Neuromuscular-blocking drugs - AbsoluteAstronomy.com

Neuromuscular-blocking drugs block neuromuscular transmission at the neuromuscular junction

Neuromuscular junction

A neuromuscular junction is the synapse or junction of the axon terminal of a motor neuron with the motor end plate, the highly-excitable region of muscle fiber plasma membrane responsible for initiation of action potentials across the muscle's surface, ultimately causing the muscle to contract...

, causing paralysis

Paralysis

Paralysis is loss of muscle function for one or more muscles. Paralysis can be accompanied by a loss of feeling in the affected area if there is sensory damage as well as motor. A study conducted by the Christopher & Dana Reeve Foundation, suggests that about 1 in 50 people have been diagnosed...

of the affected skeletal muscle

Skeletal muscle

Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...

s. This is accomplished either by acting presynaptically via the inhibition of acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

(ACh) synthesis or release or by acting postsynaptically at the acetylcholine receptors of the motor nerve end-plate. While there are drugs that act presynaptically (such as botulinum toxin

Botulinum toxin

Botulinum toxin is a protein produced by the bacterium Clostridium botulinum, and is considered the most powerful neurotoxin ever discovered. Botulinum toxin causes Botulism poisoning, a serious and life-threatening illness in humans and animals...

and tetanus toxin), the clinically-relevant drugs work postsynaptically.

In clinical use, neuromuscular block is used adjunctively to anesthesia

Anesthesia

Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

to produce paralysis

Paralysis

, so that surgery

Surgery

Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...

, especially intra-abdominal and intra-thoracic surgeries, can be conducted with fewer complications. Because the appropriate dose of neuromuscular-blocking drug may paralyze muscles required for breathing (i.e., the diaphragm), mechanical ventilation

Mechanical ventilation

In medicine, mechanical ventilation is a method to mechanically assist or replace spontaneous breathing. This may involve a machine called a ventilator or the breathing may be assisted by a physician, respiratory therapist or other suitable person compressing a bag or set of bellows...

should be available to maintain adequate respiration

Respiration (physiology)

'In physiology, respiration is defined as the transport of oxygen from the outside air to the cells within tissues, and the transport of carbon dioxide in the opposite direction...

.

Patients are still aware of pain even after full conduction block has occurred; hence, general anesthetics and/or analgesic

Analgesic

An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....

s must also be given to prevent anesthesia awareness

Anesthesia awareness

Anesthesia awareness, or unintended intra-operative awareness occurs during general anesthesia, on the operating table, when the patient has not been given enough of the general anesthetic or analgesic to render the patient unconscious during general anesthesia...

.

Quaternary ammonium muscle relaxants are quaternary ammonium salts used as drugs

DRUGS

Destroy Rebuild Until God Shows are an American post-hardcore band formed in 2010. They released their debut self-titled album on February 22, 2011.- Formation :...

for muscle relaxation

Muscle relaxant

A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...

, most commonly in anesthesia

Anesthesia

Anesthesia, or anaesthesia , traditionally meant the condition of having sensation blocked or temporarily taken away...

. It is necessary to prevent spontaneous movement of muscle during surgical operations

Surgery

. Muscle relaxants inhibit neuron

Neuron

A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...

transmission to muscle by blocking the nicotinic acetylcholine receptor

Nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors, or nAChRs, are cholinergic receptors that form ligand-gated ion channels in the plasma membranes of certain neurons and on the postsynaptic side of the neuromuscular junction...

. 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

Chemical synthesis

In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...

molecules.

History

Curare

Curare is a common name for various arrow poisons originating from South America. The three main types of curare are:* tubocurare...

is a crude extract

Extract

An extract is a substance made by extracting a part of a raw material, often by using a solvent such as ethanol or water. Extracts may be sold as tinctures or in powder form....

from South American plants. It was known in the 19th century to have a paralysing effect

Paralysis

. D-tubocurarine

Tubocurarine

Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation...

a mono-quaternary alkaloid

Alkaloid

Alkaloids are a group of naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids...

was isolated from Chondodendron tomentosum in 1942, and it was shown to be the active chemical in curare that had the paralysing effect. At that time, it was known that curare and, therefore, d-tubocurarine worked at the neuromuscular junction

Neuromuscular junction

. The isolation of tubocurarine and its marketing as the drug Intocostrin led to more research in the field of neuromuscular-blocking drugs. Scientists figured out that the potency of tubocurarine was related to the separation distance between the two quaternary ammonium heads.

