paralytic agent

Neuromuscular-blocking drugs, or Neuromuscular blocking agents (NMBAs), block transmission at the neuromuscular junction, causing paralysis of the affected skeletal muscles. This is accomplished via their action on the post-synaptic acetylcholine (Nm) receptors.

In clinical use, neuromuscular block is used adjunctively to anesthesia to produce paralysis, firstly to paralyze the vocal cords, and permit endotracheal intubation, and secondly to optimize the surgical field by inhibiting spontaneous ventilation, and causing relaxation of skeletal muscles. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation should be available to maintain adequate respiration.

This class of medications helps to reduce patient movement, breathing, or ventilator dyssynchrony and allows lower insufflation pressures during laparoscopy. It has several indications for use in the intense care unit. It can help reduce hoarseness in voice as well as injury to the vocal cord during intubation. In addition, it plays an important role in facilitating mechanical ventilation in patients with poor lung function.

Patients are still aware of pain even after full conduction block has occurred; hence, general anesthetics and/or analgesics must also be given to prevent anesthesia awareness.

Nomenclature

Neuromuscular blocking drugs are often classified into two broad classes:
*Pachycurares, which are bulky molecules with nondepolarizing activity
*Leptocurares, which are thin and flexible molecules that tend to have depolarizing activity.

It is also common to classify them based on their chemical structure.
*Acetylcholine, suxamethonium, and decamethonium
Suxamethonium was synthesised by connecting two acetylcholine molecules and has the same number of heavy atoms between methonium heads as decamethonium. Just like acetylcholine, succinylcholine, decamethonium and other polymethylene chains, of the appropriate length and with two methonium, heads have small trimethyl onium heads and flexible links. They all exhibit a depolarizing block.
* Aminosteroids

Pancuronium, vecuronium, rocuronium, rapacuronium, dacuronium, malouètine, dihydrochandonium, dipyrandium, pipecuronium, chandonium (HS-310), HS-342 and other HS- compounds are aminosteroidal agents. They have in common the steroid structural base, which provides a rigid and bulky body. Most of the agents in this category would also be classified as non-depolarizing.
* Tetrahydroisoquinoline derivatives
Compounds based on the tetrahydroisoquinoline moiety such as atracurium, mivacurium, and doxacurium would fall in this category. They have a long and flexible chain between the onium heads, except for the double bond of mivacurium. D-tubocurarine and dimethyltubocurarine are also in this category. Most of the agents in this category would be classified as non-depolarizing.
* Gallamine and other chemical classes
Gallamine is a trisquaternary ether with three ethonium heads attached to a phenyl ring through an ether linkage. Many other different structures have been used for their muscle relaxant effect such as alcuronium (alloferin), anatruxonium, diadonium, fazadinium (AH8165) and tropeinium.
*Novel NMB agents
In recent years much research has been devoted to new types of quaternary ammonium muscle relaxants. These are asymmetrical diester isoquinolinium compounds and bis-benzyltropinium compounds that are bistropinium salts of various diacids. These classes have been developed to create muscle relaxants that are faster and shorter acting. Both the asymmetric structure of diester isoquinolinium compounds and the acyloxylated benzyl groups on the bisbenzyltropiniums destabilizes them and can lead to spontaneous breakdown and therefore possibly a shorter duration of action.

Classification

These drugs fall into two groups:

*Non-depolarizing blocking agents: These agents constitute the majority of the clinically relevant neuromuscular blockers. They act by competitively blocking the binding of ACh to its receptors, and in some cases, they also directly block the ionotropic activity of the ACh receptors.
*Depolarizing blocking agents: These agents act by depolarizing the sarcolemma of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

Non-depolarizing blocking agents

A neuromuscular non-depolarizing agent is a form of neuromuscular blocker that does not depolarize the motor end plate.

