Depolarising: Suxamethonium

Depolarising neuromuscular blockade: suxamethonium

Suxamethonium, also called succinylcholine, remains the prototypical depolarising neuromuscular blocking drug and is still one of the most examined drugs in the Primary FRCA. It is a diacetylcholine molecule: two acetylcholine molecules linked back-to-back through their acetyl groups. This structure explains both its agonist activity at nicotinic acetylcholine receptors and its rapid hydrolysis by plasma cholinesterase. Its unique clinical value is the combination of very rapid onset and very short duration after a single dose; its unique danger is that it is not simply a short-acting muscle relaxant, but a pharmacological trigger for several rare but catastrophic complications.

Core physicochemical and pharmacological properties

Neuromuscular junction physiology relevant to suxamethonium

The adult skeletal muscle nicotinic acetylcholine receptor is a pentameric ligand-gated cation channel composed of two alpha1, one beta1, one delta and one epsilon subunit arranged around a central pore. Two acetylcholine molecules bind at the alpha-delta and alpha-epsilon interfaces. Channel opening permits predominantly sodium influx and potassium efflux, depolarising the motor endplate and triggering voltage-gated sodium channels in the perijunctional membrane. A self-propagating muscle action potential then leads to calcium release from the sarcoplasmic reticulum via dihydropyridine and ryanodine receptor coupling, producing contraction.

Suxamethonium acts as an agonist at the same nicotinic receptor but is not rapidly hydrolysed by synaptic acetylcholinesterase. It therefore remains at the receptor long enough to produce sustained endplate depolarisation. This is the basis of phase I block. The surrounding voltage-gated sodium channels enter an inactivated state and cannot reset until the membrane repolarises. Although the endplate is depolarised, the muscle fibre becomes electrically inexcitable. The initial asynchronous activation of motor units produces visible fasciculations, followed by flaccid paralysis.

Adult versus fetal or extrajunctional receptors

The fetal nicotinic receptor contains a gamma subunit instead of epsilon: alpha2 beta delta gamma. It has a longer mean channel open time, lower conductance, greater sensitivity to agonists and a wider distribution across the muscle membrane. In adult denervated, immobilised, burned or critically ill muscle, extrajunctional receptors are upregulated and fetal-type or alpha7-like receptors may appear beyond the motor endplate. These receptors greatly increase potassium efflux when depolarised by suxamethonium, explaining the life-threatening hyperkalaemia seen in susceptible states. This is an important Primary FRCA concept: the dangerous hyperkalaemia is not simply due to fasciculations; it is due to receptor proliferation and altered channel behaviour.

Phase I and phase II block

Phase II block is mechanistically complex. Proposed mechanisms include receptor desensitisation, channel blockade, impaired presynaptic mobilisation of acetylcholine, altered ion gradients, and interaction with non-junctional receptors. In examination answers, state that phase II block follows prolonged exposure and has electrophysiological features similar to non-depolarising block, particularly fade on peripheral nerve stimulation.

Pharmacokinetics and plasma cholinesterase

After IV injection, most suxamethonium is hydrolysed in plasma before reaching the neuromuscular junction. Only a small fraction reaches motor endplates. The drug is not terminated by acetylcholinesterase within the synaptic cleft; rather, paralysis ends when plasma concentrations fall and drug diffuses away from the junction. This explains why plasma cholinesterase deficiency prolongs blockade dramatically.

Genetic variants and prolonged apnoea

Plasma cholinesterase is encoded by the BCHE gene on chromosome 3. The normal allele is conventionally called U. The atypical allele A is resistant to inhibition by dibucaine. The fluoride-resistant allele F and silent alleles also occur. The dibucaine number is not the enzyme activity; it is the percentage inhibition of plasma cholinesterase by dibucaine under test conditions.

The incidence of clinically important inherited atypical cholinesterase is often quoted around 1:2,500-1:3,200 for homozygous atypical variants in European populations, with heterozygosity much commoner. Acquired reduction in plasma cholinesterase activity is more frequent but usually produces less dramatic prolongation unless combined with genetic susceptibility.

Acquired causes of reduced plasma cholinesterase activity

• Physiological: pregnancy and puerperium, especially late pregnancy; neonates and infants have lower activity but usually adequate clinical recovery.
• Hepatic disease: reduced synthesis in severe liver dysfunction.
• Malnutrition and malignancy: reduced protein synthesis and enzyme activity.
• Renal failure: variable reduction; uraemia may contribute.
• Burns and major trauma: reduced enzyme may coexist with receptor upregulation; the latter is the more dangerous reason to avoid suxamethonium after the early period.
• Drugs: organophosphates, ecothiopate eye drops, anticholinesterases, metoclopramide, esmolol, cytotoxic agents such as cyclophosphamide, monoamine oxidase inhibitors, and some local anaesthetic esters may reduce activity or compete for hydrolysis.