Further research led to the development of synthesized

Chemical synthesis

molecules with different curariform effects, depending on the distance between the quaternary ammonium groups. One of the synthesized bis-quaternaries was decamethonium

Decamethonium

Decamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...

a 10-carbon

Carbon

Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

bis-quaternary compound. Following research with decamethonium, scientists developed suxamethonium, which is a double acetylcholine molecule that was connected at the acetyl

Acetyl

In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...

end. The discovery and development of suxamethonium lead to a Nobel Prize in medicine in 1957. Suxamethonium showed different blocking effect in that its effect was achieved more quickly and augmented a response in the muscle

Muscle

Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...

before block. Also, tubocurarine effects were known to be reversible by acetylcholinesterase inhibitor

Acetylcholinesterase inhibitor

An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...

s, whereas decamethonium and suxamethonium block were not reversible.

Another compound malouétine that was a bis-quaternary steroid was isolated from the plant Malouetia bequaertiana and showed curariform activity. This led to the synthetic drug pancuronium

Pancuronium

Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...

a bis-quaternary steroid and subsequently other chemicals that had better pharmacological properties as drugs.

These molecules discussed above and research devoted to them led to many other compounds with different pharmacological properties and research in drug development

Drug development

Drug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...

as well as they helped to better the understanding the physiology

Physiology

Physiology is the science of the function of living systems. This includes how organisms, organ systems, organs, cells, and bio-molecules carry out the chemical or physical functions that exist in a living system. The highest honor awarded in physiology is the Nobel Prize in Physiology or...

of neurons and receptors

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

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, succinylcholine, and decamethonium

Succinylcholine was synthesised by connecting two acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

molecules and has the same number of heavy atoms between methonium heads as decamethonium

Decamethonium

Decamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...

. 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

Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...

, vecuronium

Vecuronium

Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation...

, rocuronium

Rocuronium

Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has...

, rapacuronium

Rapacuronium

Rapacuronium is a rapidly acting, non-depolarizing neuromuscular blocker formerly used in modern anaesthesia, to aid and enable endotracheal intubation, which is often necessary to assist in the controlled ventilation of unconscious patients during surgery and sometimes in intensive care...

, dacuronium, malouètine, duador, dipyrandium, pipecuronium, chandonium (HS-310), HS-342 and other HS- compounds are aminosteroidal agents. They have in common the steroid

Steroid

A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...

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

Tetrahydroisoquinoline

Tetrahydroisoquinoline is a secondary amine with the chemical formula C9H11N.-Reactions:Like other secondary amines, tetrahydroisoquinoline can be oxidized to the corresponding nitrone using hydrogen peroxide, catalyzed by selenium dioxide....

moiety such as atracurium

Atracurium

Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical...

, mivacurium

Mivacurium

Mivacurium chloride is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during...

, 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

Mivacurium

. D-tubocurarine

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

Gallamine triethiodide is a non-depolarising muscle relaxant. It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine. Gallamine triethiodide has a parasympatholytic effect on the cardiac vagus nerve which causes...

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

Alcuronium

Alcuronium is a peripherally acting muscle relaxant in the curare alkaloid family. It is a semi-synthetic substance derived from toxiferine.- Effects :...

(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

Acid

An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...

. 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
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...

the plasma membrane of the skeletal muscle fiber. This persistent depolarization makes the muscle fiber resistant to further stimulation by ACh.

Non-depolarizing blocking agents

A neuromuscular nondepolarizing agent is a form of neuromuscular blockers that do not depolarize the motor end plate.

The quaternary ammonium muscle relaxants belong to this class.

Below are some of the more common agents that act as competitive antagonist

Competitive antagonist

A competitive antagonist is a receptor antagonist that binds to a receptor but does not activate the receptor. The antagonist will compete with available agonist for receptor binding sites on the same receptor...

s against acetylcholine at the site of postsynaptic acetylcholine receptors.

Tubocurarine

Tubocurarine

, found in curare

Curare

Curare is a common name for various arrow poisons originating from South America. The three main types of curare are:* tubocurare...

of the South American plant Pareira, Chonodendron tomentosum, is the prototypical non-depolarizing neuromuscular blocker. It has a slow onset (>5 min) and a long duration of action (1–2 hours). Side-effects include hypotension

Hypotension

In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, which is partially explained by its effect of increasing histamine

Histamine

Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...

release, a vasodilator, as well as its effect of blocking autonomic ganglia

Autonomic ganglion

Autonomic ganglia are clusters of neuronal cell bodies and their dendrites and are essentially a junction between autonomic nerves originating from the central nervous system and autonomic nerves innervating their target organs in the periphery....

