Local Anaesthetics Mechanism and Structure

Local Anaesthetics - Mechanism of Action

• Local anaesthetics block voltage-gated sodium channels, preventing action potentials.
• They don't cause loss of consciousness.
• They work by plugging the pores of the sodium channels.
• Anaesthetic molecules can use hydrophilic or hydrophobic pathways to reach the channels.
• Hydrophilic pathway: ionised anaesthetics pass through the open channel.
• Hydrophobic pathway: unionised anaesthetics pass through the axon membrane.
• The ionised form of the anaesthetic has a stronger affinity for the channels.
• The channels are more open/inactive during action potentials, so anaesthetics are more effective at blocking these channels.

Local Anaesthetics - Structure

• General structure: aromatic region and basic amine side chain joined by an ester or amide bond.
• Molecules are weak bases (pKa range 8-9).
• Ionised in acidic environments, forming cations.
• Ester bonds metabolise more quickly, leading to shorter half-lives (short-acting).
• Amide bonds metabolise more slowly, leading to longer half-lives (long-acting).

Local Anaesthetics - Pain Sensation

• Nociceptors detect damaging stimuli (e.g., tissue injury, extreme temperatures).
• They generate action potentials in response to noxious stimuli.
• These potentials are transmitted to the brain, causing the sensation of pain.

Local Anaesthetics - Side Effects

• Side effects are caused by systemic absorption.
• Cardiovascular effects: reduced myocardial contractility, heart block, dysrhythmia, vasodilation.
• Central nervous system effects: depressive at low and very high concentrations, stimulatory at medium concentrations (restlessness, tremors, agitation).
• Risk of death due to respiratory depression at very high concentration.
• Different anaesthetics have different side effect profiles due to structural differences.

Modes of Administration

• Surface anaesthesia: applied to surfaces such as the mouth, nose, airway, cornea, urinary tract, etc.
• Infiltration anaesthesia: injected directly into tissues.
• Nerve block anaesthesia: injected near nerve trunks to block peripheral sensation.
• Regional anaesthesia: used to anaesthetise large areas (e.g., Bier's block).
• Intravenous regional anaesthesia: injected into veins in a region blocked off from main circulation, commonly used for limb surgery (lidcaine, prilocaine).

Types of Anaesthesia

• Spinal anaesthesia: injected into the cerebrospinal fluid, deep to the dura mater, to block spinal cord, usually used in lower body or abdominal surgeries (lidcaine).
• Epidural anaesthesia: injected into the epidural space, outside the dura mater, to block spinal roots, commonly used in childbirth or other surgeries (lidcaine, bupivacaine, ropivacaine).