localAnesthetics08Oct - Local Anesthetics Local by Brendan...

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Unformatted text preview: Local Anesthetics Local by Brendan Astley MD October 2008 Local Anesthetics Local Used at multiple sites throughout the body: Epidural Spinal Peripheral nerve blocks IV (Bier Block) Skin sites locally Amides and Esters Amides Lidocaine (Xylocaine) Bupivacaine (Marcaine) Etidocaine (Duranest) Mepivacaine Mepivacaine (Carbocaine) (Carbocaine) Prilocaine (Citanest) Ropivacaine Chloroprocaine Chloroprocaine (Nesacaine) (Nesacaine) Cocaine (crack) Procaine Tetracaine (Pontocaine) Mechanism of Action Mechanism Local anesthetics work in general by binding to Local sodium channel receptors inside the cell and thereby inhibiting action potentials in a given axon. They work the best when the axon is firing. work The Cell membrane consists of ion pumps, most The notably the Na/K pump that create a negative 70mV resting potential by pumping 2 K+ intracellular for every 3 Na+ it pumps extracellular. every Mechanism of Action (cont’d) Mechanism If the resting potential encounters the proper If chemical, mechanical or electrical stimuli to reduce the membrane potential to less than -55 mV then an action potential is produced that allows the influx of sodium ions. LA act here to block the Na influx. sodium The influx allows the membrane potential to further The increase to +35mV temporarily. increase Sodium and potassium channels along with the Sodium sodium/potassium pump eventually returning a given axon back to it’s resting membrane potential after an action potential. action Mechanism of Action Mechanism Benzocaine…. Does not exist in a charged form how does it Does work? work? Most likely by expanding the lipid membrane of Most the axon and therefore inhibiting the transport mechanisms of Na and K ions. mechanisms General Structure General A lipophilic group…usually a benzene ring A Hydrophilic group…usually a tertiary amine These are connected by an intermediate chain These that includes an ester or amide linkage that LAs are weak bases Lipid solubility Lipid Most lipid soluble: Increased lipid solubility also equals greater potency and Increased longer duration of action. longer Tetracaine Bupivicaine Ropivacaine Etidocaine Why? Because it has less of a chance of being cleared by blood flow Decreased lipid solubility means a faster onset of action. Decreased What else effects onset of action??? pKa pKa Local anesthetics with a pKa closest to physiological Local pH will have a higher concentration of nonionized base that can pass through the nerve cell membrane, and generally a more rapid onset. and The charged cation form more avidly binds to the The Na+ channel receptors inside the cell membrane. Na+ pKa > 7.4 more cations, pKa < 7.4 more anions Not all Axons are equal Not Αα− Motor with fast conduction 70-120m/s, diameter 12-20mm, myelinated and not very sensitive to local anesthetic anesthetic Aα- Type Ia and Ib- proprioception fast conduction Type again 70-120m/s, same diameter as above, a little more sensitive to LA, myelinated more Aβ- Touch pressure and proprioception, smaller Touch diameter 5-12mm and slower conduction 30-70m/s, myelinated and as sensitive to LA as type Ia and Ib fibers fibers Not all Axons are equal Not Aγ - motor (muscle spindle) smaller diameter motor 3-6mm, slower conduction 15-30m/s same LA sensitivity as type Ia and Ib fibers sensitivity Αδ- Type III fibers, pain, cold temperature and Type touch, smaller diameter 2-5mm, 12-30m/s, more sensitive to LA than the above fibers and myelinated. myelinated. Not all Axons are equal Not B fibers- Preganglionic autonomic fibers, <3mm diameter, 314m/s conduction speed and very sensitive to LA. Some 14m/s myelination. myelination. C fibers- Type IV fibers in the dorsal root, pain warm and cold fiberstemp. and touch, .4-1.2mm in diameter, slow conduction again at .5-2m/s, very sensitive to LA, not myelinated. at C fibers- Postganglionic sympathetic fibers, smaller diameters fibersat .3-1.3mm, slow conduction at .7-2.3m/s, very sensitive to LA and no myelination. LA In general this all means that the autonomic nerves are In blocked before the sensory nerves which are blocked before the motor nerves. the AMIDES AMIDES Bupivacaine, Etidocaine and RopivacaineBupivacaine, very high potency and lipid solubility, very long duration and protein binding also. long Lidocaine, Prilocaine and Mepivacaine- have Lidocaine, intermediate potency and lipid solubility and intermediate duration of action and protein binding. binding. ESTERS ESTERS Chloroprocaine and Procaine- have low Chloroprocaine potency and lipid solubility and also low duration and protein binding. duration Cocaine- has intermediate potency and Cocainesolubility and intermediate duration and protein binding protein Tetracaine- has high potency and lipid Tetracainesolubility along