DCM 2101 · CNS Pharmacology
Local Anaesthetic Agents: Pharmacology, Techniques and Toxicity
Local anaesthetic agents are medicines that produce a reversible loss of sensation in a limited area without loss of consciousness. They are central to safe minor surgery, dental work, wound care, obstetrics, regional anaesthesia, and acute pain control. A clinician must understand much more than the name of the drug: the quality and safety of a block depend fundamentally on nerve physiology, drug chemistry, accurate dosing, injection site vascularity, and specific patient factors.
This chapter explores the profound neuropharmacology of local anaesthetics, heavily expands the profiles of individual agents (amides and esters), details modern regional techniques, and provides rigorous, step-by-step management protocols for life-threatening complications such as Local Anaesthetic Systemic Toxicity (LAST) and Methaemoglobinaemia.
Learning objectives
- Explain the molecular mechanism by which local anaesthetics interrupt nerve conduction (state-dependent blockade).
- Relate physicochemical properties (pH, pKa, lipid solubility, and protein binding) to clinical onset, potency, and duration of action.
- Evaluate comprehensively the individual profiles of major esters and amides, including their mechanisms of action, indications, contraindications, side effects, and drug interactions.
- Choose a sensible technique based on the surgical requirement and use adjuncts (vasoconstrictors and alkalinising agents) safely.
- Calculate maximum safe dosages accurately based on patient weight and specific agent.
- Recognise, prevent, and begin immediate emergency management of LAST using current lipid-emulsion protocols.
1. Neurophysiology: What normally happens in a peripheral nerve?
To understand local anaesthetics, one must first understand normal nerve conduction:
- Resting Potential: The nerve cell maintains a negative resting membrane potential (approx. -70mV) via the Na+/K+ ATPase pump.
- Depolarisation: A sensory stimulus causes the membrane to reach a threshold potential. Voltage-gated sodium (Na+) channels open rapidly, and a massive influx of Na+ enters the axon.
- Propagation: This depolarisation travels along the nerve axon as an action potential, transmitting the pain signal to the dorsal horn of the spinal cord and up to the brain.
- Repolarisation: Potassium (K+) efflux then repolarises the membrane, resetting it for the next signal.
Core Pharmacological Mechanism (The “Use-Dependent” Block)
Local anaesthetic agents reversibly block voltage-gated sodium channels from the inside of the nerve membrane. They specifically target channels that are actively opening or in an inactivated state during rapid firing. If Na+ channel opening is prevented, the action potential cannot be generated or propagated: the brain perceives no pain. Because they bind more eagerly to rapidly firing channels, they exhibit use-dependent (or state-dependent) blockade.
2. Pharmacokinetics: How a local anaesthetic reaches the channel
Most LA agents are formulated as weak bases (hydrochlorides) and exist in equilibrium between two forms: an uncharged, lipid-soluble base (B) and a charged, water-soluble cation (BH+).
- Crossing the sheath: Only the uncharged, lipid-soluble base (B) can physically penetrate the lipid bilayer of the nerve epineurium and axon membrane.
- Blocking the channel: Once inside the slightly more acidic intracellular environment of the axon, the drug re-equilibrates. The newly formed charged cation (BH+) physically plugs the Na+ channel from the inside.
| Physicochemical Property | Determines | Clinical Consequence |
|---|---|---|
| pKa (Dissociation Constant) | Onset of action | Lower pKa (closer to body pH of 7.4) means more drug exists in the uncharged base form. This results in a faster onset (e.g., Lignocaine pKa 7.9 is faster than Bupivacaine pKa 8.1). |
| Lipid Solubility | Potency | High lipid solubility allows easier penetration of nerve membranes, resulting in greater potency and tissue penetration, but also raises the risk of severe cardiovascular toxicity. |
| Protein Binding (Alpha-1 acid glycoprotein) | Duration of action | High protein binding means the drug firmly attaches to the Na+ channel and local tissues, resulting in a longer duration of action (e.g., Bupivacaine > Lignocaine). |
Why blocks fail in infected or inflamed tissue
Inflamed or infected tissue is highly acidic (pH 5.0 – 6.0). In this low-pH environment, the Henderson-Hasselbalch equation dictates that the vast majority of the local anaesthetic remains in the ionised (charged) state outside the nerve. Because charged molecules cannot cross the lipid membrane, less drug reaches the inside of the axon. A painful abscess will respond poorly to direct infiltration. Solution: Use systemic analgesia, perform a regional nerve block proximally through healthy (normal pH) tissue, or carefully alkalinise the LA agent with sodium bicarbonate.
