Medical Pharmacology Chapter 15: Local Anesthetics

• Local anesthetics are weak bases;  pKa somewhat above physiologic pH

  •  less than 50% of molecules are in the lipid-soluble,  un-ionized form at pH 7.4

    • At pH 7.4:   5% of tetracaine (pontocaine) molecules are un-ionized

  • Local infection (acidosis) increases the ionized drug fraction (less drug available to penetrate across membranes and bind to intracellular local anesthetic receptor)

  • Local anesthetics with pKs closest to physiologic pH are associated with more rapid onset of action (better ratio of ionized to  un-ionized drug)

• Vasodilator properties of the local anesthetic

  •  Affects both apparent  potency and duration of action.

  •  Lidocaine (Xylocaine) causes greater vasodilation compared to mepivacaine (Carbocaine) and therefore is associated with:

    1. Enhanced systemic absorption

    2. Shorter duration of action.

• Lipid solubility:

  •  Bupivacaine (Marcaine) and etidocaine (Duranest) (similar vasodilation).

  •  Following epidural: mepivacaine (Carbocaine) plasma concentration higher than that for etidocaine (Duranest).

    • Etidocaine (Duranest): greater lipid solubility leads to increased tissue sequestration (reduced drug available).

• Absorption and Distribution:

  • Factors:

    •  Injection site

      • Vascularity:

        • Highly vascular area (e.g. tracheal mucosa): promotes rapid absorption resulting in higher blood levels

        • Poorly vascular area (tendon) is associated with relatively poor absorption

      • Regional anesthesia (block of large nerves):

        • Maximum blood levels (highest to lowest)

          • Intercostal (highest)  > caudal > epidural > brachial plexus > sciatic nerve {lowest}

    •  Dosage:

      •  Presence of vasoconstrictors (e.g. epinephrine)

        • Reduced systemic absorption due to local vasoconstriction

          •  Increased neuronal uptake (higher local concentration)

          •  Blood levels: reduced as much as 1/3

        • The presensce of vasoconstrictors have a particularly significant effect for local anesthetics with intermediate/short duration of action (e.g.,procaine (Novocain), lidocaine (Xylocaine), mepivacaine (Carbocaine) [not prilocaine (Citanest)])

          •  Vasoconstrictor addition has a lesser effect for more lipid soluble (longer-acting) agents: bupivacaine (Marcaine), etidocaine (Duranest). The lipid solubility of these agents tend to keep them in the local tissue site intrinsically.

          •  Cocaine is the local anesthetic with intrinsic sympathomimetic, vasoconstrictive properties.

        • Spinal anesthesia: Enhancement and prolongation of local anesthetic spinal anesthesia by:

          1. Activating α₂ adrenergic receptors (inhibit substance P release and reduce dorsal horn neural activity).

             Addition of clonidine (α₂ receptor agonist, Catapres) to local anesthetic solutions enhance the local anesthetic effect through reduction in neuronal activity and inhibition to substance P release).

          2. Reduced systemic absorption.

          3. Increased local neuronal uptake.

    •  Chemical properties of the drug.

  • Plasma concentration is determined by:

    1.  Rate of tissue distribution.

    2.  Rate of drug clearance.

    3.  Consider lidocaine (Xylocaine) distribution-- IV infusion: duration = 1-minute.

       •  Initial high uptake into lungs and redistribution to highly perfusion tissues (heart, kidney, brain).

         • Redistribution: limited solubility important. A highly soluble agent in a tissue will be more likely to remain in that initial site of concentration.

         • Following distribution to brain, kidney, heart-- redistribution to other tissues (less perfused)-- e.g. muscle, fat.

  • Other factors influencing local anesthetic distribution/plasma concentrations.

    •  Patient age, liver function, cardiovascular status, protein binding.

  • "Amide" local anesthetic agents more widely distributed compared to "ester" local anesthetics.

  • Pulmonary Extraction

    • Pulmonary extraction from the venous circulation limits the amount of local anesthetic (lidocaine (Xylocaine), bupivacaine (Marcaine), and prilocaine (Citanest)) that will reach the systemic circulation.

    • Bupivacaine (Marcaine): dose-dependent, first pass extraction (saturable, uptake).

      •  Propranolol (Inderal) inhibits bupivacaine (Marcaine) extraction.

      •  Propranolol (Inderal) reduces lidocaine (Xylocaine) and bupivacaine (Marcaine) plasma clearance.

  • Placental Transfer

    • Dependency:

      • Plasma protein binding influences:

        • Rate and extent of local anesthetic diffusion across the placenta.

    • Ester-local anesthetics are not associated with significant placental transfer, due to rapid hydrolysis.

    •  Fetal acidosis  which may occur during prolonged labor,  promotes, by ion trapping mechanism, accumulation of local anesthetic in the fetus.

  • Clearance:

    • Amides are cleared by the liver (hepatic) with minimal renal excretion of unchanged drug.

    • Esters exhibit rapid clearance, showing short elimination halftime due to rapid hydrolysis.

Miller, R.D., Local Anesthesia, in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, pp 425-433.

Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181.