What Is Neuromuscular Junction?
Neuromuscular Junction: Anatomy And Physiology
Motor neurons and muscle cells are separated by a twelfth and bind with acetylcholine receptors on the muscle and plate.
Acetylcholine receptors generally consist of a five-protein subunit ring within a center ion channel.
The receptor protein subunit consists of two alpha subunits and one each of Beta, Delta and Epsilon subunits.
The Alpha subunits are the only subunits capable of binding with acetylcholine and both subunits open the ion channel. This will allow for the flow of potassium out through the channel and the flow of sodium and calcium in through the channel.
The extrajunctional acetylcholine receptors and can be found in anywhere else in the muscle membrane and are also known as fetal or immature receptors. These receptors are normally found a muscle tissue and contain a gamma subunit instead of an epsilon subunit the.
ACH stores vesicle contains 10 to 40 molecules or quanta of acetylcholine. The nerve usually releases more than 200 quanta at any given time. The number of quanta released is very sensitive to the extracellular calcium concentration. The more extracellular calcium is present, the more quanta will be released.
When enough receptors are occupied the muscle cell will depolarize and voltage-gated sodium channels will open and calcium will be released from the sarcoplasmic reticulum.
The intracellular calcium causes the interaction between actin and myosin causing a muscle contraction. The amount of acetylcholine released and activated and activated receptors usually exceed the required amount of muscle for muscle contraction.
There are two physiological conditions in, which this buffer zone may not be present: Eaton-Lambert and Myasthenia Gravis.
In case of Eaton-Lambert syndrome, there is a decreased amount of acetylcholine released by the neuron. In Myasthenia Gravis, the number of acetylcholine receptors is decreased.
After binding to acetylcholine receptors, acetylcholine is then hydrolyzed by acetylcholinesterase into acetylcholinesterase, causing the channel to close and the muscle to relax.
Neuromuscular Blocking Drugs
Neuromuscular blocking drugs are highly water soluble and do not readily cross the blood-brain barrier, the renal tubular epithelium, the gastrointestinal epithelium or the placenta.
The potency of neuronal blocking drugs is determined by the dose required for each to reach 95% suppression rate of a single twitch. In general, neuromuscular blocking drugs affect small, rapid, moving skeletal muscles such as those in the eyes and fingers faster, than they do the larger muscles such as found in the diaphragm.
The dose of neuromuscular blocking drug necessary to produce a neuromuscular blockade of the diaphragm is about twice as much that is as needed to produce neuromuscular paralysis.
Neuromuscular blocking drugs are separated into two classes based on their mechanism of action: depolarizing and non-depolarizing.
Currently, there is only one depolarizing agent – Succinylcholine. There are several different nondepolarizing agents available.
Currently, there are no short-acting on depositing agents available in the United States. Instead, Atracurium, Cisatracurium, Vecuronium, and Rocuronium are all intermediate acting. And Pancuronium is classified as long acting.
Structurally Succinylcholine choline closely resembles acetylcholine and competitively binds to acetylcholine receptors on the neuromuscular end-plate. However, Succinylcholine is not metabolized by acetylcholinesterase, thus this resulting in a prolonged binding to acetylcholine receptors and prolonged depolarization of the muscle end-plate.
The prolonged end-plate depolarization causes relaxation of the muscle inflates. And a muscle end-plate is then unable to depolarize.
Succinylcholine is essentially an acetylcholine receptor agonist.
Nondepolarizing agents bind to acetylcholine receptor but do not cause the necessary conformational change to open the ion channels and produce a muscle contraction.
Electronically Evoked Mechanical Response
Only one of the alpha-subunits needs to be bound to a non-polarizing neuromuscular blocking drug in order to receive this achieve this result. Non-depolarizing agents competitively antagonize acetylcholine receptors.
Based on the type of neuromuscular blocking drug utilized, electrically evoked mechanical responses administered as seen from a utilization of a neurostimulator will differ.