with a long duration of action and high protein binding and Plasma protein binding Plasma What protein are LAs bound??? Mostly α1-acid glycoprotein Mostly -acid To a lesser degree albumin Absorption Absorption Mucous membranes easily absorb LA Skin is a different story… It requires a high water conc. for penetration and a It high lipid concentration for analgesia high Which LAs can we use for this? EMLA cream- 5% lidocaine and 5% prilocaine in an oilwater emulsion An occlusive dressing placed for 1 hour will penetrate 35mm and last about 1-2 hours. Typically 1-2 grams of drug per 10cm2 of skin Rate of systemic absorption Rate Intravenous > tracheal > intercostal > caudal > Intravenous paracervical > epidural> brachial plexus > epidural sciatic > subcutaneous subcutaneous Any vasoconstrictor present?? High tissue binding also decreases the rate of High absorption absorption Metabolism Metabolism Amides… N-dealkylation and hydroxylation P-450 enzymes, liver, slower process than esterase activity Prilocaine>lidocaine>mepivacaine>ropivacaine>bupivacai ne Prilocaine has a metabolite…. o-toluidine o-toluidine This causes methemoglobin to form (Benzocaine can also This cause methemoglobin to form) cause Treated with methylene blue 1-2mg/kg over 5 minutes Reduces methemoglobin Fe3+ to hemoglobin Fe2+ Metabolism Metabolism Esters… Procaine and benzocaine are metabolized to… Pseudocholinesterase PABA (p-aminobenzoic acid) allergy risk Tetracaine intrathecal has it’s action Tetracaine terminated by… terminated No esterase activity intrathecally therefore No absorption into bloodstream terminates it’s action absorption Clinical Uses Clinical Esters Benzocaine- Topical, duration of 30 minutes to 1 Topical, hour hour Chloroprocaine- Epidural, infiltration and Epidural, peripheral nerve block, max dose 12mg/kg, duration 30minutes to 1 hour duration Cocaine- Topical, 3mg/kg max., 30 minutes to one Topical, hour hour Tetracaine- Spinal, topical, 3mg/kg max., 1.5-6 Spinal, hours duration Clinical Uses Clinical Bupivacaine- Epidural, spinal, infiltration, peripheral Epidural, nerve block, 3mg/kg max., 1.5-8 hours duration nerve Lidocaine- Epidural, spinal, infiltration, peripheral Epidural, nerve block, intravenous regional, topical, 4.5mg/kg or 7mg/kg with epi, 0.75-2 hours duration or Mepivacaine- Epidural, infiltration, peripheral nerve Epidural, block, 4.5mg/kg or 7mg/kg with epi, 1-2 hours block, Prilocaine- Peripheral nerve block (dental), 8mg/kg, Peripheral 30 minutes to 1 hour duration 30 Ropivacaine- Epidural, spinal, infiltration, peripheral Epidural, nerve block, 3mg/kg, 1.5-8 hours duration nerve Systemic Toxicity Systemic Blockage of voltaged-gated Na channel affects Blockage action potential propagation throughout the body…therefore the potential is present for systemic toxicity. systemic Mixtures of LA have additive affects i.e. a 50% toxic dose of lidocaine and a 50% toxic i.e. dose of bupivicaine have 100% the toxic affect of either drug either Systemic Toxicity Systemic Neurological Symptoms include cicumoral numbness, tongue Symptoms paresthesia, dizziness, tinnitus, blurred vision, restlessness, agitation, nervousness, paranoia, slurred speech, drowsiness, unconsciousness. slurred Muscle twitching heralds the onset of tonic-clonic Muscle seizures with respiratory arrest to follow. seizures Local anesthetic toxicity Local Seizure treatment: Thiopental 1-2mg/kg abruptly terminates seizure Thiopental activity activity Benzos and hyperventilation…decrease CBF and Benzos therefore drug exposure. These raise the threshold of local anesthetic-induced seizures of Chloroprocaine injected intrathecally can Chloroprocaine cause prolonged neurotoxicity. This is likely due to a preservative no longer used with this agent. (Sodium bisulfate) agent. Local anesthetic toxicity Local Repeated doses of 5% lidocaine and .5% tetracaine Repeated may be responsible for cauda equina syndrome following infusion through small bore catheters in spinal anesthetics. Pooling of drug around the cauda equina resulted in Pooling permanent neurological damage permanent Animal studies suggest that neuro damage is: Animal Lido=tetracaine>bupivacaine>ropivacaine. Also perservative free chloroprocaine may be neurotoxic Local anesthetic toxicity Local Transient Neurological Symptoms This is associated with dysethesia, burning pain and This aching in lower ext, buttocks. aching Follows spinal anesthesia with variety of agents Follows (lido), attributed to radicular irritation and resolves in 1 week usually week Risk factors include Lidocaine intrathecally Lithotomy position Obesity Outpatient status Local anesthestic toxicity Local Respiratory center may be depressed Respiratory (medullary)…postretrobulbar apnea syndrome (medullary)…postretrobulbar Lidocaine depresses hypoxic respiratory drive Lidocaine (PaO2) (PaO2) Direct paralysis of phrenic or intercostal Direct nerves