The quaternary ammonium muscle relaxants belong to this class. Quaternary ammonium muscle relaxants are quaternary ammonium salts used as drugs for muscle relaxation, most commonly in anesthesia. It is necessary to prevent spontaneous movement of muscle during surgical operations. Muscle relaxants inhibit neuron transmission to muscle by blocking the nicotinic acetylcholine receptor. What they have in common, and is necessary for their effect, is the structural presence of quaternary ammonium groups, usually two. Some of them are found in nature and others are synthesized molecules.

Below are some more common agents that act as competitive antagonists against acetylcholine at the site of postsynaptic acetylcholine receptors.

Tubocurarine, found in curare of the South American plant Pareira, ''Chondrodendron tomentosum'', is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (<5 min) and a long duration of action (30 mins). Side-effects include hypotension, which is partially explained by its effect of increasing histamine release, a vasodilator, as well as its effect of blocking autonomic ganglia. It is excreted in the urine.

This drug needs to block about 70–80% of the ACh receptors for neuromuscular conduction to fail, and hence for effective blockade to occur. At this stage, end-plate potentials (EPPs) can still be detected, but are too small to reach the threshold potential needed for activation of muscle fiber contraction.

The speed of onset depends on the potency of the drug, greater potency is associated with slower onset of block. Rocuronium, with an ED₉₅ of 0.3 mg/kg IV has a more rapid onset than Vecuronium with an ED₉₅ of 0.05mg/kg. Steroidal compounds, such as rocuronium and vecuronium, are intermediate-acting drugs while Pancuronium and pipecuronium are long-acting drugs.

In larger clinical dose, some of the blocking agent can access the pore of the ion channel and cause blockage. This weakens neuromuscular transmission and diminishes the effect of acetylcholinesterase inhibitors (e.g. neostigmine). Nondepolarizing NBAs may also block prejunctional sodium channels which interfere with the mobilization of acetylcholine at the nerve ending.

Depolarizing blocking agents

A depolarizing neuromuscular blocking agent is a form of neuromuscular blocker that depolarizes the motor end plate. An example is succinylcholine. Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine. However, these agents are more resistant to degradation by acetylcholinesterase, the enzyme responsible for degrading acetylcholine, and can thus more persistently depolarize the muscle fibers. This differs from acetylcholine, which is rapidly degraded and only transiently depolarizes the muscle.

These agents have two phases of block with notably different characteristics. During phase I (''depolarizing phase''), succinylcholine interacts with nicotinic receptor to open the channel and cause depolarization of the end plate, which later spread to and result in depolarization of adjacent membranes. As a result, there is a disorganised contraction of muscle motor unit. This causes muscular fasciculations (muscle twitches) while they are depolarizing the muscle fibers. The muscle fiber is then held in a partially depolarised state leading to relaxation.

Further administration of the agent leads to phase II block which has a similar clinical behaviour to non-depolarising blocking agents. Phase II block is characterised by complete membrane repolarisation however there is still ongoing neuromuscular blockade, the mechanism of phase II block is not fully understood. Phase I block effect is increased by cholinesterase inhibitors as increase in acetylcholine levels leads to deepening of the phase I block due to the membrane potential being pushed further away from repolarisation, however in phase II block cholinesterase inhibitors inhibit the block.

The prototypical depolarizing blocking drug is succinylcholine (suxamethonium). It is the only such drug used clinically. It has a rapid onset (30 seconds) but very short duration of action (5–10 minutes) because of hydrolysis by various cholinesterases (such as butyrylcholinesterase in the blood). The patient will experience fasciculation due to the depolarisation of muscle neurone fibres and seconds later, flaccid paralysis will occur. Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group. Decamethonium is sometimes, but rarely, used in clinical practice.

It is indicated for rapid sequence intubation.

Dosing/onset of action

IV dose 1-1.5mg/kg or 3 to 5 x ED₉₅

Paralysis occurs in one to two minutes.

Clinical duration of action (time from drug administration to recovery of single twich to 25% of baseline) is 7-12 minutes.

If IV access is unavailable, intramuscular administration 3-4mg/kg. Paralysis occurs at 4 minutes.