3. Differential block: Why pain goes before motor power
Not all nerve fibres are blocked at the same time. Local anaesthetics block smaller, myelinated, and rapidly firing fibres before larger, unmyelinated ones. The exact order of blockade is clinically crucial to assess before surgery:
| Fibre Type | Anatomy / Myelination | Function Lost | Clinical Order of Blockade |
|---|---|---|---|
| Type B | Small, myelinated | Autonomic / Sympathetic | 1st (Earliest): Vasodilation and warmth occur first. |
| Type C & A-delta | Small, unmyelinated (C) / myelinated (A-delta) | Pain and Temperature | 2nd: Loss of sharp pain and cold sensation. |
| Type A-gamma & A-beta | Medium, myelinated | Touch and Pressure | 3rd: Patient may still feel pulling/pressure despite pain relief. |
| Type A-alpha | Large, heavily myelinated | Motor function & Proprioception | 4th (Last): Muscle paralysis occurs last and wears off first. |
Clinical Pearl: This explains why a patient may feel pressure or movement despite excellent analgesia, and why a block must always be tested with cold (ice) or a sharp point before incision, rather than simply assuming the block is complete.
4. Classification: Esters and Amides
Local anaesthetics are divided into two distinct chemical classes based on the intermediate chain linking their lipophilic aromatic ring to their hydrophilic amine group. A simple memory aid: Amides have two “i”s in their generic name, Esters have only one “i”.
Esters (e.g., Cocaine, Procaine, Tetracaine, Benzocaine)
- Metabolism: Rapidly hydrolysed in the blood by plasma pseudocholinesterase.
- Allergy Risk: High. Metabolism produces Para-Aminobenzoic Acid (PABA), a known highly allergenic compound.
- Cautions: Patients with atypical pseudocholinesterase will have severely prolonged half-lives of these drugs.
Amides (e.g., Lignocaine, Bupivacaine, Ropivacaine, Prilocaine)
- Metabolism: Biotransformed in the liver by Cytochrome P450 enzymes (dealkylation and hydrolysis).
- Allergy Risk: Extremely rare. A reported “allergy” is usually a reaction to the preservative (methylparaben), an intravascular adrenaline rush, or a vasovagal syncopal episode.
- Cautions: Clearance is significantly reduced in severe liver disease (cirrhosis), low cardiac output (heart failure), and states of poor hepatic perfusion. Toxicity can accumulate rapidly in these patients.
5. Detailed Pharmacological Profiles of Major Agents
Lignocaine (Lidocaine)
- Class: Amide (Intermediate duration). Also a Class Ib antiarrhythmic.
- MOA: Rapid block of fast voltage-gated Na+ channels.
- Indications: Versatile for infiltration, peripheral nerve blocks, epidurals, topical mucosal anaesthesia, and IV management of ventricular arrhythmias.
- Contraindications: Severe heart block (without pacemaker), Adams-Stokes syndrome, Wolff-Parkinson-White syndrome.
- Side / Adverse Effects: Transient Neurologic Symptoms (TNS) if used in spinals. Dose-dependent LAST (tinnitus, perioral numbness, seizures).
- Interactions: Beta-blockers and cimetidine decrease hepatic clearance, increasing toxicity risk.
- Max Dose: 3 mg/kg (plain); 7 mg/kg (with adrenaline).
Bupivacaine
- Class: Amide (Long duration).
- MOA: Highly lipophilic, heavily protein-bound Na+ channel blocker. Binds strongly to resting and inactive channels.
- Indications: Spinal and epidural anaesthesia (especially obstetrics), prolonged peripheral nerve blocks.
- Contraindications: Absolute contraindication in IVRA (Bier Block) due to massive cardiotoxicity risk.
- Side / Adverse Effects: Profound, highly refractory Cardiotoxicity. It binds tightly to cardiac Na+ channels causing broad QRS, severe bradycardia, ventricular fibrillation, and asystole that resists standard resuscitation.
- Max Dose: 2 mg/kg (plain); rarely exceeds 150 mg total in a single adult dose.
Ropivacaine & Levobupivacaine
- Class: Amides (Long duration).
- MOA: Single pure S-enantiomers (unlike Bupivacaine which is a racemic mixture).
- Indications: Epidurals and major nerve blocks where motor-sparing is desired (favours sensory C-fibres over motor A-alpha fibres at low concentrations).
- Advantages: Significantly reduced lipophilicity leading to a wider margin of safety for cardiotoxicity compared to bupivacaine.
- Contraindications: Hypersensitivity to amides. Caution in severe hepatic impairment.
