Presentation on theme: "The Pharmacology & Toxicology of Local Anesthetics"— Presentation transcript:
1The Pharmacology & Toxicology of Local Anesthetics Terry C. Wicks, CRNA, MHSCatawba Valley Medical CenterHickory, NC
21st: Our Focal Point, Nerve Fiber Types & Differential Blockade...
3Mechanism of Action (Na+) Excitable membranes maintain an (ATPase) electro-chemical gradient.Sodium channels open briefly when the membrane is stimulated.Sodium ions flow down the concentration gradient resulting in depolarization.CNSCardiacSkeletalDRGDRGSNSPeripheral
4Mechanism of Action (Na+) Exert their effects by binding to receptors in or near the voltage gated sodium channel.Interrupt conduction in excitable tissues including axons, dendrites and muscle.Dull sensation distal to the site of blockade.
5Mechanism of Action (Na+) Sodium channels exist in three states:Open (conducting) high affinityClosed-resting (non-conducting) low affinityClosed-inactive (non-conducting) high affinityTonic blockade (closed resting)Phasic blockade (open & closed inactive)
7Mechanism of Action (K+) Local anesthetics will engage potassium channels.Blockade may be more stereo-selective for K+ than for Na+ channelsDelayed repolarization may increase the refractory period, and action potential duration.Racemic bupivacaine is 3x more potent at binding to CV sarcolemmal KATP channels than levo-bupivacaine or ropivacaine.
9Minimum Blocking Concentration In vitro: independent of fiber diameterIn vivo: other factors influence clinical drug performanceNerve length and myelinationRate of traffic (use dependence)Important for anti-arrhythmic effects orUse at low concentrationsLA concentration & volumeRate of diffusion of the drug
10Minimum Blocking Concentration The concentration that just halts impulse propagation3 nodes of Ranvier for myelinated fibers or 5-6 mm for unmylinated fibersCritical blocking length [CBL]As the concentration of LA increases the critical blocking length decreases.
11Other Receptors I G protein coupled receptors Ca++/Mg++ ATPase Anti-inflammatory effects: Inhibition of human polymorphonuclear neutrophil priming without interfering with normal immune response.Relative potency: chloroprocaine>tetracaine> procaine>lidocaine> mepivacaine>bupivacaine.Anti-thrombotic effects: Inhibit platelet activating factor without interfering with normal coagulation.Ca++/Mg++ ATPaseSome calcium channel blocking drugs exert mild local anesthetic action (verapamil).Others lack LA action but prolong local anesthetic effects (nifedipine & nicardipine).Spinal cord modulation of calcium channels may contribute to neuraxial anesthetic effects.Blockade of calcium channels impairs skeletal, smooth, and cardiac muscle function.Major abdominal surgery patients had:Reduced parenteral opioid requirementsEarly return of bowel functionReduced post-operative fatigueShortened hospital stayBeneficial effects probably mediated by visceral NMDA & G protein coupled receptors (analgesia, antihyperalgesia, antinflammatory)Not beneficial to major orthopedic patients
12Other Receptors II NMDA (N-methyl-D-aspartic acid) glutamate receptor. AMPA (a-amino-3-hydroxyl-5- methyl-4-isoxazolepropionic acid) receptor.Regional Anesthesia & Pain Medicine:January/February Volume 29 - Issue 1 - p 36–44Special articleThe Neurobiology of Infant Pain: Development of Excitatory and Inhibitory Neurotransmission in the Spinal Dorsal HornPattinson, Damian B.Sc.a; Fitzgerald, Maria Ph.D.a
14Dissociative Properties Exist as weak bases, uncharged & able to penetrate tissue membranes (lipophilic).In solution separate into charged cations and Cl- (hydrophilic).As pH decreases ionization increases.
15pKa =Ph of 50% Dissociation Local AnestheticpKaBenzocaine3.5Lidocaine7.8Bupivacaine & Ropivacaine8.1Chloroprocaine9.1
16Lipid Solubility Correlates with: PotencyDuration of actionProtein bindingToxicity
17Prototypical Local Anesthetics Ester LinkedAmide LinkedLipophilic Linkage HydrophilicLipophilic Linkage Hydrophilic
18Molecular Pharmacology Tertiary amines derived from ammonia as weak basesThree part structurallipophilic “head”carbon chainhydrophilic “tail”
19Molecular Pharmacology Ester Linked AgentsAmide Linked AgentsHydrolyzed by plasma esteraseschloroprocaineprocainetetracainebenzocainecocaineBio-transformed by hepatic enzymeslidocaine, prilocaine, etidocainemepivacaine, levo- bupivacaine, bupivacaine,ropivacaine
20Molecular Pharmacology Lengthening the para-amino aromatic chain prolongs action and increases potency.Adding a piperidine ring to the tail makes the compound resistant to hydrolysis.Adding substituents to the aminoacyl carbon creates chiral molecules (asymmetrically substituted carbon)mepivacaineropivacainebupivacaine
21Molecular Pharmacology Sterioisomers have similar physico- chemical, but often have different pharmacodynamic propertiesRacemic solutions have equal concentrations of S (sinister) and R (rectus)Typically the S isomer is less toxic.