. It is excreted in the urine

Urine

Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

.

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 potential

End-plate potential

End plate potentials are the depolarizations of skeletal muscle fibers caused by neurotransmitters binding to the postsynaptic membrane in the neuromuscular junction. They are called "end plates" because the postsynaptic terminals of muscle fibers have a large, saucer-like appearance...

s (EPPs) can still be detected, but are too small to reach the threshold potential

Threshold potential

The threshold potential is the membrane potential to which a membrane must be depolarized to initiate an action potential.It often can be between −40 and -55 mV, but it can vary based upon several factors...

needed for activation of muscle fiber contraction.

Comparison of non-depolarizing neuromuscular blocking agents
Agent	Time to onset (seconds)	Duration (minutes)	Side-effects	Clinical use	Storage
Rapacuronium Rapacuronium Rapacuronium is a rapidly acting, non-depolarizing neuromuscular blocker formerly used in modern anaesthesia, to aid and enable endotracheal intubation, which is often necessary to assist in the controlled ventilation of unconscious patients during surgery and sometimes in intensive care... (Raplon)
Mivacurium Mivacurium Mivacurium chloride is a short-duration non-depolarizing neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during... (Mivacron)	90	12-18	hypotension Hypotension In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the... (transiently), by release of histamine	No longer manufactured secondary to marketing, manufacturing, financial concerns	refrigerated
Atracurium Atracurium Atracurium besylate is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical... (Tracrium)	90	30 min or less	hypotension Hypotension In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the... , transiently, by release of histamine Toxic metabolite called laudanosine Laudanosine Laudanosine or N-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however such concentrations are unlikely to be produced consequent... , greater accumulation in individuals with renal failure	widely	refrigerated
Doxacurium (Nuromax)		long	hypotension Hypotension In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the... , transiently, by release of histamine Toxic metabolite called laudanosine Laudanosine Laudanosine or N-methyltetrahydropapaverine is a recognized metabolite of atracurium and cisatracurium. Laudanosine decreases the seizure threshold, and thus it can induce seizures if present at sufficient threshold concentrations; however such concentrations are unlikely to be produced consequent... , greater accumulation in individuals with renal failure
Cisatracurium Cisatracurium Cisatracurium is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation... (Nimbex)	90	60-80	does not cause release of histamine		refrigerated
Vecuronium Vecuronium Vecuronium is a muscle relaxant in the category of non-depolarizing blocking agents. Vecuronium bromide is indicated as an adjunct to general anesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation... (Norcuron)	60	30-40	Few, may cause prolonged paralysis and promote muscarinic block	widely	non-refrigerated
Rocuronium Rocuronium Rocuronium is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia, to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.Introduced in 1994, rocuronium has... (Zemuron)	75	45-70	may promote muscarinic block		non-refrigerated
Pancuronium Pancuronium Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :... (Pavulon)	90	180 or more	tachycardia Tachycardia Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate... (slight) (no hypotension)	widely	non-refrigerated
Tubocurarine Tubocurarine Tubocurarine is a neuromuscular-blocking drug or skeletal muscle relaxant in the category of non-depolarizing neuromuscular-blocking drugs, used adjunctively in anesthesia to provide skeletal muscle relaxation during surgery or mechanical ventilation... (Jexin)	300 or more	60 - 120	hypotension Hypotension In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the... (by ganglion-block and histamine release) Bronchoconstriction Bronchoconstriction Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus.... (by histamine release)	rarely
gallamine Gallamine Gallamine triethiodide is a non-depolarising muscle relaxant. It acts by combining with the cholinergic receptor sites in muscle and competitively blocking the transmitter action of acetylcholine. Gallamine triethiodide has a parasympatholytic effect on the cardiac vagus nerve which causes... (Flaxedil)	300 or more	60 - 120	tachycardia Tachycardia Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...
Pipecuronium	90	180 or more	tachycardia Tachycardia Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate... (slight) (no hypotension)		non-refrigerated

Depolarizing blocking agents

A neuromuscular depolarizing blocking agent is a form of neuromuscular blocker that will depolarize the motor end plate.

An example is succinylcholine.

Depolarizing blocking agents work by depolarizing the plasma membrane of the muscle fiber, similar to acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

. However, these agents are more resistant to degradation by acetylcholinesterase

Acetylcholinesterase

"Acetylcholinesterase, also known as AChE or acetylcholine acetylhydrolase, is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic nervous system, where its activity serves to terminate...

