Suxamethonium

[CEACCP 2004 Vol 4(1) "Pharmacology of neuromuscular blocking drugs"; SH4:p216-219]

• The only depolarising NMBD still in clinical use is suxamethonium
• Aka succinylcholine or scoline

Structure

• Suxamethonium is two acetylcholine molecules joined together by their acetyl groups
• The two ends have a quaternary ammonium group each

Pharmacodynamics

Mechanism of action

• Depolarising NMBDs are agonists at ACh receptor
  * Suxamethonium is a partial agonist
• Quaternary ammonium groups in suxamethonium bind to the two alpha-subunits of a nicotinic ACh receptor
  --> Ligand-gated channel opens
  --> Depolarisation
  --> Threshold potential reached
  --> Voltage-gated Na+ channel opens and action potential is generated
• Voltage-gated Na+ channel first open, then close and becomes inactivated
  * Membrane potential must be restored before these voltage-gated Na+ channels can be re-activated
• Normally, with ACh, the process is very quick because ACh is broken down by acetylcholinesterase
  --> nACh receptor closes
  --> Membrane potential is restored
• Suxamethonium is NOT metabolised by acetylcholinesterase
  --> Ligand-gated channel is kept open
  --> Membrane potential not restored
  --> Voltage-gated Na+ channels stay inactivated
  --> Junctional transmission is blocked (Phase I block)
  --> Muscle becomes flaccid

NB:

• Nicotinic ACh receptor is a ligand-gated channel
  * When open, it allows cations such as Na+, K+, Ca2+ to go through
  * But mostly Na+
• Prolonged opening of junctional nAChRs
  --> Leakage of K+ from muscle cells
  --> Serum K+ concentration increase by 0.5 mEq/L on average
• Suxamethonium also act on presynaptic nAChRs, but the effect is minor

Effects

• Relaxation of skeletal muscles
  * Phase I blockade
• No direct action on smooth muscles (including uterus)

Side effects

Adverse side effects of suxamethonium include:

• Cardiac dysrhythmia
• Hyperkalaemia
• Myalgia
• Sustained skeletal muscle contraction
• Myoglobinuria
• Increased gastric pressure
• Increased intraocular pressure (IOP)
• Increased incracranial pressure (ICP)
• Can trigger malignant hyperthermia

Cardiac dysrhythmia

• Suxamethonium may on cardiac muscarinic cholinergic receptors
  --> Mimic effect of ACh
  --> Leads to sinus bradycardia, junctional rhythm, or sinus arrest
  * More pronounced in paediatric patients
• More likely to occur when second dose of suxamethonium is administered 5 minutes after the first dose
  * Possible bradycardic role of metabolites (succinylmonocholine and choline)
• Increase in HR and BP may also occur due to actions on autonomic nervous system

Hyperkalaemia

• Suxamethonium 1mg/kg
  --> An increase of approximately 0.5 mmol/L in serum K+ concentration
• Increase in K+ is more pronounced in:
  * Clinically unrecognised muscular dystrophy
  * Unhealed 3rd degree burn
  * Denervation leading to skeletal muscle dystrophy
  * Severe skeletal muscle trauma
  * Upper motor neuron lesion
• Extrajunctional nAChRs is responsible for hyperkalaemia in denervation and UMN lesion
• Not influenced by pretreatment with nonparalysing dose of nondepolarising NMBDs

Hyperkalaemia and muscular disorder

• Use of suxamethonium in some male children with undiagnosed myopathy
  --> Muscle contractures
  --> Rhabdomyolysis and hyperkalaemia
• Duchenne muscular dystrophy (1 in 3,300 male) is the most common
  * X-linked
• Becker muscular dystrophy (1 in 33,000 male)
  * X-linked (tend to manifest in male children)

Myalgia

[CEACCP]

• Worse in ambulatory patients
• More common in the young and healthy with a large muscle mass

Myoglobinuria

• Reflect skeletal muscle damage
• Occurs in paediatrics, rarely in adults
  * Reason unknown

Increased intragastric pressure

• Suxamethonium produces increase in intragastric pressure
  * Related to the intensity of skeletal muscle faciculation
  * Highly variable
• Also associated with corresponding increase in lower oesophageal sphincter pressure
  --> No increased tendency to regurgitation [CEACCP]
• In paediatric population
  --> Skeletal muscle faciculation is minimal to absent
  --> Tend not to have the increased intragastric pressure

Increased intraocular pressure

• Suxamethonium causes maximal increase in IOP about 2-4 minutes after administration
  * Average increase = 4-8 mmHg
• The increase in IOP lasts for about 5-10 minutes
• Mechanism unknown (most likely multifactorial)
  * Increases iin choroidal blood volume
  * Extra-ocular muscle tone
  * Aqueous humour outflow resistance
• Traditionally, suxamethonium is avoided in open eye injury
  * Due to concerns over expulsion of global content
  * But the theory never really be substantiated

Increased intracranial pressure

• Not consistently observed

Sustained skeletal muscle contraction

• In children, incomplete jaw relaxation and masseter jaw rigidity is not uncommon
  * Incidence = 4.4% in paediatrics
  * Considered normal
• Must differentiate from response to malignant hyperthermia
• Sustained skeletal muscle contraction may occur in
  * Myotonia congenita
  * Myotonia dystrophica
  --> May interfere with ventilation and become life-threatening

