The Pharmacology & Toxicology of

Local Anesthetics

Terry C. Wicks, CRNA, MHSCatawba 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.

• Sodium channels open briefly when the membrane is stimulated.

• Sodium ions flow down the concentration gradient resulting in depolarization.

CNS

CardiacSkeletal

DRG

DRG

PeripheralSNS

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)

Model of Local Anesthetic Binding

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•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.

Physicochemical 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

Local Anesthetic pKaBenzocaine 3.5

Lidocaine 7.8

Bupivacaine & Ropivacaine

8.1

Chloroprocaine 9.1

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

Prototypical Local Anesthetics

Lipophilic Linkage Hydrophilic

Lipophilic Linkage Hydrophilic

Ester Linked Amide Linked

Molecular Pharmacology•Tertiary amines

derived from ammonia as weak bases

•Three part structural▫lipophilic “head”▫carbon chain▫hydrophilic “tail”

Molecular PharmacologyEster Linked Agents Amide Linked Agents

Hydrolyzed by plasma esterases

chloroprocaineprocainetetracainebenzocainecocaine

Bio-transformed by hepatic enzymes

lidocaine, prilocaine, etidocaine

mepivacaine, levo-bupivacaine, bupivacaine,ropivacaine

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 AmidesLidocaine 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: 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

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

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•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 therapyNewly 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.

During Injection…uh oh…

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

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?terrywickscrna@gmail.com

Planar v. Nonplanar LAsLidocaine Ropivacaine