local anesthetics a case-based review. the na+ channel- site of la action ...
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Local Anesthetics
A Case-Based Review
The Na+ Channel- Site of LA Action
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Summary
Block Na+ channels with loss of nerve conduction
Therefore we call the result of LA action…
Conduction Block
Case 1: Mom with Liver Disease
Plan is epidural for laborWhat are key concerns related to use of
0.125% bupivacaine?
Structure and metabolism
Structure: Local Anesthetics
Structure of the LA moleculeHeadTailIntermediate chain
N
Lipophilic Head(Benzene Ring)
Hydrophilic Tail(Quaternary Amide)
Intermediate Chain(Hydrocarbon)
Ester(-CO-)
Amide(-NHC-)
R
R
H+
Adopted from:Barash PG, Cullen BF, & Stoelting RK. (eds) Clinical Anesthesia 1997. J.B. Lippincott
Metabolism
LA Structures: Esters vs. Amides
Main issue: metabolic pathway Esters
Ester hydrolysis by plasma cholinesterase Amides
N-dealkylation and hydroxylation in the liver
This patient has pre-existing liver disease- we would worry about accumulation of the drug
Entiomers
Substances of opposite shape Molecules existing in mirror image forms
Left and right handed
When dissolved in solution rotate polarized light Optical isomers
Important concept in LA toxicity Right handed molecules such as bupivacaine are
more toxic
Case 2: You are working in a dental practice The next patient has an abscessed
tooth You suggest deep sedation, the
dentist insists on trying to get a decent block with local
You end up with deep sedation due to patient discomfort
Why?
Pus
ie - How they get in there and do their job
How LA’s Work
Ionized/Non-ionized Pairs
Local AnestheticMolecule
pH of site pH of solution
Intrinsic structure
pKa
Variables Affecting Ionization
Adjuncts
H+Non-H+
Local Anesthetics and Ionization: Both ionized and non-ionized forms are needed for function
In infected tissue, the LA is completely ionized and won’t work- hence the need
for sedation or GA
Onset Speed: 1/Ionization
Adopted from: Datta, S (1993) Pharmacology of Local Anesthetic Agents in Barash, PG (ed) ASA Refresher Courses in Anesthesiology, 21:241-254., Young and MacKenzie, 1994; Carpenter and Mackey, 1990; Strichartz and Covino, 1992,Stoelting Pharmacology and Physiology 1999. Hemmings 2000, pg. 295
Case 3: Differential Block
Your obstetric patient is a difficult epidural placement. On the third attempt you get the epidural and
administer a test dose with no change in BP or HR observed.
You then give a bolus dose of 8 cc of 0.125% bupivacaine. The patient begins complaining of blurred vision and a metallic taste
Her LOC then becomes depressed
Systemic Toxicity
CNS toxicity: due to peak serum local anesthetic blood levels Accidental intravascular injection is the most
common etiologic factor in severe systemic reactions
Toxicity can be gradual Same variables:
Site, vascularity, total dose, use of a vasoconstrictor….
Systemic Toxicity Symptoms: Mild neurological symptoms to coma or
death Excitatory symptoms
Selective depression of inhibitory neurons Depression of CNS
Na channel block centrally Depression of heart
Takes a much higher blood level
Lipid soluble agents are more potent and more toxic
Clinical Potency: Clinical Toxicity
Adopted from:
Mulroy, MF (1996) Pharmacology and Toxicity of Local Anesthetics in Barash, PG (ed) ASA Refresher Courses in Anesthesiology, 24:193-204.
Treatment of Toxicity
Get assistance Airway
Oxygen, ventilation, intubation or airway equipment Drugs to stop seizure
Benzodiazepines Barbiturates Other drugs/interventions
Post seizure management
Toxic Dose Ranges- AmidesAmide LA Max Dose Plain Max Dose + EpiArticaine N/A 7
Bupivacaine 2.5 3
Dibucaine 1 N/A
Etidocaine 4 N/A
Lidocaine 4.5 7
Mepivacaine 4.5 7
Prilocaine 8 N/A
Ropivacaine 3 N/A
Doses are in mg/kg, dose ranges change depending on site of injection
Toxic Dose Ranges- Esters
Ester LA Max Dose Plain
Max Dose + Epi
Chloroprocaine 12 N/A
Cocaine 3 N/A
Procaine 12 N/A
Tetracaine 3 N/A
Doses are in mg/kg, dose ranges change depending on site of injection
Site of Injection: Likelihood of Toxicity
IVTracheal
IntercostalCaudal
ParacervicalEpidural
Brachial plexusSciatic/FemoralSubcutaneous
MostMost
Least Least
Vas
cula
rity
Tox
icit
y L
ikli
hoo
dSchematic is illustrative in nature and not intended to reflect absolute correlation
Case 4: Will the Spinal Last?
Your patient presents for a BKA You administer a Lidocaine 2% (80mg) SAB
with epi The surgeon runs into trouble and the case
approaches 90 minutes
Duration = Protein Binding = Lipid Solubility
Protein binding. protein binding = duration
Lipid solubility lipid solubility= duration
Lipid Solubility: Duration
Adopted from :Datta, S (1993) Pharmacology of Local Anesthetic Agents in Barash, PG (ed) ASA Refresher Courses in Anesthesiology, 21:241-254.
Datta, S (1993) Pharmacology of Local Anesthetic Agents in Barash, PG (ed) ASA Refresher Courses in Anesthesiology, 21:241-254. Stoelting RK, Pharmacology and Physiology in Anesthetic Practice, 1999
Protein Binding: Duration
Adjuncts also Prolong Duration
Vasoconstrictors Epinephrine/Phenylephrine/ Levonordefrin
Prolong duration Minimize effect of LA vasodilatation toxicity intensity of block bleeding
Morgan 2006
Morgan 2006
And Don’t Give Me Any of Those Local Anesthetics!
Get Me the Imported Stuff!