Physiology of neuromuscular transmission/neuromuscular block

• Neuromuscular transmission


  The process by which nerves transmit electrical impulses to muscles through the neuromuscular junction
• Neuromuscular transmission


  Acetylcholine released from the nerve ending binds to the endplate nicotinic acetylcholine receptors on the post junctional muscle membrane
• Neuromuscular Junction (NMJ)


  A synaptic connection between the terminal end of a motor nerve and a muscle (skeletal/ smooth/ cardiac)
• Neuromuscular Junction


  • Made up of a motor neurone and a motor endplate with a synaptic cleft or junctional gap dividing them
  • Site for the transmission of action potential from nerve to the muscle
• Why study the Neuromuscular Junction?


  • Understanding its structure and physiology is important
  • NMJ is critical in the production of skeletal muscle contraction
  • For safe use of muscle relaxant drugs during anaesthesia and intensive care
  • To understanding pathological state affecting the NMJ
• Motor neurone


  • Nerves that control the skeletal muscle activity
  • Originate in the ventral horn of the spinal cord and travel up to a metre to the muscles they supply
  • Cell body is at its proximal end
  • Information travels from the cell body down the axon
  • Axons are 10-20µm in diameter
• Motor neurone


  • Axons are surrounded by myelin sheath (insulator) produced by schwan cells
  • Myelin sheath speed up nerve conduction
  • Nodes of ranvier interrupt the myelin sheath
  • Action potential jumps between nodes of ranvier, causing rapid conduction of the nerve impulse (saltatory conduction)
• Motor unit


  • Each motor neurone connects to several skeletal muscle fibres
  • The number of muscle fibres varies from a few to several thousands
  • Fine motor needs few fibres (eg eye muscle) while coarse actions need several thousand fibres (thigh muscle)
  • Each skeletal muscle fibre has only one neuromuscular junction
• Motor neurone


  1. The axon divides into telodendria, the ends of which, the terminal buttons, synapse with the motor endplate

  2. There is a gap of 20nm between the two known as the junctional gap or synaptic cleft

  3. Release of the neurotransmitter, acetylcholine, occurs in the synaptic cleft

  4. Acetylcholine subsequently binds to the receptors on the motor endplate
• Motor endplate


  • A highly specialized region of the sarcolemma of a muscle fibre
  • Oval in shape
  • Covers an area of about 3000µm2
  • Deeply folded surface with multiple crests and secondary clefts
  • Nicotinic acetylcholine receptors are located on the crests of the folds in excessive numbers (1-10 million) and concentration (10,000- 20,000µm2)
• Peri-junctional zone


  • The area of muscle around the motor endplate
  • Potential developed at the motor endplate is converted to action potential at the peri-junctional zone and this propagates through the muscle to initiate contraction
• Acetylcholine synthesis, storage and release

  1. Choline + acetyl-coenzyme A (acetyl-coA) = acetylcholine

  2. It takes place in the terminal axoplasm of motor neurones

  3. Catalysed by the enzyme choline acetyltransferase

  4. Acetyl-coA is synthesized from pyruvate in the mitochondria in the axon terminals
• Acetylcholine synthesis, storage and release cont'd

  1. Approx. 50% of the choline is extracted from extracellular fluid and other 50% from acetylcholine breakdown at NMJ

  2. Choline is mainly from diet with small proportion from hepatic synthesis

  3. Choline acetyltransferase is produced on the ribosomes of the motor neurones cell bodies

  4. Choline acetyltransferase activity is inhibited by acetycholine and increased nerve stimulation
• Acetylcholine synthesis, storage and release cont'd

  1. Acetylcholine molecules are stored in vesicles within terminal button

  2. Each vesicle contain approx. 10,000 molecules of acetylcholine

  3. The vesicles are: 1% immediately releasable, about 80% readily releasable and the remainder form the stationary store

  4. Arrival of nerve impulse, large numbers of P-type calcium channels open and calcium enter the cell + depolarization of the presynaptic terminal
• Acetylcholine synthesis, storage and release cont'd

