Local anesthetics

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Mechanism of Action - The Nerve Blockers

Local Anesthetic Blocking Sodium Channel

  • Reversibly block nerve conduction by binding to voltage-gated sodium ($Na^+$) channels from inside the axon, preventing depolarization.
  • State-Dependent Blockade: Higher affinity for open or inactivated channels than for resting channels.
  • pH Influence: ↓ efficacy in acidic/infected tissue; the ionized, charged form cannot easily cross the nerve membrane to reach its target.

Use-Dependent Blockade: Nerves that are more active (higher frequency of depolarization) are blocked more rapidly. The more the channel opens, the more access the drug has.

Amides vs. Esters - A Tale of Two 'i's

  • Amides: Have two 'i's in their name (e.g., Lidocaine, Bupivacaine, Ropivacaine).
    • Metabolized by the liver (CYP450).
    • Longer acting and more stable.
    • Allergic reactions are rare.
  • Esters: Have only one 'i' in their name (e.g., Procaine, Cocaine, Benzocaine).
    • Metabolized in plasma by pseudocholinesterases.
    • Shorter acting and less stable.
    • Higher allergy potential due to para-aminobenzoic acid (PABA) metabolite.

📌 Mnemonic: Amides have two 'i's; Esters have one.

⭐ Allergic reactions to one ester anesthetic indicate likely sensitivity to other esters, but cross-reactivity with amides is rare.

Clinical Use & Potency - The Numbing Game

  • Applications: Used for topical anesthesia, infiltration (e.g., suturing), peripheral nerve blocks, and spinal/epidural anesthesia.
  • Physicochemical Properties:
    • Potency ∝ Lipid Solubility (more lipid-soluble drugs cross membranes easier).
    • Duration ∝ Protein Binding (more binding keeps drug at Na+ channel).
  • pH & Onset:
    • Anesthetics are weak bases. The un-ionized form penetrates the nerve sheath.
    • Infection → acidic tissue (↓pH) → traps anesthetic in ionized form → ↓efficacy.
  • Vasoconstrictors (e.g., Epinephrine): Added to prolong duration & reduce systemic toxicity.

Order of Blockade: Small, myelinated fibers (pain, temp) are blocked first, followed by touch/pressure, and finally motor function.

Local Anesthetic Mechanism: pH, Ionization, Nerve Block

Systemic Toxicity - When Good Drugs Go Bad

  • Results from excessive plasma concentration, often via accidental intravascular injection or rapid absorption. CNS effects typically precede cardiovascular toxicity.
  • CNS Manifestations (Biphasic):
    • Early (Excitation): Tinnitus, perioral numbness, metallic taste, agitation, muscle twitching, leading to seizures.
    • Late (Depression): Drowsiness, coma, respiratory arrest.
  • Cardiovascular Effects:
    • Hypotension, arrhythmias (VT/VF), bradycardia.
    • Myocardial depression (↓ contractility).
  • Management: Airway support, benzodiazepines for seizures, and IV lipid emulsion therapy.

⭐ Bupivacaine is the most cardiotoxic local anesthetic due to its high potency and strong binding to cardiac Na+ channels, making resuscitation challenging.

Local Anesthetic Systemic Toxicity (LAST) Progression

High‑Yield Points - ⚡ Biggest Takeaways

  • Local anesthetics reversibly block voltage-gated Na+ channels, with increased affinity for activated/inactivated states.
  • Blockade is most effective on small, myelinated fibers, leading to loss of pain and temperature first.
  • Amides (e.g., lidocaine) are metabolized by the liver; esters (e.g., procaine) risk allergic reactions via PABA.
  • Co-administration with epinephrine causes vasoconstriction, prolonging anesthesia and reducing systemic absorption.
  • Bupivacaine carries a high risk of severe cardiotoxicity.
  • Treat systemic toxicity with intravenous lipid emulsion.

Practice Questions: Local anesthetics

Test your understanding with these related questions

During a nerve conduction study, which of the following ions is primarily responsible for the rapid upstroke of the action potential?

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Flashcards: Local anesthetics

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What type of local anesthetic are procaine, cocaine, tetracaine, and benzocaine? _____

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What type of local anesthetic are procaine, cocaine, tetracaine, and benzocaine? _____

Esters

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