Local anaesthetics
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Local Anaesthetics
1. The Local Anaesthetic Molecule
A typical local anaesthetic molecule has three parts:
- Hydrophobic aromatic ring - gives lipophilicity, membrane penetration
- Intermediate chain - either an ester (—C—O) or amide (—NHC—) linkage
- Hydrophilic tertiary amine - partially protonated at physiologic pH, bearing positive charge
This gives rise to the two major classes:
FIG. 25.1 - Miller's Anesthesia, 10e: Lidocaine (aminoamide) vs Procaine (aminoester)
2. Classification
| Class | Linkage | Examples | Metabolism |
|---|---|---|---|
| Aminoesters | Ester (-CO-O-) | Cocaine, Procaine, Chloroprocaine, Tetracaine, Benzocaine | Plasma pseudocholinesterase (rapid) |
| Aminoamides | Amide (-NH-CO-) | Lidocaine, Bupivacaine, Ropivacaine, Prilocaine, Levobupivacaine, Mepivacaine | Hepatic microsomal enzymes (slower) |
Memory aid: Amides have two "i"s in their generic names (lidocaine, bupivacaine); esters have one.
3. Mechanism of Action
Local anaesthetics block voltage-gated Na+ channels, preventing the propagation of action potentials.
The resting nerve:
- The membrane maintains a resting potential of -60 to -90 mV
- At rest it is relatively impermeable to Na+ but selectively permeable to K+
- The Na+/K+ ATPase pump sustains ion gradients
How blockade occurs:
- Local anaesthetics bind to Site 9 on the alpha subunit of the Na+ channel (distinct from the tetrodotoxin binding site, Site 1)
- The neutral (uncharged) form of the drug crosses the lipid membrane; the charged (cationic) form binds to the receptor inside the channel
- Binding reduces Na+ conductance, slows the rate of depolarization, and eventually abolishes the action potential
Use-dependent (phasic) blockade:
- Both the open and inactivated states of the channel bind local anaesthetics more avidly than the resting state
- Repeated depolarization (high-frequency firing) increases drug binding and deepens the block - clinically useful because rapidly firing nociceptive fibers are blocked preferentially
- This is explained by the modulated receptor model
The role of pH and pKa:
- Most local anaesthetics have a pKa of 7.6-9.1, so at physiologic pH (7.4) the majority of molecules are in the charged (ionized) form
- The uncharged form penetrates the nerve sheath; the charged form blocks the channel
- Lower pKa → more uncharged drug at pH 7.4 → faster onset (e.g., lidocaine has a lower pKa than chloroprocaine)
- In infected/acidic tissue: drug remains ionized → reduced efficacy - this explains why local anaesthetics are less effective in inflamed tissue
4. Structure-Activity Relationships
| Property | Clinical Implication |
|---|---|
| ↑ Hydrophobicity (larger alkyl groups) | ↑ Potency, ↑ Duration of action |
| ↑ Protein binding | ↑ Duration of action |
| Lower pKa | Faster onset |
| Enantiomers | S(-) enantiomers (ropivacaine, levobupivacaine) have less cardiotoxicity than racemic mixtures |
5. Differential Nerve Block
Nerve fibers are blocked in a specific order:
| Fiber Type | Modality | Diameter | Myelination | Blocked First? |
|---|---|---|---|---|
| C | Pain, temperature, autonomic | <1 µm | Unmyelinated | Yes |
| Aδ | Sharp pain, temperature | 1-4 µm | Thinly myelinated | Early |
| Aβ | Touch, pressure | 6-12 µm | Myelinated | Later |