Use of succinylcholine infusion or repeated bolus administration increase the risk of Phase II block and prolonged paralysis. Phase II block occurs after large doses (>4mg/kg). This occurs when the post-synaptic membrane action potential returns to baseline in spite of the presence of succinylcholine and causes continued activation of nicotinic acetylcholine receptors.

Comparison of drugs

The main difference is in the reversal of these two types of neuromuscular-blocking drugs.
* Non-depolarizing blockers are reversed by acetylcholinesterase inhibitor drugs since non-depolarizing blockers are competitive antagonists at the ACh receptor so can be reversed by increases in ACh.
* The depolarizing blockers already have ACh-like actions, so these agents have prolonged effect under the influence of acetylcholinesterase inhibitors. Administration of depolarizing blockers initially produces ''fasciculations'' (a sudden twitch just before paralysis occurs). This is due to depolarization of the muscle. Also, post-operative pain is associated with depolarizing blockers.

The ''tetanic fade'' is the failure of muscles to maintain a fused tetany at sufficiently high frequencies of electrical stimulation.
* Non-depolarizing blockers have this effect on patients, probably by an effect on presynaptic receptors.
* Depolarizing blockers do not cause the tetanic fade. However, a clinically similar manifestation called Phase II block occurs with repeated doses of suxamethonium.
This discrepancy is diagnostically useful in case of intoxication of an unknown neuromuscular-blocking drug.

Physiology at the Neuromuscular Junction

Neuromuscular blocking agents exert their effect by modulating the signal transmission in skeletal muscles. An action potential is, in other words, a depolarisation in neurone membrane due to a change in membrane potential greater than the threshold potential leads to an electrical impulse generation. The electrical impulse travels along the pre-synaptic neurone axon to synapse with the muscle at the neuromuscular junction (NMJ) to cause muscle contraction.

When the action potential reaches the axon terminal, it triggers the opening of the calcium ion gated channels, which causes the influx of Ca²⁺. Ca²⁺ will stimulate the release of neurotransmitter in the neurotransmitter containing vesicles by exocytosis (vesicle fuses with the pre-synpatic membrane).

The neurotransmitter, acetylcholine(ACh) binds to the nicotinic receptors on the motor end plate, which is a specialised area of the muscle fibre's post-synaptic membrane. This binding causes the nicotinic receptor channels to open and allow the influx of Na⁺ into the muscle fibre.

Fifty percent of the released ACh is hydrolysed by acetylcholinesterase (AChE) and the remaining bind to the nicotinic receptors on the motor end plate. When ACh is degraded by AChE, the receptors are no longer stimulated and the muscle cannot be depolarized.

If enough Na⁺ enter the muscle fibre, it causes an increase in the membrane potential from its resting potential of -95mV to -50mV (above the threshold potential -55mV) which causes an action potential to spread throughout the fibre. This potential travels along the surface of the sarcolemma. The sarcolemma is an excitable membrane that surrounds the contractile structures known as myofibrils that are located deep in the muscle fibre. For the action potential to reach the myofibrils, the action potential travels along the transverse tubules (T-tubules) that connects the sarcolemma and center of the fibre.

Later, action potential reaches the sarcoplasmic reticulum which stores the Ca²⁺ needed for muscle contraction and causes Ca²⁺ to be released from the sarcoplasmic reticulum.

Mechanism of action

Quaternary muscle relaxants bind to the nicotinic acetylcholine receptor and inhibit or interfere with the binding and effect of ACh to the receptor. Each ACh-receptor has two receptive sites and activation of the receptor requires binding to both of them. Each receptor site is located at one of the two α-subunits of the receptor. Each receptive site has two subsites, an anionic site that binds to the cationic ammonium head and a site that binds to the blocking agent by donating a hydrogen bond.

Non-depolarizing agents
A decrease in binding of acetylcholine leads to a decrease in its effect and neuron transmission to the muscle is less likely to occur. It is generally accepted that non-depolarizing agents block by acting as reversible competitive inhibitors. That is, they bind to the receptor as antagonists

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