Drugs and the neuromuscular junction Flashcards
What is the normal anatomy and physiology of the neuromuscular junction?
- Motor nerves/ pyramidal neurones originate in layer V of the pre-central gyrus (primary motor cortex)
- Axons pass through internal capsule, transverse the middle portion of the cerebral peduncle of the midbrain and then the basal pons to enter pyramids of medulla
- 90% axons decussate before reaching upper cervical spinal cord and enter spinal cord to become lateral corticospinal tract
Where do these axons terminate in the cord?
- Synapse directly on alpha motor neuron, contributing to rapid voluntary movement
- Synapse with interneuron s responsible for reflexes
- Synapse occasionally in the dorsal horn
Describe ACh metabolism
- acetyl-CoA and choline by choline acetyltransferase
- Generates free coenzyme A (regenerated to acetyl-CoA by pyruvate decarboxylation and supply of acetate anions)
- ACh is stored in vesicles, released into synaptic cleft following electrical stimulation
- Acetylcholinesterase- choline and acetate
Examples of clinical situations involving abnormal function of the neuromuscular junction
- Presynaptic= botulism
- Synaptic= myasthenia gravis, neuromuscular blockade (anaesthesia)
- Spasm
Which are the common drug classes used to influence neuromuscular function?
- Decrease neuromuscular transmission= toxins that block ACh release (botulinum toxin), nicotinic ACh receptor blockers (atracurium, suxamethonium)
- Increase neuromuscular transmission= anti-cholinesterase
- Direct relaxing effect on muscle= direct muscle relaxants (dantrolene)
Describe the botulinum toxin
- Anaerobic soil bacterium Clostridium botulinum
- Acute lethal toxin- ability to paralyse muscles
- Improperly preserved foods, destroyed by heating
- Protease enzyme break down proteins required for docking of synaptic vesicles with the presynaptic membrane
- Toxin inhibits transmitter release, lowering transmitter conc in cleft
What are the clinical uses of the botulinum toxin?
Cosmetics/ cervical dystonia/ achalasia/ blepharospasm/ hyperhydrosis/ overactive bladder/ vocal cord dysfunction
What are the commonly used neuromuscular blocking drugs?
- Non-depolarising blockers= antagonise the nicotinic cholinergic receptor, based or curare alkaloids (atracurium, rocuronium, vecuronium, pancuronium)
- Depolarising blockers= initial agonism of receptor followed by continued binding and shutting of the ion channel= suxamethonium (two linked ACh molecules), broken down by acetylcholinesterase but more slowly than ACh
Describe suxamethonium?
- Mimics ACh at the neuromuscular junction
- Hydrolysis much slower so depolarisation is prolonged
- Action cannot be reversed
- Paralysis is usually preceded by painful muscle fasciculations
- Excessive salivation
- Prolonged paralysis low or atypical plasma cholinesterase (genetic variation) assisted ventilation
What are the commonly used anticholinesterase drugs?
- Reduce the rate of breakdown of ACh and therefore potentiate cholinergic transmission
- Myasthenia gravis= muscle weakness secondary to autoimmune-mediated reduction in cholinergic receptor function
- Reversal of neuromuscular blockade= induced as part of anaesthesia (given with atropine)
- Increasing cholinergic activity in the autonomic nervous system (glaucoma)/ brain (Alzheimer’s)
How are reversible anticholinesterases used for myasthenia gravis?
Autoimmune condition/ antibodies directed at nicotinic ACh receptors
Diagnosis= short-acting anticholinesterases (edrophonium), increase duration of action of ACh
Treatment= long-acting anticholinesterases (pyridostigmine)
Describe irreversible anticholinesterases
Most reversible when rapidly hydrolysed
Phosphate ester bond and resist hydrolysis
Neuromuscular junction unresponsive= widespread muscle paralysis, respiratory failure, cholinergic crisis
Sarin, organophosphates
pralidoxime hydrolysing agent- administered rapidly before the cholinesterase binding is acetylated and becomes completely irreversible
What are the symptoms of cholinergic crisis?
Salivation/ lacrimation/ urination/ defecation/ GI motility/ emesis/ miosis
What are the commonly used skeletal muscle relaxants?
Relieve chronic muscle spasm- MS/ neurological damage
- Drugs acting centrally/CNS to reduce descending stimulatory signals to the muscle (baclofen/ diazepam)
-Drugs acting peripherally (dantrolene)
-Acting on both sites (cannabis)
Reduction in muscle tone- increase in disability
Describe directly acting muscle relaxants
Dantrolene sodium- skeletal
Inhibits calcium release from sarcoplasmic reticulum (prerequisite for interaction of contractile proteins myosin and actin) so prevents muscle contraction
Indicates chronic severe spasticity of voluntary muscle/ malignant hyperthermia
