Local Anesthetics A Case-Based Review

The Na+ Channel- Site of LA Action english/other/cea_dh01.html

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 labor What are key concerns related to use of 0.125% bupivacaine? Structure and metabolism

Structure: Local Anesthetics Structure of the LA molecule Head Tail Intermediate 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 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 Anesthetic Molecule 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: , Young and MacKenzie, 1994; Carpenter and Mackey, 1990; Strichartz and Covino, 1992, Stoelting Pharmacology and Physiology 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:

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- Amides Amide LAMax Dose PlainMax Dose + Epi ArticaineN/A7 Bupivacaine2.53 Dibucaine1N/A Etidocaine4N/A Lidocaine4.57 Mepivacaine4.57 Prilocaine8N/A Ropivacaine3N/A Doses are in mg/kg, dose ranges change depending on site of injection

Toxic Dose Ranges- Esters Ester LAMax Dose Plain Max Dose + Epi Chloroprocaine12N/A Cocaine3N/A Procaine12N/A Tetracaine3N/A Doses are in mg/kg, dose ranges change depending on site of injection

Site of Injection: Likelihood of Toxicity IV Tracheal Intercostal Caudal Paracervical Epidural Brachial plexus Sciatic/Femoral Subcutaneous Most Least Vascularity Toxicity Liklihood Schematic 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:

Datta, S (1993) Pharmacology of Local Anesthetic Agents in Barash, PG (ed) ASA Refresher Courses in Anesthesiology, 21: 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

And Don’t Give Me Any of Those Local Anesthetics! Get Me the Imported Stuff!