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The Pharmacology & Toxicology of Local Anesthetics

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1 The Pharmacology & Toxicology of Local Anesthetics
Terry C. Wicks, CRNA, MHS Catawba Valley Medical Center Hickory, NC

2 1st: Our Focal Point, Nerve Fiber Types & Differential Blockade...

3 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 DRG SNS Peripheral

4 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.

5 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)

6 Model of Local Anesthetic Binding

7 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. Racemic bupivacaine is 3x more potent at binding to CV sarcolemmal KATP channels than levo-bupivacaine or ropivacaine.

8 Minimum Blocking Concentration

9 Minimum Blocking Concentration
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

10 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.

11 Other 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++ ATPase Some 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 requirements Early return of bowel function Reduced post-operative fatigue Shortened hospital stay Beneficial effects probably mediated by visceral NMDA & G protein coupled receptors (analgesia, antihyperalgesia, antinflammatory) Not beneficial to major orthopedic patients

12 Other 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 36–44 Special article The Neurobiology of Infant Pain: Development of Excitatory and Inhibitory Neurotransmission in the Spinal Dorsal Horn Pattinson, Damian B.Sc.a; Fitzgerald, Maria Ph.D.a

13 Physicochemical Properties

14 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.

15 pKa =Ph of 50% Dissociation
Local Anesthetic pKa Benzocaine 3.5 Lidocaine 7.8 Bupivacaine & Ropivacaine 8.1 Chloroprocaine 9.1

16 Lipid Solubility Correlates with:
Potency Duration of action Protein binding Toxicity

17 Prototypical Local Anesthetics
Ester Linked Amide Linked Lipophilic Linkage Hydrophilic Lipophilic Linkage Hydrophilic

18 Molecular Pharmacology
Tertiary amines derived from ammonia as weak bases Three part structural lipophilic “head” carbon chain hydrophilic “tail”

19 Molecular Pharmacology
Ester Linked Agents Amide Linked Agents Hydrolyzed by plasma esterases chloroprocaine procaine tetracaine benzocaine cocaine Bio-transformed by hepatic enzymes lidocaine, prilocaine, etidocaine mepivacaine, levo- bupivacaine, bupivacaine, ropivacaine

20 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

21 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.

22 Molecular Pharmacology: Chiral Molecules
As described by Walter White, Episode 2, Season 1, “Breaking Bad”

23 The Pharmacology of Local Anesthetics…
Selected Agents

24 Procaine “novacaine” 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)

25 Chloroprocaine 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

26 Tetracaine 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 mg

27 Aminoacyl Amides Straight chain hydrophilic amino tail
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

28 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 Continuous 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.

29 Mepivacaine... 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

30 Ropivacaine... Formulated as the S enantiomer.
Potency, onset, duration, and dosage, similar to bupivacaine with less motor blockade toxicity and arrhythmogenicity.

31 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

32 Local Anesthetic Toxicity & Adverse Effects
Manifestations & Management

33 Allergic Reactions Reaction typically follows prior sensitization
Can be either systemic or localized Diagnosis based on history and symptoms Cross sensitivity is unlikely Methylparaben (preservative) & PABA (metabolic by product) are common allergens

34 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 Can result from excessive doses of lidocaine, prilocaine or benzocaine Methylene blue restores hemoglobin to its reduced state Patient should be monitored for reoccurrence

35 Myotoxicity High concentrations of LAs inhibit myocyte energy production at the mitochondrial level Effects myocardial and skeletal muscle Effects are proportional to lipid solubility Uncouple oxidatitive phosphorylation Impairment of intracellular enzyme systems Reduce energy and ATP production Bupivacaine>ropivacaine, absent with lidocaine

36 Neurotoxicity Elevation of intracellular Ca++
Membrane disruption and permanent depolarization Activation of caspase enzymes Dose and exposure related elevations of intracellular Ca++ Possible injury due to membrane disruption and permanent depolarization Activation of caspase enzymes resulting in cell death Solubilization 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

37 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

38 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

39 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

40 Systemic Toxicity: CNS
Vertigo, tinnitus, dysphoria Restlessness, numbness of tongue, circumoral tissues Slurred speech, muscle twitching Tonic clonic seizures CNS depression, coma, & apnea Metabolic & respiratory acidosis lower the seizure threshold Tonic clonic seizures (source in the amygdala)

41 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)

42 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. Don’t forget post injection patients monitoring for at least 30 minutes. ASA Newsletter April 2012 Vol 76 No

43 Treatment Of Toxicity Effective airway management Stop seizures ACLS
100% oxygen (hypoxia) Effective ventilation (respiratory acidosis) Stop seizures Benzo’s Propofol ACLS Lipid Rescue Cardiopulmonary Bypass Hyperventilation & supplemental oxygen Airway support (Sch if required) Benzodiazepines or barbiturates CPR, ACLS, amiodarone and/or vasopressin? Cardiopulmonary bypass Persistence Regional Anesthesia & Pain Medicine Vol. 35 No. 2 March-April 2010

44 Lipid Infusion: Cardiac Arrest
Intralipid 20% 1.5 ml/kg over 1 minute Continue infusion at 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 Lipid emulsion was predicted to reduce heart tissue bupivacaine concentration by 11% within 3min of initiating therapy and brain concentration by 18% within 15 min The 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 pp Newly created registry of lipid use is accessible at

45 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 In 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 April Now 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 #

46 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 Weinberg and Rubenstein. Anesthesia and Analgesia. April 2012 • Volume 114 • Number Also, 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).

47 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. 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

48 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.

49 During Injection…uh oh…

50 Management iphone app: Lipid ALS
Additional 2.5 mg versed, 150 mg propofol. Positive pressure hyperventilation with 100% oxygen. Oral airway. Spill contents of crash cart on floor. ABG: ph 7.01, PO2 111, PCO2 90, HCO3 23, BE –10. 12 Lead EKG. Chest X-ray. Patient regained consciousness after one hour 15 minutes. iphone app: Lipid ALS

51 Resolution

52 Lessons learned Trust no one. Monitor as if you were doing GA.
Check your equipment & set the alarms. Never fly alone. An ounce of prevention…

53 Questions?

54 Planar v. Nonplanar LAs Lidocaine Ropivacaine

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