| Aα | Motor, proprioception | 12-20 µm | Heavily myelinated | Last |
Clinical sequence: autonomic block → pain/temperature → touch/pressure → proprioception → motor
6. Common Drugs and Dosing
(Bailey and Love's Short Practice of Surgery, 28e; Pye's Surgical Handicraft, 22e)
| Drug | Max Dose (plain) | Max Dose (+adrenaline) | Key Features |
|---|---|---|---|
| Lidocaine | 3 mg/kg (200 mg) | 7 mg/kg (500 mg) | Rapid onset, good tissue diffusion, most popular |
| Bupivacaine | 2 mg/kg | 2 mg/kg | Long-acting, highly cardiotoxic - NEVER use IV |
| Prilocaine | 6 mg/kg | 9 mg/kg | Least systemic toxicity; causes methaemoglobinaemia |
| Ropivacaine | 3-4 mg/kg | - | Less cardiotoxic than bupivacaine; sensory > motor separation |
| Levobupivacaine | 2 mg/kg | - | S(-) isomer of bupivacaine; fewer cardiotoxic properties |
| Chloroprocaine | - | - | Ester; very short-acting, fastest onset |
Lidocaine dosage table (Pye's Surgical Handicraft):
| Concentration | Max volume (plain) | Max volume (+adrenaline 1:200,000) |
|---|---|---|
| 0.5% (5 mg/mL) | 40 mL | 100 mL |
| 1% (10 mg/mL) | 20 mL | 50 mL |
| 2% (20 mg/mL) | 10 mL | 25 mL |
| 4% (40 mg/mL) | 5 mL (topical only) | - |
7. Additives: Adrenaline (Epinephrine)
Adding adrenaline to a local anaesthetic solution:
- Hastens onset (vasoconstriction reduces systemic absorption, so more drug remains locally)
- Prolongs duration of block
- Allows a higher total dose (reduces rate of absorption)
- Provides a haemostatic dry field (wait at least 5 minutes before incision)
Contraindications to adrenaline:
- End-arterial locations (digits, nose, penis, ear lobes) - risk of ischaemic necrosis
- Cardiovascular disease
- Patients on tricyclic antidepressants or MAO inhibitors
8. Local Anaesthetic Systemic Toxicity (LAST)
LAST occurs with accidental intravascular injection or overdose.
CNS toxicity (appears first, at lower plasma levels):
- Prodromal: circumoral numbness/tingling, metallic taste, light-headedness, tinnitus, visual disturbances
- Excitatory: slurred speech, disorientation, muscle twitching, seizures
- CNS depression: unconsciousness, respiratory arrest
Cardiovascular toxicity (requires higher plasma levels):
- Na+ channel blockade in cardiac tissue → conduction disturbances, arrhythmias
- Negative inotropy → cardiovascular collapse
- Bupivacaine is particularly dangerous: cardiac Na+ channels unbind it very slowly ("fast in, slow out"), and toxicity is resistant to resuscitation
- Ropivacaine and levobupivacaine were developed specifically to reduce this risk
Treatment of LAST:
- Stop injection immediately
- Call for help; 100% O2
- Secure airway; benzodiazepine/propofol for seizures (20-50 mg propofol or 1-2 mg midazolam)
- If cardiac arrest: CPR + 20% lipid emulsion (Intralipid) - the cornerstone of treatment
- Bolus: 1.5 mL/kg over 1 minute, then 0.25 mL/kg/min infusion
- Acts as a "lipid sink," sequestering the hydrophobic drug from cardiac tissue
- Small doses of epinephrine (0.5-1 mcg/kg increments)
- Amiodarone for bupivacaine-induced ventricular tachyarrhythmias
- Avoid vasopressin, calcium channel blockers, beta-blockers
9. Specific Toxicity Concerns
| Drug | Special Toxicity |
|---|---|
| Prilocaine | Methaemoglobinaemia (due to o-toluidine metabolite) - treat with methylene blue |
