BIOS5140 - anaesthesia

University of Kent: BIOS5140

  • Focus: Pharmacology of Anaesthesia, Analgesia, and Opioids

Local Anaesthesia

  • Definition: Local anaesthetics target the electrical excitability of neurons.

  • Mechanism:

    • They inhibit voltage-gated sodium ion channels (VGSC), reducing sodium ion entry into axons.

    • This impairment affects the opening of ion channels, decreasing the ability of axons to reach the threshold level for depolarization.

    • Primarily impacts neurons involved in nociception (pain perception), specifically Ad and C fibres, due to their small diameter.

    • Delivered via methods such as topical application, injection, or dural space injection.

    • Preferred over general anaesthesia for patient safety and outpatient surgical procedures.

Action Potential and Ion Channel Behavior

  • Sodium and Potassium Channels:

    • Rapid opening of sodium channels during action potential upstroke, followed by delayed potassium channel opening and sodium channel inactivation during repolarisation.

    • Membrane Potential:

      • Em (membrane potential): rapid change upon sodium channel activation.

      • gNa (membrane conductance to Na+), gK (membrane conductance to K+).

  • Action Potential Characteristics:

    • Depolarisation occurs as sodium ions enter the axon, leading to local depolarisation.

    • Action potential threshold: adjacent sodium channel opens at -50 mV, reaching -20 mV.

    • Potassium efflux results in repolarisation back to resting potential (-80 mV).

Voltage-Gated Ion Channels

  • Conformations of Channels:

    • Resting State: m-gate closed, h-gate open (at -70 mV).

    • Active State: both gates open (at -50 mV).

    • Inactivated State: m-gate open, h-gate closed (at -20 mV).

    • Cycles among these states depending on membrane depolarisation during action potentials.

Gating Mechanism

  • Functionality of m-gate and h-gate:

    • m-gate as voltage sensor opens at -50 mV; h-gate (physical closure) at -20 mV.

    • Following potassium efflux, both gates reset to their resting states (-70 mV).

Mechanism of Action for Local Anaesthetics

  • Drug Properties:

    • Must be lipid-soluble to penetrate membranes; enter as protonated, activated form post-membrane entry.

    • Binds to inactivated sodium channel state, blocking further action potential propagation by keeping h-gate closed.

Local Anaesthetic Structure

  • Weak Bases with Three Chemical Regions:

    1. Lipophilic Region: Usually aromatic, facilitating plasma membrane penetration.

    2. Hydrophilic Region: Typically a secondary/tertiary amine for protonation and activation in the axon.

    3. Ester or Amide Linker: Key for the structural integrity of the local anaesthetic.

  • Active once protonated in the acidic intracellular environment where they inhibit sodium channel cycling.

Interactions and Use Dependence of Local Anaesthetics

  • Lipid Solubility Impact: Determines how effectively they can block sodium channels, with ion interaction pathways.

  • Highly active neurons frequently open sodium channels, impacting effectiveness.

Clinical Applications of Local Anaesthetics

  • Variability in Effectiveness: Speed of onset and duration differ across agents.

    • Examples:

      • Lidocaine, Prilocaine, Articaine: Rapid onset, short-to-medium duration; ideal for minor surgeries.

      • Bupivacaine: Slow onset, long duration; used in epidural anaesthesia in labour.

  • Potential Side Effects:

    • Primarily cardiovascular due to off-target effects; minimized with local application.

General Anaesthesia Overview

  • General Mechanism: Operate through various targets, correlated with lipid solubility.

  • Functionality: Primarily reduces synaptic transmission in specific CNS regions and can affect cardiac/respiratory functions.

  • Preferred Protocol for In-Patient Surgeries:

    • Administration of pre-med anxiolytics, injected anaesthetics, peri-operative opioids, inhaled general anaesthetics, neuromuscular blockers, antiemetics, muscarinic antagonists, and acetylcholinesterase inhibitors post-surgery.

  • Close patient monitoring is essential throughout surgical procedures.