Local Anesthetics (SPR2024) PDF

LOCAL ANESTHETICS Gregory Collins, DNP, CRNA ADVANCED PHARMACOLOGY OF ANESTHETIC AGENTS NRAN 80424 – SPR 2024 1 LOCAL ANESTHETICS OUTLINE: CHEMISTRY MECHANISMS OF ACTION NERVE CONDUCTION PHARMACOKINETICS DRUG PROFILES APPLICATIONS ADVERSE EFFECTS TOXICITY/INJURY READING: FLOOD / 10 BARASH / 22 MILLE...

LOCAL ANESTHETICS Gregory Collins, DNP, CRNA ADVANCED PHARMACOLOGY OF ANESTHETIC AGENTS NRAN 80424 – SPR 2024 1 LOCAL ANESTHETICS OUTLINE: CHEMISTRY MECHANISMS OF ACTION NERVE CONDUCTION PHARMACOKINETICS DRUG PROFILES APPLICATIONS ADVERSE EFFECTS TOXICITY/INJURY READING: FLOOD / 10 BARASH / 22 MILLER / 29 2 CHEMISTRY CLASSIFICATION AMIDES: ESTERS: Lidocaine (Xylocaine) Mepivacaine (Carbocaine) Prilocaine (Citanest) Bupivacaine (Marcaine) Ropivacaine (Naropin) Levobupivacaine (Chirocaine) Procaine (Novocaine) Chloroprocaine (Nesacaine) Tetracaine (Pontocaine) Benzocaine (Hurricane spray) Cocaine 3 HYDROPHILIC LIPOPHILIC CHEMISTRY STRUCTURE 4 CHEMISTRY PROPERTIES BARASH ONSET, DURATION, & POTENCY are related to: pKa, LIPID SOLUBILITY, PROTEIN BINDING, CONCENTRATION/DOSE, VASOACTIVE PROPERTIES 5 CHEMISTRY PROPERTIES pKa: LAs are weak bases Only the neutral, non-protonated form can penetrate lipid membrane Percentage of drug in neutral, nonprotonated form is INVERSELY proportional to pKa Lower pKa generally equates to more rapid ONSET MILLER 6 CHEMISTRY PROPERTIES LIPID SOLUBILITY: “By far the most important physiochemical property of local anesthetics is their lipophilicity.” –Barash ONSET: Increased lipid solubility results in more rapid penetration of lipid membrane, but may also result in sequestration of drug in other lipid soluble compartments (myelin, “intra”-membrane) Net result…increased lipid solubility delays onset of action 7 CHEMISTRY PROPERTIES LIPID SOLUBILITY: “By far the most important physiochemical property of local anesthetics is their lipophilicity.” –Barash DURATION: Increased lipid solubility increases duration of action due to slow release of drug from lipid depot POTENCY: Increased lipid solubility equates to increased potency → Higher Na+ channel receptor affinity → Ability to alter conformation of Na+ channel from within membrane 8 CHEMISTRY PROPERTIES LIPID SOLUBILITY: “By far the most important physiochemical property of local anesthetics is their lipophilicity.” –Barash A drug molecule that exhibits PROFOUND LIPOPHILICITY will rapidly enter lipid BILAYER, but may become sequestered, unable to reach intracellular compartment. This will DELAY ONSET. (BUPIVACAINE, TETRACAINE) 9 CHEMISTRY PROPERTIES LIPID SOLUBILITY: “By far the most important physiochemical property of local anesthetics is their lipophilicity.” –Barash A drug molecule that exhibits MODERATE LIPOPHILICITY will efficiently enter and exit lipid bilayer to reach intracellular compartment. This will SPEED ONSET. (LIDOCAINE, MEPIVACAINE) 10 CHEMISTRY PROPERTIES PROTEIN BINDING: Increased protein binding correlates with increased duration of action CONCENTRATION/DOSE: Increasing dose/concentration results in more rapid onset VASOACTIVE PROPERTIES: Most LAs are vasodilatory; vasodilation reduces duration of action Cocaine (ropivacaine, levobupivacaine) is exception; vasoconstriction increases duration of action 11 CHEMISTRY PROPERTIES ONSET: ↑ CONCENTRATION/DOSE… ↑ number of molecules of drug… ↑ SPEED OF ONSET ↓ pKa… ↑ ratio of neutral, unprotonated molecules of drug… ↑ SPEED OF ONSET DURATION: ↑ PROTEIN BINDING… ↓ free drug molecules… ↓ metabolism of