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Succinylcholine

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Succinylcholine chemical structure
Succinylcholine

2,2'-[(1,4-dioxobutane-1,4-diyl)bis(oxy)]bis
(N,N,N-trimethylethanaminium)
IUPAC name
CAS number
306-40-1
ATC code

M03AB01

PubChem
5314
DrugBank
APRD00159
Chemical formula {{{chemical_formula}}}
Molecular weight 290.399 g/mol
Bioavailability NA
Metabolism By pseudocholinesterase, to succinylmonocholine and choline
Elimination half-life
Excretion Renal (10%)
Pregnancy category {{{pregnancy_category}}}
Legal status {{{legal_status}}}
Routes of administration Intravenous, Intramuscular

succinylcholine (also known as Suxamethonium chloride or informally as sux) is a medication widely used in emergency medicine and anesthesia to induce muscle relaxation, usually to make endotracheal intubation possible. Suxamethonium is sold the trade names Anectine and Scoline.

Suxamethonium acts as a depolarizing neuromuscular blocker. It imitates the action of acetylcholine at the neuromuscular junction, acting on muscle type nicotinic receptors, but it is degraded not by acetylcholinesterase but by butyrylcholinesterase, a plasma cholinesterase. This hydrolysis by butyrylcholinesterase is much slower than that of acetylcholine by acetylcholinesterase.

Chemistry

Suxamethonium is a white crystalline substance, it is odourless; solutions have a pH of about 4, the dihydrate melts about 160 °C, the anhydrous melts at about 190 °C; it is highly soluble in water (1 gram in about 1 mL), soluble in alcohol (1 gram in about 350 mL), slightly soluble in chloroform, and practically insoluble in ether. Suxamethonium is a hygroscopic compound.[1] The compound consists of two acetylcholine molecules that are linked by their acetyl groups.

History

It has been in use since the pharmacological properties of succinylcholine were discovered around 1950 by K.H. Ginzel, H Klupp, and Gerhard Werner in Vienna, Austria.

Effects

There are two phases to the blocking effect of suxamethonium; Phase 1 block is the principal paralytic effect.

Phase 1 block

Binding of suxamethonium to the nicotinic acetylcholine receptor results in opening of the receptor's nicotinic sodium channel; sodium moves into the cell, a disorganised depolarisation of the motor end plate occurs and calcium is released from the sarcoplasmic reticulum. This results in fasciculation.

In the normal muscle, following depolarisation, acetylcholine is rapidly hydrolysed by acetylcholinesterase and the muscle cell is able to 'reset' ready for the next signal.

Suxamethonium has a longer duration of effect than acetylcholine and is not hydrolysed by acetylcholinesterase. It does not allow the muscle cell to 'reset' and keeps the 'new' resting membrane potential below threshold. When acetylcholine binds to an already depolarised receptor it cannot cause further depolarisation.

Calcium is removed from the muscle cell cytosol independent of repolarisation (depolarization signalling and muscle contraction are independent processes). As the calcium is taken up by the sarcoplasmic reticulum, the muscle relaxes. This explains muscle flaccidity rather than tetany following fasciculation.

Phase 2 block

Following infusion or repeated doses of suxamethonium, phase 2 block may occur. The receptor blockade takes on characteristics of a non-depolarising neuromuscular block (ie. fade in response to nerve stimulation, however unlike non-depolarizing neuromuscular blocking agents it cannot be reversed).


Organophosphorus poisoning, An example of the phases of blocking

Phase 1

At the phase 1 block, the membrane is fully depolarised and the muscle fibre is therefore inexcitable. This is a phase of 'sustained depolarisation'. This can occur with organophosphorus poisoning. The organophosphorus compound (for example dyflos) is an anticholinesterase. This will cause a decrease in the function in Acetylcholine esterase, which leaves the post-synaptic cell with more ACh available to activate it. The constant depolarisation causes a phase 1 block.

In pharmacological terms, the Phase 1 block is potentiated by the anticholinesterase, and can be antagonised (opposed) by competitive blockers of this.

In this case, the poisonous organophosphorus compound can be antagonised (opposed) by atropine (which effectively reduces the available ACh) and pralidoxime.

