Local Anesthetic: Mechanism of Action and Prolongation

Mechanism of Action

• Local anesthetics inhibit voltage-gated sodium channels, preventing the initiation and propagation of action potentials.
• Only the unionized fraction of the drug can cross the lipid membrane to reach the intracellular site of action; once inside, the ionized form binds reversibly to the open sodium channel.
• The ratio of unionized to ionized drug is determined by the drug’s pKa and the intracellular pH, which influences onset and effectiveness.
• Local anesthetics provide differential neural blockade based on factors such as nerve fiber size, myelination, and firing frequency.
  • Small, unmyelinated, rapidly firing fibers are blocked earlier than large, myelinated, slowly firing fibers.^1,2
• Order of blockade reflects this differential sensitivity: Temperature > Pain > Proprioception and Touch > Motor.¹

Classification

Local anesthetics are divided into two categories: esters and amides.

• Esters: Ester local anesthetics are more susceptible to hydrolysis by pseudocholinesterase, leading to a shorter duration of action. They also have a relatively higher allergic potential due to the para-aminobenzoic acid metabolite.^1,2
  • Examples: Procaine, chloroprocaine, tetracaine
• Amides: Amide local anesthetics typically undergo hepatic metabolism, have a longer duration of action, and a lower allergic potential due to the methylparaben metabolite.^1,2 Their metabolism may be reduced in conditions like hepatic dysfunction, pregnancy, and the use of certain medications.
  • Examples: Lidocaine, bupivacaine, ropivacaine

Uptake and Metabolism

• The speed at which a local anesthetic diffuses into the cell is influenced by the fraction of unionized drug, concentration of the local anesthetic, proximity of the nerve to the site of injection, and lipid solubility.
• Fraction of Unionized Drug: The fraction of unionized drug is the important determinant of the onset of action.
  • This relates to pKa, the pH at which the concentrations of ionized and unionized forms are equal.
  • The pKa relative to tissue pH is critical, as only the unionized form of the drug can cross the nerve membrane.
  • The higher the proportion of unionized drug, the faster it diffuses into nerves, and the faster the onset of the drug’s action.^1,2
  • Infected tissue tends to be acidic, which can slow the onset of action by reducing the amount of unionized drug.
• Concentration of the local anesthetic
  • A higher drug concentration results in a steeper diffusion gradient across the nerve membrane. This accelerates drug diffusion into the nerve, resulting in a faster onset.
• Proximity of the nerve to the site of injection
  • The closer the drug is deposited to the nerve, the faster the onset.
• Lipid solubility:
  • Higher lipid solubility determines potency and allows more rapid nerve penetration, increasing duration of action and volume of distribution.
• Peak plasma concentrations: These are determined by the injection site, dose, and the solution’s vasoactive properties.
  • Order of peak concentration after a single dose (from highest to lowest): intrapleural > intercostal > epidural > brachial plexus > subcutaneous.¹
  • Local anesthetic distribution follows the degree of perfusion: first to high-flow organs (brain, heart, lungs), then muscle and fat.¹

Prolongation of Action

• Prolongation of local anesthetics is influenced by several factors, including protein binding, site vascularity, dose, additives (adjuncts), patient factors, lipid solubility, formulation, and temperature.
• Protein binding (the most important intrinsic factor)
  • Strong binding to tissue and plasma proteins slows drug clearance, leading to a longer duration.
  • Example: Bupivacaine > Ropivacaine > Lidocaine
• Site of vascularity
  • The greater the vascularity at the site of injection, the faster the drug is absorbed, reducing the duration of action.
• Dose
  • Higher tissue concentrations prolong the local effect, though there is a ceiling effect.
• Additives
  • Vasoconstrictors: Epinephrine is commonly used to achieve local vasoconstriction by activating α1-adrenergic receptors, thereby delaying systemic absorption of local anesthetics. Concentrations greater than 1:200,000 (5 µg/ml) confer little advantage.^2,4
    • The effect of epinephrine on prolonging the duration of action of local anesthetics varies by agent. Vasoconstriction slows systemic absorption for all local anesthetics, but the degree of prolongation depends on the drug’s protein binding and lipid solubility.
  • Short-acting agents (e.g., lidocaine) gain the most benefit, while long-acting agents (e.g., bupivacaine) see minimal added duration, typically less than 60 minutes of prolongation.⁵
    • There is no increase in heart rate or blood pressure when epinephrine is added to the block. However, the peak plasma concentration decreases by 50%, and the time to peak is doubled, thereby greatly reducing the risk of systemic local anesthetic toxicity.⁶
  • Clonidine: Believed to work by activating ɑ2 adrenergic receptors and hyperpolarizing cation channels; block duration is prolonged by an average of 2-3 hours.⁷
    • Studies have demonstrated increased risk of bradycardia, sedation, and hypotension.⁷
    • The typical dose is 1 mcg/mg (up to 100 mcg) per block.
  • Dexmedetomidine: Believed to work by activating ɑ2 adrenergic receptors and hyperpolarizing cation channels; has 7 times greater affinity than clonidine.⁴
    • Block duration is prolonged by an average of 2-3 hours.⁷
    • The typical dose is 1 mcg/mg (up to 100 mcg) per block.
  • Opioids: Buprenorphine, morphine, and fentanyl have been closely studied.
    • Buprenorphine exerts antihyperalgesic effects, believed to be mediated by its action at μ, κ, and δ receptors. Demonstrates some block-prolonging capabilities but also carries a risk of PONV.⁴
    • Morphine and fentanyl are not recommended for routine use in blocks. Neither opioid has demonstrated significant block prolonging capabilities, conferring a strong side effect profile, significantly increasing nausea and vomiting for patients.⁴
  • Dexamethasone: Unclear mechanism of action. Associated with anti-inflammatory properties through transcription factor effects; likely works through vasoconstrictive effects. Increase in block prolongation on average of 3-4 hours.⁹
    • Historically, there has been a theoretical risk of peripheral neurotoxicity with perineural dexamethasone from animal studies; however, more recent studies suggest this association is not true.¹⁰
    • Intravenous dexamethasone versus perineural dexamethasone remains controversial, but perineural dexamethasone is likely better for certain blocks with no additional benefit to a dose greater than 2-4 mg total for the entire block.
    • Dexamethasone’s ability to prolong analgesia may help decrease the risk of rebound pain after a single-shot peripheral nerve block.
• Patient factors
  • Age and Comorbidities: Older patients or those with certain comorbidities (e.g., hepatic disease, renal disease, hypoalbuminemia) may alter clearance and prolong the effect.
• Lipid solubility
  • • Higher lipid solubility modestly increases the duration the drug stays within the nerve membrane.
• Formulation type
  • Liposomal or Extended-release Formulations: These theoretically allow for a slower, sustained release of anesthetic, prolonging the duration of action. However, recent studies demonstrated no benefit compared to plain bupivacaine.
• Temperature
  • Lower temperatures can subtly slow the metabolism and absorption of local anesthetics, prolonging their effects, but is less impactful than the above factors.