drug… ↑ DURATION ↑ LIPOPHILICITY… ↑ time to release drug from lipid depots… ↑ DURATION ↑ VASODILATION… ↑ blood flow/washout of drug… ↓ DURATION POTENCY: ↑ LIPOPHILICITY… ↑ affinity for receptor… ↑ alteration of Na+ channel… ↑ POTENCY 12 CHECK YO-SELF… The pKa of a local anesthetic is most reliably correlated with which pharmacologic parameter? a) b) c) d) Duration Onset Potency Toxicity Select the TRUE correlation regarding pharmacologic property to pharmacologic parameter. a) b) c) d) ↑ protein binding = ↓ duration ↓ lipid solubility = ↑ potency ↑ pKa = ↑ speed of onset ↑ lipid solubility = ↑ potency 13 MECHANISM OF ACTION NERVE ANATOMY 14 MECHANISM OF ACTION NERVE ANATOMY PERIPHERAL NERVE: MYELINATED FIBERS Surrounded by myelin, interrupted by nodes of Ranvier Na+ ion channels concentrated at nodes Allow for passage of ions/drugs Create neuronal excitation and propagation of impulse UNMYELINATED FIBERS Encased by continuous Schwann cells without interruption ↑MYELINATION = more RAPID CONDUCTION ↑DIAMETER = more RAPID CONDUCTION 15 MECHANISM OF ACTION NERVE ANATOMY 16 MECHANISM OF ACTION NERVE ANATOMY BARASH 17 MECHANISM OF ACTION IMPULSE CONDUCTION RESTING MEMBRANE POTENTIAL ~ -60 to -70 mV Maintained by Na+/K+ pump, expels Na+ extracellularly in exchange for K+ intracellularly – against concentration gradient ACTION POTENTIAL Activation of voltage-gated Na+ channels in sufficient numbers to reach THRESHOLD POTENTIAL 18 MECHANISM OF ACTION IMPULSE CONDUCTION 19 MECHANISM OF ACTION IMPULSE CONDUCTION DISRUPTION OF IMPULSE CONDUCTION: LOCAL ANESTHETICS DO… Decrease rate of depolarization by preventing Na+ influx such that threshold potential is never reached LOCAL ANESTHETICS DO NOT… Alter RESTING MEMBRANE POTENTIAL Alter THRESHOLD POTENTIAL 20 MECHANISM OF ACTION SODIUM CHANNEL 21 MECHANISM OF ACTION SODIUM CHANNEL 22 MECHANISM OF ACTION SODIUM CHANNEL TONIC vs PHASIC INHIBITION FREQUENCY DEPENDENT BLOCKADE LA molecules access receptor only when Na+ channel is in ACTIVATED-OPEN states and bind with highest affinity in INACTIVE state TONIC INHIBITION Time between action potentials exceeds time for dissociation of LA from receptor on Na+ channel ★ Slower firing fibers (fewer action potentials per unit time) are less susceptible to blockade PHASIC INHIBITION Time between action potential is less than time needed for dissociation of LA from receptor on Na+ channel Also known as use-dependent blockade ★ Faster firing fibers (more action potentials per unit time) are more susceptible to blockade 23 MECHANISM OF ACTION SODIUM CHANNEL RECEPTOR BOUND W/ HIGH AFFINITY RECEPTOR ACCESSIBLE 24 MECHANISM OF ACTION PHASIC BLOCKADE SUSCEPTIBILITY TO BLOCKADE: B PREGANGLIONIC SYMPATHETIC MOST SUSCEPTIBLE Aδ SENSORY / Aγ MOTOR Aα MOTOR / Aβ SENSORY C SENSORY LEAST SUSCEPTIBLE Conditions that increase action potential frequency, thus increase susceptibility to blockade: Tissue injury Chronic pain, neuropathy 25 MECHANISM OF ACTION DIFFERENTIAL BLOCK Clinical SEQUENCE OF BLOCKADE when increasing LA concentrations: B PREGANGLIONIC SYMPATHETIC FIRST BLOCKED Aδ SENSORY / Aβ SENSORY Aα MOTOR / Aγ MOTOR C SENSORY LAST BLOCKED SYMPATHETIC / SENSORY / MOTOR blockade will reach different, sequential levels following neuraxial anesthesia 26 CHECK YO-SELF… Local anesthetics can access the intracellular receptor in voltage-gated sodium channels only when the channel is in the __________ state. a) b) c) d) Resting Active-open Active-closed Inactive Regarding differential blockade, which type of