the pharmacology toxicology of local anesthetics
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The Pharmacology & Toxicology of Local Anesthetics. Terry C. Wicks, CRNA, MHS Catawba Valley Medical Center Hickory, NC. 1st: Our Focal Point, Nerve Fiber Types & Differential Blockade. Mechanism of Action (Na + ). Excitable membranes maintain an ( ATPase ) electro-chemical gradient.

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the pharmacology toxicology of local anesthetics

The Pharmacology & Toxicology of Local Anesthetics

Terry C. Wicks, CRNA, MHS

Catawba Valley Medical Center

Hickory, NC

mechanism of action na
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.








mechanism of action na1
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 na2
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
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.
minimum blocking concentration1
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
minimum blocking concentration2
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
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
Other Receptors II
  • NMDA (N-methyl-D-aspartic acid) glutamate receptor.
  • AMPA (a-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid) receptor.
dissociative properties
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.
lipid solubility correlates with
Lipid Solubility Correlates with:
  • Potency
  • Duration of action
  • Protein binding
  • Toxicity
prototypical local anesthetics
Prototypical Local Anesthetics

Ester Linked

Amide Linked

Lipophilic Linkage Hydrophilic

Lipophilic Linkage Hydrophilic

molecular pharmacology
Molecular Pharmacology
  • Tertiary amines derived from ammonia as weak bases
  • Three part structural
    • lipophilic “head”
    • carbon chain
    • hydrophilic “tail”
molecular pharmacology1
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,


molecular pharmacology2
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 pharmacology3
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
Molecular Pharmacology: Chiral Molecules

As described by Walter White, Episode 2, Season 1, “Breaking Bad”

procaine novacaine
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)
  • 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
  • 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
aminoacyl amides
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
  • 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
  • Formulated as the S enantiomer.
  • Potency, onset, duration, and dosage, similar to bupivacaine with less motor blockade toxicity and arrhythmogenicity.
  • 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
allergic reactions
Allergic Reactions
  • Reaction typically follows prior sensitization
  • Can be either systemic or localized
  • Diagnosis based on history and symptoms
  • Cross sensitivity is unlikely
  • 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
  • High concentrations of LAs inhibit myocyte energy production at the mitochondrial level
  • Effects myocardial and skeletal muscle
  • Effects are proportional to lipid solubility
  • Elevation of intracellular Ca++
  • Membrane disruption and permanent depolarization
  • Activation of caspaseenzymes
transient neurologic symptoms
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
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
systemic toxicity
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 cns
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
systemic toxicity cvs
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
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

treatment of toxicity
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

lipid infusion cardiac arrest
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

lipid infusion why does it work
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
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
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.


local anesthetic toxicity a case report
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.
  • 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

lessons learned
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…
planar v nonplanar las
Planar v. Nonplanar LAs