| Bupivacaine | Refractory ventricular arrhythmia and cardiac arrest |
| Cocaine | Vasoconstriction + sympathomimetic effects; only LA with intrinsic vasoconstrictive action |
| Benzocaine | Methaemoglobinaemia (topical use) |
10. Clinical Techniques
Topical anaesthesia: EMLA cream (lidocaine + prilocaine), cocaine 4-10% (nasal/ENT), benzocaine sprays
Infiltration: Direct injection into tissues; use dilute solutions (0.5%) for large areas
Peripheral nerve block: Higher concentrations (1-2%) for faster, denser block
Neuraxial:
- Spinal (subarachnoid): small volumes, hyperbaric or isobaric solutions; rapid dense block
- Epidural: larger volumes, slower onset; used for surgical anaesthesia and labour analgesia
IV regional anaesthesia (Bier's block): Prilocaine 0.5% is the drug of choice; bupivacaine is absolutely contraindicated due to cardiac risk if tourniquet fails
Additives to enhance block:
- Adrenaline (epinephrine)
- Clonidine (α2-agonist): prolongs and intensifies block; may be added epidurally, intrathecally, or with peripheral nerve blocks
- Dexamethasone: prolongs peripheral nerve blocks
11. Conditions Reducing Max Safe Dose
Reduce doses in:
- Low body weight / children
- Elderly / debility
- Hepatic disease (impaired amide metabolism)
- Renal impairment
- Epilepsy
- Heart block
Key references:
- Miller's Anesthesia, 10e, Chapter 25 - The Local Anesthetic Molecule; Mechanism of Action
- Sabiston Textbook of Surgery - Local Anesthetic Drugs, p.1552-1560
- Bailey and Love's Short Practice of Surgery, 28e, Table 23.2
- Morgan & Mikhail's Clinical Anesthesiology, 7e - Local Anesthetic Overdose
Skeletal muscle relaxants
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Skeletal Muscle Relaxants
Skeletal muscle relaxants divide into two broad categories: (1) Neuromuscular Blocking Drugs (NMBDs) - act at the neuromuscular junction (NMJ), used in anaesthesia; and (2) Centrally Acting Spasmolytic/Antispasmodic Drugs - act in the CNS/spinal cord, used for spasticity and muscle spasm.
Part 1 - Neuromuscular Blocking Drugs (NMBDs)
The Normal Neuromuscular Junction
Before understanding NMBDs, recall how the NMJ works:
- An action potential arrives at the motor nerve terminal
- Ca2+ influx triggers acetylcholine (ACh) release into the synaptic cleft
- ACh diffuses to bind nicotinic ACh receptors (nAChR) on the motor end plate - a pentameric receptor (2α, 1β, 1γ/ε, 1δ subunits)
- Two ACh molecules must bind (at α-β and δ-α subunit interfaces) to open the ion channel
- Na+/K+ flux produces an end plate potential; if large enough, a muscle action potential propagates along the entire fiber
- Released ACh is rapidly hydrolyzed by acetylcholinesterase (AChE) in ~80-100 μs
NMBDs are quaternary ammonium compounds - highly water-soluble, so they do not cross the blood-brain barrier or placenta.
Classification of NMBDs
| Category | Mechanism | Example |
|---|---|---|
| Depolarizing | Binds nAChR as ACh agonist; sustained depolarization → flaccid paralysis | Succinylcholine (suxamethonium) |
| Non-depolarizing - Aminosteroids | Competitive antagonism at nAChR | Rocuronium, Vecuronium, Pancuronium |
| Non-depolarizing - Benzylisoquinolines | Competitive antagonism at nAChR | Atracurium, Cisatracurium, Mivacurium |
A. Depolarizing NMBDs: Succinylcholine (Suxamethonium)
Structure: Two ACh molecules joined together.