nerve fibers would be affected first? a) b) c) d) Aδ sensory Aα motor C sensory B preganglionic sympathetic 27 PHARMACOKINETICS 28 PHARMACOKINETICS ABSORPTION Amount of LA in systemic circulation influenced by: Site of injection Dose/concentration Use of vasoconstricting agents Pharmacologic characteristics of LA In general, rates of absorption from greatest to least: IC > caudal > epidural > BP > fem/sci FLOOD 29 PHARMACOKINETICS DISTRIBUTION Two-compartment model Rapid uptake and equilibration into highly-perfused tissues (brain, heart) Pulmonary extraction (primarily amides) is significant → Moderates potential for systemic toxicity → Bupivacaine: dose dependent, finite (able to quickly saturate), inhibited by propranolol Protein binding is inversely proportional to plasma concentration 30 PHARMACOKINETICS METABOLISM ESTERS Subject to hydrolysis of ester bond by plasma cholinesterase (some in liver) Rate varies: chloroprocaine (fastest), tetracaine (slowest); toxicity inversely proportional to rate of hydrolysis Metabolites are pharmacologically inactive Para-aminobenzoic acid (PABA) can be antigenic Renal excretion of metabolites Abnormal plasma cholinesterase levels or activity increases risk for systemic toxicity Cocaine is unique with more hepatic based metabolism 31 PHARMACOKINETICS METABOLISM AMIDES Enzymatic degradation in liver by carboxylesterases and C-P450 Dependent on hepatic blood flow and protein binding Rate varies: lidocaine (fastest), bupivacaine (slowest) Clearance decreased in hepatic dysfunction, presence of VAs Slower and more complex than esters…greater chance for cumulative effects and systemic toxicity Renal excretion of metabolites 32 PHARMACOKINETICS METABOLISM BARASH 33 CHECK YO-SELF… Injection of local anesthetic at which site would result in the FASTEST systemic absorption? a) b) c) d) Caudal Femoral Sciatic Epidural Which of the following would likely prolong the metabolism and elimination of lidocaine the greatest? a) b) c) d) Plasma cholinesterase deficiency Hepatic disease Renal dysfunction Heart failure 34 LOCALINDIVIDUAL ANESTHETICS AGENTS BARASH 35 PROCAINE NOVOCAINE ESTER First commercially available, injectable LA Derived from PABA Slow onset: very high pKa (8.9), short duration: low lipid solubility, minimal protein binding Historical use in spinal anesthesia (SAB), high incidence of N/V & allergic reaction Rare use now outside of dental applications 36 CHLOROPROCAINE NESACAINE ESTER Derived from procaine Rapid onset despite high pKa (8.7) Rapid metabolism, able to deliver in high concentrations (2%-3%) Short duration: very minimal protein binding Useful in conversion of epidural analgesia to anesthesia Rapid onset, short duration, limited systemic toxicity Historical concerns with neurotoxicity in SAB (preservative?) Reduces effects of concurrent/subsequent epidural bupivacaine, opioids 37 TETRACAINE PONTOCAINE ESTER Predominant use as topical agent in ophthalmology, occasional SAB Very potent (↑ lipophilic) Long duration (↑ protein bound, slow ester hydrolysis) Profound motor and sensory block Supplied in solution or in crystalline form (allows baricity adjustment) 38 BENZOCAINE HURRICAINE ESTER Unique chemistry, pKa 3.5 → rapid onset Predominant use in spray topicalization of mucous membranes → Cetacaine = benzocaine + tetracaine + butyl aminobenzoate Duration 30-60 min Potential to produce methemoglobinemia (doses >300 mg, neonates) 39 COCAINE COKE, BLOW, NOSE CANDY, FLORIDA SNOW ESTER Produces intense vasoconstriction