Local Anesthetic Agents

What does anesthesia mean?

Aesthesia - feeling or sensation

An - used to mean "absence of"

• Anaesthesia - absence of feeling or sensation

What are the differences between local and general anesthesia?

• Local means there is a localized or defined area lacking feeling, targets the peripheral nervous system

  • Typically have a localized administration

• General refers effecting the central nervous system, very broadly

  • Typically have systemic administration

Is it preferred to use local anesthetics or GA in large animals and why?

In general, local anesthetics are used in large animals as an alternative to GA as it can be dangerous for the animal and those treating them. Increasing use in a small animal setting. 

What are the seven main ways in which local anesthetics are used in a clinical setting?

• The how and when

1. Topical anaesthesia

• To desensitise mucous membranes (oral, ocular, nasal etc)

• Or to desensitise intact skin (EMLA cream)

2. Local infiltration

• To desensitise dermal and subcutaneous tissues for minor surgery

  • Small injections around site of interest, giving a defined area which lacks sensation

3. Instillation into a cavity or wound

• Inter-pleural anaesthesia

• Intra-articular anaesthesia

  • Can be used diagnostically to assert where the pain is coming from (e.g. equine lameness)

4. Intravenous regional anaesthesia (Bier's block)

• IV administration of lidocaine distal to a tourniquet

• To desensitise distal limb e.g. digit amputation

5. Peripheral nerve blocks

• Used diagnostically & therapeutically

• Many possibilities e.g. Paravertebral, Intercostal, Brachial Plexus, & dental nerve blocks.

6. Epidural (extradural) block

• To desensitise perineum, hindlimb & caudal abdomen

7. Systemic administration

• IV infusion of lidocaine in very painful patients

  • Risky due to the side effects, usually only done in a critical care setting

What is pain?

Pain: an unpleasant sensory & emotional experience associated with actual or potential tissue damage

Describe the pathway of pain in the body from receptor to brain.

• Nociceptor (Transduction): (a specialized pain receptor) Detects noxious stimulus and generates an action potential

• Afferent Fibre (Transmission): Carries the action potential to the CNS

• Spinal Cord – Dorsal Horn (Modulation): Processes and modulates incoming signals

• Brain (Perception): Produces the conscious experience of pain

What is nociception?

Nociception: detection of noxious stimuli that actually or potentially cause damage to an organism

How does an action potential occur in a neuron?

1. Resting membrane potential

• The neuron is at rest (~ –70 mV).

• Inside is negative compared to outside.

• Maintained by the sodium–potassium pump (Na⁺ out, K⁺ in) and leaky K⁺ channels.

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2. Stimulus and depolarization to threshold

• A stimulus causes some Na⁺ channels to open.

• Na⁺ enters the cell, making the inside less negative.

• If the membrane potential reaches the threshold (≈ –55 mV), an action potential is triggered.

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3. Rapid depolarization

• Voltage-gated Na⁺ channels open fully.

• A sudden influx of Na⁺ makes the inside positive (up to +30 mV).

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4. Repolarization

• Na⁺ channels close (inactivate).

• Voltage-gated K⁺ channels open, allowing K⁺ to exit.

• The inside of the cell becomes negative again.

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5. Hyperpolarization

• K⁺ channels stay open slightly too long.

• The membrane becomes more negative than resting (around –80 mV).

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6. Return to resting potential

• K⁺ channels close.

• The Na⁺/K⁺ pump restores ion balance.

• The neuron returns to its resting state, ready for another impulse.

What affects the ability of drugs to cross membranes?

The charge of the drug affects their ability to cross, to be able to diffuse across a cell membrane a drug molecule must be uncharged

• Uncharged, weak bases are non-polar, thus are able to cross

Describe the mechanism of action in local anasthetic, resulting in “numbness”. 

Mechanism of Action of Local Anesthetics

1. Target: Afferent Nerve Fibres

   • Pain signals begin at the nociceptor, where a noxious stimulus generates an action potential.

   • This action potential normally travels along afferent fibres toward the spinal cord and brain.

   • Local anesthetics specifically act on these fibres to block the signal before it reaches the CNS.

2. Sodium Channel Blockade

   • Action potentials depend on the rapid influx of sodium (Na⁺) through voltage-gated sodium channels.

   • Local anesthetics bind to these sodium channels (from the intracellular side) and block Na⁺ entry.

   • Without sodium influx, the neuron cannot depolarize → no action potential is generated or propagated.

3. Prevention of Initiation & Conduction

   • Initiation blocked: The nociceptor may detect a stimulus, but it cannot trigger a successful action potential.

   • Conduction blocked: Even if a small action potential is generated, it cannot travel along the axon to the spinal cord.

   • Net effect: Pain information never reaches the brain, so no conscious perception of pain occurs.

4. Weak Bases and Ionization

   • Local anesthetics are weak bases.

   • In tissue (pH ~7.4), part of the drug exists in an uncharged (lipid-soluble) form → this allows it to cross the nerve membrane.

   • Once inside the axon, the drug re-equilibrates, and the charged form binds to the sodium channel to block it.

     • The charged form is the active form of the drug.

   • This explains why local anesthetic efficacy can be reduced in acidic environments (e.g., infected tissue), since more of the drug remains ionized and cannot cross the membrane effectively.

