ACh 2 Flashcards
Curare
• Muscle nAChRs are selectively
blocked by curare (arrow poison) • Curare is a competitive antagonist
of ACh • When bound to receptor, curare
elicits no response • Antidote: acetylcholinesterase
inhibitor
NMJ blockers (NMBs)
Cause paralysis of skeletal muscles. • Can work presynaptically (e.g. botulinum
toxin) or postsynaptically (those used clinically). • Widely used clinically in conjunction with anaesthesia to
prevent muscle movement during surgery (only when artificial
ventilation is available!), but they have no sedative or analgesic
effects. • Two types: non-depolarising and depolarising NMB agents.
Non-depolarising NMB agents
Non-depolarising blocking agents competitively block the
binding of ACh to the nAChRs (e.g. tubocurarine, rocuronium). • Majority of clinically-used NMB agents. • Usually poorly absorbed and rapidly excreted, so given IV.
What (partly) reverses effect of NMBs?
administration of
neostigmine (anticholinesterase) post- operatively, but requires addition of atropine (glycopyrronium) to block unwanted muscarinic effects.
Depolarising NMB agents
depolarising the motor end plate. • Produce transient twitching of skeletal muscle “fasciculation”
before neuromuscular block. • Succinylcholine (suxamethonium) is the only one used
clinically. • Fast onset (30 s) / offset (5-10 min). • Side effects include bradycardia, hyperkalaemia, malignant
hyperthermia – 65% mortality rate!
Neuromuscular junction
Diagram
Neuromuscular junction and embryogenesis
Agrin: • During embryogenesis, agrin initiates formation of NMJ, in the presence of MuSK and Lrp4. • This is key for AChR clustering (together with Rapsyn) and fold formation. • In adults, it regulates the maintenance and regeneration of density lipoprotein receptor-related protein 4 postsynaptic NMJ.
Neuromuscular junction pathology
• Autoinmune disorders:
o Myasthenia gravis: autoantibodies against AChRs
o Neonatal myasthenia gravis: when maternal anti-AChRs antibodies transferred to foetus o Neuromyotonia (Isaac’s syndrome): hyperexcitation of motor nerves
• Genetic disorders:
o Congenital myasthenic syndromes: mutations in
presynaptic, synaptic and postsynaptic proteins
Discovery of myasthenia gravis
Jon Lindstrom 1970s
generated antibodies to purified ACh receptor; inject reference with these antibodies causes muscle weakness similar to patients with MG; autoimmune theory confirmed with later patients studies
Myasthenia gravis
Autoinmune disorder, caused by antibodies targeting the neuromuscular
junction. • Symptoms: muscular weakness and
fatigability • Usually affects ocular (ptosis), bulbar
(mouth and throat) and proximal extremity muscles. • Prevalence: 150-300 per 1,000,000
individuals
myasthenia gravis and nicotinic receptors
Loss of nAChRs coupled with reduction in junctional folds and enlargement of synaptic cleft. • Repetitive muscle stimulation leads to progressively decreasing MUSCLE (not nerve) action potentials, with decreasing muscle power.
Myasthenia gravis: autoantibodies
Diagram
Myasthenia gravis: treatment
• Symptomatic drug therapy:
o AChE inhibitors (e.g. pyridostigmine, neostigmine)
o Drugs that increase ACh presynaptic release (e.g.
3,4-diaminopyridine (blocks pre-syn. K channels))
• Immunosuppressive drug therapy
• Thymectomy
Congenital myasthenic syndromes
• Group of inherited disorders caused by mutations in
genes encoding for proteins essential for maintaining
the integrity of neuromuscular transmission.
• At least 20 different genes known to cause CMS, most confined to NMJ but some ubiquitously expressed.
• Principal clinical feature: fatigable weakness
• UK prevalence: 9.2 cases per million children under 18
Congenital myasthenic syndromes
Types
Table