Unique hepatic metabolism & renal excretion of parent drug Primary topical use in procedures of nasopharynx (4% or 10% solutions) Very low therapeutic index, very high abuse potential 40 LIDOCAINE XYLOCAINE AMIDE First commercially available aminoamide LA Rapid onset: low pKa (7.9), intermediate duration: moderate protein binding, moderate lipophilicity Most versatile LA agent: → Wound infiltration: 0.5%-2% → Topicalization of mucous membranes: 4% nebulized → Tumescent anesthesia: large volumes, dilute lidocaine SQ before liposuction → Neuraxial anesthesia/analgesia: 1%-2% epidural, 5% spinal → IV regional anesthesia (Bier block): 0.25-0.5% → Regional anesthesia (nerve block, interfascial plane block): 2% → Blunting hemodynamic response, increases in ICP/IOP to laryngoscopy → Antiarrhythmic: IV bolus/IV infusion → Chronic neuropathic pain: low doses, effective transdermal 41 MEPIVACAINE CARBOCAINE AMIDE Similar pharmacology to lidocaine Rapid onset: low pKa (7.6), intermediate duration: moderate protein binding, less vasodilation than lidocaine Regional anesthesia (nerve block): 1%-1.5% Less desirable for neuraxial in OB: poor fetal metabolism 42 PRILOCAINE CITANEST AMIDE Similar pharmacology to lidocaine → More rapidly metabolized → Decreased CNS toxicity → Less vasodilation (less need for vasoconstrictor additive) Metabolite o-toluidine can accumulate after large doses (>600 mg) and precipitate methemoglobinemia Common use in EMLA cream (added to lidocaine) Becoming popular in SAB for outpatient procedures 43 BUPIVACAINE MARCAINE AMIDE Relatively slow onset; prolonged duration: highly protein bound, very lipid soluble Sensory block > motor block at lower concentrations (motor blockade Ropivacaine less intense, shorter duration of motor block compared to bupivacaine Ultra-short onset of chloroprocaine is due to concentration, despite high pKa Chloroprocaine can decrease effectiveness of subsequent bupivacaine and opioids 56 CLINICAL APPLICATIONS SPINAL ANESTHESIA SPINAL ANESTHESIA Onset, duration, and baricity are primary considerations for LA choice Drug Usual Concentration (%) Usual Volume(mL) Total Dose(mg) Procaine 10.0 1-2 100-200 Lidocaine 1.5, 5.0 1-2 Mepivacaine 4 Tetracaine Dibucaine Bupivacaine Glucose Conc (%) Duration (min) Hyperbaric 5.0 30-60 30-100 Hyperbaric 7.5 30-90 1-2 40-80 Hyperbaric 9.0 30-90 0.25-1.0 1-4 5-20 Hyperbaric 5.0 75-150 0.25 2-6 5-20 Hypobaric 0 75-150 1.0 1-2 5-20 Isobaric 0 75-150 0.25 1-2 2.5-5.0 Hyperbaric 5.0 75-180 0.5 1-2 5-10 Hypobaric 0 75-180 0.06 5-20 3-12 Isobaric 0 75-180 0.5 3-4 15-20 Isobaric 0 75-150 0.75 2-3 15-22.5 Hyperbaric 8.25 75-150 Baricity 57 CLINICAL APPLICATIONS SPINAL ANESTHESIA SPINAL ANESTHESIA Dose determined by 1) Height of patient 2) Segmental level of desired anesthesia 3) Duration of desired anesthesia Lidocaine has higher reported incidence of transient neurological symptoms (TNS) Addition of epinephrine significantly prolongs duration of tetracaine, no significant effects on duration of bupivacaine 58 CLINICAL APPLICATIONS TUMESCENT ANALGESIA TUMESCENT ANALGESIA Large volumes of dilute LA plus dilute epinephrine Infiltrated in SQ space for liposuction Typical agents: lidocaine < 0.1%, epinephrine 1:1,000,000 Doses of 35-55 mg/kg delivered with reported safety Chance for peak serum LA concentrations to occur up to 20 hr post infiltration Concomitant LAs and sedation medications can produce untoward outcomes 59 CLINICAL APPLICATIONS TOPICAL ANESTHESIA TOPICAL ANESTHESIA Mucous membranes for