Suxamethonium Atracurium

Recent developments have led to agents with a built-in functional group that allows more rapid metabolism. Initially, the presence of ester groupings, as in suxamethonium, allowed fairly rapid metabolism in the body via esterase enzymes that hydrolyse these linkages. The enzyme involved appears to be a non-specific serum acetylcholinesterase (see Box 13.4). Even better is the inclusion of functionalities that allow additional degradation via an elimination reaction. Such an agent is atracurium. 

Nevertheless, some interactions of benzodiazepines with muscle relaxants used in anesthesia have been described. Diazepam has been reported to potentiate the effects of tubocurare (163) and gallamine (164) and to reduce the effects of suxamethonium (164). However, in 113 patients undergoing general anesthesia, intravenous diazepam 20 mg, lorazepam 5 mg, and lormetaze-pam 2 mg did not potentiate the neuromuscular blocking effects of vecuronium or atracurium (162). 

In 113 patients undergoing general anesthesia, intravenous midazolam 15 mg slowed recovery of the twitch height after vecuronium and atracurium compared with diazepam. The recovery index was not altered (162). However, in another study in 20 patients, midazolam 0.3 mg/kg did not affect the duration of blockade, recovery time, intensity of fasciculations, or adequacy of relaxation for tracheal intubation produced by suxamethonium 1 mg/kg, nor the duration of blockade and adequacy of relaxation for tracheal intubation produced by pancuronium 0.025 mg/kg in incremental doses until 99% depression of muscle-twitch tension was obtained (161). Furthermore, in 60 patients undergoing maintenance anesthesia randomly assigned to one of six regimens (etomidate, fentanyl, midazolam, propofol, thiopental plus nitrous oxide, or isoflurane plus nitrous oxide), midazolam did not alter rocuronium dosage requirements (165). 

Prior administration of suxamethonium potentiates the action of atracurium by about 30% (69). 

Stirt JA, Katz RL, Murray AL, Schehl DL, Lee C. Modification of atracurium blockade by halothane and by suxamethonium. A review of clinical experience. Br J Anaesth 1983 55(Suppl l) S71-5. 

Caldwell JE, Heier T, Kitts JB, Lynam DP, Fahey MR, Miller RD. Comparison of the neuromuscular block induced by mivacurium, suxamethonium or atracurium during nitrous oxide entanyl anaesthesia. Br J Anaesth 1989 63(4) 393-9. 

For tracheal intubation the usual dose is 0.1 mg/kg. When given after suxamethonium, 0.05 mg/kg is sufficient for good abdominal relaxation. Further doses of about one-quarter to one-third of the initial dose are given at intervals of 30-40 minutes to maintain relaxation. Reversal is easily achieved with neostigmine, provided there is some spontaneous return of neuromuscular transmission beforehand. If the evoked twitch height is less than 10% of the control value, there can be difficulty in reversing the blockade this apphes to aU non-depolarizing relaxants, except perhaps vecuronium and atracurium. 

Other measures, much disputed, include the prior injection of diazepam (58,59), procaine or hdocaine (57), vitamin C, suxamethonium itself (10 mg), and aspirin (51,52). The combined use of atracurium 0.05 mg/kg and hdocaine 1.5 mg/kg reduced the incidence of postoperative myalgia to 5% compared with 75% in controls (57). