Local anaesthetics

What are local anaesthetics

Drugs that reversibly block nerve conduction by inhibiting voltage-gated Na⁺ channels in peripheral nerves, producing a localised loss of sensation without loss of consciousness.

Why are voltage-gated Na⁺ channels ideal targets for local anaesthetics?

Because Na⁺ channels are essential for:

• Action potential initiation,

• Action potential propagation,

• Sensory signal transmission (including pain).
  Blocking them prevents neuronal excitability

In which part of the nervous system do local anaesthetics primarily act?

The peripheral nervous system (PNS), particularly sensory afferent fibres transmitting pain.

Which two ionic currents determine the nerve action potential?

1. Inward Na⁺ current – causes depolarisation

2. Outward K⁺ current – causes repolarisation/hyperpolarisation

What effect do local anaesthetics have on potassium channels?

Local anaesthetics do not significantly affect K⁺ channels; their action is selective for voltage-gated Na⁺ channels.

Why does blocking Na⁺ channels prevent action potential propagation?

Because propagation depends on sequential opening of Na⁺ channels along the axon; blocking them prevents depolarisation of adjacent membrane.

What are the functional gates of a voltage-gated Na⁺ channel?

• m-gate (activation gate) – opens rapidly during depolarisation

• h-gate (inactivation gate) – closes shortly after opening

What are the three functional states of a Na⁺ channel?

• Resting – closed but able to open

• Open – conducting Na⁺

• Inactivated – closed and unable to open until repolarisation

What is the role of Naᵥ β-subunits?

• Modulate channel kinetics,

• Affect channel expression and localisation,

• Influence sensitivity to drugs and toxins.

What are the three structural components common to all local anaesthetics?

• Aromatic (lipophilic) ring – membrane penetration

• Intermediate linkage – ester or amide

• Basic amine group – weak base properties

How do ester and amide local anaesthetics differ pharmacologically?

• Esters: plasma esterase metabolism, short-acting, higher allergy risk

• Amides: hepatic metabolism, longer-acting, lower allergy risk

Give examples of ester and amide local anaesthetics.

• Esters: Cocaine

• Amides: Lidocaine

What is the fundamental mechanism of action of local anaesthetics?

They reversibly block voltage-gated Na⁺ channels, preventing action potential generation and conduction

Why must local anaesthetics cross the neuronal membrane to act?

Because their binding site is located on the intracellular side of the Na⁺ channel pore.

Why are local anaesthetics described as weak bases?

They have a pKa of ~8–9, meaning they exist in both ionised and unionised forms at physiological pH.

Which form of a local anaesthetic crosses the membrane and which blocks the channel?

• Unionised (B) → crosses the membrane

• Ionised (BH⁺) → binds to and blocks the Na⁺ channel pore

What is the hydrophilic pathway of local anaesthetic action?

• Accounts for ~90% of effect

• LA enters through open Na⁺ channels

• Produces use-dependent block

What is the hydrophobic pathway of local anaesthetic action?

• Accounts for ~10% of effect

• Unionised LA diffuses through lipid membrane

• Not use-dependent

Why is use-dependence clinically important?

Because rapidly firing nerves (e.g. pain fibres) are blocked more effectively, improving selectivity and efficacy.

What is meant by use-dependent block?

The greater the frequency of action potentials:

• The more Na⁺ channels open,

• The greater the LA access,

• The stronger the block.

Which Na⁺ channel state do local anaesthetics bind with highest affinity?

The inactivated state

How does state-dependent binding enhance LA efficacy?

It stabilises Na⁺ channels in the inactivated state, preventing recovery and repeated firing.

Which nerve fibres are blocked first by local anaesthetics?

Small-diameter fibres:

• C fibres (slow pain),

• Aδ fibres (fast pain).

Why is fibre selectivity clinically beneficial?

Because pain sensation is blocked before touch and motor function, allowing analgesia without paralysis.

Why are inflamed tissues resistant to local anaesthetics?

Inflammation lowers tissue pH → more LA becomes ionised → less membrane penetration → reduced block.

How does pKa relate to LA effectiveness?

The closer the pKa is to physiological pH, the greater the proportion of unionised drug and faster onset

What is surface (topical) anaesthesia?

Application of LA directly to skin or mucous membranes

What is infiltration anaesthesia and its main risk?

Injection into tissue to block nerve endings; main risk is systemic toxicity from vascular injection

What is nerve block anaesthesia used for?

Injection near a nerve trunk to block an entire nerve distribution

What is spinal anaesthesia and its major risks?

Injection into the subarachnoid space; risks include infection, respiratory paralysis, and cardiac depression.

How does epidural anaesthesia differ from spinal anaesthesia?

Epidural is injected into the epidural space, requires larger doses, and is commonly used in obstetrics.