nerves LA cardio toxicity LA All LA’s depress spontaneous Phase IV All depolarization and reduce the duration of the refractory period refractory Myocardial contractility and conduction Myocardial velocity are depressed at higher concentrations velocity All LA’s except cocaine cause smooth muscle All relaxation and therefore vasodilation (art) whick can lead to brady, heart block and hypotension…cardiac arrest. hypotension…cardiac LA cardio toxicity LA Major cardiovascular toxicity usually results Major from 3 times the blood concentration of LA that causes seizures. that Therefore cardiac collapse is usually the Therefore presenting sign under GA. presenting R isomer of bupivacaine avidly blocks cardiac isomer sodium channels and dissociates very slowly. Making resuscitation prolonged and difficult. Making LA cardio toxicity LA Levo-bupivacaine (S isomer) is no longer Levo-bupivacaine avaliable in the US but had a cardiovascular profile similar to ropivacaine. profile Ropivacaine has a larger therapeutic index and Ropivacaine it is 70% less likely to cause severe cardiac dsyrhythmias than bupivacaine dsyrhythmias Also ropviacaine has greater CNS tolerance The improved safety profile is due to a lower The lipid solubility lipid LA toxicity treatment LA Supportive care: intubation, vasopressors, appropriate Supportive defibrillation, fluids, stop injection of LA, anything else…. else…. Intralipid…Bolus 1cc/kg of 20% intralipid, Intralipid…Bolus 0.25cc/kg/min of 20% intralipid for 10 minutes 0.25cc/kg/min Bolus can be repeated every 5 minutes up to a Bolus maximum of 8cc/kg of 20% intralipid Cardiac support should be continued as ACLS Cardiac dictates dictates Epi and vasopresin should likely both be used in the Epi resusitation efforts (animal model data from A & A) resusitation Lipid, Not Propofol, Treats Bupivacaine Overdose Lipid, Guy Weinberg, MD, Paul Hertz, MD, and Janet Newman, MD Department of Anesthesiology, University of Illinois, Chicago, IL, [email protected] Guy To the Editor: To Mayr et al. (1) recently reported the comparative efficacies of epinephrine, vasopressin, and a combination of the two drugs in a porcine model of bupivacaine overdose. They used a single Mayr (1) 5 mg/kg IV bolus of bupivacaine, applied advanced cardiac life support 1 min after asystole, and administered drugs 2 min later and at 5-min intervals thereafter. Monophasic countershocks were applied as dictated by rhythm disturbance. Rates of survival were 5/7 for vasopressin, 4/7 for epinephrine, 7/7 in the combined treatment group, and 0/7 in controls. By comparison, we reported that injecting a 20% lipid emulsion in combination with cardiac massage leads to successful return of normal hemodynamics in 9/9 dogs after a bolus injection By of 10 mg/kg bupivacaine (2). Lipid infusion in 6 of these dogs was delayed for 10 min to approximate a clinical scenario. A normal rhythm was established in all 9 dogs within 5 min; no (2) Lipid electrical counter shock was required. No control animal demonstrated return of BP or HR. Dogs and pigs may differ in terms of susceptibility to bupivacaine cardiac toxicity; the porcine and canine models may not be completely comparable for this and other reasons. However, Dogs we and others (3) believe the rapid return of normal rhythm and hemodynamics in both dogs and rats following massive bupivacaine overdose (twice the dose used in Mayr’s study), (3) indicates superior efficacy of lipid rescue for bupivacaine toxicity to drugs, such as epinephrine and vasopressin that are components of the generic ACLS protocol for cardiopulmonary arrest (4). Perhaps Dr. Mayr will consider comparing combined epinephrine/vasopressin with lipid rescue in the porcine model of bupivacaine cardiac toxicity. (4) Perhaps Mayr et al. (1) also incorrectly cite us as indicating that "....a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and, therefore, this strategy Mayr (1) has been suggested as a potential means to improve outcomes from such toxicity." We have never recommended use of propofol for treating bupivacaine overdose, and strongly suspect never that its use in cardiac arrest will impede resuscitation. W e have recommended treating bupivacaine-associated cardiac arrest by injecting a 1 mL/kg bolus of 20% lipid emulsion (such as Intralipid) and starting an infusion of 0.25 mL/kg/min We for 10 min, while continuing basic life support (5). The bolus could be repeated every 5 min, two or three times if needed. The upper dose limit of 20% lipid emulsion is not known, but a (5) The total of more than 8 mL/kg is not likely to be needed, nor successful if lower doses are not. Note that this protocol will deliver a significant volume load (several hundred mL in an adult). The standard formulation of propofol is 10% lipid and 1% propofol. Therefore, gram quantities of propofol would accompany our recommended regimen and only half the dose of lipid, the necessary ingredient, would be delivered. Propofol is not an acceptable treatment for bupivacaine overdose. Propofol References Mayr VD, Raedler C, Wenzel V, et al. A comparison of epinephrine and vasopressin in a porcine model of cardiac arrest after rapid intravenous injection of bupivacaine. Anesth Analg Mayr 2004; 98: 1426–31.