Lecture 64: Local Anesthetics Richard D. Minshall, PhD Tobias Piegeler, MD Departments of Anesthesiology and Pharmacology February 28th, 2012Outline A. Pharmacologic aspects: Basic structural characteristics Mechanism of nerve conduction Mechanisms of local anesthetic action Characteristics of local anesthetic action Metabolism Why are vasoconstrictors often added to the local anesthetic preparations? B. Clinical Aspects: Problem-based learning with clinical vignettesChemical structure Procaine Lidocaine Bupivacaine Tetracaine H2N C O CH2 CH2 N C2H5 C2H5 O HN C O CH2 CH2 N CH3 CH3 O C4H9 C O N CH3 CH3 NH C4H9 C O CH3 CH3 NH CH2 N C2H5 C2H5 Lipophilic group Linker Hydrophilic group Ester-linked Amide-linkedLocal anesthetics… are drugs used to prevent or relieve pain in specific regions of the body without loss of consciousness reversibly block pain sensation by blocking nerve conduction DefinitionNeural transmissionResting potentialAction potential- - - - - - - ++++ + + + + + + + - - - - - - Mechanism of action Local anesthetics reversibly bind to the voltage-gated Na+ channel (VGSC) block Na+ influx and thus block action potential and nerve conduction. Local anesthetics Propagation failureVGSC(1) I II III IV Catterall WA, Neuron 2000; 26(1):13-25 LAVGSC(2) Pink: Local anesthetic binding site in the inner cavity of the pore In Segment 6 of Domain IV (IVS6-Helix) Green: Binding site for Tetrodrotoxin Catterall WA, Neuron 2000; 26(1):13-25- - - - - - - ++++ + + + + Local anesthetics + + + - - - - - - ++++ + ++ ++ ++ + + + + + + + + + + + + + + Propagation failure Influence of fiber type Local anesthetics more effectively block small nerve fibers!Different nerve fiber typesUse-dependent block Nerves with higher firing frequency and more positive membrane potential are more sensitive to local anesthetic block!Influence of pH + + + + + Low pH High pH Normal pH + + + + + + + + +Reason for pH influence? closed BH+ B + H+ B B BH+ BH+ open inactivated Na+ extracellular intracellular H+ +Metabolism 1. Most ester-linked local anesthetics are quickly hydrolyzed by plasma cholinesterase (exception: cocaine) 2. Amide-linked local anesthetics undergo oxidative dealkylation/oxygenation by monooxygenases and hydroxylation by carboxylesterase in the liver 3. Water-soluble metabolites are excreted in the urine.Vasoconstrictor addition 1. Local anesthetics are removed from depot site mainly by absorption into blood. 2. Addition of vasoconstrictor drugs (e.g. epinephrine) reduces absorption of local anesthetics, thus prolonging anesthetic effect and reducing systemic toxicity. NOTE: Do not use vasoconstrictors in areas with (functional) end arteries possible development of necrosis due to prolonged
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