Mechanism - Phase I (Depolarizing Block):
- Binds nAChR and opens the channel, causing transient muscle fasciculations
- Sustained depolarization keeps the membrane unresponsive to further ACh
- Succinylcholine is NOT metabolized at the synapse (no AChE there) - it stays until it diffuses away
- Systemically, plasma pseudocholinesterase hydrolyzes it to succinylmonocholine, then succinic acid + choline
- Augmented, NOT reversed, by anticholinesterases
Phase II (Desensitization Block):
- With prolonged exposure, the end plate repolarizes but becomes desensitized ("closed-channel block")
- Behaves like a nondepolarizing block - may show sustained fade on tetanus
- Can paradoxically be partially reversed by anticholinesterases at this stage
Pharmacokinetics:
| Parameter | Value |
|---|---|
| Onset | 45-60 seconds |
| Duration | 6-10 minutes (spontaneous respiration); full recovery ~15 min |
| Metabolism | Plasma pseudocholinesterase |
Dose: 1.5 mg/kg IV (based on total body weight, even in obesity)
Why succinylcholine remains the gold-standard for RSI:
- Fastest onset of all NMBDs
- Shortest duration - spontaneous breathing returns if intubation fails
- Complete and reliable paralysis
Adverse Effects:
| Effect | Mechanism | Clinical Note |
|---|---|---|
| Fasciculations | Initial depolarization of all motor units | Pre-treatment with small non-depolarizing dose reduces fasciculations and post-op myalgia |
| Hyperkalaemia | K+ efflux during depolarization; normal rise 0.5-1 mEq/L | Dangerous in burns, crush injury, spinal cord injury, prolonged immobilization (>24 hrs) - can cause cardiac arrest |
| Bradycardia | Cardiac muscarinic receptor stimulation | Esp. in children and with repeat doses; treated with atropine |
| Tachycardia/HTN | Nicotinic ganglionic stimulation | |
| ↑ Intraocular pressure | Extraocular muscle contraction | Caution in open globe injury |
| ↑ Intragastric pressure | Abdominal muscle fasciculations | Offset by ↑ LOS tone; aspiration risk not proven |
| ↑ Intracranial pressure | Controversial; mechanism unclear | |
| Malignant hyperthermia | Triggers abnormal Ca2+ release from sarcoplasmic reticulum | Rare but life-threatening; treat with dantrolene |
| Prolonged block | Pseudocholinesterase deficiency (genetic) | Usually 20-30 min extra; rarely significant in ED |
| Myalgias | Post-fasciculation | Common next-day complaint |
Contraindications:
- Burns/crush injury/denervation/immobilization (>24 hrs) - hyperkalaemia risk
- Personal or family history of malignant hyperthermia
- Myopathies (Duchenne muscular dystrophy - rhabdomyolysis)
- Known pseudocholinesterase deficiency
B. Non-depolarizing NMBDs
Mechanism: Competitive antagonism at the α-subunit binding sites of the nAChR. Block ACh access; prevent channel opening. Characterized by:
- Fade on tetanic/TOF stimulation (vs. no fade with succinylcholine in Phase I)
- Post-tetanic facilitation (brief post-tetanic reversal)
- Reversed by anticholinesterases
Aminosteroid Compounds
| Drug | Onset | Duration | Dose | Elimination | Notes |
|---|---|---|---|---|---|
| Rocuronium | 60-90 s (fast); 1.2 mg/kg → ~60 s | Intermediate (30-60 min) | 0.6-1.2 mg/kg | Hepatic/biliary | Reversal by sugammadex; alternative to succinylcholine for RSI at 1.2 mg/kg |
| Vecuronium | 3-5 min | Intermediate (25-40 min) | 0.1 mg/kg | Hepatic/biliary | No cardiovascular effects; accumulates in ICU |
| Pancuronium | 3-5 min | Long (60-90 min) | 0.1 mg/kg | Renal (70%) | Vagolytic → tachycardia and ↑BP; cheap |
| Pipecuronium | 3-5 min | Long | 0.07-0.085 mg/kg | Renal | Minimal cardiovascular effects |
Benzylisoquinolinium Compounds
| Drug | Onset | Duration | Dose | Elimination | Notes |
|---|---|---|---|---|---|
| Atracurium | 3-5 min | Intermediate (25-35 min) | 0.5 mg/kg | Hofmann elimination + ester hydrolysis (organ-independent) | Releases histamine; laudanosine metabolite (neurotoxic in excess) |
| Cisatracurium | 3-5 min | Intermediate | 0.1-0.2 mg/kg | Hofmann elimination | Isomer of atracurium; no histamine release; preferred in ICU and renal/hepatic failure |
