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How the release of and actions of acetylcholine at the neuromuscular junction can be modified by drugs

By Edited Jun 11, 2016 0 0

Acetylcholine

Acetylcholine (ACh) has functions in the peripheral nervous system (PNS) and the central nervous system(CNS). ACh is the only neurotransmitter used in the somatic nervous system. In the PNS, ACh activates muscle and is a major neurotransmitter released by the autonomic nervous system neurons. In the CNS, they form the cholinergic system which causes excitatory actions.

Anatomy of neuromuscular junction

Skeletal Muscles

Skeletal muscles are activated by somatic nerve cells which are composed of somatic motor neurons. These motor neurons are found within the brain and spinal chord, their thread like structures called axons extend all the way to the muscle cells to which they serve. The ends of the unmylinated axons divide up heavily into branches as they meet the muscle fibre and form a neuromuscular junction (NMJ). For each skeletal muscle fiber there is usually only one NMJ. The muscle fibres and the axon terminals remain separated by a space of around 1-2nm, this space is known as the synaptic cleft. The cleft is filled with a gel like substance composed of glycoprotein and collagen fibers. The presynaptic active zones are found at the end of axon terminals and contain synaptic vesicles; these are small membranous sacs containing the neurotransmitter, ACh. The neurotransmitter is released when an action potential reaches the axon terminal. The sarcomere opposite the presynaptic active zone is folded into groves to provide a large surface area, they are called postjunctional folds. The folds contain ACh receptors.

Mechanism of action

calcium channels

The voltage gated calcium channels located within the axons open when an action potential arrives at the end of the axon allowing calcium ions to flow into the cytosol of the neuron from the extracellular fluid. The prescence of calcuim causes the synaptic vesicles to fuse with the membrance of the axons and release ACh into the synaptic cleft by methods of exocytosis. The ACh diffuses across the cleft and attaches itself to the many millions of ACh receptors on the sarcomere or the Ach is inactivated by acetylcholinesterase.ACh receptors are ligand gated, when the receptors are bound by ACh, sodium and potassium ions are allowed to pass in and out of the muscles cystool. Due to differences in the electrochemical gradient, more sodium ions diffuse in than potassium ions moving out. This causes the interior of the membrane potential to become slightly less negative, this process is known as depolarization.

Depolarisation

Depolarisation initally brings a local effect known as end plate potential but soon after the effects become widespread when the action potential moves all over from the NMJ to the surface of the muscle fibre. Muscle contraction is initiated after the release of calcium ions from the sarcoplasmic reticulum. ACh is broken down into its constituents, choline and acetic acid by acetylcholinesterase, this enzyme can be found in the synaptic cleft. The breakdown stops contious muscle fibre contraction from taking place if there is no addition nerve stimulus.

Synthesis, release and degradation of Acetylcholine

Synthesis of Ach takes place in nerve terminals when the enzyme choline acetyltransferase(CAT) transfers the acetyl group from the acetyl coenzyme A to the choline compound. The choline compound is transferred into the nerve terminal by a specific carrier. The rate limiting process of the production of ACh is the availability of choline in the nerve terminal. After the synthesis of ACh, it is stored inside a synaptic vesicle where the concentration of ACh is very high, around 100mmol/l. The release of the vesicle occurs by exocytosis when calcium enters the nerve terminal.

Synaptic Cleft

Acetylcholinesterase is found in abundantly in the synaptic cleft and is involved in the hydrolysis of Ach into its inactive metabolite constituent choline and acetate. 

Drugs acting on the acetylcholine system

The ACh system can be stimulated by using agonist or the system can be inhibited by the use of its antagonist. Cholinergic transmission can be influenced by affecting the synthesis, release and destruction of ACh.

Drugs affecting the release and actions of acetylcholine in the NMJ

Drugs that act presynaptically

Drugs that inhibit acetylcholine synthesis

Hemicholinium blocks the transport of choline into the nerve terminal and limits the production of ACh because choline is a component of ACh.  

Vesamicol blocks the anitporter and therefore prevents the transport of ACh after its synthesis into synaptic vesicles and therefore reduces its release.

Drugs that inhibit acetylcholine release

Aminoglycoside antibiotics such as streptomyocin prevent the entry of calcium ions into the nerve terminal, this prevents the release of ACh due to neuromuscular blockade. The drug can cause unwanted effects such as muscle paralysis which can be reversed by administrating the patient with calcium ions. 