Precurarisation

• Pretreatment of a nonparalysing dose of nondepolarising NMBDs could decrease or prevent the occurrence of:
  * Cardiac dysrhythmia
  * Myalgia
  * Increased intragastric pressure
  * Increased intraocular pressure
• Pretreatment does NOT influence the magnitude of K+ increase
• Precurarisation reduces the potency of suxamethonium
  --> Larger dose is required

Pharmacokinetics

Absorption

IV, IM

Metabolism

• Suxamethonium is rapidly hydrolysed by plasma cholinesterase (pseudocholinesterase) before reaching NMJ
  * See [Esterases]
• Initial metabolite = succinylmonocholine
  --> Much weaker NMBDs (about 1/20 to 1/80 the potency)
• Succinylmonocholine is subsequently hydrolysed
  --> Succinic acid and choline
• Metabolism is prolonged in patients with atypical plasma cholinesterase
  * See [Atypical plasma cholinesterase]

Elimination

• About 10% excreted in urine unchanged [PI]

Action profile

IV

• Onset of action = 30-60 seconds
• Duration of action = 3-5 minutes

 

IM

• Onset of action = 2-3 minutes
• Duration of action = 10-30 minutes

Pharmaceutics

Presentation

• 100mg/2mL
• pH = 3 - 5

Storage

• Store at 2-8 degrees Celcius

Clinical

Administration

There is a wide variability in responses to suxamethonium
--> There is no single perfect intubating dose

• Endotracheal intubation dose
  = 0.5 - 1 mg/kg [SH4:p216]
  = 1-1.5 mg/kg [SH4:p217; CEACCP article]
  = 0.6 mg/kg IV (range 0.3-1.1 mg/kg) [PI]
• In paediatric
  * IV dose = 1-2 mg/kg
  * IM dose = up to 2.5mg/kg
  * Should not exceed 150mg

ED95

• ED95 for suxamethonium is 0.27mg/kg IV
  --> Normal dose of 1mg/kg is 3-4 times the ED95
• Reduction of dose to 0.6mg/kg still produce acceptable intubating condition
  * But diaphragm recovery is not faster
• Spontaneous breathing may start within 5 minutes of suxamethonium 1mg/kg
  * But 90% twitch height recovery is greater than 10 minutes (or 12-15 minutes [CEACCP])
  --> Diaphragm recovers BEFORE adductor pollicis muscle

NB:

• A preoxygenated healthy adult can experience 8 minutes of apnoea before PaO2 decreases to 90%

Contraindication

Contraindicated in:

• History of malignant hyperthermia
• Plasma cholinesterase abnormalty
  * Genetic (atypical plasma cholinesterase)
  * Severe liver disease
  * Drug-induced (neostigmine, metoclopramide)
• Duchenne's muscular dystrophy, Becker's muscular dystrophy
• Myopatheis associated with elevated creatinine phosphokinase (CPK) values
• Allergy
• Severe hyperkalaemia
• Acute narrow angle glaucoma
• Open eye injury

Interaction

• Digoxin or verapamil
  --> Increased risk of cardiac arrhythmia
• Drugs that may prolong the effect of suxamethonium include:
  * Lignocaine
  * Oxytocin
  * Oral contraceptive pills
  * Some nonpenicillin antibiotics (e.g. gentamicin, tobramycin)
  * Beta-adrenergic blockers (propanolol)
  * Phenytoin, carbamazepine
  * Magnesium
  * Cimetidine
  * Quinine, chloroquine
  * Terbutaline
  * High dose corticosteroids
  * Cytostatic agents (e.g. cyclophosphamide, azathioprine)
• Duration of non-NMBDs administered subsequent to suxamethonium may be increased

Special considerations

Malignant hyperthermia

• Suxamethonium is a recognised trigger of MH

Hypersensitivity

• 1 in 4000
• Hypersensitivity reaction to suxamethonium tend to be classic Type 1 anaphylaxis
• Accounts for 50% of hypersensitivity reactions to NMBDs

Eletrolyte imbalance

• Hypokalaemia or hypocalcaemia require reduced doses of suxamethonium
  * [PI on MIMS]

Obesity

• Obesity is associated with increased activity of plasma cholinesterase
  --> Higher doses may be required (if dosage is based on lean body mass)

Paediatrics

• IV bolus of suxamethonium may result in profound bradycardia or even asystole
  * More common after a second dose
  * Pre-treatment with atropine reduce the risk of bradycardia
• In male paediatric patients, risk of undiagnosed myopathy

Pregnancy

• Pregnancy is associated with decreased plasma cholinesterase activity
  * 40% [SH4:p218] or 25% [PI] decrease
  * But duration of action might not be significantly increased due to increased Vd
• Category A
  * But according to PI, safety with regard to foetal development has not been established

Myasthenia gravis

• In myasthenia gravis
  --> Decrease in functional nAChRs
  --> Decreased response to ACh (and thus suxamethonium)
  --> ED95 is 2.6 times the normal (i.e. higher doses required)
  * [SH4:p219]