, 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.

There are two phases to the depolarizing block. During phase I (depolarizing phase), they cause muscular fasciculation

Fasciculation

A fasciculation , or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers...

s (muscle twitches) while they are depolarizing the muscle fibers. Eventually, after sufficient depolarization has occurred, phase II (desensitizing phase) sets in and the muscle is no longer responsive to acetylcholine released by the motoneurons. At this point, full neuromuscular block has been achieved.

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

Butyrylcholinesterase

Butyrylcholinesterase is a non-specific cholinesterase enzyme that hydrolyses many different choline esters...

in the blood). Succinylcholine was originally known as diacetylcholine because structurally it is composed of two acetylcholine molecules joined with a methyl group. Decamethonium

Decamethonium

Decamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...

is sometimes, but rarely, used in clinical practice.

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
Acetylcholinesterase inhibitor
An acetylcholinesterase inhibitor or anti-cholinesterase is a chemical that inhibits the cholinesterase enzyme from breaking down acetylcholine, increasing both the level and duration of action of the neurotransmitter acetylcholine.- Uses :Acetylcholinesterase inhibitors:* Occur naturally as...

drugs since they 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 will have prolonged effect under the influence of acetylcholinesterase inhibitors. The administration of depolarizing blockers will initially exhibit fasciculations (a sudden twitch just before paralysis occurs). This is due to the 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

Tetany

Tetany has two meanings, though both are related to the muscular system.* Tetany * Tetany The terms "tetany" and "tetanus" are distinct....

at sufficiently-high frequencies of electrical stimulation.

Non-depolarizing blockers will have this effect on patients, probably by an effect on presynaptic receptors.
Depolarizing blockers will not.

This discrepancy is diagnostically useful in case of intoxication of an unknown neuromuscular-blocking drug.

Mechanism of action

Quaternary muscle relaxants bind to the nicotinic acetylcholine receptor

Nicotinic acetylcholine receptor

and inhibit or interfere with the binding and effect of ACh

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

to the receptor

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

. Each ACh-receptor

Acetylcholine receptor

An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...

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

Hydrogen bond

A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...

.

Non-depolarizing agents
A decrease in binding of acetylcholine leads to a decrease in its effect and neuron

Neuron

transmission to the muscle

Muscle

is less likely to occur. It is common understanding that non depolarizing agents block by acting as reversible competitive inhibitors

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

. That is they bind to the receptor as antagonists

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

and that leaves fewer receptors available for acetylcholine to bind to.

Depolarizing agents
Depolarizing agents produce their block by binding to and activating the receptor, causing contraction and after that paralysation. They bind to the receptor and cause depolarization by opening channels just like acetylcholine does. This causes repetitive excitation that lasts longer than a normal acetylcholine excitation and is most likely explained by depolarizing agents resistance to the enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

acetylcholine esterase. The constant depolarization and triggering of the receptors keeps the endplate resistant to activation by acetylcholine. Therefor a normal neuron transmission to muscle can not cause contraction of the muscle because the endplate is depolarized and thereby the muscle paralysed.

Binding to the nicotinic receptor
Shorter molecules like acetylcholine need two molecules to activate the receptor, one at each receptive site. Decamethonium congeners, which prefer straight line conformations (their lowest energy state), will likely span the two receptive sites with one molecule (binding inter-site). Longer congeners will be required to bend when fitting the receptive sites.

The more energy a molecule needs to bend and fit will usually result in lower potency.

Structural and conformational action relationship

Conformational study on neuromuscular blocking drugs is relatively new and developing. Traditional SAR

Structure-activity relationship

The structure–activity relationship is the relationship between the chemical or 3D structure of a molecule and its biological activity. The analysis of SAR enables the determination of the chemical groups responsible for evoking a target biological effect in the organism...

studies do not specify environmental factors on molecules. Computer

Computer

A computer is a programmable machine designed to sequentially and automatically carry out a sequence of arithmetic or logical operations. The particular sequence of operations can be changed readily, allowing the computer to solve more than one kind of problem...

-based conformational searches assume the molecules to be in vacuo
Vacuum
In everyday usage, vacuum is a volume of space that is essentially empty of matter, such that its gaseous pressure is much less than atmospheric pressure. The word comes from the Latin term for "empty". A perfect vacuum would be one with no particles in it at all, which is impossible to achieve in...