[Abstract/Free Full Text] 2004; Weinberg G, Ripper R, Feinstein DL, Hoffman W. Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28: 198–202. [ISI] [Medline] Groban L, Butterworth J. Lipid reversal of bupivacaine toxicity: has the silver bullet been identified? Reg Anesth Pain Med 2003; 28: 167–9. [ISI][Medline] Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 2: toxicology in ECC. The American Heart Guidelines Association in collaboration with the International Liaison Committee on Resuscitation. Circulation 2000; 102 (suppl 8): I223–8. [Medline] Association Weinberg G. Lipid rescue: caveats and recommendations for the "Silver Bullet" [letter]. Reg Anesth Pain Med 2004; 29: 74–5. Response Viktoria D. Mayr, MD, Claus Raedler, MD, Volker Wenzel, MD, Karl H. Lindner, MD, and Hans-Ulrich Strohmenger, MD Univ. Klinik f. Anaesthesie u. Allg. Intensivmedezin, Viktoria Innsbruck, Austria, [email protected] In Response: In W e would like to thank Weinberg et al. for their interest in our work, as well as for their constructive comments. First, we sincerely apologize for having incorrectly cited Weinberg et al. We by confounding propofol and intralipid; we completely agree with their statement that propofol administration cannot be recommended for managing a bupivacaine overdose. When indicating in the Discussion section that "... a lipid infusion such as propofol increases the dose of bupivacaine required to induce cardiac arrest, and therefore, this strategy has been suggested as a potential means to improve outcomes from such toxicity," we did not suggest to use propofol for treating bupivacaine toxicity, nor that Dr. Weinberg et al. used propofol for treating bupivacaine toxicity. We share the same opinion that usage of propofol in cardiac arrest may impede resuscitation. With our statement about a "lipid infusion such as propofol...", we only wanted to state the reason why we did not use propofol but isoflurane and nitrous oxide to maintain anesthesia in our experiment. Instead of saying "... a lipid infusion such as propofol...", it would have been better to state "... as propofol is a lipid infusion which may increase the dose of bupivacaine required to induce cardiac arrest..." Second, beneficial lipid effects during massive bupivacaine overdose as described by Weinberg et al. resulted in impressive outcome data. However, their conclusion drawn in the letter that these results indicate the superiority of this treatment regime in comparison to advanced cardiac life support including epinephrine and vasopressin has not been proven. The comparative investigation of the epinephrine/vasopressin combination and the lipid rescue protocol in the same animal model of bupivacaine cardiac toxicity can only provide reliable information in this respect. True Allergic Reactions to LA’s True Very uncommon Esters more likely because of p-aminobenzoic Esters acid (allergen) acid Methylparaben preservative present in amides Methylparaben is also a known allergen is Local Anesthetic Musculoskeletal Local Cause myonecrosis when injected directly into Cause the muscle the When steroid or epi added the myonecrosis is When worsened worsened Regeneration usually takes 3-4 weeks Ropivacaine produces less sereve muscle Ropivacaine injury than bupivacaine injury Drug Interactions Drug Chloroprocaine epidurally may interfere with the analgesic Chloroprocaine effects of intrathecal morphine effects Opioids and α2 agonists potentiate LA’s Opioids Propranolol and cimetidine decrease hepatic blood flow and Propranolol decrease lidocaine clearance decrease Pseudocholinesterase inhibitors decrease Ester LA metabolism Dibucaine (amide LA) inhibits pseudocholinesterase used to Dibucaine detect abn enzyme detect Sux and ester LA need pseudochol. for metabolism therefore Sux adminstering both may potentiate their activity adminstering LA potentiate nondepolarizing muscle relaxant blockade Other agents with LA properties Other Meperidine TCAs (amitriptyline) Volatile anesthetics Ketamine Tetrodotoxin (blocks Na channels from the Tetrodotoxin outside of the cell membrane) Animal studies suggest that when used in low doses with vasoconstrictors it will significantly prolong duration of action of LA. duration Bibliography Bibliography Clinical Anesthesiology, Morgan and Mikhail ...
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This note was uploaded on 12/16/2011 for the course BIOLOGY 101 taught by Professor Mr.wallace during the Fall '11 term at Montgomery College.

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