bronchoscopy, endoscopy, awake fiberoptic intubation →Lidocaine 4% (nebulized), 2% (viscous), 2% (jelly) →Benzocaine 5%-20%, Cetacaine Intact skin prior to IV start, minor procedure →Eutectic mixture of local anesthetics (EMLA) – lidocaine 2.5% + prilocaine 2.5% Open skin, wound →TAC (tetracaine, epinephrine, cocaine), LET (lidocaine, epinephrine, tetracaine) 60 CLINICAL APPLICATIONS SYSTEMIC INFUSION PERIOPERATIVE PAIN MANAGEMENT Ubiquitous part of ERAS protocols Demonstrable, complex anti-inflammatory properties Greatest effect on post-op pain, opioid consumption seen in GI surgery CHRONIC NEUROPATHIC PAIN Some syndromes respond to low dose LA infusion Benefits may last weeks, months Likely related to suppression of high-frequency, ectopic impulses 61 CLINICALTACHYPHYLAXIS APPLICATIONS TACHYPHYLAXIS Repeated injection of same dose results in decreased response Longer periods of perceived pain between injections increases tachyphylaxis Short periods with no pain between injections decreases tachyphylaxis Thought to result from central sensitization 62 CLINICAL APPLICATIONS ADDITION OF VASOCONSTRICTORS VASOCONSTRICTORS Decrease the rate of vascular absorption of LA Increases “density” of blockade (more drug to site of action, 𝛼2 agonist effect) Prolongs duration (decreased vascular clearance of LA from injection site) Decreases systemic absorption, toxicity Effect dependent on: → Properties of individual LA – more effective in short/moderate duration → Site of injection – more effective in infiltration and peripheral nerve injection Epinephrine (1:200,000) most common – phenylephrine, norepinephrine also used Avoid injection into sites with potential for vascular compromise May accentuate systemic HTN, increase HR 63 CLINICAL APPLICATIONS ADDITION OF VASOCONSTRICTORS FLOOD 64 CLINICAL APPLICATIONS ADJUSTMENT OF pH pH ADJUSTMENT Speeds onset of block Increases depth/density of block Increases segmental spread of epidural block Mechanism – increases the fraction of non-ionized drug molecules Typical technique is to add 1 ml NaHCO3 to 9 ml of LA Particularly useful with formulations of LA with epinephrine 65 CLINICAL APPLICATIONS MIXTURES OF LOCAL ANESTHETICS MIXTURES OF LAs Combination to balance best qualities of onset and duration Evidence demonstrates mixed results depending on agents and ratios Toxicities of each agent are additive, not independent or synergistic Caution combining chloroprocaine with bupivacaine in epidural space 66 CLINICAL APPLICATIONS LIPOSOMAL FORMULATIONS LIPOSOMAL FORMULATIONS Molecule of LA encapsulated in liposome or cyclodextrin Slow breakdown of liposome results in extended release of LA Prolongs duration of block, reduces systemic absorption of LA Liposomal bupivacaine (Exparel) most common Approved for selective nerve blocks, interfascial plane blocks, infiltration Can only be combined with bupivacaine (1:2 ratio), normal saline 67 CHECK YO-SELF… Dose determination for spinal anesthesia should include all EXCEPT: a) b) c) d) Height of patient Segmental level of desired anesthesia Weight of patient Duration of desired anesthesia The primary mechanism by which the addition of epinephrine increases the duration of action for local anesthetics is: a) b) c) d) Increase in non-ionized fraction of drug Decrease in protein binding of drug Increase in heart rate and cardiac output Decrease in vascular absorption of drug 68 ADVERSE EFFECTS ALLERGIC REACTIONS ALLERGIC REACTIONS Reports of adverse reactions after injection of LA are common Estimated