3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.7. Neuromuscular blocking drugs
                      3.1.3.7.1. Depolarising NMBDs
 3.1.3.7.1.1. Suxamethonium 

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]