaine) was synthesized by Alfred Einhorn in 1905 - an amino ester, low potency, prone to allergic reactions.
• Lidocaine (Xylocaine) was developed by Löfgren and Lundquist in 1944 - an amino amide with rapid onset, potency, and low allergenic potential. All subsequent LAs have been amino amides.
• Bupivacaine was introduced in 1965 (synthesized 1957). By 1980, reports emerged of simultaneous seizures and cardiovascular collapse from intravascular injection.
• Ropivacaine was introduced in 1996 as a safer long-acting alternative - structurally similar to bupivacaine but approximately 25% less potent.

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2. Anatomy of Nerves Relevant to LA Action

Peripheral Nerve Structure

• Individual nerve fibers surrounded by endoneurium (loose connective tissue)
• Perineurium - dense collagenous layer surrounding each fascicle
• Epineurium - outermost layer encasing groups of fascicles
• These layers act as barriers to passive diffusion of local anesthetics

Myelinated vs. Unmyelinated Fibers

• Myelinated fibers: wrapped by Schwann cells (PNS) or oligodendrocytes (CNS); interrupted by nodes of Ranvier; conduct by saltatory conduction
• Unmyelinated C fibers: embedded in Schwann cells without wrapping; conduct slowly

Nerve Fiber Classification (Table 22-1)

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3. Mechanism of Action

Voltage-Gated Sodium Channels (VGSC)

• The key target of all local anesthetics is the voltage-gated Na⁺ channel
• VGSCs exist in three states: resting (closed), open (activated), inactivated
• LA binding is intracellular at the inner vestibule of the channel, mediated by hydrophobic interactions
• LAs preferentially bind the open and inactivated states (use-dependent or phasic block) - rapidly firing nerves are more sensitive
• Binding blocks Na⁺ influx → prevents membrane depolarization → blocks action potential propagation

Mechanism of Nerve Blockade

• LAs must penetrate the nerve membrane to reach the binding site
• The uncharged (free base) form crosses the membrane; the cationic (charged) form binds the channel from inside
• Three consecutive nodes of Ranvier must be blocked for complete conduction failure in myelinated fibers
• Degree of nerve blockade depends on both drug concentration and volume

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4. Chemical Properties and Structure-Activity Relationships

Basic Structure

1. A lipophilic aromatic ring (benzene derivative)
2. An intermediate chain - either an ester or amide linkage
3. A hydrophilic amine (tertiary or quaternary amine)

Classification

Physicochemical Properties Governing Activity

Stereoisomerism

• Bupivacaine is a racemic mixture; the R(+) enantiomer is more cardiotoxic
• Levobupivacaine (S(-) enantiomer) and ropivacaine (pure S(-) enantiomer) have improved cardiovascular safety profiles

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5. Additives to Increase Local Anesthetic Activity

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6. Pharmacokinetics

Systemic Absorption

Intercostal > Caudal/Epidural > Brachial plexus > Femoral/Sciatic

• Tissue vascularity is the main determinant
• For a given site, peak plasma level is directly proportional to dose (near-linear relationship)
• More lipid-soluble agents are absorbed slower (sequestered in lipid-rich compartments)
• At low concentrations, potent agents cause local vasoconstriction reducing absorption; at high concentrations, vasodilation predominates

Distribution

• Rapid distribution after systemic absorption
• Depends on organ perfusion, partition coefficient, and plasma protein binding
• Well-perfused organs (heart, brain) accumulate higher concentrations - coinciding with toxicity targets
• Volume of distribution (VDss): larger for more lipid-soluble agents

Protein Binding

• LAs bind primarily to α₁-acid glycoprotein (AAG) and secondarily to albumin
• AAG is an acute phase reactant - elevated in surgical stress, malignancy, trauma; decreased in neonates, liver disease, pregnancy

Elimination

• Rapid hydrolysis; para-aminobenzoic acid (PABA) is the main metabolite - responsible for allergic reactions
• Patients with pseudocholinesterase deficiency are at risk for prolonged effect

• Slower elimination; hepatic blood flow and enzyme activity are important determinants
• Hepatic disease, cardiac failure, elderly patients → reduced clearance → higher plasma levels

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7. Clinical Use of Local Anesthetics

Methods of Administration

• Topical/surface (mucous membranes, skin - EMLA cream)
• Infiltration (subcutaneous, intradermal)
• Peripheral nerve blocks (regional anesthesia)
• Neuraxial (spinal/intrathecal, epidural, caudal)
• Intravenous regional (Bier block - uses lidocaine only)

Clinical Profile of Selected Agents (Table 22-9)

Differential Sensory vs. Motor Block

• Bupivacaine at low concentrations allows sensory block > motor block - useful in obstetric epidurals
• Ropivacaine has less intrinsic motor-blocking activity compared to bupivacaine at equianalgesic doses

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8. Toxicity of Local Anesthetics

8a. Local Anesthetic Systemic Toxicity (LAST)