that ~1% of reported effects attributable to true allergy to LA → Occurrence of urticaria, laryngeal edema, bronchospasm likely related to allergy → Occurrence of syncope, seizure, hypotension, tachycardia likely related to inadvertent intravascular injection Most common true allergy likely secondary to para-aminobenzoic acid (PABA) No cross-sensitivity between esters and amides → Exception is allergy to methylparaben, potential preservative in both classes 69 ADVERSE EFFECTS LOCAL TOXICITY NEURAL TISSUE TOXICITY In-vitro exposure of de-sheathed nerve tissue to high concentrations of LA results in injury Range of severity from non-specific, patchy pain and/or paresthesia to transient neurologic symptoms to cauda equina syndrome Unclear whether range is due to distinct injury patterns or spectrum of same injury Spinal nerves and nerve roots are much more susceptible than peripheral nerves LA-induced increases in intracellular Ca++ concentrations may be responsible Permanent neurologic injury after regional anesthesia very rare event 70 ADVERSE EFFECTS LOCAL TOXICITY TRANSIENT NEUROLOGIC SYMPTOMS (TNS) Distinct sequela of neurotoxic injury after SAB injection of LA Moderate to severe pain in lower back, buttocks, posterior thighs Usually noted 6-36 hr after resolution of spinal block Associated with normal sensory/motor exam Full recovery typical between 1-7 days Highest incidence after intrathecal injection of lidocaine (vs other LAs) Highest incidence after injection of 5% lidocaine, but only slight reduction when reducing concentration 71 ADVERSE EFFECTS LOCAL TOXICITY TRANSIENT NEUROLOGIC SYMPTOMS (TNS) Potential confounding etiologic factors in TNS → Patient positioning → Early mobilization → Needle trauma → Isolated pooling of LA → Ischemia from nerve stretching → Muscle spasm → Myofascial trigger points → Irritation of dorsal root ganglia 72 ADVERSE EFFECTS LOCAL TOXICITY CAUDA EQUINA SYNDROME Significant outcome resulting from diffuse injury across lumbosacral plexus Presents as various degrees of sensory loss, bowel/bladder dysfunction, paraplegia Reports associated with use of hyperbaric 5% lidocaine via microcatheters for continuous intrathecal applications → Possibly related to high-concentration of lidocaine in small area without adequate mixing of CSF More commonly caused by trauma, hematoma, abscess 73 ADVERSE EFFECTS SYSTEMIC TOXICITY METHEMOGLOBINEMIA Oxidation of hemoglobin to methemoglobin Implicated with topical administration of prilocaine, benzocaine, cetacaine (lidocaine) Central cyanosis occurs with methemoglobin concentrations >15% Treatment: methylene blue 1-2 mg/kg IV over 5 min Caution as methylene blue can clear before complete conversion of methemoglobin to hemoglobin and continued systemic absorption of LA from tissue 74 ADVERSE EFFECTS SYSTEMIC TOXICITY LOCAL ANESTHETIC SYSTEMIC TOXICITY (LAST) Secondary to excess plasma concentrations of LAs Plasma concentrations are determined by rate of entrance into plasma against rates of redistribution and clearance Accidental intravascular injection is most common cause (epidural, PNB) Magnitude of systemic absorption depends upon: → Total dose → Vascularity of injection site (see slide #27) → Presence of vasoconstrictor → Properties of the LA drug LA agents differ in regard to incidence and severity of CNS toxicity and cardiovascular toxicity 75 ADVERSE EFFECTS SYSTEMIC TOXICITY CNS TOXICITY All LAs readily cross BBB Produce a predictable pattern of CNS changes: →Low plasma concentrations → mild