, which is not the case in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

. Solvation models take into account the effect of a solvent on the conformation of the molecule. However, no system of solvation can mimic the effect of the complex fluid composition of the body

The division of muscle relaxants to rigid and non-rigid is at most qualitative. The energy

Energy

In physics, energy is an indirectly observed quantity. It is often understood as the ability a physical system has to do work on other physical systems...

required for conformational changes may give a more precise and quantitative picture. Energy required for reducing onium head distance in the longer muscle relaxant chains may quantify their ability to bend and fit its receptive sites Using computers it is possible to calculate the lowest energy state conformer and thus most populated and best representing the molecule. This state is referred to as the global minimum. The global minimum for some simple molecules can be discovered quite easily with certainty. Such as for decamethonium

Decamethonium

Decamethonium is a depolarizing muscle relaxant or neuromuscular blocking agent, and is used in anesthesia to induce paralysis.- Pharmacology :...

the straight line conformer is clearly the lowest energy state. Some molecules, on the other hand, have many rotatable bonds and their global minimum can only be approximated.

Molecular length and rigidity

Neuromuscular blocking agents need to fit in a space close to 2 nanometres, which resembles the molecular length of decamethonium. Some molecules of decamtehonium congeners may bind only to one receptive site. Flexible molecules will have a greater chance of fitting receptive sites. However, the most populated conformation may not be the best-fitted one. Very flexible molecules are, in fact, weak neuromuscular inhibitors with flat dose-response curves. On the other hand, stiff or rigid molecules tend to fit well or not at all. If the lowest-energy conformation fits, the compound will have high potency because there will be a great concentration of molecules close to the lowest-energy conformation. Molecules can be thin but yet rigid. Decamethonium for example needs relatively high energy to change the N

Nitrogen

Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

-N

Nitrogen

distance.

In general, molecular rigidity contributes to potency, while size affects whether a muscle relaxant will show a polarizing or a depolarizing effect. Cations must be able to flow through the trans-membrane tube of the ion-channel

Ion channel

Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...

to depolarize the endplate. Small molecules may be rigid and potent but unable to occupy or block the area between the receptive sites. Large molecules, on the other hand, may bind to both receptive sites and hinder depolarizing cations independent of whether the ion-channel is open or closed below. Having a lipophilic

Lipophilic

Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...

surface pointed towards the synapse will enhance this effect by repelling cations. The importance of this effect varies between different muscle relaxants and classifying depolarizing from non-depolarizing blocks is a complex issue. The onium heads are usually kept small and the chains connecting the heads usually keep the N-N distance at 10 N or O atoms. Keeping the distance in mind the structure of the chain can vary (double bonded, cyclohexyl, benzyl, etc.)

Succinylcholine has a 10-atom

Atom

The atom is a basic unit of matter that consists of a dense central nucleus surrounded by a cloud of negatively charged electrons. The atomic nucleus contains a mix of positively charged protons and electrically neutral neutrons...

distance between its N

Nitrogen

atoms, like decamethonium. Yet it has been reported that it takes two molecules, as with acetylcholine, to open one nicotinic ion channel

Nicotinic acetylcholine receptor

. The conformational explanation for this is that each acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

moiety of succinylcholine prefers the gauche (bent, cis) state. The attraction between the N and O

Oxygen

Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...

atoms is greater than the onium head repulsion. In this most populated state, the N-N distance will be shorter than the optimal distance of ten carbon atoms and too short to occupy both receptive sites. This similarity between succinyl- and acetyl-choline also explains its acetylcholine-like side-effects.
Comparing molecular lengths, the pachycurares dimethyltubocurarine and d-tubocurarine both are very rigid and measure close to 1.8 nm in total length. Pancuronium

Pancuronium

Pancuronium is a muscle relaxant with various purposes. It is the second of three drugs administered during most lethal injections in the United States.- Mode of action :...

and vecuronium

Vecuronium

measure 1.9 nm, whereas pipecuronium is 2.1 nm. The potency of these compounds follows the same rank of order as their length. Likewise, the leptocurares prefer a similar length. Decamethonium, which measures 2 nm, is the most potent in its category, whereas C11 is slightly too long. Gallamine

Gallamine

despite having low bulk and rigidity is the most potent in its class, and it measures 1.9 nm. Based on this information one can conclude that the optimum length for neuromuscular blocking agents, depolarizing or not, should be 2 to 2.1 nm.

