The somatic nervous system 1 Flashcards
Where are cell bodies in the somatic nervous system?
In the brain stem.
What is the somatic nervous system?
Conscious decisions sending signals to leg muscles, postural muscles etc. and outside bits of the eyes.
What neurotransmitter and receptor is involved in the somatic nervous system?
ACh on nicotinic receptors.
What is a motor unit?
The motor neuron and the muscle fibre it innervates.
Is the motor neuron myelinated in the somatic nervous system?
Yes - there is rapid conduction down the motor neurons.
What happens when an action potential is conducted along a motor nerve?
There is depolarisation and an influx of calcium at the nerve terminal. ACH released into the synapse and binds to nicotinic receptors.
What is ACh metabolised by?
Acetylcholine esterases.
What subunits do the nicotinic receptors contain?
Alpha, beta, delta and gamma subunits.
How many sites does ACh bind to on nicotinic receptors?
Two sites.
What are the two sites of Na+ influx at the neuromuscular junction end plate?
ACh binding to receptors causes Na+ influx which generates an end plate potential, which then initiates the opening of proximal voltage gated Na+ channels. This causes amplification of ion influx and action potential in the muscle cell.
How is the signal at an NMJ terminated?
ACh esterase.
What is the idea of excitation-contraction coupling in skeletal muscle?
A Na+ driven action potential opens L-type calcium channels, which stimulates Ca2+ induced Ca2+ release from intracellular stores.
How does smooth and skeletal muscle contraction differ?
Skeletal muscle contraction is due to nicotinic receptors and ion influx, whereas smooth muscle contraction is due to g protein coupled and muscarinic receptors - more of the contraction is due to phospholipase C.
What is the most common way to interfere with cholinergic transmission?
Blocking nicotinic cholingergic receptors at NMJs.
How can ACh be decreased at NMJs?
Inhibit ACh synthesis or release.
How can ACh be increased/the effect increased at the NMJ?
Enhanced nicotinic effects.
What may induction motor reflexes interfere with in surgery?
Insertion of tubes for the surgery.
Why might muscle spasm occur in surgery?
Mechanical manipulation of limbs and nerves.
When are reflexes suppressed in anaesthesia?
Not until deep anaesthesia.
What can be used to make it easier to insert tubes during surgery?
Transient neuromuscular blockers.
What do neuromuscular junction blocking drugs interfere with?
The post-synaptic action of ACh.
What are the differences between non-depolarising agents and depolarising blocking agents?
Non-depolarising - ACh receptor antagonists (no efficacy), whereas depolarising are weak nicotinic agonists.
How do depolarising blocking agents work?
They cause depolarisation weakly, but then remain bound so depolarisation cannot occur again.
What is curare?
A non-depolarising agent that is a mixture of alkaloids found in south american plants, including d-tubocurarine.
What effect does curare have?
It causes paralysis by blocking neuromuscular transmission, but not nerve conduction or muscle contractility.
What is curare originally used for?
Poison arrows by indigenous south american peoples.
Why is curare safe to eat animals that have been poisoned with it?
It doesn’t cross the GI tract for long.
What action does d-tubocararine have?
It binds to nicotinic receptors are NMJs as an antagonist.
Why does tubocararine need to block a lot of receptors to have any effect?
Much more ACh is released than needed, so most receptors (90%) need to blocked to have an effect.
What synthetic derivatives of d-tubocararine are now used clinically?
Atracurium, pancuronium and gallium.
What effect does tubocararine have on neuromuscular transmission?
Nerve stimulation normally initiates end-plate potential which initiates an action potential. Tubocurarine reduces the end plate potential amplitude so that no action potential is generated.
Why do clinically used non-depolarising NM blocking drugs ideally have shorter durations of action?
You don’t want a high level of block after the surgery has been completed.
What is duration of non-depolarising NM blocking drugs determined by?
Susceptibility to cholinesterases and clearance - half life.
What is alpha-bungarotoxin?
It irreversibly binds to the nicotinic ACh receptors at the NMJ, and inhibits ACh binding.
What is alpha-bungarotoxin useful for?
Receptor studies.
What are some of the unwanted effects of non-depolarising blockers?
Hypotension, histamine release from mast cells, respiratory failure.
Why is hypotension a side effect of non-depolarising blockers?
There is ganglion blockade as the agents are selective but not specific, so will affect transmission at the ganglion as well at the NMJ.
What effect can histamine release from mast cells due to non-depolarising blockers have?
