L9 Clinical Pharmacology Local anaesthetics

Overview

This lecture covers local anaesthetics (LAs) as a drug class: how they differ from analgesics and general anaesthetics, their clinical uses and routes of administration, their chemistry (ester vs amide classes and how this determines metabolism and allergy risk), their molecular mechanism of action at voltage-sensitive Na+ channels (VSSCs), the pKa/ionisation chemistry that governs onset and potency, the differential block of nerve fibre types, and the systemic toxicity (LAST) that limits their safe use, including adjunct vasoconstrictors and treatment of toxicity with lipid emulsion.

Purpose, Clinical Use and Ideal Properties

• Nociceptive pain requiring LA intervention arises when surgical incision or trauma creates an “inflammatory cocktail of noxious stimuli” that activates nociceptors — the free nerve endings of Aδ fibres found in skin, muscle, joints, bone and viscera.
• Analgesia = no pain: analgesics (opioids, NSAIDs) block pain sensation without blocking nerve transmission.
• Anaesthesia = no sensation or consciousness:
  • Local anaesthetics block sensation in a defined (local) region without affecting consciousness or other mental processes.
  • General anaesthetics (GAs) cause loss of consciousness without necessarily blocking peripheral nerve signals; LAs are used alongside GAs in some operations (e.g. amputations) to prevent injury signals reaching the CNS, and for chronic pain.
• Choice of anaesthetic, route, and dose depend on: nature of treatment, extent of area to be anaesthetised, route of anaesthesia, anatomical region, pathological state of the patient (e.g. tissue infection, cardiac status, BP), and age/condition of the patient.
• LAs are applied to achieve localised analgesia, blocking nerve transmission when applied locally (NOT intravenously), producing local loss of pain, temperature, touch, pressure and all other sensation limited to the site of administration.
• LAs provide a differential nerve block in a concentration-dependent manner, acting primarily on peripheral and central small afferent sensory fibres; higher concentrations are usually needed to affect motor fibres, unless the LA is placed adjacent to them (e.g. epidural block).
• Clinical considerations:
  • Generally indicated for surgery when consciousness is required; most widely used during “minor” procedures.
  • Contraindications: extensive surgical procedures (risk of high-dose LA toxicity), allergies/hypersensitivities to some LAs, local inflammation at the injection site, infections and ischaemia at the injection site.
  • Precautions: paediatric, elderly or pregnant patients.
• Ideal characteristics of local anaesthetics:
  • Produce a nervous-system-selective and reversible block of sensation.
  • Active by topical or injectable routes.
  • Stabilise all excitable membranes, including motor neurones.
  • Rapid onset with rapid reversibility (washout).
  • Adequate anaesthetic duration (30–60 mins).
  • Non-irritant/non-toxic, locally and systemically.
  • Minimal systemic toxicity (high therapeutic index, low incidence of adverse effects).

Routes of Administration and Techniques

Routes of LA administration: epidural, intrathecal, nerve block, infiltration (subcutaneous & intradermal), and topical (gel).

Route determines target: epidural/intrathecal act near the spinal cord (epidural space / subarachnoid space, near the spinothalamic tract); nerve block targets a peripheral nerve bundle; infiltration and topical act on peripheral pain fibres in skin/subcutaneous tissue.

Local infiltrative vs nerve block:

	Local Infiltrative	Nerve Block
Technique	LA injected s.c. or i.d. directly and/or indirectly into tissues	Single injection targeted at a nerve
Volume	Large volumes needed, distorts anatomy	Efficient use of small anaesthetic volumes
Comfort	Decreased patient comfort — large volume required causes more pain	Fast onset, adequate analgesia
Adjuncts	Used with adrenaline (contraindicated for perivascular infiltration)	—
Needle	Fine needle (25–29G) required	Single injection sufficient
Other	—	Considered superior in confined spaces; skill/imaging reduces risk of direct trauma to neurovascular bundles

• Example: digital nerve blocks — both palmar and dorsal digital nerves lie closely associated with a digital artery and vein; injection sites are at the base of the finger.

Nerve and Local Anaesthetic Structure

Structural barriers to LAs — a peripheral nerve is built from nested connective-tissue layers the drug must cross:

1. Nerve fibres are encased in loose connective tissue — the endoneurium.
2. Fibres are grouped into fascicles by dense collagenous perineurium.
3. The whole nerve is surrounded by a thicker outer layer, the epineurium.