Characteristics of mechanical response for a phase one block due to the relaxation with succinylcholine are a decreased, contraction to which decrease amplitude but sustained the response to continuous stimulation.
Electronically evoke to mechanical responses that carry a phase two block also closely resemble those that occur with the administration of nondepolarizing neuromuscular blocking agents.
There is a dose-related decrease in twitch height, a fade to TOF, a fade to Tetany and Post Tetanic potentiation.
Plasma Cholinesterase Activity
Plasma cholinesterase is responsible for the hydrolysis of acetylcholine and succinylcholine. A decrease in the level of plasma cholinesterase will result in decreased hydrolysis of acetylcholine and the prolongation of a neuromuscular blockade from succinylcholine.
Persons with abnormal plasma cholinesterase may present with a prolonged paralysis after succinylcholine administration.
Normal plasma cholinesterase activity is used to gauge the degree of a typical plasma cholinesterase. Normally, dibucaine will inhibit 80% of normal plasma cholinesterase activity. In the presence of atypical plasma cholinesterase, only 20% of the activity will be inhibited.
In normal WK number is 80. Any number lower than that is considered abnormal.
Adverse Effects Of Neuromuscular Blocking Drugs
The administration of succinylcholine can result in cardiac dysrhythmias, hyperkalemia, myalgia, myoglobinuria, increased gastric pressure, increased intraocular pressure, increased intracranial pressure and sustained skeletal muscle contractions, also known as fasciculation.
Current nondepolarizing neuromuscular blocking drugs have a very low side effect profile. However, Pancuronium can cause tachycardia by blocking vagal muscarinic receptors in the SA node.
Articurium can cause a histamine release at higher doses, which can result in bronchospasm, skin flushing.
Altered Response To Non-depolarizing NMBD
Different drugs have different effects on nondepolarizing non-muscular blocking drugs. The following drugs will enhance the effects of nondepolarizing neuromuscular blocking drugs:
- Volatile anesthetics;
- Aminoglycoside antibiotics;
- Local anesthetics;
- Cardiac dysrhythmias;
Hypothermia will increase the duration of action of vecuronium due to a decreased clearance and slower rate of slight site equilibration.
Potassium levels can also enter the effect of neuromuscular blocking drugs. A decrease in serum potassium causes hyperpolarization of cell membranes. This reduces the effect of depolarizing of a neuromuscular drug and increased effect of nondepolarizing neuromuscular blocking drugs.
An increase in potassium concentration will have the opposite effects of each.
Burns cause a decrease sensitivity to nondepolarizing neuromuscular muscle blocking drugs theoretically related to altered receptor affinity.
Acetylcholinesterase And Anticholinesterase Agents
Acetylcholinesterase is located near the acetylcholine receptors on the neuromuscular end-plate. Acetylcholine is rapidly hydrolyzed to clean and acetate.
Once the cetyl choline is broken down it diffuses from the receptors and repolarization of the endplate can occur.
Acetylcholinesterase prevents the breakdown of acetylcholine by biding with active anticholinesterase. It prevents the breakdown of acetylcholine by combining with the active center of acetylcholinesterase. This causes an increase in the amount of acetylcholine available at the neuromuscular end-plate as well as an increased lifespan of acetylcholine.
Neostigmine is one of the most commonly used agents for reversal, which does pose an increased risk for post-op nausea and vomiting.
Pyridostigmine, which has the shortest duration of action, forms an electrostatic bond with acetylcholinesterase.
Neostigmine and pyridostigmine reversibly bind with a negatively charged enzyme site by electrostatic positively charged nitrogen. And by a very stable carbamylated enzyme is thus formed, which is unable to break down acetylcholine.
Edrophonium reversibly binds with the enzyme by electrostatic positively charged nitrogen, briefly causing a catalytic binding with acetylcholine. This explains the difference in duration of action between neostigmine and edrophonium.
The increase in acetylcholine can produce such effects as Vagal-like bradycardia, bronchospasm, intestinal spasm, incontinence, salivation, and nausea.