| Mivacurium | 2-3 min | Short (15-20 min) | 0.2 mg/kg | Plasma pseudocholinesterase | Shortest-acting non-depolarizing NMBD |
Pharmacokinetics of nondepolarizing NMBDs:
- All are inactive orally (highly polar, given IV/IM only)
- Volume of distribution ≈ 80-140 mL/kg (slightly larger than blood volume)
- Duration of block correlates with elimination half-life
- Renal-excreted drugs (pancuronium, vecuronium to a degree) → longer action in renal failure
- Liver-metabolized drugs → shorter, but prolonged in hepatic failure
- All steroidal agents metabolized to 3-hydroxy, 17-hydroxy, or 3,17-dihydroxy metabolites (40-80% as potent as parent); accumulation possible in ICU
Factors Affecting Neuromuscular Block
| Factor | Effect |
|---|---|
| Volatile anaesthetics (isoflurane > sevoflurane > desflurane > halothane > N2O) | Potentiate nondepolarizing block (CNS depression + ↑ muscle blood flow + ↓ membrane sensitivity) |
| Aminoglycosides, polymyxins | Enhance block (Ca2+-channel block at presynaptic terminal) |
| Magnesium | Enhances block (competes with Ca2+) |
| Acidosis, hypothermia | Prolong block |
| Myasthenia gravis | Exquisitely sensitive to nondepolarizing NMBDs; resistant to succinylcholine |
| Eaton-Lambert syndrome | Resistant to both classes (impaired presynaptic ACh release) |
| Burns, immobilization | Resistance to nondepolarizing NMBDs (upregulation of extrajunctional receptors) |
Monitoring Neuromuscular Block: Train-of-Four (TOF)
- Four supramaximal stimuli at 2 Hz; compare amplitude of 4th to 1st twitch (TOF ratio)
- TOF ratio <0.9 = clinically significant residual paralysis
- Quantitative monitoring is the current standard; avoid subjective assessment alone
| TOF count | Depth of block |
|---|---|
| 0 twitches | Profound block |
| 1-2 twitches | Deep block |
| 3-4 twitches | Moderate/shallow block |
| TOF ratio ≥0.9 | Adequate recovery |
Reversal of Neuromuscular Block
1. Anticholinesterases (for nondepolarizing NMBDs and Phase II succinylcholine block)
Mechanism: Inhibit AChE → ↑ ACh at NMJ → outcompetes NMBD for receptor binding.
| Drug | Dose | Duration | Notes |
|---|---|---|---|
| Neostigmine | 0.04-0.07 mg/kg IV | 30-60 min | Most commonly used; must give anticholinergic (glycopyrrolate or atropine) to block muscarinic side-effects |
| Edrophonium | 0.5-1 mg/kg IV | Shorter | Not available in the US since 2018 |
| Pyridostigmine | - | Longer | Used in Asia; rarely used in US |
Must co-administer: Glycopyrrolate (0.2 mg per 1 mg neostigmine) or atropine to prevent bradycardia, salivation, bronchospasm, increased gut motility.
Key limitation: Anticholinesterases have a ceiling effect - ineffective when block is profound (TOF count = 0). Also cannot be used to reverse benzylisoquinoliniums with sugammadex.
2. Sugammadex (for rocuronium and vecuronium only)
Mechanism: Modified γ-cyclodextrin - a hollow, doughnut-shaped molecule with a hydrophobic cavity and hydrophilic exterior. Encapsulates rocuronium/vecuronium in a 1:1 tight complex (association:dissociation = 25,000,000:1 for rocuronium). This removes free drug from plasma, creating a concentration gradient that draws drug off the NMJ back into plasma, where it is immediately captured.
No anticholinergic co-administration needed - does not affect cholinergic transmission at all.
| TOF | Sugammadex Dose | Time to Recovery |
|---|---|---|
| Reappearance of T2 (moderate block) | 2 mg/kg | ~2-3 min |
| 1-2 post-tetanic counts (deep block) | 4 mg/kg | ~3-4 min |
| Immediate reversal (e.g., can't intubate, can't oxygenate, 1.2 mg/kg rocuronium given 3 min prior) | 16 mg/kg | ~1.5 min |
Reintubation after sugammadex: If rocuronium (1.2 mg/kg) is re-administered within 5 minutes of sugammadex reversal, a complete block can be re-established. After 5-30 minutes, a higher dose of rocuronium is needed. Succinylcholine can be used for re-intubation at any time.
Part 2 - Centrally Acting Muscle Relaxants (Spasmolytics)
These drugs are used for spasticity (upper motor neuron lesions - stroke, MS, spinal cord injury, cerebral palsy) and acute muscle spasm (musculoskeletal pain). They act on the CNS or directly on muscle, not the NMJ.
