Suxamethonium hydrolysis

Mivacurium chloride is a non-depolarizing muscle relaxant, a benzylisoquinolinium diester compound with a duration of approximately twice that of suxamethonium. In vitro (1), it is metabolized to a significant extent by plasma cholinesterase, and minimally by acetylcholinesterase. The rate of metabolism in vitro is directly related to plasma cholinesterase activity. In pooled human plasma the rate of hydrolysis of mivacurium was 70% that of suxamethonium. Its half-life is 5-10 minutes compared with 2-5 minutes for suxamethonium. The in vitro hydrolysis of mivacurium by purified human plasma cholinesterase occurs at 88% of the rate for suxamethonium (2). There was a poor correlation between the duration of action of bolus doses of mivacurium and the plasma cholinesterase activity in individual patients (2), a finding that has also been reported by others (3). However, the average infusion rate to maintain around 95 % blockade in individual patients correlated significantly with the patients plasma cholinesterase activities (4). While metabolites have been detected in both urine and bile, mivacurium seems to depend principally on ester hydrolysis for its plasma clearance, so that reduced activity of plasma cholinesterase is likely to result in a prolonged duration of action. 

Suxamethonium consists of two acetylcholine molecules linked together. Initially, it acts like acetylcholine by depolarizing the motor end-plate. However, unlike acetylcholine, which on dissociation from the receptor is immediately destroyed by acetylcholinesterase present in the neuromuscular junction, suxamethonium is hydrolysed by a (pseudo)cholinesterase present in the plasma but not at the neuromuscular junction. Most of an injected dose of suxamethonium is normally destroyed before it reaches the neuromuscular junction. If the activity of plasma cholinesterase in a particular patient is reduced, more of the suxamethonium reaches the neuromuscular junction and its action is proportionately prolonged. The molecules of suxamethonium that reach the acetylcholine receptor sites interact repeatedly with them, producing prolonged depolarization of the motor end-plate, which becomes surrounded by an electrically inactive zone. The end-result is flaccid paralysis. The action of suxamethonium is terminated by diffusion away from the neuromuscular junction. Hydrolysis results in choline and succinylmonocholine, which has a very weak competitive blocking action and is further slowly hydrolysed by plasma cholinesterase to choline and succinic acid. 

SUtilains [ban, inn, usan] (BAX 1515 Travase ) is an ENZYME derived from Bacillus subtilis. It is a proteolytic enzyme used for wound debridement in moist conditions, suxamethonium chloride [ban. inn] (succinyichoiine chloride [usan] suxamethonium bromide [ban] succinoylcholine Scoline Quelicin Anectine ) is a bistrimethylethanaminium derivative, a NICOTINIC CHOLINOCEPTOR AGONIST, a (depolarizing) NEUROMUSCULAR BLOCKING AGENT, which can be used as a SKELETAL MUSCLE RELAXANT in anaesthesia relaxant. Its action is short-lived due to hydrolysis by plasma cholinesterase, suxamethonium bromide suxamethonium chloride. 

The ester groups are susceptible to chemical and enzymatic hydrolysis. Once hydrolysis occurs, the molecule can no longer bridge the two receptor sites and becomes inactive. Suxamethonium has a duration of action of five minutes, but suffers from other side-effects.3 Furthermore, about one person in every two thousand lacks the enzyme which hydrolyses suxamethonium. 

Holst-Larsen, H., The hydrolysis of suxamethonium in human blood. Br. J. Anaesth. 48, 887-892 (1976). 

P8. Peck, A. W., Hydrolysis of suxamethonium by plasma from subjects responding to the drug with prolonged apnoea, and by plasma from their relatives. Pharmacol. Clin. 2, 6-12 (1969). 

Its depolarizing neuromuscular blocking effect is very transient because of its rapid hydrolysis by cholinesterases. It does not cause histamine liberation and hence it is well tolerated. Single-dose therapy of suxamethonium chloride is generally used to relax the skeletal muscle for orthopedic manipulation, endotracheal intubation, in laryngospasm and also to check the intensity of convulsions in patients receiving electroshock treatment (electroconvulsive therapy). 

Uncertain. Some local anaesthetics (ester-type ) such as procaine appear to inhibit plasma cholinesterase, which might prolong the activity of suxamethonium. There may additionally be competition between suxamethonium and procaine for hydrolysis by plasma cholinesterase, which metabolises them both. These effects are particularly important in patients with abnormal plasma cholinesterase. Therapeutic procainamide plasma concentrations of 5 to 10 micrograms/mL have been found to inhibit cholinesterase activity by 19 to 32%. ... 

Two new nondepolarizing bis-benzyl tetrahydro isoquinoline muscle relaxants with negligible cardiovascular effects are now undergoing clinical trials. Mivacurium (BW B1090U) (65a) has a short-lasting action, with an ED95 of 0.1 mg/kg. The substance is rapidly hydrolysed by plasma cholinesterase—at nearly 90% of the rate of suxamethonium—and some hydrolysis by liver esterases may also take place as well. The recovery time is about half that of vecuronium and atracurium. Minor cutaneous side effects occur sometimes (551-553). Mivacurium has been approved for general use (1992). 

Suxamethonium is used as a musde relaxant and its activity is terminated by hydrolysis of one of its ester linkages. 

Figure 16.27 Hydrolysis of and removal of suxamethonium from the AChNR.

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