sensory distrubances →High plasma concentrations → excitation, tonic-clonic seizures →Higher, rapid increases in plasma concentrations → CNS depression, coma, apnea Potential for CNS toxicity correlates with potency of LA Factors which may increase potential for CNS toxicity: →Decreased protein binding of LA →Decreased clearance of LA →Systemic acidosis →Hypercapnia →Rate of injection 76 ADVERSE EFFECTS SYSTEMIC TOXICITY FLOOD 77 ADVERSE EFFECTS SYSTEMIC TOXICITY CARDIOVASCULAR (CV) TOXICITY Systemic CV toxicity generally seen at plasma concentrations greater than that for CNS toxicity Potential for CV toxicity correlates with potency of LA More potent, more lipid-soluble LAs have greater potential for CV toxicity Increasing plasma concentrations of less potent LAs (lidocaine) typically produce hypotension, bradycardia, and hypoxia Increasing plasma concentration of more potent LAs (bupivacaine) more often produce CV collapse, ventricular dysrhythmias which are resistant to resuscitation 78 ADVERSE EFFECTS SYSTEMIC TOXICITY BUPIVACAINE (% OF ANIMALS) LIDOCAINE (% OF ANIMALS) SINUS TACHYCARDIA 0 100 SUPRAVENTRICULAR TACHYCARDIA 60 9 AV HEART BLOCK 60 0 VENTRICULAR TACHYCARDIA 80 0 PVCs 100 0 WIDENED QRS 100 0 ST-T WAVE CHANGE 60 40 CARDIAC CHANGE 79 ADVERSE EFFECTS SYSTEMIC TOXICITY SELECTIVE CV TOXICITY LIDOCAINE vs BUPIVACAINE: Equivalent effects on myocardial contractility (reduced Ca++ influx from sarcoplasmic reticulum) Bupivacaine produces significantly greater effect on cardiac electrophysiology Bupivacaine has much higher affinity for resting and inactive cardiac sodium channels Bupivacaine dissociates from receptor much more slowly during repolarization and diastole 80 ADVERSE EFFECTS SYSTEMIC TOXICITY BARASH 81 ADVERSE EFFECTS SYSTEMIC TOXICITY SELECTIVE CV TOXICITY BUPIVACAINE vs ROPIVACAINE/LEVOBUPIVACAINE Similar potency/effect in clinical applications Ropivacaine/levobupivacaine exhibit ~30%-40% less potential for cardiac toxicity Likely exhibit decreased affinity for sodium channels in brain and myocardium 82 ADVERSE EFFECTS SYSTEMIC TOXICITY BARASH 83 ADVERSE EFFECTS SYSTEMIC TOXICITY BARASH 84 ADVERSE EFFECTS SYSTEMIC TOXICITY BARASH 85 ADVERSE EFFECTS SYSTEMIC TOXICITY TREATMENT OF LAST Airway management → Control ventilations to prevent hypercarbia, hypoxia Suppression of seizure activity → IV benzodiazepines ACLS for arrhythmias → Smaller doses of epinephrine → Avoid vasopressin, 𝛽-blockers, Ca++ channel-blockers Lipid emulsion therapy → 20% intralipid → 1.5 ml/kg bolus, 0.25 ml/kg/min infusion → Repeat bolus, double infusion for refractory instability → Consider cardiopulmonary bypass if above therapies fail 86 ADVERSE EFFECTS SYSTEMIC TOXICITY NYSORA.COM 87 ADVERSE EFFECTS SYSTEMIC TOXICITY 88 NYSORA.COM ADVERSE EFFECTS SYSTEMIC TOXICITY TREATMENT OF LAST Very difficult to treat, poor outcomes PREVENTION IS PARAMOUNT! → Test-dose with epidurals → Incremental injection in PNBs 89 CHECK YO-SELF… Select the TRUE statement(s) regarding methemoglobinemia. a) b) c) d) Central cyanosis occurs with methemoglobin levels greater than 15% Not a concern with amide local anesthetics Duration of local anesthetic/contributing agent can outlast duration of treatment Treated with indigo carmine IV push The potential for both neuro and cardiac toxicity is directly correlated to the __________ of local anesthetics. (Select all that apply) a) b) c) d) Protein binding Vasoactive properties Lipid solubility Potency 90 SUMMARY STUDY GUIDE WILL BE POSTED TO D2L! 91