The Pharmacology & Toxicology of Local Anesthetics

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.

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 • 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

12. Other Receptors II • NMDA (N-methyl-D-aspartic acid) glutamate receptor. • AMPA (a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid) receptor.

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

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 • Caudaequina 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 10-15 mg

27. Aminoacyl Amides Lidocaine Family Mepivacaine Family • Straight chain hydrophilic amino tail • Hydrolysed by hepatic cytochrome P450 enzymes • Includes: • lidocaine • prilocaine • etidocaine • Piperidinering based hydophilicamino tail • Dealkylatedin 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

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

34. Methemoglobinemia • Methemoglobinemiais 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

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

36. Neurotoxicity • Elevation of intracellular Ca++ • Membrane disruption and permanent depolarization • Activation of caspaseenzymes

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. CaudaEquina 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 clonicseizures • CNS depression, coma, & apnea • Metabolic & respiratory acidosis lower the seizure threshold

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. ASA Newsletter April 2012 Vol 76 No 4 22-25

43. Treatment Of Toxicity • Effective airway management • 100% oxygen (hypoxia) • Effective ventilation (respiratory acidosis) • Stop seizures • Benzo’s • Propofol • ACLS • Lipid Rescue • Cardiopulmonary Bypass 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 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.

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

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

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. Visit www.lipidrescue.org

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 • 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