- Max Dose (Ropivacaine): 3 mg/kg. Do not confuse their “safer” profile with absolute safety in massive overdose.
Prilocaine
- Class: Amide (Intermediate duration).
- MOA: Standard Na+ channel blockade, but unique hepatic and renal metabolism into o-toluidine.
- Indications: IVRA (Bier block) due to very low cardiotoxicity, EMLA cream (topical skin eutectic mixture).
- Contraindications: Congenital methaemoglobinaemia, severe anaemia, G6PD deficiency, or concurrent use of other oxidising agents.
- Adverse Effects: Methaemoglobinaemia. The o-toluidine metabolite oxidises haemoglobin (Fe2+ to Fe3+), causing severe hypoxia and cyanosis.
- Max Dose: 6 mg/kg (plain).
Tetracaine & Chloroprocaine (Esters)
- Chloroprocaine: Ultra-short acting. Destroyed rapidly by plasma cholinesterases. Highly favoured in epidurals for emergent Caesarean sections due to its extremely rapid onset and negligible foetal toxicity.
- Tetracaine (Amethocaine): Long-acting ester. Highly potent and toxic. Used almost exclusively for topical ophthalmic anaesthesia or historical heavy spinal blocks. Severe risk of PABA allergy.
Cocaine & Benzocaine (Esters)
- Benzocaine: Exclusively topical (mucous membranes/throat sprays). High lipophilicity. Black Box Warning: Extreme risk of Methaemoglobinaemia. Avoid indiscriminate use, especially in children and teething gels.
- Cocaine: The only LA that produces profound vasoconstriction. MOA: Blocks Na+ channels AND blocks the reuptake of norepinephrine/dopamine. Historically used for ENT topical surgery to shrink mucosa. Extreme risk of hypertension, arrhythmias, coronary vasospasm, and addiction. Contraindicated with MAOIs.
6. Choosing the Technique
The choice of block must match the anatomical site, duration of surgery, and patient physiology.
- Topical anaesthesia: Applied to skin (EMLA) or mucosa (lidocaine spray) for superficial procedures. Absorption is highly variable and can be massive from inflamed vascular mucosa (e.g., urethra, tracheobronchial tree).
- Infiltration anaesthesia: Injected directly into and around the operative site (e.g., laceration repair, excision of lipomas).
- Field block: Creates a continuous ring or wall of anaesthesia proximal to the target area. Useful when direct injection into an infected cyst or abscess is undesirable.
- Peripheral nerve or plexus block (e.g., Brachial Plexus, Femoral): Deposits drug near a named nerve or plexus, anaesthetising a vast anatomical territory. Modern standard requires Point-of-Care Ultrasound (POCUS) guidance to ensure accurate spread and avoid intravascular injection.
- Intravenous Regional Anaesthesia (IVRA / Bier Block): Intravenous injection of LA (strictly Prilocaine or Lignocaine, NEVER Bupivacaine) into an exsanguinated limb isolated by a tightly controlled double-pneumatic tourniquet. Premature deflation causes instantaneous, massive LAST. Must only be performed in equipped theatres.
- Neuraxial techniques (Spinal and Epidural): Spinal involves injecting into the subarachnoid space (CSF); epidural into the epidural space. These provide profound regional anaesthesia (lower half of body) but cause sympathectomy leading to profound vasodilation and hypotension. Requires meticulous asepsis, pre-loading with IV fluids, and vasopressor availability.
6A. Dose, concentration and volume: The calculation that prevents harm
Local anaesthetic safety is fundamentally a total-dose problem. Percentage alone does not tell you the dose. You must convert percentage to milligrams.
The 1% Rule: 1% solution = 10 mg/mL.
- 1% Lignocaine = 10 mg/mL
- 2% Lignocaine = 20 mg/mL
- 0.5% Bupivacaine = 5 mg/mL
Worked Example: Patient weighs 70kg. Maximum dose of plain lignocaine is 3 mg/kg. Total max dose = 210 mg. If using a 1% solution (10 mg/mL), the absolute maximum volume you can inject is 21 mL (210 mg ÷ 10 mg/mL). Always calculate this before picking up the syringe.
If mixing LAs, their toxicities are additive. Do not use the max dose of one and then the max dose of another.
6B. Practical block assessment and aftercare
Before incision, test the dermatomal territory with cold (ice pack) or sharp pinprick. During recovery, the anaesthetised limb is completely vulnerable. Protect the insensate limb from heat burns, pressure sores, and crush injuries. Educate the patient that driving or weight-bearing is strictly prohibited until full motor and proprioceptive function returns.