Classification
| Drug | Site of Action | Mechanism |
|---|---|---|
| Baclofen | Spinal cord (presynaptic) | GABA-B agonist |
| Diazepam | Spinal cord + supraspinal | GABA-A positive allosteric modulator |
| Tizanidine | Spinal cord interneurons | α2-adrenergic agonist (↓ excitatory neurotransmitter release) |
| Dantrolene | Skeletal muscle sarcoplasmic reticulum | Blocks ryanodine receptor (RyR1) → ↓ Ca2+ release |
| Carisoprodol / Meprobamate | CNS (nonspecific) | Sedation via GABA-A agonism |
| Cyclobenzaprine | CNS | TCA-like structure; ↓ tonic somatic motor activity |
| Methocarbamol | CNS (polysynaptic inhibition) | Nonspecific |
Key Drugs in Detail
Baclofen
- GABA-B receptor agonist (specifically); structural analogue of GABA
- Inhibits both monosynaptic and polysynaptic reflex transmission in the spinal cord
- Three mechanisms: closure of presynaptic Ca2+ channels, ↑ postsynaptic K+ conductance, ↓ cyclic-AMP synthesis
- Dose: 40-80 mg/day; toxicity at ≥150-200 mg/day
- Intrathecal baclofen pump for severe spasticity
- Side effects: fatigue, dizziness, confusion, weakness, nausea
- Overdose: Agitation, seizures, flaccid paralysis, coma, respiratory depression; treat with physostigmine 1-2 mg slow IV
Diazepam
- Facilitates GABA-A at spinal cord level (also supraspinal)
- Effective even after cord transection (spinal cord mechanism)
- Dose: 4 mg/day titrated to max 60 mg/day
- Main limitation: sedation at effective doses
Tizanidine
- α2-agonist at spinal interneurons - reduces release of excitatory neurotransmitters from descending pathways
- May also have postsynaptic inhibitory effects
- Less sedating than diazepam at equivalent muscle-relaxant doses
Dantrolene
- Unique - acts peripherally on skeletal muscle (not CNS)
- Blocks the ryanodine receptor (RyR1) on the sarcoplasmic reticulum → ↓ Ca2+ release → ↓ excitation-contraction coupling
- Primary use: Malignant hyperthermia (triggered by volatile anaesthetics or succinylcholine)
- IV dantrolene 2.5 mg/kg, repeat until symptoms resolve (max 10 mg/kg)
- Also used for: spasticity, neuroleptic malignant syndrome
- Side effects: muscle weakness (including respiratory muscles), hepatotoxicity (with long-term oral use)
Summary Comparison Table
| Feature | Succinylcholine | Rocuronium | Vecuronium | Atracurium | Cisatracurium |
|---|---|---|---|---|---|
| Class | Depolarizing | Aminosteroid | Aminosteroid | Benzylisoquinoline | Benzylisoquinoline |
| Onset | <1 min | 1-2 min (1.2 mg/kg) | 3-5 min | 3-5 min | 3-5 min |
| Duration | 6-10 min | 30-60 min | 25-40 min | 25-35 min | 25-35 min |
| Reversal | Spontaneous only | Sugammadex | Sugammadex or neostigmine | Neostigmine only | Neostigmine only |
| Metabolism | Pseudocholinesterase | Hepatic/biliary | Hepatic/biliary | Hofmann + ester hydrolysis | Hofmann elimination |
| Safe in renal failure? | Yes | Caution | Caution | Yes | Yes |
| Safe in hepatic failure? | Yes | Caution | Caution | Yes | Yes |
| Histamine release? | No | No | No | Yes | No |
| Cardiovascular effect | Brady/tachy (muscarinic/nicotinic) | Minimal | None | Hypotension (histamine) | None |
Key References:
- Miller's Anesthesia, 10e - Chapter 24 (Reversal, Sugammadex), Chapter 11 (NMJ physiology)
- Katzung's Basic & Clinical Pharmacology, 16e - Chapter 27 (NMBDs, Spasmolytic Drugs)
- Rosen's Emergency Medicine - Neuromuscular Blocking Agents
- Forensic Medicine & Toxicology, 36e - Baclofen toxicity
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