Chemical structure of an LA molecule — three parts:

1. Lipophilic group — usually an aromatic benzene ring.
2. Intermediate chain (link):
   • Ester link (e.g. cocaine, procaine).
   • Amide link (e.g. lignocaine, bupivacaine).
3. Hydrophilic amine group (acts as base proton acceptor).

.

Ester vs amide examples:

• Esters: procaine, tetracaine, benzocaine.
• Amides: lidocaine (lignocaine), bupivacaine, articaine.

LA allergic (hypersensitivity) reactions are mainly linked to esters, not amides. A patient reactive to one ester is likely hypersensitive to all esters, but allergy is unlikely to extend from ester to amide anaesthetics.

Metabolism and Elimination

	Esters (e.g. cocaine, procaine)	Amides (e.g. lignocaine, bupivacaine, articaine)
Metabolism	Rapidly (<10 min) hydrolysed in plasma, mostly by pseudocholinesterase, to water-soluble by-products excreted in urine	Hepatically metabolised by microsomal CYP-450 (CYP3A4) to inactive agents (articaine is also metabolised in tissue/plasma by hydrolysis)
Elimination speed	Fast elimination	Slow diffusion & elimination
Allergy	One by-product is para-aminobenzoic acid (PABA), the common cause of allergic reactions with ester LAs	True allergic reactions are rare, especially with lidocaine
Risk factor	Pseudocholinesterase deficiency poses a toxic risk	—

• Systemic absorption away from the deposition site causes offset/termination of LA effect — the reverse of most other drugs, where absorption produces onset.
• Factors affecting LA absorption/duration: vascularity/blood flow of the administration area, lipid and protein binding, and addition of vasoconstrictors.
• Lignocaine/lidocaine specifics: low pKa gives rapid induction (1–2 min) with medium duration (1–3 hr); the amide linker gives lignocaine a lower pKa and a greater proportion in the lipid-soluble (non-ionised) form at physiological pH; lignocaine binds tightly to the VSSC, giving fast induction and a long half-life.
  • LA solutions are formulated as hydrochloride salts; localised injection pain is associated with the resulting low pH and cold solution.
  • Buffering with sodium bicarbonate raises the solution’s pH, increasing the proportion of unionised LA, which penetrates nerve membranes faster and prolongs duration.

Mechanism of Action

LAs (‘caine drugs) are voltage-sensitive sodium channel (VSSC) blockers; small-diameter pain fibres are most sensitive.

• The VSSC exists in 3 main states: resting/closed → open → inactivated.
  1. At rest, neuronal membranes are mostly impermeable to Na+ and hold a negative resting membrane potential.
  2. Membrane depolarisation activates Na+ channels, switching them from closed to an open, current-conducting state.
  3. Opening of VSSCs and rapid Na+ influx depolarises adjacent Na+ channels in sequence, conducting the action potential.
  4. The channel then enters an inactivated state (a “ball and chain”-like plug from inside), producing a voltage refractory period before returning to resting/closed.
• LAs exhibit use-dependent block: they reversibly block “open” (used) channels from inside the axon and stabilise channels in the inactivated conformation, blocking the fast upstroke of the action potential.
• Local anaesthetics block the voltage-dependent Na+ channels, preventing Na+ influx and hence nerve transmission and perception of pain; with anaesthetic bound, membrane potential remains at −70 mV (no action potential propagation).
• Because Na+ cannot flow in, K+ cannot flow out, inhibiting nerve depolarisation.
• Conduction along myelinated axons is normally saltatory (~200 m/s), jumping between Nodes of Ranvier. LA inhibition at a few nodes prevents downstream nerve impulses from propagating to the ganglion.
• LAs can also affect K+ and Ca2+ channels and some GPCRs, though Na+ channel block is the primary mechanism.

Getting to the binding site (lipophilicity):

• The aromatic group on the LA confers lipophilicity/hydrophobicity.
• LAs must diffuse from the extracellular space, across the nerve cell membrane, into the cytosol — requiring lipid solubility (hydrophobicity), but not so much that the LA stays trapped in the membrane; a moderate degree of hydrophobicity is required.
• The LA then binds to the LA docking site on the VSSC, which is only exposed when the channel is open.
• The more hydrophobic the LA, the more tightly it binds the docking site, giving greater potency and a longer duration of action.