7. Adjuvants: Adrenaline and Bicarbonate
Adrenaline (Epinephrine)
Adding a vasoconstrictor (usually 1:200,000 adrenaline) causes local alpha-1 receptor activation, profoundly constricting local blood vessels. This achieves three clinical goals:
- Slows systemic uptake into the bloodstream, significantly raising the safety margin (increasing allowable max dose).
- Prolongs the duration of the nerve block by keeping the LA at the target site longer.
- Provides excellent local haemostasis (bloodless surgical field).
Cautions: Classically taught to avoid in end-arterial fields (fingers, toes, nose, penis, pinna) due to risk of ischaemic necrosis, though modern literature shows dilute adrenaline (1:100,000 or less) is generally safe in fingers of healthy patients. Avoid in severe peripheral vascular disease or unstable angina.
Sodium Bicarbonate
LAs are packaged at a low pH to maintain chemical stability and solubility. Adding 1mEq of Sodium Bicarbonate per 10mL of Lignocaine raises the pH closer to physiological levels, increasing the uncharged lipid-soluble fraction. This significantly speeds up the onset of the block and dramatically reduces the pain/burning sensation during tissue infiltration.
8. Adverse Effects and Complications
| Problem | Recognition and Prevention |
|---|---|
| Injection pain/Haematoma | Use a fine-bore needle, buffer with bicarbonate, inject slowly, and apply post-injection compression. |
| Nerve injury (Neuropraxia) | If the patient reports sudden, sharp “electric shock” pain radiating down the limb, the needle is intraneural. Stop and withdraw immediately. Never inject against high resistance. |
| Infection / Abscess | Strict asepsis. Never pass a needle through obviously infected cellulitic skin to reach a deep nerve. |
| Neuraxial Hypotension | Sympathetic blockade (T4 level and below) causes massive venous pooling. Anticipate, pre-hydrate, monitor BP constantly, and treat early with ephedrine or phenylephrine. |
| Systemic toxicity (LAST) | Potentially life-threatening CNS and cardiovascular collapse from rapid systemic absorption or direct IV injection. (Detailed below). |
9. Local Anaesthetic Systemic Toxicity (LAST)
LAST is a terrifying, time-critical, and highly lethal iatrogenic emergency. It occurs due to inadvertent direct intravascular injection or rapid systemic absorption from highly vascular spaces (e.g., intercostal blocks, epidurals). Bupivacaine is the most dangerous offender due to its high lipid solubility and prolonged cardiac binding.
Clinical Progression of LAST
- Early CNS Excitation: Circumoral (around the mouth) tingling or numbness, severe metallic taste, tinnitus (ringing ears), visual disturbances, slurred speech, severe anxiety, and muscle twitching.
- Late CNS Depression: Generalised tonic-clonic seizures, followed by profound coma and respiratory arrest.
- Cardiovascular Toxicity: Follows CNS signs (or may happen simultaneously with Bupivacaine). Bradycardia, heart block, massive widening of the QRS complex, refractory hypotension, ventricular tachycardia/fibrillation, and sudden asystole.
Immediate Response & The Intralipid Protocol for LAST
- Stop the Injection Immediately! Call for senior anaesthetic help and bring the LAST rescue kit.
- Airway & Breathing: Hyperventilate with 100% Oxygen. Hypoxia, hypercapnia, and acidosis drastically worsen LAST by trapping more LA inside cardiac myocytes. Intubate early if seizing.
- Seizure Control: Use small doses of Benzodiazepines (Midazolam). Avoid Propofol if the patient is hypotensive, as it worsens cardiovascular collapse.
- Cardiovascular Support: Use ACLS protocols but with modifications: Avoid vasopressin, calcium channel blockers, and beta-blockers. Reduce adrenaline doses (use <1mcg/kg aliquots) as large doses worsen arrhythmias. Avoid Lignocaine for arrhythmias (do not treat LA toxicity with another LA!).
- Administer 20% Lipid Emulsion (Intralipid) immediately:
- Mechanism: Creates a “lipid sink” in the blood, actively drawing the highly lipid-soluble LA molecules out of the brain and cardiac tissues, whilst also providing a direct energy substrate to the poisoned myocardium.
- Dose: 1.5 mL/kg IV bolus over 1 minute, followed by an infusion at 0.25 mL/kg/min.
- Repeat bolus every 3-5 minutes for refractory cardiovascular collapse. Continue infusion until haemodynamically stable for at least 15 minutes.