Pharmacodynamics and dosing

The ED95 of suxamethonium for the adductor pollicis is approximately 0.3 mg/kg. Intubating doses exceed this to ensure rapid diaphragm, laryngeal and jaw relaxation. Laryngeal muscles have faster onset and recovery than adductor pollicis because of higher blood flow and different fibre composition. The diaphragm is relatively resistant but has rapid onset and recovery. For rapid sequence induction, 1 mg/kg IV is traditional; 1.5 mg/kg provides more reliable profound block but may prolong recovery. Dose should usually be based on total body weight because plasma volume and extracellular fluid scale better with total body weight, although this must be balanced against increased duration in severe obesity.

Clinical uses

• Rapid sequence induction: historically the standard relaxant for aspiration-risk patients because of fast onset and short duration.
• Emergency airway rescue: useful where rapidly reversible paralysis is desirable, although this advantage is limited if hypoxia occurs before recovery.
• Electroconvulsive therapy: short duration and excellent seizure modification.
• Laryngospasm: small IV doses, e.g. 0.1-0.5 mg/kg depending on severity and clinical context, or IM dose if no IV access, may break severe refractory laryngospasm; oxygenation and deepening anaesthesia remain immediate priorities.

Adverse effects and mechanisms

Hyperkalaemia

A normal intubating dose of suxamethonium increases serum potassium by approximately 0.3-0.5 mmol/L in healthy adults. This is usually clinically insignificant. In susceptible patients, potassium may rise by several mmol/L within minutes, causing ventricular arrhythmias, sine-wave ECG, pulseless electrical activity or asystole.

The mechanism is depolarisation-induced potassium efflux through nicotinic receptor channels. Risk is massively increased when extrajunctional acetylcholine receptors are upregulated or when fetal-type receptors are re-expressed. These receptors are more widely distributed, have longer open times and allow greater potassium efflux. The risk is not prevented by defasciculation.

Chronic renal failure alone is not an absolute contraindication if serum potassium is normal and no neuropathy or immobility exists. This is a common viva trap. However, in emergency renal failure with unknown or elevated potassium, suxamethonium may be dangerous.

Malignant hyperthermia

Suxamethonium is a recognised trigger of malignant hyperthermia, especially with volatile anaesthetics. MH is a pharmacogenetic disorder of skeletal muscle calcium regulation, most commonly due to variants in RYR1 and less commonly CACNA1S. Trigger exposure causes uncontrolled calcium release from sarcoplasmic reticulum through ryanodine receptor type 1, leading to sustained contraction, hypermetabolism, oxygen consumption, carbon dioxide production, heat generation, acidosis, hyperkalaemia and rhabdomyolysis.

Early signs are unexplained rising end-tidal CO2, tachycardia, masseter spasm, rigidity and acidosis; hyperthermia is often late. UK and Association of Anaesthetists/MH Association guidance emphasises immediate trigger cessation, calling for help, 100% oxygen, active cooling, hyperkalaemia treatment, correction of acidosis and dantrolene. Dantrolene dose is 2-2.5 mg/kg IV initially, repeated as required until control; large cumulative doses may be needed. Post-crisis monitoring in ICU is required because recrudescence can occur.

Masseter muscle rigidity

Masseter spasm after suxamethonium may range from increased jaw tone to true masseter muscle rigidity preventing mouth opening. It is more common in children and in association with volatile induction. It may be an early sign of MH but is not diagnostic alone. Management requires oxygenation, assessment for generalised rigidity, end-tidal CO2, temperature, CK, potassium and acidosis. Elective surgery should usually be postponed if significant rigidity occurs, and MH precautions instituted.

Bradycardia and arrhythmias

Suxamethonium can produce bradycardia, junctional rhythm, ventricular ectopy and, rarely, asystole. Mechanisms include stimulation of cardiac muscarinic receptors and autonomic ganglia, sinus node effects, and hyperkalaemia. Bradycardia is more common in children, after repeated doses, and in patients receiving potent vagotonic stimuli. Atropine 20 micrograms/kg IV in children, or glycopyrrolate/atropine in adults according to context, may be used prophylactically or therapeutically. Repeated suxamethonium doses in children are particularly associated with profound bradycardia.