22Molecular Pharmacology: Chiral Molecules As described by Walter White, Episode 2, Season 1, “Breaking Bad”
23The Pharmacology of Local Anesthetics… Selected Agents
24Procaine “novacaine” Prototype amino-ester local anesthetic Metabolized by hydrolysis in the serumSlow onset, duration of about one hourCurrently used as a substitute for lidocaine for SAB of short durationCauda equina syndrome has been reported after procaine spinal anesthesia (10% sol)
25Chloroprocaine Hydrolyzed 4 times faster than procaine Fetal & maternal metabolism is rapidSodium bisulfite: myo & neuro toxicityEDTA: calcium binding & back painHigh diffusability, rapid onset, short durationDose: up to 600 mg
26Tetracaine High lipid solubility and potency (toxicity) Metabolized 1/3-1/4 the rate of chloroprocaine76% protein boundEpinephrine prolongs duration by >50%Dose: topical 100 mg, SAB mg
27Aminoacyl Amides Straight chain hydrophilic amino tail Lidocaine FamilyMepivacaine FamilyStraight chain hydrophilic amino tailHydrolysed by hepatic cytochrome P450 enzymesIncludes:lidocaineprilocaineetidocainePiperidine ring based hydophilic amino tailDealkylated in the liver and renally excretedIncludesmepivacainebupivacaine & (levo)ropivacaine
28Lidocaine The “standard” local anesthetic Has anticonvulsant and antiarrhythmic propertiesEpinephrine increases duration by 50%Dose: 5 mg/kg plain, 7 mg/kg with epiFor local, IV regional, SAB, epidural, and peripheral nerve blockContinuous infusions of lidocaine (bolus 100 mg or 1.5 mg/kg followed by infusions of 1.5 to 3 mg/kg/hr) have been shown in numerous studies to reduce post operative analgesic requirements for patients undergoing lap cholecystectomy, radical prostatectomy, and major abdominal surgery, often up to 72 hours post op. Not effective for total hip arthroplasty.
29Mepivacaine... Toxicity similar to lidocaine Rapid onset, duration slightly longer than lidocaineSolution is a racemic mixture of R & SDose: 5 mg/kg plain, 7 mg/kg with epiClinical application similar to lidocaine
30Ropivacaine... Formulated as the S enantiomer. Potency, onset, duration, and dosage, similar to bupivacaine with less motor blockade toxicity and arrhythmogenicity.
31BupivacaineMore lipid soluble (28 x), potent (4 x) and toxic than mepivacaineDuration 4-6 hrs (95% protein bound)Solution is a racemic mixture of R & SNo prolongation of effects by epiWide spread applicationMax dose: 2.5 mg/kg
33Allergic Reactions Reaction typically follows prior sensitization Can be either systemic or localizedDiagnosis based on history and symptomsCross sensitivity is unlikelyMethylparaben (preservative) & PABA (metabolic by product) are common allergens
34MethemoglobinemiaMethemoglobinemia is the result of oxidation of hemoglobinCentral cyanosis will be evident when methemoglobin levels exceed 15%Treated by administration of methylene blue1-2 mg/kg over 5 minutesCan result from excessive doses of lidocaine, prilocaine or benzocaineMethylene blue restores hemoglobin to its reduced statePatient should be monitored for reoccurrence
35MyotoxicityHigh concentrations of LAs inhibit myocyte energy production at the mitochondrial levelEffects myocardial and skeletal muscleEffects are proportional to lipid solubilityUncouple oxidatitive phosphorylationImpairment of intracellular enzyme systemsReduce energy and ATP productionBupivacaine>ropivacaine, absent with lidocaine
36Neurotoxicity Elevation of intracellular Ca++ Membrane disruption and permanent depolarizationActivation of caspase enzymesDose and exposure related elevations of intracellular Ca++Possible injury due to membrane disruption and permanent depolarizationActivation of caspase enzymes resulting in cell deathSolubilization of cell membranes by local anesthetic micelles (L.A.s have both lipid and water soluble elements)Injuries are most frequent with lidocaine although they do occur with other local anesthetics
37Transient Neurologic Symptoms Pain and dysesthesia in buttocks and lower extremities after resolution of spinal anesthesiaSx occur without sensory or motor deficits, normal MRI and EP studiesMost common after lidocaine spinals, but can occur with other local anestheticsCourse is self limiting, & treatment is symptomatic
38Cauda Equina SyndromePermanent bladder and bowel dysfunction, loss of sensory and motor function in LEFirst report after continuous SAB, but there are reports after single shot SABsMost commonly lidocaine is the offending agent, but does occur with other agents
39Systemic ToxicitySeverity is proportional to the rate of delivery to central circulationDoseTissue vascularityUse of vasoconstrictorsToxicity of drugRate of redistribution & metabolism
40Systemic Toxicity: CNS Vertigo, tinnitus, dysphoriaRestlessness, numbness of tongue, circumoral tissuesSlurred speech, muscle twitchingTonic clonic seizuresCNS depression, coma, & apneaMetabolic & respiratory acidosis lower the seizure thresholdTonic clonic seizures (source in the amygdala)