The CAR for long-chain bisquaternary tetrahydroisoquinolines like atracurium, cisatracurium, mivacurium, and doxacurium is hard to determine because of their bulky onium heads and large number of rotatable bonds

Chemical bond

A chemical bond is an attraction between atoms that allows the formation of chemical substances that contain two or more atoms. The bond is caused by the electromagnetic force attraction between opposite charges, either between electrons and nuclei, or as the result of a dipole attraction...

and groups. These agents must follow the same receptive

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

topology as others, which means that they do not fit between the receptive sites without bending. Mivacurium

Mivacurium

for example has a molecular length of 3.6 nm when stretched out, far from the 2 to 2.1 nm optimum. Mivacurium, atracurium, and doxacurium have greater N-N distance and molecular length than d-tubocurarine even when bent. To make them fit, they have flexible connections that give their onium heads a chance to position themselves beneficially. This bent N-N scenario probably does not apply to laudexium and decamethylene bisatropium, which prefer a straight conformation.

Beers and Reich's law

It has been concluded that acetylcholine and related compounds must be in the gauche
Gauche
Gauche can refer to:* Gauche , an implementation of the Scheme programming language.* In stereochemistry, gauche refers a specific conformer...

(bent) configuration when bound to the nicotinic receptor.) Beers and Reich's studies on cholinergic receptors in 1970 showed a relationship affecting whether a compound was muscarinic or nicotinic. They showed that the distance from the centre of the quaternary N atom to the van der Waals

Van der Waals radius

The van der Waals radius, r, of an atom is the radius of an imaginary hard sphere which can be used to model the atom for many purposes. It is named after Johannes Diderik van der Waals, winner of the 1910 Nobel Prize in Physics, as he was the first to recognise that atoms had a finite size and to...

extension of the respective O atom (or an equivalent H-bond acceptor) is a determining factor. If the distance is 0.44 nm then the compound will show muscarinic properties, and if the distance is 0.59 nm then nicotinic properties will be dominant.)

Rational design

Pancuronium remains one of the few muscle relaxants logically and rationally designed from structure-action relationship data. A steroid

Steroid

skeleton was chosen because of its appropriate size and rigidness. Acetylcholine moieties were inserted to increase receptor affinity. Although having many unwanted side-effects, a slow onset of action and recovery rate it was a big success and at the time the most potent neuromuscular drug available. Pancuronium and some other neuromuscular blocking agents block M2-receptors and therefore affect the vagus nerve

Vagus nerve

The vagus nerve , also called pneumogastric nerve or cranial nerve X, is the tenth of twelve paired cranial nerves...

, leading to hypotension

Hypotension

and tachycardia

Tachycardia

Tachycardia comes from the Greek words tachys and kardia . Tachycardia typically refers to a heart rate that exceeds the normal range for a resting heart rate...

. This muscarinic blocking effect is related to the acetylcholine moiety on the A ring on pancuronium. Making the N atom on the A ring tertiary, the ring loses its acetylcholine moiety, and the resulting compound, vecuronium, has nearly 100 times less affinity to muscarin receptors while maintaining its nicotinic affinity‎ and a similar duration of action.‎ Vecuronium is, therefore, free from cardiovascular effects. ‎ The D ring shows excellent properties validating Beers and Reich's rule with great precision. As a result, vecuronium has the greatest potency and specificity of all mono-quaternary compounds.

Potency

Two functional groups contribute significantly to aminosteroid

Aminosteroid

Aminosteroids are a group of drugs with a similar structure based on a steroid nucleus. Examples are the muscle relaxants rocuronium, vecuronium, pipecuronium and pancuronium....

al neuromuscular blocking potency, it is presumed to enable them to bind the receptor at two points. A bis-quaternary two point arrangement on A and D-ring (binding inter-site) or a D-ring acetylcholine moiety (binding at two points intra-site) are most likely to be successful. A third group can have variable effects. The quaternary and acetyl groups on the A and D ring of pipecuronium prevent it from binding intra-site (binding to two points at the same site). Instead, it must bind as bis-quaternary (inter-site). These structures are very dissimilar from acetylcholine and free pipecuronium from nicotinic or muscarinic side-effects linked to acetylcholine moiety. Also, they protect the molecule from hydrolysis by cholinesterases, which explain its nature of kidney excretion. The four methyl-groups

Methyl group

Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

on the quaternary N atoms make it less lipophilic than most aminosteroids. This also affects pipecuroniums metabolism by resisting hepatic uptake, metabolism, and biliary

Bile

Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...

excretion. The length of the molecule (2.1 nm, close to ideal) and its rigidness make pipecuronium the most potent and clean one-bulk bis-quaternary. Even though the N-N distance (1.6 nm) is far away from what is considered ideal, its onium heads are well-exposed, and the quaternary groups help bringing together the onium heads to the anionic centers of the receptors without chirality issues.