  1. Triggers 100-300 vesicles to fuse with the presynaptic membrane

  2. Exocytosis and release of acetylcholine into the synaptic cleft

  3. This causes brief depolarization in the muscle that triggers a muscle action potential

  4. Depleted vesicles are rapidly replaced and the empty vesicles are recycled
• Acetylcholine Receptors

  • They are the post-junctional receptors of the motor endplate
  • They are nicotinic acetylcholine receptors
  • Average of 50 million of them are on a normal endplate, situated on the crests of the junctional folds
  • Each is a protein with five polypeptide subunits that form a ring structure around a central, funnel-shaped pore (the ion channel)
• Acetylcholine Receptors cont'd

  • Adult receptor has two identical α (alpha) subunits, one β (beta), one δ (delta) and one ε (epsilon) subunit
  • In the foetus, a γ (gamma) subunit replaces the ε
  • Acetylcholine molecules bind to specific sites on the α subunits
  • When both α are occupied, conformational change occurs and ion channel open for just 1 msec
• Acetylcholine Receptors cont'd

  1. Movement of all cations usually occur but sodium ions movement predominate in terms of quantity and effect

  2. Depolarization then occurs, the cell becomes less negative compared with the extracellular surroundings

  3. At a threshold of -50m v (from -80 m v), voltage –gated sodium channels open

  4. Rate of depolarization increases resulting in endplate potential (EPP) of 50-100m v

  5. Muscle action potential is triggered resulting in muscle contraction
• Acetylcholine Receptors cont'd

  • There are also extra-junctional and pre-junctional receptors outside the motor end plate
  • Denervation injuries and burns are associated with increases in the number of extra-junctional receptors on the muscle membrane
  • They have structure of immature foetal receptors with increased sensitivity to depolarizing muscle relaxants and reduced sensitivity to non-depolarizing muscle relaxants
  • Prejunctional receptors have positive feedback role and causes an increase in transmitter production
• Acetylcholinesterase


  • It rapidly breakdown acetylcholine to choline and acetate for effective function of acetylcholine as a "switch"
  • It breaks down acetylcholine within 1 msec of being released
  • This is followed by repolarization of motor endplate to the resting state
• Neuromuscular Blocking Drugs


  • They block neuromuscular transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles
  • They are used in anaesthesia to impair neuromuscular transmission and provide skeletal muscle relaxation
  • They allow the anaesthetist to perform tracheal intubation, facilitate ventilation, provide optimal surgical operating condition (e.g. during laparotomy)
• Neuromuscular Blocking Drugs


  • Botulinium toxin and tetanus toxin act presynaptically
  • Current clinically important drugs act postsynaptically at the acetylcholine receptors of the motor endplate
• Suxamethonium


  • Structurally it is two ACh molecules joined together
  • Acts as an agonists at nicotinic ACh receptors
• Suxamethonium mechanism of action

  1. Binds with the two alpha sub-units of the receptor mimicking ACh, resulting in membrane depolarization

  2. Succinylcholine is not metabolized by AChesterase, so a prolonged activation of the ach receptors is produced

  3. The sodium receptors at the end-plate and the peri junctional zone remain inactivated and junctional transmission is blocked

  4. The muscle becomes flaccid

  5. Block is called phase 1 or accommodation block

  6. It is often preceded by muscle fasciculation, probably the result of the prejunctional action of succinylcholine
• Suxamethonium pharmacokinetics & pharmacodynamics


  • The dose of succinylcholine required for tracheal intubation is about 1.0–1.5 mg kg−1
  • This dose produces profound block within 60s - faster than any other NMBD presently available
  • Recover within 3 min and is complete within 12–15 min
• Suxamethonium pharmacokinetics & pharmacodynamics cont'd


