Neuromuscular blocking agents

·         Motor endplate and ACh receptor.

·         Non-depolarizing neuromuscular blockade.

Neuromuscular junction

1.       Skeletal muscles are innervated by somatic efferent nerve fibers from the spinal cord which are fast-conducting myelinated group A axons.

2.    The nerve fiber upon making contact with a muscle fiber, extends into the junctional cleft within the muscle fibre membrane which forms junctional folds enclosing secondary clefts.

3.       Acetylcholinesterase is embedded within a layer of basement membrane present in the junctional clefts.

4.       Nicotinic receptor:

a.    Has a pentameric structure with two functional domains: the ACh-binding sites and the agonist-gated ion channel.

b.       Involved in the transduction of the chemical signal into an electrical event that leads to muscle contraction.

c.       Binding of two molecules of ACh to the receptor results in transient opening of a cation-selective channel that allows influx of sodium ions.

5.       Depolarization of the plasma membrane results in a propagating action potential conducted into the muscle fiber interior via transverse T tubules, causing release of intracellular stores of calcium ions.

Non-depolarizing (competitive) blocking agents

1.       Mechanism of action:

a.    Act by reversibly competing with endogenous acetylcholine for nicotinic receptor sites.

b.       Their blocking action is surmountable and can be overcome by increasing the concentration of acetylcholine.

c.    At higher doses, they can cause blockade by occlusion of open ion channels termed use-dependent block – such a blockade are of a non-competitive nature and increasing agonist concentration will enhance the blockade.

2.       Neuromuscular blocking effects:

a.       General muscle weakness followed by complete flaccid paralysis of muscles which become non-excitable to stimulation.

b.       Small rapidly moving muscles such as those of the fingers and eyes are affected first, followed by the large muscles of the trunk and limbs and lastly the diaphragm and intercostal muscles.

c.       Reversal of blockade: anticholinesterases increase acetylcholine concentration at junctional cleft to displace the blocking agent from the nicotinic sites.

3.       Potency of agents:

a.       Pancucuronium (6).

b.       Metocurine (4).

c.       Atracuirum (>1).

d.    D-tubocurarine (1) – duration of action: 30 – 60min.

e.       Gallamine (0.2).

4.       Unwanted effects:

a.       Histamine release: can cause hypotension and bronchospasm, especially with the use of tubocurarine.

b.       Blockade of autonomic ganglia: cause hypotension, especially with the use of tubocurarine.

c.       Blockade of M2 receptors by gallamine and pancuronium increase release of noradrenaline from such nerve endings.

d.       Blocking noradrenaline uptake into sympathetic nerve endings by pancuronium.

e.       Hypersensitivity reactions: least likely with pancuronium.

5.    Most non-depolarizing drugs possess a quarternary nitrogen and are, therefore poorly lipid soluble.

6.    Drug potentiating blockade:

Depolarizing blocking agents

1.       Mechanism of action:

a.    Act by a persistent depolarization of the postjunctional membrane with consequent closure of Na channels but with increased K permeability, creating zones of inexcitability which an action potential cannot propagate.

b.       Phase I (Depolarizing block): typical persistent depolarization of postjunctional membrane; an anticholinesterase will potentiate the block.

b.       Phase II (Desensitization block): after prolonged or repeated exposure to a depolarizing agent; exhibits some features of competitive blockade.

c.       Transient muscle fasciculations over chest and abdomen precede onset of flaccid muscle paralysis following i.v. administration of succinylcholine.

d.    The arm, neck and leg muscles are affected first followed by the facial, pharyngeal and respiratory muscles.

2.       Pharmacokinetics:

a.       Succinylcholine has a very short duration of action (5 – 10min) because it is rapidly hydrolyzed by pseudocholinesterase in the plasma and liver.

b.    The onset of paralysis very rapid (usually within 1 min) and recovery from blockade after a usual dose is also fast.

c.    A few individuals may experience prolonged blockade due to a genetically-determined abnormal variant of pseudocholinesterase which has a very low capacity to hydrolyze succinylcholine.

3.       Unwanted effects

a.       Bradycardia and arrhythmias can result from repeated injections of succinylcholine.

b.       Succinylcholine depolarization causes a release of potassium from muscle which can be enough to cause cardiac arrest in susceptible patients, e.g. those with burns, severe injury of the head.

c.       Muscle pain: postoperative muscle pain and stiffness lasting 1 – 3 days often follow succinylcholine use.

d.       Raised intragastric pressure: promoting vomiting and increase potential hazard of aspiration of gastric contents.

e.       Hypersensitivity reactions especially with succinylcholine.

f.       Malignant hyperpyrexia: a genetic predisposition to a rare, but often fatal condition, involving intensive muscle spasm and rigidity and a sudden rise in body temperature; esp with succinylcholine and halothane.

4.       Uses:

a.       Surgery and intensive therapy units to provide muscular relaxation.

b.       Convulsions, e.g. electroconvulsion therapy to prevent injury.

c.       Status epilepticus, tetanus or convulsant drug poisoning.

5.       Baclofen:

a.    Half-life: 3h.

b.       Structurally related to GABA.

c.       Inhibits reflex activity mainly in the spinal cord.

d.       Reduces spasticity and flexor spasms but has not action on voluntary muscle power.