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 hypoperfusion!!!What’s the problem? Too much local anesthetic!Corning JL: Spinal anaesthesia and local medication of the cord. New York State Med J 42:483 (1885) Bier A: Versuche über Cocainisirung des Rückenmarkes. Deutsche Zeitschrift für Chirurgie 1899;51:361. HistoryToday Examples of local anesthetic use: Infiltration Field block Nerve block Intravenous regional block Spinal anesthesia Epidural nerve block Topical anesthesiaCase 1 67 y.o. male with a histologically proven malignancy in the right sidewall of his bladder presenting for a TUR-B. PMH: COPD w/ 90 py (and counting...), FEV1 = 65% VC, HTN, no known CAD or CVD Meds: Tiotropium bromide inhaler ACE-I Previous surgeries/anesthesias: Cystoscopy 01/2012 under GA PONV Vitals: HR 78/min, BP 135/78, RR 14/min, Pulse regular, SpO2 91% at room air Auscultation: S1, S2, no murmurs, rhythmic, lungs with discrete basal expansion crackling rales on both sides Proposed anesthesia?Case 1 Spinal Anesthesia! (Hyperbaric) Bupivacaine +/- opioidIs that enough? SPA: testing the effect Try to establish the area where the patient will recognize a cool pack as a warm sensation or won’t recognize it at all! Spinal segments correlate with dermatomes! T10 is sufficient for cystoscopy NOTE: 1. Hypotension due to loss of sympathetic tone (C fibers T5-L1!) 2. High spinal above T4 block of the Nn. accelerantes = sympathetic cardiac acceleratorsObturator nerveObturator nerve block General technique for a block with a nerve stimulator: 1. Stimulation started at e.g. 2 mA for 0.1 ms at 1 Hz 2. Advance the needle at the correct location until desired muscle twitching is visible 3. Current is gradually decreased to 0.2 mA to confirm proximity to the nerve 4. After confirmation of needle position, LA is injectedCase 2 You are on call. It‘s 3 am in the morning. You receive a call from the OB resident requesting your service for a 27 y.o. female, gravida 1, para 0 in the labor room, otherwise healthy. “She just needs a little pain relief“, the resident tells you... When you enter the room, you find a profusely sweating young woman in serious distress and pain, who is yelling at an exhausted young male, who seems to be her husband, as well as at the mid-wife, who tries to calm her down. Now she starts screaming at you… Procedure?Case 2 Epidural Anesthesia!Epidural Anesthesia(1) Disinfection and prepping Skin and subcutaneous infiltration Needle insertionEpidural Anesthesia(2) Needle advancement with loss of resistance technique Catheter insertion Then: 1. Test dose of LA with epinephrine Tachycardia? 2. Start of LA: e.g. ropivacaine 0.1% („walking epidural“) +/- low dose sufentanilCase 2: Unforeseen… The epidural works fine, the mother stopped yelling and swears to name her baby after you for taking her pain away and you get back to bed. 4 am: The OB resident tells you now, that they have to do a non-emergent C-section on your patient due to unforeseen positioning of the baby. And now? General anesthesia with a high risk of aspiration and airway problems? Solution: Change the ropivacaine from 0.1% to 0.33% and give a bolus. Check the effect (dermatomes!) and repeat and/or raise continuous infusion until effective analgesia is reached.Case 3 A 37 y.o. male with a fracture of the distal radius after an accident with his bicycle is scheduled for ambulant surgical repair of the fracture. PMH: healthy Meds: None Past surgeries: None Vitals: excellent You decide to cover the patients needs with a
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