Local Anesthetics

LA Basics - Nerve Numbeners

• Mechanism: Reversibly block voltage-gated Na+ channels (VGSCs) → ↓ Na+ influx → prevent action potential generation & conduction.
• Site of Action: Intracellular side of Na+ channel.
• Active Form: Ionized (cationic) form blocks channel; Unionized (uncharged base) form penetrates nerve sheath.
  • LAs are weak bases (pKa 7.5-9.0).
  • Infected tissue (acidic pH) → ↑ ionized form → ↓ efficacy.
• Order of Blockade (Sensitivity):
  • Small, myelinated (B, Aδ - pain, temp) > Small, unmyelinated (C - pain) > Large, myelinated (Aγ, Aβ, Aα - proprioception, touch, motor).
  • 📌 Mnemonic: Before All Clinical Manifestations (B > Aδ > Aγ > Aβ > Aα > C - note: C fiber sensitivity varies)

⭐ LAs exhibit use-dependent blockade: higher frequency of nerve stimulation leads to greater blockade because channels are more often in open/inactivated states, which LAs bind with higher affinity than resting state. This is also known as phasic block.

Structure & Types - Chemical Coats

• LA Structure:
  • Lipophilic (aromatic) head: ↑Potency, lipid solubility.
  • Intermediate chain: Ester/Amide linkage; determines metabolism, allergy.
  • Hydrophilic (amine) tail: Ionization, Na+ channel binding.
• Linkage Types:
  • Esters ($-COO-$):
    • Plasma pseudocholinesterase metabolism.
    • ↑ Allergy risk (PABA metabolite).
    • E.g., Procaine, Tetracaine, Benzocaine.
    • 📌 Esters: PABA → Allergy.
  • Amides ($-NHCO-$):
    • Hepatic enzyme (CYP450) metabolism.
    • ↓ Allergy risk.
    • E.g., Lidocaine, Bupivacaine.
    • 📌 Amides: two 'i's in name.

⭐ Cocaine is the only naturally occurring LA; unique vasoconstrictor (inhibits norepinephrine reuptake).

LA Kinetics - Journey Through Body

• Absorption (A):
  • Site vascularity dictates speed (e.g., Intercostal > Epidural > Brachial > SubQ).
  • Vasoconstrictors (e.g., adrenaline): ↓ absorption, ↑ duration, ↓ toxicity.
• Distribution (D):
  • Vessel-rich groups (brain, heart, liver, kidney) first.
  • Bound to α1-acid glycoprotein (AAG); free drug is active.
• Metabolism (M):
  • Esters (1 'i'): Plasma pseudocholinesterase (fast; PABA → allergy).
  • Amides (2 'i's): Liver CYP450 (slow).
    • Prilocaine → o-toluidine → Met-Hb (Rx: Methylene Blue).
• Excretion (E):
  • Renal (metabolites).

⭐ Ion trapping: LAs (weak bases) accumulate in acidic fetal plasma or inflamed tissue, ↑ local concentration.

Clinical Applications - Numbing Targets

• Topical Anesthesia: Mucous membranes (cornea, oral cavity, GU tract).
• Infiltration Anesthesia: Direct tissue injection for minor procedures; numbs local sensory nerve endings.
• Nerve Blocks: Injection near specific nerves/plexuses.
  • Dental procedures (e.g., Inferior alveolar nerve).
  • Limb surgery (e.g., Brachial plexus, Femoral nerve).
• Spinal (Intrathecal) Anesthesia: Into CSF (subarachnoid space); targets nerve roots for lower abdominal/limb surgery.
• Epidural Anesthesia: Into epidural space; targets nerve roots (e.g., labor analgesia, postoperative pain).
• Intravenous Regional Anesthesia (Bier Block): IV into exsanguinated, tourniquet-isolated limb.

⭐ Spinal anesthesia is typically administered into the subarachnoid space at the L3-L4 or L4-L5 intervertebral level in adults to avoid puncturing the spinal cord (conus medullaris usually ends at L1-L2).

Toxicity & Management - Danger Zones

• Systemic Toxicity (LAST): Dose-dependent.
  • CNS: Early (circumoral numbness, tinnitus, metallic taste, lightheadedness). Late (muscle twitching, tremors, generalized seizures, unconsciousness, coma, respiratory arrest).
  • CVS: Initially hypertension/tachycardia, then ↓BP, bradycardia, arrhythmias (esp. Bupivacaine - ventricular), asystole.
• Allergic Reactions: Rare with amides; esters (PABA metabolite) more common.
• Methemoglobinemia: Prilocaine, Benzocaine. Treat with Methylene Blue 1-2 mg/kg IV.
• Danger Zones (Systemic Absorption Rate): 📌 Intercostal > Caudal > Epidural > Brachial Plexus > Sciatic/Femoral > Subcutaneous ("ICE-BS").

⭐ Bupivacaine: high cardiotoxicity. For severe LAST: IV Lipid Emulsion (20%) is key. Bolus 1.5 mL/kg, then 0.25 mL/kg/min infusion.

High‑Yield Points - ⚡ Biggest Takeaways

• Mechanism: Block voltage-gated Na+ channels, preventing action potentials.
• Sensitivity: Small, myelinated fibers (pain, temp) blocked first; sensory > motor.
• Inflamed (acidic) tissue ↓ efficacy due to ↑ ionization.
• Toxicity: CNS effects (seizures) usually precede cardiac toxicity. Bupivacaine is highly cardiotoxic.
• Metabolism: Amides (two 'i's - Lidocaine) in liver; Esters (one 'i' - Procaine) by plasma pseudocholinesterase (PABA allergy).
• Vasoconstrictors (epinephrine) prolong action, ↓ systemic toxicity.
• Cocaine: Ester LA with intrinsic vasoconstrictor activity (NET blockade).