Lecture 64 Local Anesthetics Richard D Minshall PhD Tobias Piegeler MD Departments of Anesthesiology and Pharmacology February 28th 2012 Outline 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 vignettes Chemical structure O Procaine C2H5 H2N C O CH2 CH2 N C2H5 Ester linked O Tetracaine CH3 HN C O CH2 CH2 N C4H9 O CH3 Bupivacaine NH C N CH3 CH3 Lidocaine NH CH3 O C CH2 C4H9 C2H5 N C2H5 Amide linked CH3 Lipophilic group Linker Hydrophilic group Definition Local 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 Neural transmission Resting potential Action potential Mechanism of action Local anesthetics reversibly bind to the voltagegated Na channel VGSC block Na influx and thus block action potential and nerve conduction Local anesthetics Propagation failure VGSC 1 I II III IV LA Catterall WA Neuron 2000 26 1 13 25 VGSC 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 Influence of fiber type Local anesthetics Propagation failure Local anesthetics more effectively block small nerve fibers Different nerve fiber types Use 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 BH B H Na extracellular B BH H B BH intracellular closed open inactivated 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 hypoperfusion
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