Mechanism 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. CNS Cardiac Skeletal DRG Peripheral SNS
Mechanism 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.
Mechanism of Action (Na + ) Sodium channels exist in three states: ▫Open (conducting) high affinity ▫Closed-resting (non-conducting) low affinity ▫Closed-inactive (non-conducting) high affinity Tonic blockade (closed resting) Phasic blockade (open & closed inactive)
Mechanism of Action (K + ) Local anesthetics will engage potassium channels. Blockade may be more stereo-selective for K + than for Na + channels Delayed repolarization may increase the refractory period, and action potential duration.
In vitro: independent of fiber diameter In vivo: other factors influence clinical drug performance ▫Nerve length and myelination ▫Rate of traffic (use dependence) Important for anti-arrhythmic effects or Use at low concentrations ▫LA concentration & volume ▫Rate of diffusion of the drug
Minimum Blocking Concentration The concentration that just halts impulse propagation 3 nodes of Ranvier for myelinated fibers or 5-6 mm for unmylinated fibers Critical blocking length [CBL] As the concentration of LA increases the critical blocking length decreases.
Other Receptors I G protein coupled receptors ▫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 ++ ATPase
Other Receptors II NMDA (N-methyl-D-aspartic acid) glutamate receptor. AMPA (a-amino-3-hydroxyl-5- methyl-4-isoxazolepropionic acid) receptor.
Dissociative 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.
Molecular 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) ▫mepivacaine ▫ropivacaine ▫bupivacaine
Molecular Pharmacology Sterioisomers have similar physico- chemical, but often have different pharmacodynamic properties Racemic solutions have equal concentrations of S (sinister) and R (rectus) Typically the S isomer is less toxic.
Molecular Pharmacology: Chiral Molecules As described by Walter White, Episode 2, Season 1, “Breaking Bad”
The Pharmacology of Local Anesthetics… Selected Agents
Prototype amino-ester local anesthetic Metabolized by hydrolysis in the serum Slow onset, duration of about one hour Currently used as a substitute for lidocaine for SAB of short duration Cauda equina syndrome has been reported after procaine spinal anesthesia (10% sol) Procaine “novacaine”
Hydrolyzed 4 times faster than procaine Fetal & maternal metabolism is rapid Sodium bisulfite: myo & neuro toxicity EDTA: calcium binding & back pain High diffusability, rapid onset, short duration Dose: up to 600 mg Chloroprocaine
High lipid solubility and potency (toxicity) Metabolized 1/3-1/4 the rate of chloroprocaine 76% protein bound Epinephrine prolongs duration by >50% Dose: topical 100 mg, SAB 10-15 mg Tetracaine
Aminoacyl Amides Lidocaine Family Mepivacaine Family Straight chain hydrophilic amino tail Hydrolysed by hepatic cytochrome P450 enzymes Includes: ▫lidocaine ▫prilocaine ▫etidocaine Piperidine ring based hydophilic amino tail Dealkylated in the liver and renally excreted Includes ▫mepivacaine ▫bupivacaine & (levo) ▫ropivacaine
Lidocaine The “standard” local anesthetic Has anticonvulsant and antiarrhythmic properties Epinephrine increases duration by 50% Dose: 5 mg/kg plain, 7 mg/kg with epi For local, IV regional, SAB, epidural, and peripheral nerve block
Toxicity similar to lidocaine Rapid onset, duration slightly longer than lidocaine Solution is a racemic mixture of R & S Dose: 5 mg/kg plain, 7 mg/kg with epi Clinical application similar to lidocaine Mepivacaine...
Ropivacaine... Formulated as the S enantiomer. Potency, onset, duration, and dosage, similar to bupivacaine with less motor blockade toxicity and arrhythmogenicity.
Bupivacaine More lipid soluble (28 x), potent (4 x) and toxic than mepivacaine Duration 4-6 hrs (95% protein bound) Solution is a racemic mixture of R & S No prolongation of effects by epi Wide spread application Max dose: 2.5 mg/kg
Local Anesthetic Toxicity & Adverse Effects Manifestations & Management
Allergic Reactions Reaction typically follows prior sensitization Can be either systemic or localized Diagnosis based on history and symptoms Cross sensitivity is unlikely
Methemoglobinemia Methemoglobinemia is the result of oxidation of hemoglobin Central cyanosis will be evident when methemoglobin levels exceed 15% Treated by administration of methylene blue1-2 mg/kg over 5 minutes
Myotoxicity High concentrations of LAs inhibit myocyte energy production at the mitochondrial level Effects myocardial and skeletal muscle Effects are proportional to lipid solubility
Neurotoxicity Elevation of intracellular Ca ++ Membrane disruption and permanent depolarization Activation of caspase enzymes
Transient Neurologic Symptoms Pain and dysesthesia in buttocks and lower extremities after resolution of spinal anesthesia Sx occur without sensory or motor deficits, normal MRI and EP studies Most common after lidocaine spinals, but can occur with other local anesthetics Course is self limiting, & treatment is symptomatic
Cauda Equina Syndrome Permanent bladder and bowel dysfunction, loss of sensory and motor function in LE First report after continuous SAB, but there are reports after single shot SABs Most commonly lidocaine is the offending agent, but does occur with other agents
Systemic Toxicity Severity is proportional to the rate of delivery to central circulation ▫Dose ▫Tissue vascularity ▫Use of vasoconstrictors ▫Toxicity of drug Rate of redistribution & metabolism
Systemic Toxicity: CVS Increased heart rate & blood pressure Appearance of ectopy Varying degrees of heart block Hypotension, bradyarrhythmia, Asystole Vasoconstriction at low doses (local) vasodilation at high doses (systemic)
Prevention of Toxicity Use lowest effective dose Inject incrementally Aspirate prior to injection Use of intravascular marker ▫Epinephrine ▫Fentanyl (laboring patients) ▫Lidocaine Use of ultrasound? Then evidence is mounting. ASA Newsletter April 2012 Vol 76 No 4 22-25
Lipid Infusion: Cardiac Arrest Intralipid 20% 1.5 ml/kg over 1 minute Continue infusion at 0.25 ml/kg/min Continue CPR Repeat bolus every 3- 5 minutes up to 3 ml kg Increase rate to 0.5 ml/kg if BP declines A maximum of 8 ml/kg is recommended Now considered a first line component of therapy Newly created registry of lipid use is accessible at www.lipidregistry.org.
Lipid 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 metabolism ▫May increase intramyocyte calcium concentrations ▫May reverse LA induced vasodilation. Used to treat toxicity from other highly lipid soluble drugs
Problems Studying Lipid Rescue Intact rodent, canine, and isolated heart models show positive results. Porcine models…not so much. Confounded by: ▫Hypoxemia and acidosis based models ▫High dose vasopressor treatment models ▫Maybe pigs don’t like lipid emulsion (compliment activated pseudo-allergy) Intralipid ® does not activate complement in humans
Lipid Infusion Anecdotal 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. Visit www.lipidrescue.org
Local Anesthetic Toxicity: A Case Report 31 y.o. male Untreated HTN Work related trauma to L hand NPO X 9 hrs Posted for debridement & tendon repair Plan: 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.