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

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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


1st our focal point nerve fiber types differential blockade

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


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.

CNS

Cardiac

Skeletal

DRG

DRG

SNS

Peripheral


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)


Model of local anesthetic binding

Model of Local Anesthetic Binding


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 concentration

Minimum Blocking Concentration


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.


Physicochemical properties

Physicochemical Properties


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.


Pka ph of 50 dissociation

pKa =Ph of 50% Dissociation


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,

    ropivacaine


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”


The pharmacology of local anesthetics

The Pharmacology of Local Anesthetics…

Selected Agents


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)


Chloroprocaine

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


Tetracaine

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


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


Lidocaine

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


Mepivacaine

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


Ropivacaine

Ropivacaine...

  • Formulated as the S enantiomer.

  • Potency, onset, duration, and dosage, similar to bupivacaine with less motor blockade toxicity and arrhythmogenicity.


Bupivacaine

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

Local Anesthetic Toxicity & Adverse Effects

Manifestations & Management


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


Methemoglobinemia

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


Myotoxicity

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

Neurotoxicity

  • 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 www.lipidregistry.org.


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.

Visit www.lipidrescue.org


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.


During injection uh oh

During Injection…uh oh…


Management

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


Resolution

Resolution


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…


Questions

Questions?

[email protected]


Planar v nonplanar las

Planar v. Nonplanar LAs

Lidocaine

Ropivacaine


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