• Systemic absorption or direct intravascular injection → elevated plasma levels → CNS and cardiovascular toxicity

1. Circumoral tingling, tongue numbness
2. Light-headedness, tinnitus, visual disturbances
3. Slurred speech, nystagmus
4. Tremors, muscle twitching
5. Tonic-clonic seizures
6. CNS depression, coma, respiratory arrest

• PR prolongation, QRS widening, AV block
• Negative inotropy, vasodilation
• Ventricular fibrillation/cardiovascular collapse (especially bupivacaine)
• Bupivacaine's R(+) enantiomer binds cardiac Na⁺ channels with high affinity and dissociates very slowly ("fast-in, slow-out")

• Patient: extremes of age, low muscle mass, female sex, arrhythmias/heart failure, hepatic insufficiency, CNS disease, low plasma protein binding
• Drug: potent anesthetics, high vascularity block site, high dose, prolonged infusion
• Setting: non-hospital settings, non-anesthesiologist

• Aspiration test before injection
• Incremental injection with fractionated doses
• Use of epinephrine as intravascular marker (tachycardia if injected IV)
• Ultrasound guidance for peripheral nerve blocks
• Use minimum effective dose

8b. Treatment of LAST

1. Stop LA injection immediately - call for help
2. Secure airway - 100% O₂, prevent hypoxia/hypercapnia/acidosis (worsen toxicity)
3. Seizure control: benzodiazepines (midazolam/diazepam) are preferred; small doses of propofol or thiopental with caution; neuromuscular blockade if prolonged
4. Cardiovascular support: ACLS principles
   • Epinephrine: limit initial bolus to <1 mcg/kg (avoid malignant arrhythmias)
   • Avoid: vasopressin, calcium channel blockers, beta-blockers, antiarrhythmics using Na/Ca channel block
   • Amiodarone for ventricular dysrhythmias
5. Intralipid (20% lipid emulsion therapy):
   • Acts as a "lipid sink" - sequesters lipophilic LAs away from cardiac tissue
   • Dose: 1.5 mL/kg IV bolus, followed by 0.25 mL/kg/min infusion
   • May repeat bolus × 2 for refractory cases
   • Consider early in severe bupivacaine toxicity

8c. Neural Toxicity

• Occur after spinal anesthesia (especially with lidocaine - highest incidence)
• Pain/dysesthesia in buttocks and legs radiating to lower extremities
• Resolves within 72 hours; associated with lithotomy position and ambulatory surgery
• Incidence lower with bupivacaine, prilocaine, procaine

• Associated with maldistribution of hyperbaric lidocaine through microcatheters
• Direct neurotoxicity from high concentration pooling

8d. Myotoxicity

• Direct injection of LAs into muscle (especially bupivacaine) → localized myonecrosis
• Usually reversible; rare systemic concern

8e. Allergic Reactions

• Amino esters - true IgE-mediated allergic reactions possible, due to PABA metabolite
• Amino amides - true allergy is extremely rare; most "reactions" are vasovagal, anxiety, or intravascular injection
• Cross-reactivity between esters exists; cross-reactivity between amides is essentially non-existent
• Many vials contain methylparaben (a PABA-related preservative) - can cause allergic reactions in ester-sensitive patients; preservative-free preparations should be used in sensitive individuals
• Skin testing approach: provocative dose testing with incremental subcutaneous injections; negative predictive value ~97%

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9. Future Therapeutics

• Extended-release formulations using liposomes and microspheres (e.g., liposomal bupivacaine - EXPAREL)
• Pharmaceutical development of site-specific or receptor-selective agents
• Sodium channel subtype-selective agents (Nav1.7/Nav1.8 selective) for pure analgesia without motor block - promising but not yet in clinical use

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10. Key Points Summary (Chapter 22)

1. LAs block pain transmission by blocking voltage-gated Na⁺ channels; binding is intracellular via hydrophobic interactions
2. Most agents are amino amides; classified by the ester or amide linkage in the intermediate chain
3. Potency correlates with lipid solubility; onset correlates with pKa (lower pKa → faster onset); duration correlates with protein binding
4. Epinephrine, dexamethasone, opioids, and α₂-agonists can extend LA block duration and reduce required doses
5. Rate of systemic absorption: intercostal > caudal/epidural > brachial plexus > femoral/sciatic
6. Amino esters are hydrolyzed by plasma esterases; amino amides are hepatically metabolized
7. LAST presents as CNS excitation progressing to seizures, then cardiovascular collapse; bupivacaine carries the highest cardiac toxicity risk
8. Treatment of LAST: stop injection, secure airway, benzodiazepines for seizures, epinephrine (<1 mcg/kg), 20% intralipid emulsion (1.5 mL/kg bolus)
9. TNS occurs most frequently after spinal lidocaine, especially in lithotomy position
10. True allergic reactions are almost exclusive to amino esters (PABA metabolite); amide allergy is exceedingly rare

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