10. Methaemoglobinaemia: A Different Toxicity Pattern
Prilocaine (via its o-toluidine metabolite) and Benzocaine are infamous for causing Methaemoglobinaemia. These drugs oxidise the iron in haemoglobin from the normal ferrous state (Fe2+) to the ferric state (Fe3+). Ferric haemoglobin cannot bind or transport oxygen, and shifts the oxygen-dissociation curve drastically to the left, suffocating tissues despite normal lung function.
- Diagnosis: The patient turns blue/slate-grey, is short of breath, and pulse oximetry classically stalls around 85% despite high-flow 100% oxygen. Blood drawn for an ABG appears visually dark “chocolate brown”. Co-oximetry is required to confirm the MetHb percentage.
- Treatment: Stop the drug, supply 100% O2, and administer Methylene Blue (1-2 mg/kg IV slowly over 5 minutes). Methylene blue acts as an electron donor to reduce Fe3+ back to Fe2+. Note: Methylene blue is absolutely contraindicated in G6PD deficiency (can cause massive haemolysis); use Vitamin C (Ascorbic Acid) instead.
10A. Distinguishing Common Reactions After Injection
- Vasovagal episode: Pallor, sweating, bradycardia, and transient syncope around needles. Action: Lie flat (Trendelenburg), lift legs, reassure.
- Adrenaline effect: Palpitations, resting tremor, bounding tachycardia soon after an adrenaline-containing injection. Action: Stop, monitor vitals, reassure it will pass in 5-10 minutes.
- LAST: Metallic taste, perioral numbness, seizures, arrhythmias. Action: Oxygen, lipid emulsion protocol, ACLS.
- Anaphylaxis: Urticaria (hives), severe wheeze, angio-oedema, hypotension. Action: IM Adrenaline 1:1000, IV fluids, antihistamines, steroids.
11. Special Patient Groups
- Children: High risk of toxicity. Calculate meticulously based on accurate current weight (mg/kg). Topical EMLA use must cover strictly limited surface areas to avoid Methaemoglobinaemia.
- Pregnancy: Progesterone increases neural sensitivity to LAs. Epidural veins are engorged, decreasing the epidural space volume and increasing the risk of intravascular injection. Doses of LAs for spinals/epidurals must be reduced by 30%.
- Liver / Cardiac Disease: Severe cirrhosis or heart failure drastically decreases the hepatic clearance of Amides. Lower the maximum allowable dose and extend the time between repeat doses.
- Bleeding Disorders / Anticoagulation: Deep nerve blocks (especially Neuraxial and Lumbar Plexus blocks) are absolutely contraindicated in fully anticoagulated patients due to the catastrophic risk of a compressive epidural/retroperitoneal haematoma. Always consult ASRA (American Society of Regional Anesthesia) guidelines for bridging timing.
12. Clinical and OSCE Pearls
- Never assume percentage = dose. A 2% solution contains 20 mg/mL. Always calculate the total milligrams administered.
- Always actively ask the awake patient during injection: “Do you taste metal? Are your lips numb? Do you hear ringing?”
- Aspirate the syringe in two planes before every single 3-5 mL aliquot to rule out intravascular placement. Note: A negative aspiration does NOT guarantee safety (the needle bevel can act as a one-way flap valve against the vessel wall).
- When asked to manage LAST in an OSCE, do not hesitate: “Stop injecting, call for senior help and the LAST kit, secure the airway with 100% O2, treat seizures with midazolam, and administer 20% Intralipid 1.5 mL/kg IV bolus.”
- Failed infiltration in an abscess is a chemical problem, not drug resistance. Acidic environments block LA penetration.
Knowledge check
1. Why does infection reduce the effectiveness of local anaesthetic infiltration?
Infected tissue is highly acidic. The low pH causes the LA molecules to become ionised (charged). Charged molecules cannot cross the lipid nerve sheath, resulting in block failure.
2. Which physico-chemical property is most associated with a long duration of action?
Protein binding. Agents that strongly bind to tissue proteins (like Bupivacaine) remain trapped at the nerve channel longer.
3. List three early symptoms that should make you suspect LAST.
Perioral (circumoral) numbness, severe metallic taste, and tinnitus (ringing in the ears).
4. Why should the clinician calculate local anaesthetic dose in milligrams rather than millilitres alone?
Because different concentrations yield massively different total doses in the same volume (e.g., 10 mL of 0.5% Bupivacaine = 50 mg; 10 mL of 2% Lignocaine = 200 mg). Toxicity depends strictly on total milligrams per kilogram of body weight.
5. Which two commonly encountered agents are especially associated with methaemoglobinaemia, and what is the antidote?
Prilocaine and Benzocaine. The antidote is IV Methylene Blue.