Adding more than two onium heads in general does not add to potency. Although the third onium head in gallamine seems to help position the two outside heads near the optimum molecular length, it can interfere unfavorably and gallamine turns out to be a weak muscle relaxant like all multi-quaternary compounds.
Considering acetylcholine a quaternizing group larger than methyl and an acyl group larger than acetyl would reduce the molecules potency. The charged N and the carbonyl

Carbonyl

In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....

O atoms are distanced from structures they bind to on receptive sites and, thus, decrease potency. The carbonyl O in vecuronium for example is thrusted outward to appose the H-bond

Hydrogen bond

donor of the receptive site. This also helps explain why gallamine, rocuronium, and rapacuronium are of relatively low potency.
In general, methyl quaternization is optimal for potency but, opposing this rule, the trimethyl derivatives of gallamine are of lower potency than gallamine. The reason for this is that gallamine has a suboptimal N-N distance. Substituting the ethyl groups with methyl groups would make the molecular length also shorter than optimal. Methoxy

Methoxy

In chemistry , methoxy refers to the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula O–CH3.The word is used in organic nomenclature usually to describe an ether...

lation of tetrahydroisoquinolinium agents seems to improve their potency. How methoxylation improves potency is still unclear.
Histamine

Histamine

release is a common attribute of benzylisoquinolinium muscle relaxants. This problem generally decreases with increased potency and smaller doses. The need for larger doses increases the degree of this side-effect. Conformational or structural explanations for histamine release are not clear.

Pharmacokinetics

Metabolism and Hofmann elimination

Deacetylating

Acetyl

vecuronium

Vecuronium

at position 3 results in a very active metabolite. In the case of rapacuronium

Rapacuronium

the 3-deacylated

Acetyl

metabolite

Metabolomics

Metabolomics is the scientific study of chemical processes involving metabolites. Specifically, metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles...

is even more potent than rapacuronium. As long as the D-ring acetylcholine

Acetylcholine

The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...

moiety is unchanged they retain their muscle relaxing effect. Mono-quaternary

Quaternary ammonium cation

Quaternary ammonium cations, also known as quats, are positively charged polyatomic ions of the structure NR4+, R being an alkyl group or an aryl group. Unlike the ammonium ion and the primary, secondary, or tertiary ammonium cations, the quaternary ammonium cations are permanently charged,...

aminosteroid

Aminosteroid

Aminosteroids are a group of drugs with a similar structure based on a steroid nucleus. Examples are the muscle relaxants rocuronium, vecuronium, pipecuronium and pancuronium....

s produced with deacylation

Acetyl

in position 17 on the other hand are generally weak muscle relaxants. In the development of atracurium

Atracurium

the main idea was to make use of Hofmann elimination

Hofmann elimination

Hofmann elimination is a process where an amine is reacted to create a tertiary amine and an alkene by treatment with excess methyl iodide followed by treatment with silver oxide, water, and heat.After the first step, a quaternary ammonium iodide salt is created...

of the muscle relaxant in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

. When working with bisbenzyl-isoquinolinium types of molecules, inserting proper features into the molecule such as an appropriate electron

Electron

The electron is a subatomic particle with a negative elementary electric charge. It has no known components or substructure; in other words, it is generally thought to be an elementary particle. An electron has a mass that is approximately 1/1836 that of the proton...

withdrawing group then Hofmann elimination

Hofmann elimination

should occur at conditions in vivo. Atracurium, the resulting molecule

Molecule

A molecule is an electrically neutral group of at least two atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their electrical charge...

, breaks down spontaneously in the body to inactive compounds

Chemical compound

A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

and being especially useful in patients with kidney

Kidney

The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

or liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

failure. Cis-atracurium

Chemical compound

is very similar to atracurium except it is more potent and has a weaker tendency to cause histamine

Histamine

release.

Structure relations to onset time

The effect of structure on the onset of action

Onset of action

Onset of action is the duration of time it takes for a drug's effects to come to prominence upon administration. With oral administration, it typically ranges anywhere from 20 minutes to over an hour, depending on the drug in question. Other methods of ingestion such as smoking or injection can...

is not very well-known except that the time of onset seems to be inversely related to potency. In general mono-quaternary aminosteroids are faster than bis-quaternary

Quaternary ammonium cation

compounds, which means they are also of lower potency. A possible explanation for this effect is that drug delivery and receptor binding are of a different timescale. Weaker muscle relaxants are given in larger doses so more molecules in the central compartment

Pharmacokinetics

Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...

must diffuse into the effect compartment

Pharmacokinetics

Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...