Ionisation State and pKa

• Most drugs are weak acids or weak bases; LAs are weak bases (proton acceptors).
• In acidic media, bases accept H+ from plasma/water and become ionised: $B+H^{+}\rightleftharpoons B{H}^{+}$.
• LAs have a pKa of 7.7–9, close to physiological extracellular pH (7.4); pKa is the pH at which the ionised:non-ionised ratio is 50:50.
• Only the non-ionised (B), more lipophilic form can cross lipid cell membranes; the ionised (BH+) form cannot traverse membranes.
• General weak-acid/weak-base ionisation behaviour: for an acid, increasing pH increases ionisation above its pKa; for a base, increasing pH increases the unionised fraction above its pKa (LAs, as bases, become more ionised at lower/more acidic pH).

Role of ionisation in nerve entry:

1. The unionised LA forms at extracellular pH 7.4 by giving up H+; being lipid soluble, it crosses the nerve membrane.
2. Inside the nerve, the more acidic intracellular pH (~7.2) promotes re-formation of the ionised form (LAH+) in the cytoplasm.
3. LAH+ then physically blocks the open Na+ channel from inside by tightly binding, promoting the inactivated voltage-gated channel state.

Clinical issue — infection: if extracellular pH drops (e.g. due to infection), the LA (a weak base) remains largely ionised and cannot penetrate the nerve, reducing anaesthetic effect. Increasing inflammatory mediators (e.g. PGE2) also change sodium channel expression and function in nociceptors.

pKa and clinical PK/PD relationships:

• The lower the pKa (closer to extracellular pH), the faster the onset of action, because more non-ionised drug is present, allowing faster diffusion to the cytoplasmic side of the nerve.
• Faster onset ← lower pKa (more uncharged at physiologic pH); higher potency ← higher lipophilicity; longer duration ← higher protein binding.

LA	Class	pKa	Elimination half-time (min)	Onset of anaesthesia (min)
Articaine	Amide	7.8	20	1–2
Lignocaine/lidocaine	Amide	7.9	90–120	1–2
Bupivacaine	Amide	8.1	210	5–8
Procaine	Ester	9.1	2	14–18

Additional pharmacologic properties reproduced from the slide’s table (pKa / protein binding % / relative potency / duration / approx. max SC dose mg/kg): chloroprocaine 9.3/unknown/intermediate/short/10; cocaine 8.7/92/low/medium/3; procaine 9.1/5/low/short/10; tetracaine 8.4/76/high/long/3; bupivacaine 8.1/95/high/long/2; etidocaine 7.9/95/high/long/4; lidocaine 7.8/70/low/medium/4.5; mepivacaine 7.9/75/intermediate/medium/4.5; prilocaine 8.0/40/intermediate/medium/8; ropivacaine 8.2/95/intermediate/long/3.

Differential Nerve Block

Local anaesthetics affect small pain fibres first, then large myelinated motor fibres last.

Fibre type	Diameter (µm)	Myelinated	Function	Anaesthetic block onset
C	0.4–1.2 / 0.3–1.3	None	Pain & touch / post-ganglionic sympathetic	Early
B	<3	Light	Pre-ganglionic vasomotor	Early
Aδ	2–5	Lightly	Pain, temperature, touch	Intermediate
Aγ	3–6	Moderate	Motor to muscle spindle	Intermediate
Aβ	5–12	Moderate	Touch & pressure	Intermediate
Aα	12–20	Heavy	Motor & proprioception	Late

• Small fibres have smaller internodal distances, so a shorter length of nerve fibre needs to be blocked to impair conduction compared with larger fibres — explaining why they block first.
• Function of the nerve fibres returns in reverse order (motor/proprioception recovers last… i.e. recovers in the order it was lost, largest/latest-blocked fibres recovering first as effect wanes) [slide states only “function returns in reverse order” without further elaboration].

Adjunct Vasoconstrictors and Treatment of Toxicity

1. Preventing LAST via adjunct vasoconstrictors — view as something to add when required, rather than omit when contraindicated. LAs are formulated with vasoconstrictors (e.g. adrenaline, felypressin [synthetic vasopressin], or clonidine) to:
   • (a) localise the LA to the injection site and prolong its action by 50–100%.
   • (b) decrease systemic toxicity by preventing distribution of LA into blood, and help provide haemostasis.
   • Caution: adverse effects of adrenaline in plasma (caution in cardiac patients); catecholamines (adrenaline & noradrenaline) increase heart rate and contractility, and can produce vasoconstriction or dilation in different regions.
   • Caution using perivascular infiltration at peripheral end arteries: fingers, toes, ears, nose, penis, wrist or ankle.
   • Adrenaline side effects: pallor, anxiety, nervousness, tachycardia, arrhythmia, increased blood pressure, and headaches.
2. Treating LAST — lipid emulsion (Intralipid® 20%, soybean/egg-based), given as an early bolus/infusion, is recommended to “mop up” LA in the circulation.