It can cause bronchospasm in sensitive individuals. It is not related to the nicotinic receptor.
What are some common depolarising blocking agents?
Decamethonium, suxamethonium.
What is the mechanism of depolarising blocking agents?
They initially bind and activate the nicotinic receptor and open the end plate voltage sensitive Na+ channels to depolarise the muscle. This is maintained at the end-plate and there is a loss of electrical excitability. As the molecules are present in the synapse longer than ACh, the receptors stays open and cannot be depolarised again.
What is the depolarising block (phase I) caused by depolarising agents?
(Na+ channels) The muscle is held in the depolarised state, and the sodium channels are refractory and are no longer open. The muscle becomes flaccid as Ca2+ is taken into the stores.
What are the three states of the sodium channel?
Resting, active and inactive.
What are the two gates of the sodium channel?
Gate v (voltage dependent) and gate t (time dependent).
How do the states of the sodium channel, in terms of gate opening and closing?
In the resting state, v is closed whilst t is open. In the active state, v opens when the surrounding membrane is depolarised and t closes soon after to inactive the channel. In the inactive state, v remains open whilst t is closed.
What are the two phases of the block caused by depolarising agents?
Depolarising block (I) and desensitisation block (II).
What is the densensitisation block?
(ACh nicotinic) Persistent stimulation leads to receptor desensitisation - this doesn’t normally occur with ACh as it is rapidly removed. The muscle partially repolarises but transmission remains blocked.
How do depolarising agents differ to ACh?
Depolarising agents are removed a lot more slowly than ACh.
What are the states of nicotinic ACh receptors?
Resting, resting with agonist bound (but channel closed), active with channel open, desensitized without agonist, desensitized with agonist bound.
What are the advantages of depolarising neuromuscular blockers?
They have rapid onset and a short duration of action, they can be used for surgery during pregnancy (doesn’t cross blood-placenta barrier - doesn’t affect newborn respiration) and are less likely to elicit histamine release.
What are some of the unwanted effects/dangers of depolarising drugs?
Bradycardia, potassium release, post-operative pain, increased intraocular pressure, prolonged paralysis, malignant hyperthermia.
Why is bradycardia an effect of depolarising drugs?
Direct muscarinic action.
Why is potassium release an effect of depolarising drugs?
There is an increase in cation permeability at the end plate that causes loss of K+. This results in hyperkalemia that can cause ventricular dysrhythmia.
Why is there an increase in intraocular pressure when using depolarising drugs?
There is contraction of extra-ocular muscles.
What are some other uses of neuromuscular blocking drugs?
Electroconvulsive therapy - depolarisation of the brain but not the muscles, lethal injections. They can be used for lethal injections to prevent spasm - implies a more peaceful death.
What are the key differences between non-depolarising and depolarising agents?
Non-depolarising block can be reversed by increasing ACh concentration, depolarising blocks produce initial fasciculation (small twitches), suxamethonium (depolarising) is hydrolysed by plasma cholinesterase and is shorter-acting than tubocurarine.
What can genetic polymorphisms in esterases result in?
Prolonged action.
How can neuromuscular blocker’s action be reversed?
Neostigmine - an AChesterase inhibitor that raises ACh in the synapse. This reverses the non-depolarising block and potentiates the depolarising block.
What are the characteristics of neostigmine?
It is a quaternary ammonium compound that competes with ACh on cholinesterase. It is lipid insoluble and does not cross the blood-brain barrier.
What is the action/onset of neostigmine?
It has an onset of within a minute, a peak in 10 minutes and a duration of 20-30 minutes.
How is neostigmine removed from the body?
It is metabolized by plasma esterases. The elimination half-life is prolonged in renal disease.
What nervous system does neostigmine stimulate?
The parasympathetic nervous system due to enhanced ACh.
What can neostigmine cause, due to parasympathetic stimulation?
Bradycardia - there is cardiac arrest after high doses.
What side effects can neostigmine have after surgery?
Postoperative nausea and vomiting, GI disturbance.
Why are antimuscarinics used with neostigmine?
Overcome the problems of this - these block out the adverse effects due to ACh effects at non-muscular junctions.
How else can neuromuscular blocker’s action be reversed?
Sugammadex - it chelates aminosteriod non-depolarising blockers.
What is the benefit is using sugammadex?
It avoids the use of cholinesterase inhibitors and avoids the use of depolarising agents - it can remove the non-depolarizing blocker without the adverse effects on the autonomic nervous system.
Why is neostigmine not used all the time?
It is expensive.