, which is the space within the mouth of the receptor, of the body. After delivery to the effect compartment then all molecules act quickly. Therapeutically this relationship is very inconvenient because low potency, often meaning low specificity can decrease the safety margin thus increasing the chances of side-effects

Adverse drug reaction

An adverse drug reaction is an expression that describes harm associated with the use of given medications at a normal dosage. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs...

. In addition, even though low potency usually accelerates onset of action

Onset of action

, it does not guaranty a fast onset. Gallamine

Gallamine

, for example, is weak and slow. When fast onset is necessary then succinylcholine or rocuronium are usually preferable.

Elimination

Muscle relaxants can have very different metabolic pathways

Metabolomics

and it is important that the drug does not accumulate if certain elimination pathways are not active, for example in kidney

Kidney

failure.

Adverse effects

Since these drugs may cause paralysis

Paralysis

of the diaphragm, mechanical ventilation should be at hand to provide respiration.

In addition, these drugs may exhibit cardiovascular effects, since they are not fully selective for the nicotinic receptor and hence may have effects on muscarinic receptors. If nicotonic receptors of the autonomic ganglia

Autonomic ganglion

or adrenal medulla

Adrenal medulla

The adrenal medulla is part of the adrenal gland. It is located at the center of the gland, being surrounded by the adrenal cortex. It is the innermost part of the adrenal gland, consisting of cells that secrete epinephrine , norepinephrine , and a small amount of dopamine in response to...

are blocked, these drugs may cause autonomic symptoms. Also, neuromuscular blockers may facilitate histamine

Histamine

release, which causes hypotension, flushing

Flushing (physiology)

For a person to flush is to become markedly red in the face and often other areas of the skin, from various physiological conditions. Flushing is generally distinguished, despite a close physiological relation between them, from blushing, which is milder, generally restricted to the face, cheeks or...

, and tachycardia.

In depolarizing the musculature, suxamethonium may trigger a transient release of large amounts of potassium

Potassium

Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

from muscle fibers. This puts the patient at risk for life-threatening complications, such as hyperkalemia

Hyperkalemia

Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...

and cardiac arrhythmias.

Certain drugs such as aminoglycoside

Aminoglycoside

An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...

antibiotics and polymyxin

Polymyxin

Polymyxins are antibiotics, with a general structure consisting of a cyclicpeptide with a long hydrophobic tail. They disrupt the structure of thebacterial cell membrane by interacting with its phospholipids...

and some fluoroquinolones also have neuromuscular blocking action as their side-effect.

Estimating effect

Methods for estimating the degree of neuromuscular block include valuation of muscular response to stimuli from surface electrodes, such as in the train-of-four test, wherein four such stimuli are given in rapid succession. With no neuromuscular blockade, the resultant muscle contractions will be of equal strength, but gradually decrease in case of neuromuscular blockade. It is recommended during use of continuous-infusion neuromuscular blocking agents in intensive care.

Reversal

The effect of non-depolarizing neuromuscular-blocking drugs may be reversed with anticholinesterases, neostigmine

Neostigmine

Neostigmine is a parasympathomimetic that acts as a reversible acetylcholinesterase inhibitor.- Synthesis :Neostigmine was first synthesized by Aeschlimann and Reinert in 1931....

, and edrophonium

Edrophonium

Edrophonium is a readily reversible acetylcholinesterase inhibitor. It prevents breakdown of the neurotransmitter acetylcholine and acts by competitively inhibiting the enzyme acetylcholinesterase, mainly at the neuromuscular junction...

, as commonly used examples. Of these, edrophonium has a faster onset of action than neostigmine, but it is unreliable when used to antagonize deep neuromuscular block. Anticholinesterases increase the amount of acetylcholine in the neuromuscular junction, so a prerequisite for their effect is that the neuromuscular block is not complete, because in case every acetylcholine receptor is blocked then it does not matter how much acetylcholine is present.

Sugammadex

Sugammadex

Sugammadex is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent and was discovered at the Newhouse research site in Scotland. . These scientists who discovered Sugammadex worked for the pharmaceutical...

is a newer drug for reversing neuromuscular block by rocuronium

Rocuronium

in general anaesthesia

General anaesthesia

General anaesthesia is a state of unconsciousness and loss of protective reflexes resulting from the administration of one or more general anaesthetic agents...

. It is the first selective relaxant binding agent (SRBA).

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