Phase 2

If the ACh receptor is 'held open' for an extended period of time, or if the concentration of the blocker is excessive (this could be vastly elevated levels of ACh from organophosphorus poisoning) then the phase two block begins.

Here the nicotinic receptors undergo desensitisation and eventually closure. They are no longer receptive to the substance which was previously opening them. This is pharmacological terms is beginning to behave like an antagonist (blocker). Here, in the phase 2 block, the resting membrane potential of the cell is restored, but the muscle remains paralysed because the receptors are temporarily unreceptive to any activation.


Medical uses

Its medical uses are limited to short-term muscle relaxation in anesthesia and intensive care, usually for facilitation of endotracheal intubation. Despite its adverse effects, including life threatening malignant hyperthermia, hyperkalaemia and anaphylaxis, it is perennially popular in emergency medicine because it arguably has the fastest onset and shortest duration of action of all muscle relaxants. The former is a major point of consideration in the context of trauma care, where endotracheal intubation may need to be completed very quickly. The latter means that, should attempts at endotracheal intubation fail and the patient cannot be ventilated, there is a prospect for neuromuscular recovery and the onset of spontaneous breathing before hypoxaemia occurs.

The recent arrival of the cyclodextrin sugammadex may well render suxamethonium obsolete. Sugammadex can be used to 'instantly' reverse the effects of longer-acting muscle relaxants, particularly rocuronium. This means that rocuronium can be given in sufficiently high dose to work quickly, and then reliably reversed when necessary, all without the unwelcome side effects of suxamethonium.

Suxamethonium is quickly degraded by plasma butyrylcholinesterase and the duration of effect is usually in the range of a few minutes. When plasma levels of butyrylcholinesterase are greatly diminished or an atypical form is present (an otherwise harmless inherited disorder), paralysis may last much longer.

Side effects

Side effects include muscle pains, acute rhabdomyolysis with hyperkalemia, transient ocular hypertension, constipation[2] and changes in cardiac rhythm including bradycardia, cardiac arrest, and ventricular dysrhythmias. In patients with neuromuscular disease or burns, a single injection of suxamethonium can lead to massive release of potassium from skeletal muscles with cardiac arrest.

Suxamethonium does not produce unconsciousness or anesthesia, and its effects may cause considerable psychological distress while simultaneously making it impossible for a patient to communicate. For these reasons, administration of the drug to a conscious patient is strongly contraindicated, except in necessary emergency situations.

Hyperkalemia

The side effect of hyperkalaemia is because the acetylcholine receptor is propped open, allowing continued flow of potassium ions into the extracellular fluid. A typical increase of potassium ion serum concentration on administration of suxamethonium is 0.5 mmol per litre, whereas the normal range of potassium is 3.5 to 5 mmol per litre. The increase is transient in normal patients. Hyperkalaemia does not generally result in adverse effects below a concentration of 6.5 to 7 mmol per litre.

Severe hyperkalemia will causes changes in cardiac electrophysiology, which, if severe, can result in asystole.

Death

This drug has occasionally been used as a paralyzing agent for executions by lethal injection, although pancuronium bromide is the preferred agent today because of its longer duration of effect and its absence of fasciculations as a side effect. It has also been used for murder by Dr. William Sybers[3] and Dr. Carl Coppolino.[4] Suxamethonium was the drug used to murder Nevada State Controller Kathy Augustine[5], and was used by surgical technician Kim Hricko in the 1998 murder of her husband Steve.[6]

See also


References

  1. Gennaro, Alfonso. Remington: The Science and Practice of Pharmacy, 20th ed. Lippincot, Wiliams and Wilkins, 2000:1336.
  2. DiPiro, Joseph, et al. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. McGraw-Hill, 2005:685.
  3. i-mass.com : international mass spectrometry web resource. URL accessed on 2007-08-14.
  4. Tracing the Untraceable - TIME
  5. includeonly>"Official's husband gets life for her murder", Seattle Times, June 30, 2007. Retrieved on 2008-05-15.
  6. Maryland Legal Briefs, 11/23/04. URL accessed on 2008-09-28.


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