Local Anesthetics: Onset, Duration of Action, and Termination of Action

Onset and Duration

pH and pKa

• Local anesthetics are weak bases and exist predominantly in the ionized form at physiologic pH. Agents with a higher pKa have a greater fraction in the ionized form, which is unable to penetrate the lipid cell membrane.¹
• Thus, a higher pKa is associated with a slower onset of action. The pKa values of commonly used local anesthetics are shown in Table 1 below. Sodium bicarbonate may be used as an adjunct to alter the local pH and increase the nonionized fraction, thereby enhancing diffusion across the lipid membrane and accelerating onset.²

Lipid Solubility

• As described in the OA summary “Local Anesthetics: Mechanism of Action and Prolongation” Link, penetration of the phospholipid membrane is essential for local anesthetic action. Thus, local anesthetics with relatively high lipid solubility (e.g., bupivacaine) tend to be more potent because they diffuse more readily through lipid-rich tissues and bind to sodium channels. However, this relationship is more robust in in vitro studies than in vivo studies.¹

Concentration

The effect of local anesthetic concentration on block quality depends on the site of injection, total dose, and type of block (neuraxial vs. peripheral). Concentration primarily influences block density, onset, and, to a limited extent, duration.

• Differential block characteristics
  • Higher concentrations: Denser sensory block, greater motor block, more pronounced sympathetic blockade.
  • Lower concentrations: Preserve motor function, provide mainly sensory analgesia
  • Concentration is the primary determinant of motor block and the degree of sympathectomy for epidural infusions, whereas total dose is the primary determinant of clinical effects with subarachnoid blocks.³
• Onset time
  • Higher concentrations result in a faster onset (i.e., more molecules cross the nerve sheath and bind to sodium channels).
  • However, pKa and lipid solubility are stronger predictors than concentration.
• Duration of action
  • Concentration has a limited effect on duration.
  • Peripheral nerve blocks: Duration mainly determined by total dose (mg).
  • Neuraxial anesthesia: Duration depends on pharmacokinetics (lipid solubility, protein binding), total dose, and adjuncts.
  • Overall, concentration modifies block quality more than true duration.

Nerve Fiber Sensitivity Variation

• Local anesthetics do not affect all nerve fibers equally. Sensitivity depends on fiber diameter, myelination, firing frequency, and anatomical location within the nerve. Small, unmyelinated C fibers are the most sensitive, followed by small, myelinated A-δ fibers, while large, myelinated A-α fibers are the least sensitive.⁴ These differences explain the classic sequence of sensory → Motor changes during a block and the reverse during recovery.

• Fiber diameter
  • Smaller-diameter fibers are blocked more easily than larger fibers.
  • Reason: Less nerve length and fewer sodium channels needed to stop conduction.
  • Approximate order of blockade (most → least sensitive):
    • B fibers: preganglionic sympathetic
    • C fibers: pain, temperature
    • A-δ fibers: fast pain
    • A-γ fibers: muscle spindle tone
    • A-β fibers: touch/pressure
    • A-α fibers: motor
• Myelination
  • Myelinated fibers are generally blocked more easily than unmyelinated fibers of the same diameter because local anesthetic only needs to block nodes of Ranvier.
    • Saltatory conduction allows action potentials to “jump” between nodes, whereas unmyelinated fibers conduct continuously and more slowly.
  • However, fiber diameter predominates: Large, myelinated fibers (A-α) are still less sensitive than small unmyelinated fibers (C fibers).
  • Small unmyelinated fibers are more sensitive because:
    • Less anesthetic penetration is needed.
    • Sodium channels are more diffusely distributed.
• Firing frequency
  • Rapidly firing fibers are more easily blocked because sodium channels cycle through open or inactivated states, which have higher affinity for local anesthetic.
  • This contributes to the strong sensitivity of pain fibers (C and A-δ), which fire rapidly during injury.
• Anatomical Arrangement (Mantle vs. Core)
  • In major peripheral nerves:
    • Mantle fibers (outer): Supply proximal structures; blocked earlier.
    • Core fibers (inner): Supply distal structures; blocked later.
  • Recovery occurs in reverse (distal first).

Termination of Action

Pharmacokinetic Profile of Local Anesthetics

• The duration of action of local anesthetics is closely associated with plasma protein binding, particularly alpha-1-acid glycoprotein (AAG).⁵ Changes in the concentration of free drug can significantly affect the pharmacokinetics and pharmacodynamics of the local anesthetic, because only the unbound drug is active. Conditions that increase protein binding or volume of distribution, such as pregnancy, myocardial infarction, renal failure, the postoperative state, and infancy, may therefore affect the pharmacokinetics of local anesthetics. Ester local anesthetics are minimally protein-bound, while amides are more extensively bound.¹
• Displacement studies show that bupivacaine has the highest affinity for AAG compared to lidocaine and mepivacaine, which accounts for its long duration of action.³ An important exception is ropivacaine compared with bupivacaine. Ropivacaine is 95% protein-bound to AAG, compared with 75% for bupivacaine (the remaining 20% is bound to albumin).⁶ Despite this protein binding, an equivalent dose of bupivacaine produces a longer duration of action than ropivacaine.⁷ Since AAG is an acute phase reactant, ropivacaine may be a safer option for patients receiving a continuous infusion of local anesthetic or those at high risk of local anesthetic systemic toxicity.

Metabolism

Metabolism also plays a crucial role:

• Esters (e.g., procaine) are rapidly hydrolyzed by plasma cholinesterases (aka pseudocholinesterases) into water-soluble, renally excreted metabolites, which results in a short duration of action.
• Cocaine is unique and undergoes hepatic hydrolysis.
• Amides undergo hepatic metabolism via amidases, making their clearance strongly dependent on hepatic blood flow and function.¹

Dose

• The duration of action of local anesthetics increases in a dose-dependent manner across regional block sites.²
• Toxic dose varies by regional block site (e.g., intercostal > caudal > epidural > brachial plexus > peripheral nerve blocks > subcutaneous), as discussed below.

Level of Absorption Among Regional Blocks

• Absorption of local anesthetics varies with vascularity of the injection site, the specific local anesthetic used, and the use of adjuvants.^2,8 Higher systemic absorption leads to both shorter duration and increased risk for toxicity.⁹
• Unsurprisingly, the highest absorption occurs with direct intravascular injection. Techniques to recognize intravascular injection include aspiration prior to injection, epinephrine added as an inadvertent intravascular marker, incremental injection, and ultrasound guidance.⁹
• Regional blocks with the greatest absorption occur in highly vascular structures, including:
  • Tracheal/interpleural
  • Intercostal blocks
  • Caudal anesthesia
  • Epidural anesthesia⁸
• Brachial plexus blocks, including interscalene, supraclavicular, and infraclavicular blocks, demonstrate moderate absorption.⁸
• Lower-extremity nerve blocks, such as femoral, sciatic, and saphenous blocks, generally have lower absorption and thus exhibit longer durations.⁷
• Among fascial plane blocks, injection volume and tissue compliance strongly influence local anesthetic spread and absorption.¹⁰
• Subcutaneous local anesthetic infiltration has the lowest absorption.⁷ It has one of the shortest durations of all techniques due to the following:
  • Relatively low tissue binding.
  • Although vascularity is low, the drug tends to diffuse rapidly and is not confined within a fascial compartment.
  • There is no nerve sheath or fascial boundary to slow redistribution or prolong the effect.