Fasciculations and postoperative myalgia

Fasciculations are due to initial depolarisation of motor endplates. Postoperative myalgia is common, especially in ambulatory, young, muscular adults and after minor surgery where pain is otherwise low. Incidence varies widely in studies, often around 10-60% depending on definition. Mechanisms include mechanical muscle injury, calcium-mediated damage and inflammatory mediators. A small priming dose of non-depolarising relaxant, for example rocuronium 0.03-0.06 mg/kg or atracurium 0.03-0.05 mg/kg given several minutes before suxamethonium, reduces fasciculations and myalgia but may cause weakness, diplopia, impaired airway protection and require a larger suxamethonium dose. Meta-analyses, including work by Schreiber and colleagues, support reduction in myalgia with precurarisation, lidocaine and NSAIDs, but the practice is less common in modern RSI because awake weakness before induction is undesirable.

Raised intra-ocular, intragastric and intracranial pressure

Suxamethonium transiently increases intra-ocular pressure by approximately 5-15 mmHg, peaking within 2-4 minutes and returning toward baseline within about 6 minutes. Mechanisms include tonic contraction of extraocular muscles, choroidal vascular dilatation and cycloplegic effects. It has historically been avoided in open-globe injury, but the clinical risk must be balanced against aspiration and failed airway risk. Modern practice often accepts suxamethonium when it is the best drug for emergency airway control, with adequate induction, opioid/lidocaine if appropriate, and avoidance of coughing or hypoxia.

Intragastric pressure may increase due to abdominal wall fasciculations, but lower oesophageal sphincter pressure also increases; net aspiration risk is not clearly increased by suxamethonium itself. Intracranial pressure may rise modestly, probably via muscle spindle afferents and cerebral haemodynamic changes, but this is usually attenuated by adequate anaesthesia, ventilation and opioid. In traumatic brain injury, hypoxia, hypercapnia and failed intubation are much more dangerous than a small transient ICP increase.

Anaphylaxis

Neuromuscular blocking agents are among the most common causes of perioperative anaphylaxis in many national series, and suxamethonium has a relatively high rate compared with several alternatives. Quaternary ammonium groups can act as antigenic determinants, and cross-reactivity between NMBAs is possible. Clinical features include hypotension, bronchospasm, urticaria, angio-oedema and cardiovascular collapse. Management follows perioperative anaphylaxis algorithms: stop suspected agents, call for help, 100% oxygen, IV adrenaline, aggressive crystalloid, vasopressors as needed, bronchodilators and later antihistamines/corticosteroids. Serum mast cell tryptase should be sampled as soon as possible after stabilisation, ideally at 1-2 hours and again at baseline after 24 hours or in follow-up. Referral for formal allergy testing is mandatory.

Contraindications and cautions

Drug interactions

• Volatile anaesthetics: potentiate neuromuscular blockade and, with suxamethonium, increase MH triggering risk in susceptible individuals.
• Anticholinesterases: neostigmine and organophosphates may prolong suxamethonium by inhibiting plasma cholinesterase and increasing acetylcholine; neostigmine is not used to reverse phase I block.
• Magnesium: reduces presynaptic acetylcholine release and decreases muscle excitability, potentiating blockade.
• Aminoglycosides, clindamycin, polymyxins, tetracyclines: may potentiate neuromuscular blockade through presynaptic and postsynaptic effects.
• Lithium: may prolong depolarising and non-depolarising block.
• Local anaesthetic ester competition: ester local anaesthetics are also hydrolysed by plasma cholinesterase; clinically relevant mainly in deficiency or high exposure.

Suxamethonium versus rocuronium for rapid sequence induction

Rocuronium 1.0-1.2 mg/kg IV provides onset approaching suxamethonium, with longer spontaneous duration, often 45-75 minutes depending on dose and patient factors. Sugammadex 16 mg/kg can reverse profound rocuronium block rapidly after immediate failed intubation, but availability, cost, correct dosing and vascular access are essential. The Cochrane review literature comparing rocuronium and suxamethonium for RSI generally finds suxamethonium more likely to produce excellent intubating conditions, especially when rocuronium is used at lower doses; high-dose rocuronium narrows the difference. Many modern airway guidelines, including Difficult Airway Society guidance, emphasise that the choice of neuromuscular blocker must be integrated into an airway plan, not treated as a substitute for oxygenation strategy, skilled laryngoscopy and front-of-neck access readiness.