What are the three states sodium channels can exist in?

1. Resting (closed, but activatable):

• Channel is closed, but ready to open if the membrane depolarizes.

• Local anesthetics have low affinity for this state.

2. Open (activated):

• Channel opens briefly during depolarization to let Na* enter.

• Local anesthetics can enter and bind more easily here.

3. Inactivated (closed, not activatable):

• After opening, the channel enters an inactivated state and cannot reopen until repolarization.

• Local anesthetics have high affinity for this state.

What is use-dependence?

Use dependence (also called frequency dependence) means that the effectiveness of a local anesthetic increases the more often a nerve is activated.

Here’s why:

• Local anesthetics bind preferentially to sodium channels when they are open or inactivated, not when they’re in the resting state.

• With repeated or rapid firing (like in pain fibres), sodium channels cycle through open/inactivated states more frequently.

• This gives local anesthetics more opportunities to bind, so the block becomes stronger with increased use of the channel.

👉 In short: the more a nerve fires, the more it gets blocked — which is why local anesthetics are especially effective at suppressing pain signals.

• Depth of blockade increases with AP frequency, more frequently it is open the more they can enter and bind

Which nerve fibers are more “susceptible” or easily able to be blocked by local anesthetics?

Both small fibers are susceptible to local anesthetics than large motor axons, which are relatively resistant. 

• Small myelinated fibres (A delta fibres): Carry fast, sharp pain. Despite being myelinated, their small diameter makes them more vulnerable to block.

• Small unmyelinated fibres (C fibres): Carry slow, dull, aching pain. Their small size also makes them highly susceptible.

What is the chemical structure of local anesthetics?

lipophilic aromatic group

• Provides lipid solubility

• Allows the drug to cross the nerve cell membrane

attached to basic, hydrophilic amine side-chain by ester or amide link

• Connects the aromatic ring to the amine group.

• Determines whether the drug is an ester (-COO-) or an amide (-NHCO-).

• This matters because:

• Esters are broken down rapidly by plasma esterases (shorter duration, higher allergy risk).

• Amides are metabolized in the liver (longer duration, more stable).

What are the physical properties of local anesthetics?

• weak bases

• largely ionised at physiological pH

• ionisation increases as pH falls

• If drug is in the charged form, they cannot pass through the membrane as easily

• inflamed tissues may be resistant

Why do local anesthetics exhibit pH dependence?

• At physiological pH:

• A portion of the drug is uncharged → can enter the nerve.

• Once inside, it re-equilibrates and the charged form blocks the sodium channel.

• In acidic environments (e.g. infected or inflamed tissue):

• More of the drug is protonated (charged).

• Ionization increases as pH falls

• Less uncharged drug available to cross the membrane.

• Result: reduced penetration and reduced anesthetic effect.

Answer the following about local anesthetics:

• What affects the speed of onset?

• What affects the duration?

• What affects lipid solubility?

• speed of onset related to degree of ionisation

• faster if more of the drug is uncharged at tissue pH, so it can cross the membrane, depends on the pH of binding

• duration related to protein-binding

• Stays in the tissue or axon longer if ^ protein binding (NOT plasma protein because locals are not administered into the plasma, they are administered in the extracellular environment)

• potency related to lipid solubility

• Greater potency if drug is highly lipid soluble so it can cross the cell membrane.

What is ionized vs unionized?

• Ionized = charged (e.g., a protonated local anesthetic, R–NH₃⁺) → water-soluble but cannot cross lipid membranes easily.

• Unionized = uncharged (e.g., R–NH₂) → lipid-soluble and can cross cell membranes.

Why might drugs like bicarbonate or adrenaline be added to local anesthetics?

1. Bicarbonate (NaHCO₃)

• Purpose: Raises the pH of the local anesthetic solution.

• Mechanism:

  • More of the drug exists in the uncharged (unionized) form at higher pH.

  • This speeds the onset because the unionized form crosses the nerve membrane more easily.

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2. Adrenaline (Epinephrine) - only appropriate for local infiltration

• Purpose: Vasoconstrictor — narrows blood vessels at the injection site.

• Mechanism:

  • Reduces local blood flow → slows systemic absorption of the anesthetic

  • Prolongs duration because more drug is retained near the nerve.

What are key features of elimination considering the…

• Ester-linked drugs

• Amide-linked drugs

Ester-linked drugs

• rapidly hydrolysed by non-specific cholinesterases, enzymes present throughout the body, meaning these drugs are metabolized quickly

• short half-lives

Amide-linked drugs

• metabolised in the liver, much more slowly

• longer half-lives

When are adverse effects from local anesthetics most likely to be seen?

Harmful effects are most likely to be seen following overdose or accidental intravenous administration

What adverse effects on the body could be seen with local anesthetics?

• CNS: initial stimulation leading to convulsions later depression leading to coma & death

• CVS: myocardial contractility & heart rate fall peripheral vasodilation

• MISC: allergic reactions are rare (ester>amide) methaemoglobinaemia?

What do the following drugs target on a cellular level?

• NSAIDs

• Local anesthetics

• NMBs

• Enzymes

• Ion Channels

• Act as competitive receptor antagonists

Local anesthetic essentially work on the ______ ____.

• They have a range of ___, such as _______ and ________.

afferent fibers

• uses, antiepileptic, antiarrhythmic