41Systemic Toxicity: CVS Increased heart rate & blood pressureAppearance of ectopyVarying degrees of heart blockHypotension, bradyarrhythmia,AsystoleVasoconstriction at low doses (local) vasodilation at high doses (systemic)
42Prevention of Toxicity Use lowest effective doseInject incrementallyAspirate prior to injectionUse of intravascular markerEpinephrineFentanyl (laboring patients)LidocaineUse of ultrasound? Then evidence is mounting.Don’t forget post injection patients monitoring for at least 30 minutes.ASA Newsletter April 2012 Vol 76 No
43Treatment Of Toxicity Effective airway management Stop seizures ACLS 100% oxygen (hypoxia)Effective ventilation (respiratory acidosis)Stop seizuresBenzo’sPropofolACLSLipid RescueCardiopulmonary BypassHyperventilation & supplemental oxygenAirway support (Sch if required)Benzodiazepines or barbituratesCPR, ACLS, amiodarone and/or vasopressin?Cardiopulmonary bypassPersistenceRegional Anesthesia & Pain Medicine Vol. 35 No. 2 March-April 2010
44Lipid Infusion: Cardiac Arrest Intralipid 20% 1.5 ml/kg over 1 minuteContinue infusion at ml/kg/minContinue CPRRepeat bolus every 3- 5 minutes up to 3 ml kgIncrease rate to 0.5 ml/kg if BP declinesA maximum of 8 ml/kg is recommendedNow considered a first line component of therapyLipid emulsion was predicted to reduce heart tissue bupivacaine concentration by 11% within 3min of initiating therapy and brain concentration by 18% within 15 minThe lipid sink is not the sole mechanism by which IV administered lipid emulsion reverses local anesthetic systemic toxicity“Validity of the Lipid Sink as a Mechanism for the Reversal of Local Anesthetic Systemic Toxicity: A Physiologically Based Pharmacokinetic Model Study”Kuo, Ilin M.S.*; Akpa, Belinda S. Ph.D.† Anesthesiology: June Vol 118 No 6 ppNewly created registry of lipid use is accessible at
45Lipid Infusion: Why does it work? Lipid emulsion may act as a “sink”.May also act as a metabolic substrate for myocytes.90% of aerobic cardiac myocyte ATP is from fatty acid metabolismMay increase intramyocyte calcium concentrationsMay reverse LA induced vasodilation.Used to treat toxicity from other highly lipid soluble drugsIn plasma bupivacaine will be distributed and bound to alpha 1 acid glycoprotein, red blood cells, plasma albumin, and to lipid micro droplets.Seems to work best on highly lipid soluble locals, i.e. bup, levo bup, and rop. Not so much on mepivacaine. This may be due to reduced nitric oxide signaling.Anesthesiology 2011; 114:293–301. February 2011.Also, dogs seems to respond better to lipid than swine, while rabbits seem to do much more poorly. When are we going to do human studies? Hmmm, probably never.The Use of Dye Surrogates to Illustrate Local Anesthetic Drug Sequestration by Lipid Emulsion. RAPM Vol 37 No 2 March AprilNow reports of many lipid soluble drug toxicity being amenable to lipid emulsion treatment.Recent animal studies suggest that bupivacaine and ropivacaine cause mitochondrial swelling the interferes with myocardial energy production (decreased myocardial energy consumption and ATP production). This effect may be reversed by lipid administration. Myocardial Accumulation of Bupivacaine and Ropivacaine is Associated with Reversible Effects on Mitochondria and Reduced Myocardial Function. Hiller et al. Anes Analg Jan 2013 Vol 116 #
46Problems Studying Lipid Rescue Intact rodent, canine, and isolated heart models show positive results.Porcine models…not so much. Confounded by:Hypoxemia and acidosis based modelsHigh dose vasopressor treatment modelsMaybe pigs don’t like lipid emulsion (compliment activated pseudo-allergy)Intralipid® does not activate complement in humansWeinberg and Rubenstein. Anesthesia and Analgesia. April 2012 • Volume 114 • NumberAlso, long chain triglycerides improve survival compared to long chain-medium chain triglyceride formulations although rate of spontaneous return of a perfusing rhythm are similar (LCFA also resulted in better HR, BP and RPP).
47Lipid InfusionAnecdotal reports of effectiveness are becoming more common place.Resolution of CV toxicity, arrhythmias, and CNS toxicity are generally prompt.Paradoxically treatment with epinephrine, and vasopressin, restores perfusion more quickly than lipid alone, but survival may be reduced.Patients may have recurrence of toxicity symptoms in the case of long acting local anesthetics. Lipid may also interfere with some lab testing and results, and my provoke pancreatitis on rare occasions.Visit
48Local Anesthetic Toxicity: A Case Report 31 y.o. maleUntreated HTNWork related trauma to L handNPO X 9 hrsPosted for debridement & tendon repairPlan: Trans-arterial axillary block with 20 cc lidocaine 2% and 20 cc Chirocaine 0.75%, with 1:200k epinephrine.Monitors, oxygen, and versed 2.0 pre- block.