Local Anaesthetic Systemic Toxicity (LAST)

Cardiac effects: LA blockade of Na+ channels on nodal tissue (SA, AV node etc.) reduces cardiac depolarisation, which can reduce myocardial excitability and pacemaker activity and prolong the refractory period of myocardial tissue; compounded by LA-induced hypotension, this can lead to cardiovascular collapse.

Vascular effects: blocking voltage-gated Na+ channels produces a direct vasodilatory action on vascular smooth muscle by:

• promoting endothelial-mediated nitric oxide release, and
• inhibiting vasoconstrictor sympathetic nerves, preventing noradrenaline release.

LA-induced vasodilation causes hypotension and allows rapid dispersion (washout) of anaesthetic away from the injection site, with potential cardio- and neurotoxic effects.

Clinical presentation is concentration-dependent:

• Serum concentration 5–10 mg/l: early, excitatory CNS toxicity — dizziness, anxiety, confusion, muscular twitching.
• Serum concentration 10–15 mg/l: disorientation, tremor, respiratory depression, seizure.
• Cardiovascular toxicity presents as arrhythmia.

The toxicity–concentration relationship (serum concentration vs time graph) shows escalating bands:

• 0–5 mg/l: below the CNS toxic threshold / within the dosage limit.
• 5–12 mg/l: light symptoms — headache, dizziness, shivering, anxiety, sensory disturbances, confusion, euphoria, slurred speech, muscular twitching.
• 12–20 mg/l: tremor, disorientation, respiratory depression, unconsciousness, cardiovascular instability.
• 20–25 mg/l: profound CNS depression, convulsion, coma, respiratory arrest, heart arrest.

.

Key Take-Home Points

• LAs are classified as amides or esters; this difference is reflected directly in their metabolism (amides mainly undergo hepatic CYP450 biotransformation).
• Speed of onset, potency, and duration depend respectively on pKa, lipid solubility, and protein binding.
• LAs enter pain fibres as non-ionised drug, then bind voltage-gated Na+ channels from inside and block the depolarising Na+ current.
• Risk of systemic absorption is decreased by avoiding intravenous and epidural routes and preferring subcutaneous and topical administration.
• Systemic (CNS and CVS) toxicity and local toxicity (neurodegeneration) limit the clinical safety and use of LAs.

Self-test

1. Define analgesia and anaesthesia, and state how a local anaesthetic’s action differs from that of a general anaesthetic.
2. List the routes of LA administration given in the lecture.
3. Compare local infiltrative and nerve block techniques in terms of volume needed, patient comfort, and needle requirements.
4. Describe the three structural connective-tissue layers a local anaesthetic must cross to reach a nerve fibre, from innermost to outermost.
5. Describe the three parts of a local anaesthetic molecule’s chemical structure.
6. Distinguish esters from amides in terms of example drugs, site/speed of metabolism, and the mechanism behind their differing allergy risk.
7. Describe the three states of the voltage-sensitive sodium channel (VSSC) and the transitions between them.
8. Explain what is meant by “use-dependent block” as it applies to local anaesthetics.
9. Describe how saltatory conduction is disrupted by local anaesthetic action at the Nodes of Ranvier.
10. Explain why a local anaesthetic needs a moderate (rather than very high or very low) degree of hydrophobicity to work effectively.
11. Explain, using the concept of pKa and ionisation state, why local anaesthetics are less effective in infected (acidic) tissue.
12. Describe the sequence by which a local anaesthetic crosses the nerve membrane and then blocks the Na+ channel from inside the cytoplasm.
13. Explain the relationships between pKa and onset of action, lipophilicity and potency, and protein binding and duration of action.
14. List the nerve fibre types in the differential block table, from earliest to latest blocked, and explain why small fibres block first.
15. A patient receives a nerve block for a finger laceration repair. Explain why adrenaline would be avoided or used with particular caution here.
16. List the two purposes of adding a vasoconstrictor to a local anaesthetic formulation.
17. A patient develops dizziness, anxiety, confusion and muscular twitching shortly after a large-volume local anaesthetic infiltration. Explain the likely cause and estimate the serum concentration range this corresponds to.
18. Describe the cardiac and vascular effects that underlie local anaesthetic systemic toxicity (LAST), and how they can combine to cause cardiovascular collapse.
19. Describe how LAST is treated once it occurs.
20. Integrative: explain how the chemical class (ester vs amide) of a local anaesthetic, its pKa, and the local tissue pH together determine how quickly and how effectively it will produce a nerve block.

