Download The Pharmacology 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...
Fiber type
Diameter um
Myelin
Function
A alpha
12-20
Yes
A beta
5-12
Yes
A gamma
3-6
Yes
Proprioception,
motor
Cutaneous
touch, motor
Muscle tone
A delta
2-5
Yes
B
1-4
Yes
C
0.3-1.2
No
Pain, touch,
temperature
Pre-ganglionic
Pain & post
ganglionic
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 (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-5methyl-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
pKa
Benzocaine
3.5
Lidocaine
7.8
Bupivacaine &
Ropivacaine
Chloroprocaine
8.1
9.1
Lipid Solubility Correlates with:
• Potency
• Duration of action
• Protein binding
• Toxicity
Prototypical Local Anesthetics
Ester Linked
Lipophilic Linkage Hydrophilic
Amide Linked
Lipophilic Linkage Hydrophilic
Molecular Pharmacology
• Tertiary amines
derived from
ammonia as weak
bases
• Three part structural
▫ lipophilic “head”
▫ carbon chain
▫ hydrophilic “tail”
Molecular Pharmacology
Ester Linked Agents
 Hydrolyzed by
plasma esterases
 chloroprocaine
 procaine
 tetracaine
 benzocaine
 cocaine
Amide Linked Agents
 Bio-transformed by
hepatic enzymes
 lidocaine, prilocaine,
etidocaine
 mepivacaine, levobupivacaine,
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 physicochemical, 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
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)
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
•
•
•
•
•
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
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
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...
• 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...
• 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 35 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 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 preblock.
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?
[email protected]
Planar v. Nonplanar LAs
Lidocaine
Ropivacaine