W32 NMJ, MG and Muscle relaxants Flashcards
Neuromuscular transmission:
What does a motor unit consist of?
- Neuromuscular Junction (NMJ) specialised synapse
-somatic neuron with skeletal muscle, termed the motor endplate
Motor unit = 1 motor neuron &
its muscle fibres
* 1 motor neuron branches and contacts several muscle fibres
* The number of muscle fibres depends on the muscle
NMJ= synapse between Neurone and Muscle Fibre
Neuromuscular Junction
What is the neurotransmitter?
What is the receptor?
- Synapse somatic motor neurone and a muscle fibre: Neuromuscular Junction (NMJ)
- Nerve impulse communicates with muscle
- Acetylcholine is the neurotransmitter at skeletal muscle NMJs
- Binds to and activates Nicotinic Acetylcholine Receptor
- Ionotropic (ligand gated ion channel)
- Post synaptic membrane termed Motor End Plate (MEP)
- Sometimes called Nm or Muscle type
nicotinic receptors
What are the events at the NMJ? (4)
- Resting state
- AP Arrival
-release of Act
-depolarisation of pre-synapse - Depolarisation of MEP
-N channels activated
-Wave of depolarisation passes down fibre
-Pre-synapse repolarises - Contraction
-MEP repolarises
-Muscle fibre repolarises
-Back to beginning
RECAP: Activity at the neuromuscular junction is acetyl cholinergic
- ACh formed in the synaptic terminal (from acetyl-CoA and Choline)
- Generated by ChAT (choline acetyl transferase)
- Packaged into vesicles
- Calcium entry causes fusion of synaptic vesicles
- ACh released into the synaptic cleft
- Some bind to Nicotinic ACh
Receptors - Non-bound - Broken down by ACh- esterase
- Choline taken up to be reused (and regenerated into Ach)
NMJ:
- The action of ACh on these Nicotinic receptors is very short-lived
=about 0.6 ms - The synaptic cleft contains large amounts of acetylcholinesterase (AChE) as well as butyrylcholinesterase
- rapidly degrades ACh (into acetate and choline)- choline is taken bacl up
NMJ route of AP:
- AP travels along axon membrane to NMG
- CA2+ channels open and Ca2+ enters presynaptic terminal
- Synaptic vesicles fuse with presynaptic terminal and Ach released from vesicles
- ACh binds stimulates nicotinc channels – Na+ enters
- Na+ enters muscle fibre – initiating AP that travels along sarcolemma and T
tubule - AP in T tubules cause sarcoplasmic reticulum to release calcium
- Entry of calcium initiates power stroke and myosin head to ‘walk ‘ along
actin molecules leading to sarcomere shortening
- Entry of calcium initiates power stroke and myosin head to ‘walk ‘ along
Myasthenia gravis
- Comparatively rare autoimmune disease (1/2000 reported)
- Autoantibody to the nicotinic (muscle-type or NM) acetylcholinemreceptor (AChR)
- Results in the destruction of postsynaptic membrane and reduction in the number of AChR available
- Fewer functional receptors are available!
- (ACh) is less likely to depolarise the muscle cell sufficiently to reach its threshold firing potential!
(inhibiting/reducing muscle activation)
Changes at NMJ? (3)
- Complement and membrane attack
complex destroys postsynaptic NMJ
membrane.
=Simplified morphology of the postsynaptic membrane of the NMJ (fewer nicotinic AchR) - Antibodies cross-link AChR molecules
-causes endocytosis of the cross-linked
AChR molecules and their degradation - Ab binding the ACh-binding sites of
the AChR
-block of AChR and interferes with
binding of ACh
* This results in failure of neuromuscular transmission
= less muscle activation, weakness of muscles, no signal to contract
Normal neurotransmission Vs in MG
Healthy skeletal muscle:
* More receptors are depolarised than the threshold required for generation
of an endplate potential.
* Repetitive nerve stimulation leads to a rapid reduction in the numbers of sensitive receptors,
* but there are sufficient remaining receptors to ensure that there is no reduction in muscle activity.
Myasthenia gravis:
* Repetitive stimulation leads to the reduction of an already small receptor
pool
* reduces receptor availability to a level at which increasing numbers of muscle fibres fail to fire
Earliest Symptoms of MG? (2)
Earliest symptom of myasthenia gravis
* Diplopia (double vision)
* Ptosis (drooping eyelids)
-weakness of the extraocular muscles
* Usually symptoms progress to involve many other muscle groups
MG- two types of treatment?
What drugs are first line in ocular MG?
- Symptomatic treatment
=Prolongation of the action of ACh through the inhibition of acetylcholinesterase (Stops breakdown) - Immunosuppression for disease control
- Anticholinesterases
* first-line treatment in ocular myasthenia gravis and as an adjunct to immunosuppressant therapy for generalised myasthenia gravis
Inhibitors of AChE:
Examples? (2)
MoA?
- Reversible inhibitors of AChE
- e.g. Physostigmine, Neostigmine
- Increases ACh duration of action at NMJ/synapse
- depolarising block in excess (as it decreases the breakdown by AChE)
Physostigmine- not for MG= Pyridostigmine
Treatments ACHE inhibitors for MG?
Pyridostigmine bromide
-onset of action delayed in oral doses
-Duration of action 3-6 h – preferable because its longer duration of action to:
* Neostigmine
-therapeutic effect for up to 4 hours
-pronounced muscarinic action is a disadvantage
* Concurrent use of an antimuscarinic agent may be necessary to block any
parasympathomimetic actions
* Muscarinic side-effects
=increased sweating, increased salivary and gastric secretions, increased gastro-
intestinal and uterine motility, and bradycardia.
=antagonised by atropine sulfate
What is the Immunosuppressant therapy for MG?
- Corticosteroids
- Generalised myasthenia gravis – prednisolone
-Azathioprine is usually started at the same time as the corticosteroid-
immunosuppressant - allows a lower maintenance dose of the corticosteroid
to be used
Skeletal muscle relaxants:
When are the medications used?
- Chronic muscle spasm or spasticity associated with neurological damage
- Increase in muscle tone caused by the increased excitability of the muscle stretch reflex
- Muscle stiffness, co-contraction of flexors and extensors, and increased resistance to muscle stretching
- Associated with increased activity of excitatory neurotransmitters or decreased activity of inhibitory neurotransmitters
- Medications reduce muscle tone by acting either on the central nervous system (CNS) or directly on skeletal muscles