Botulinum toxin is a neurotoxin protein produced by bacillus Clostridium botulinum, the toxins contain two subunits. One of the subunits is used for the binding of the toxin to the cell so it can enter the nerve, the other subunit is used to bring about toxicity within the nerve. The toxin contain several components, each component inactivates a different functional protein. The toxin prevents the interaction between the synaptic vesicle which stores the ACh and the cell membrane. The toxins act as a protease enzyme which breaks down the protein structures in the terminal axon membrane which the synaptic vesicles bind to. This drug prevents the release of ACh. Beta- bungarotoxin is a drug which works in a similar way to botulinum toxin.

Postynaptic Agents

Non depolarising blockers such as tubocurarine bind as a competitive antagonist to the Ach receptors and blocks Ach from binding to its receptors. The binding prevents receptors from becoming activated and muscle contraction cant take place and therefore muscle undergoes paralysis. In order to prevent cholinergic transmission from taking place around 80-90% of the nicotinic acetyl choline receptors will need to be blocked by the antagonist since the all of the Ach released by the nerve terminal is not required to generate an action potential in the muscle. These types of drugs have are poorly absorbed orally and so need to be administered intravenously.

Depolarising blocking agents such as suxamethonium act as a non-competitive agonist, they initially activate receptors causing depolarisation but they block any further activation. Depolarising blockers initially act in the same way as ACh by increasing the cation permeability of the end plate. However, depolarising blockers remain attached to the receptors unlike ACh which is released and rapidly hydrolysed. The attachment of the depolarising blocker with the receptor can cause sustained depolarisation and result in the loss of electrical excitability. Receptor desensitisation can be brought about by continued administration because the depolarising blocker ends up having similar characteristic of the non-depolarising blockers. The only depolarising blocking agent used in a clinical setting is suxamethonium due to its rapid onset and short duration of four minutes. It is also rapidly hydrolysed by plasma cholinesterase.

Drugs that enhance cholinergic transmission

Myasthenia gravis is a neuromuscular disease, where suffers experience a fluctuation in muscle weakness and fatigue due to antibodies which block the ACh receptors at the postsynaptic NMJ, the disease can be treated with anticholinesterase.

Anticholinesterase are used to inhibit cholinesterase, this allows for more ACh to be present and increases the duration of the neurotransmitter and therefore enhances cholinergic transmission. Acetylcholinesterase is inhibited the amount of free ACh and the rate of ACh leakage by the choline carrier is increased, in normal conditions the rate of leakage of ACh is insignificant. In normal circumstances each stimulus only causes one action potential in the muscle fibre because ACh is rapidly hydrolysed but when Acetylcholinesterase is inhibited the one action potential changes to a number of action potential being sent to the same muscle fibre. If a large portion of ACh receptors are blocked a large portion ACh which would normally attach to the blocked receptors will be destroyed by acetylcholinesterase. Using an anticholinesterase inhibits the cholinesterase and allows the ACh a greater chance of binding to a free receptor so the end point potential can be achieved. The use of anticholinesterase can cause prolonged muscle contractions. Large dosages of anticholinesterase can give rise to muscle twitching because the continuous release of ACh can initiate action potential because the end plate potential has be achieved. Paralysis may follow due to depolarisation block. 

There are three types of anticholinesterase available, short duration, medium duration and irreversible anticholinesterase. The class of the anticholinesterase is determined by the type of interaction the drug has with the active site of the enzyme.

The most important type of short duration anticholinesterase is edrophonium. This drug has a short duration of 2-10minutes. The binds to the active site of the cholinesterase enzyme through electrostatic attractions, the ionic bond formed with the enzyme are readily causes the drug to have a short duration. Edrophonium is not used for therapeutically but is used to diagnose myasthenia gravis. Medium duration anticholinesterase includes neostigmine which can be used to reverse the effects of non depolarising blockers such as tubocurarine. The anticholinesterase neostigmine can restore the cholinergic transmission which was blocked by tubocurarine.  Irreversible anticholinesterases are organophosphorous compounds such as parathion and ecothiopate. The organic group of the drugs is released causing the serine hydroxyl group of the cholinesterase enzyme phosphorylated resulting in the enzyme to become inactive. With ecothiopate the enzyme is able to hydrolyse Ach but only at very slow rates and over a few days. Other irreversible anticholinesterase drugs such a dyflos, the hydrolysis of ACh is negligible and the activity of the inactive cholinesterase enzyme depends on the synthesis of new enzymes.

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