Management of prolonged apnoea after suxamethonium

Prolonged apnoea is managed by recognising that the patient is paralysed but not necessarily unconscious. The priority is anaesthesia, oxygenation and ventilation, not pharmacological reversal.

1. Maintain anaesthesia and analgesia: prevent awareness while paralysed. Use volatile or IV anaesthesia as appropriate.
2. Ventilate with 100% oxygen initially: then adjust to normal oxygenation and normocapnia. Continue until neuromuscular recovery.
3. Use peripheral nerve stimulation: distinguish persistent phase I from phase II or non-depolarising block; document TOF and clinical recovery.
4. Review drug history: anticholinesterases, organophosphates, pregnancy, liver disease, renal failure, malignancy.
5. Send investigations: plasma cholinesterase activity and dibucaine number, ideally after recovery and not immediately after transfusion of plasma-containing products if avoidable.
6. Avoid routine FFP: fresh frozen plasma contains cholinesterase but exposes the patient to transfusion risk; supportive ventilation is safer in most cases.
7. Counsel and refer: provide written warning, document prominently, advise family testing when inherited deficiency is suspected, and recommend medical alert identification.

Emergency management of suxamethonium-related hyperkalaemic arrest

If cardiovascular collapse occurs shortly after suxamethonium, treat as hyperkalaemia while continuing advanced life support. Give calcium chloride 10% 10 ml IV or calcium gluconate 10% 30 ml IV to stabilise myocardium, repeat guided by ECG. Shift potassium intracellularly with insulin 10 units soluble insulin IV plus 25 g glucose, salbutamol nebulisation or IV according to local protocol, and sodium bicarbonate 50 mmol if severe acidosis or arrest. Remove potassium using dialysis when appropriate, diuretics if renal function and circulation permit, or potassium binders for non-arrest situations. Treat rhabdomyolysis aggressively with fluids, monitoring CK, potassium, calcium, phosphate, renal function and urine output.

Investigations after suspected complications

Primary FRCA viva discussion points

• Why does suxamethonium cause paralysis if it is an agonist? Because sustained endplate depolarisation inactivates adjacent voltage-gated sodium channels; the muscle membrane cannot generate further action potentials.
• Why does acetylcholinesterase not terminate its action? Suxamethonium is hydrolysed mainly by plasma cholinesterase; synaptic acetylcholinesterase does not rapidly remove it from the receptor environment.
• Can neostigmine reverse suxamethonium? No for phase I block; it may prolong block. Phase II responses are unpredictable and not a routine strategy.
• Is renal failure a contraindication? Not if potassium is normal and there is no neuropathy, immobility or myopathy; hyperkalaemia itself is the issue.
• Does suxamethonium cross the placenta? Minimal transfer because it is ionised and rapidly hydrolysed; fetal paralysis is not expected after standard maternal dosing.
• What is the safest response to prolonged apnoea? Continue anaesthesia and mechanical ventilation until recovery; do not wake a paralysed patient.

Controversies and recent practice trends

The main controversy is whether suxamethonium should remain the default RSI relaxant in the era of high-dose rocuronium and sugammadex. Advocates of suxamethonium cite fastest onset, superior excellent intubating conditions in some evidence syntheses, short spontaneous duration and familiarity. Critics cite unpredictable catastrophic complications, contraindication burden, postoperative myalgia, MH triggering and the fact that return of spontaneous breathing may be too slow to rescue a rapidly desaturating patient. Rocuronium-sugammadex strategies are attractive but depend on immediate drug availability, correct 16 mg/kg dosing for emergency reversal, and recognition that sugammadex is not a substitute for oxygenation or front-of-neck access.

A second controversy is suxamethonium in open-globe injury. The IOP rise is real, but evidence that it worsens ocular outcome is limited and confounded. Many anaesthetists prioritise rapid, smooth intubation and avoidance of coughing, bucking, hypoxia and hypertension. A third is precurarisation: it reduces fasciculations and myalgia but can produce distressing weakness before induction and may compromise airway reflexes; it is rarely essential for modern RSI.

Classification of neuromuscular blockers for context

For the Primary FRCA, suxamethonium should be understood not as a list of side effects but as a coherent pharmacological system: a quaternary ammonium agonist, rapidly hydrolysed in plasma, producing depolarising block at nicotinic receptors, with complications predictable from receptor distribution, potassium flux, cholinesterase biology and skeletal muscle calcium handling.