Answers

Reveal answers

1. Analgesia is the absence of pain (achieved by analgesics such as opioids/NSAIDs without blocking nerve transmission); anaesthesia is absence of sensation or consciousness. Local anaesthetics block sensation in a defined local region without affecting consciousness, whereas general anaesthetics cause loss of consciousness without necessarily blocking peripheral nerve signals.
2. Epidural, intrathecal, nerve block, infiltration (subcutaneous & intradermal), and topical (gel).
3. Local infiltrative needs large volumes (which can distort anatomy and cause more pain) and a fine needle (25–29G); nerve block uses small, efficient volumes with a single injection, has faster onset, and is considered superior in confined spaces.
4. Endoneurium (loose connective tissue around individual fibres) → perineurium (bundles fibres into fascicles) → epineurium (thick outer layer around the whole nerve).
5. A lipophilic group (usually an aromatic benzene ring), an intermediate chain/link (ester or amide), and a hydrophilic amine group.
6. Esters (e.g. procaine, tetracaine, benzocaine) are hydrolysed rapidly (<10 min) in plasma by pseudocholinesterase, producing PABA as a by-product, which is the common cause of ester-LA allergy; amides (e.g. lidocaine, bupivacaine, articaine) are metabolised slowly by hepatic CYP3A4, and true allergic reactions are rare.
7. Resting/closed (impermeable to Na+, negative resting potential) → open (activated by depolarisation, conducts Na+ current) → inactivated (plugged from inside, voltage refractory period) → back to resting/closed.
8. LAs preferentially and reversibly block channels that are in the “open” (used) state, binding from inside the axon and stabilising the inactivated conformation — so more active/firing channels are blocked more effectively.
9. Conduction normally jumps between Nodes of Ranvier at high speed; LA inhibition at a few nodes prevents impulses generated downstream of the blocked nodes from propagating onward to the ganglion.
10. Enough hydrophobicity is needed for the LA to diffuse through the lipid membrane into the cytosol, but too much causes it to stay trapped within the membrane rather than reaching the cytoplasmic binding site on the channel.
11. LAs are weak bases; only the non-ionised (B) form is lipid-soluble and can cross the membrane. In acidic (infected) extracellular tissue, more of the drug is protonated to the ionised (BH+) form, which cannot cross the membrane, so less drug reaches the nerve cytoplasm and the block is less effective.
12. The non-ionised form (B) crosses the extracellular-to-membrane boundary by diffusion; inside the more acidic cytoplasm (pH ~7.2) it re-ionises to LAH+, which then binds tightly inside the open Na+ channel, promoting the inactivated state.
13. Lower pKa (closer to extracellular pH 7.4) → more non-ionised drug present → faster onset; higher lipophilicity → tighter binding to the channel docking site → higher potency; higher protein binding → longer duration of action.
14. Earliest to latest: C and B fibres (early), then Aδ, Aγ, Aβ (intermediate), then Aα (late). Small fibres have shorter internodal distances, so a shorter length of nerve needs to be blocked to impair conduction, making them block first.
15. Fingers are a peripheral end-artery site; the lecture specifically cautions against perivascular infiltration with vasoconstrictors at end arteries (fingers, toes, ears, nose, penis, wrist, ankle) due to risk of excessive vasoconstriction/ischaemia.
16. To localise the LA to the injection site and prolong its action by 50–100%, and to decrease systemic toxicity by preventing distribution of LA into the blood (also helping with haemostasis).
17. This corresponds to early, excitatory CNS toxicity from systemic LA absorption (LAST), consistent with a serum concentration of roughly 5–10 mg/l.
18. Cardiac: Na+ channel block on nodal tissue reduces cardiac depolarisation, myocardial excitability, and pacemaker activity, and prolongs the refractory period; combined with LA-induced hypotension (from vasodilation, due to NO release and inhibition of vasoconstrictor sympathetic nerves), this can precipitate cardiovascular collapse.
19. With early bolus/infusion of lipid emulsion (Intralipid® 20%, soybean/egg-based) to “mop up” LA circulating in the bloodstream.
20. Amides are metabolised slowly (hepatic CYP450) versus esters metabolised rapidly (plasma pseudocholinesterase) — affecting duration of systemic exposure. A lower pKa (closer to tissue pH 7.4) means more non-ionised drug is available to cross the nerve membrane, giving faster onset; but if local tissue pH is lowered (e.g. by infection), even a low-pKa LA becomes more ionised and less able to cross the membrane, slowing or reducing the block regardless of its inherent pKa advantage.