  1. Recovery from phase 1 block occurs as succinylcholine diffuses away from the neuromuscular junction, down a concentration gradient as the plasma concentration decreases

  2. It is metabolized by plasma cholinesterase - previously called pseudocholinesterase

  3. Prolonged exposure of the neuromuscular junction to succinylcholine can result in: desensitization block or phase II block
• Suxamethonium indications and uses


  • When rapid tracheal intubation is required eg emergency situation
  • When a rapid sequence induction (RSI) is required – in patients at risk of aspiration
  • When rapid recovery of neuromuscular function may be required eg in modified electroconvulsive therapy
• Suxamethonium side effects

  • Bradycardia - it stimulates muscarinic receptors in the sino-atrial node, especially in patients with a high vagal tone (e.g. children) and after repeated doses
  • Muscle pain - most often experienced the day after surgery and is worse with early ambulation, more common in the young and healthy adults with a large muscle mass, not relieved by conventional analgesics, precurarization can prevent it sometimes
• Suxamethonium side effects cont'd

  • Hyperkalaemia - serum potassium levels increase by 0.5mmol/L, patients with pre-existing hyperkalaemia are at risk of cardiac arrhythmias and death, exaggerated in burns, muscular dystrophies and spinal cord injuries, maximal risk of hyperkalaemia in burn patients occurs during days 9-60 after the burn, use within the first 2-3 days after a severe burn injury is regarded as safe
• Suxamethonium side effects cont'd


  • Increased intragastric pressure
  • Malignant hyperthermia - may be triggered by suxamethonium, its use is absolutely contraindicated in susceptible patients
  • Anaphylaxis - accounts for about 50% of hypersensitivity reactions to nmbds, reactions generally represent classic type 1 anaphylaxis (IgE-antibody mediated), are more common after repeated exposure to the drug
• Suxamethonium side effects cont'd


  • Increased intra-ocular pressure - there is a theoretical risk of expulsion of vitreal contents with the use of suxamethonium in patients with a penetrating eye injury, the cause is multifactorial (increase in choroidal blood volume, increase in extra-ocular muscle tone, aqueous humour outflow resistance), this risk must be balanced with the risk of aspiration of gastric contents in emergency surgery
• Suxamethonium side effects - Phase II block


  • It occurs after repeated boluses or a prolonged infusion of succinylcholine
  • In patients with atypical plasma cholinesterase, phase II block can develop after a single dose of the drug
  • The block is characterized by fade of the train-of-four (TOF) twitch response, tetanic fade and post-tetanic potentiation, which are all features of competitive block (Non depolarizing NMBs)
  • After the initial depolarization, the membrane potential gradually returns towards the resting state
• Anaphylaxis


  Accounts for about 50% of hypersensitivity reactions to nmbds
• Anaphylaxis


  • Reactions generally represent classic type 1 anaphylaxis (IgE-antibody mediated)
  • Are more common after repeated exposure to the drug
• Increased intra-ocular pressure


  Theoretical risk of expulsion of vitreal contents with the use of suxamethonium in patients with a penetrating eye injury
• Cause of increased intra-ocular pressure

  • Increase in choroidal blood volume
  • Increase in extra-ocular muscle tone
  • Aqueous humour outflow resistance
• Increased intra-ocular pressure risk


  Must be balanced with the risk of aspiration of gastric contents in emergency surgery
• Phase II block


  • Occurs after repeated boluses or a prolonged infusion of succinylcholine
  • In patients with atypical plasma cholinesterase, phase II block can develop after a single dose of the drug
• Phase II block


  • Characterized by fade of the train-of-four (TOF) twitch response, tetanic fade and post-tetanic potentiation, which are all features of competitive block (Non depolarizing NMBs)
• Mechanism of phase II block


  1. After the initial depolarization, the membrane potential gradually returns towards the resting state

  2. Even though the neuromuscular junction is still exposed to the drug neurotransmission remains blocked throughout