Neuromuscular Transmission-Sequence of Events, Neuromuscular

Blockers, Their Mechanisms & Clinical Importance

RK Goit, Lecturer

Department of Physiology

• all skeletal muscles is under voluntary or reflex control by motor neurons

• a motor nerve fiber divides into several branches

• each branch of the motor nerve fiber innervates one muscle fiber

• each single motor neuron & the muscle fibers it innervates is called a motor unit

• The junction between a motor nerve fiber & a muscle fiber is known as the neuromuscular junction.

presynaptic portion of neuromuscular junction

• as the axon of motor neuron approaches the muscle fiber, it loses its myelin sheath & divides extensively into several fine branches- axon terminal

• terminal is covered by Schwann cells

• each terminal is expanded at its end to form a knobby structure- synaptic knob (terminal bottom)

• terminal bottom lies in the groove (synaptic trough) in the surface of muscle fiber

• vesicles are clustered around specific points- active zones

synaptic cleft

• gap between the terminal bottom & the muscle fiber, which is about 20-30 nm wide

• muscle fiber is covered by basement membrane or basal lamina, consisting of collagen, glycoproteins & other extracellular matrix proteins (neurexins)

• also contain acetylcholinesterase

postsynaptic portion of neuromuscular junction

• the part of the sarcolemma that lies directly under the terminal button known as end-plate membrane (motor end-plate)

• invaginated membrane is called the synaptic gutter or synaptic trough

• at the bottom of the gutter are numerous smaller folds of the muscle membrane- subneural clefts

– contains numerous Ach receptors

Ach receptor

• ACh receptor are nicotinic type

• each receptor is a protein complex (molecular weight of 275,000)

• composed of two α & one each of β, δ, & γ

• channel remains constricted until 2 Ach molecules attach respectively to the 2 α subunit proteins

– this causes a conformational change that opens the channel

A, Weakened end plate potential recorded in a curarized muscleB, Normal end plate potential C, Weakened end plate potential caused by botulinum toxin

• several deadly toxins which block neurotransmitter release

• tetanus toxin & botulinum toxins B, D, F, & G act on synaptobrevin, & botulinum toxin C acts on syntaxin

• botulinum toxins A & B act on SNAP-25

• on the positive side, local injection of small doses of botulinum toxin ("botox") has proved effective in the treatment of a wide variety of conditions

– injection into the lower esophageal sphincter to relieve achalasia

– injection into facial muscles to remove wrinkles

Drugs that stimulate the muscle fiber by acetylcholine-like action• methacholine, carbachol, & nicotine, have the same effect on

the muscle fiber as does acetylcholine• drugs are not destroyed by cholinesterase or are destroyed so

slowly that their action often persists for many minutes to several hours

Drugs that stimulate the neuromuscular junction by inactivating acetylcholinesterase• neostigmine & physostigmine inactivate acetylcholinesterase for

up to several hours• diisopropyl fluorophosphate inactivates acetylcholinesterase for

weeksDrugs that block transmission at the neuromuscular junction• a group of drugs known as curariform drugs can prevent

passage of impulses from the nerve ending into the muscle• D-tubocurarine blocks the action of acetylcholine on the muscle

fiber acetylcholine receptors

Myasthenia gravis

• occurs in about 1 in every 20,000 persons

• patients have developed immunity against their own acetylcholine-activated ion channels

• the end plate potentials that occur in the muscle fibers are mostly too weak to stimulate the muscle fibers

• if the disease is intense enough, the patient dies of paralysis (paralysis of the respiratory muscles)

• disease usually can be ameliorated for several hours by administering neostigmine or some other anticholinesterase drug

Lambert–Eaton Syndrome

• muscle weakness is caused by an autoimmune attack against Ca2+ channels in the nerve endings

• proximal muscles of the lower extremities are primarily affected, producing a waddling gait & difficulty raising arms

• about 40% of patients with LEMS also have cancer, especially small cell cancer of the lung

• a syndrome similar to LEMS can occur after the use of aminoglycoside antibiotics, which impair Ca2+ channel function

References

• Textbook of Medical Physiology, 12/E Guyton & Hall

• Ganong Review of Medical Physiology, 23/E

Thank You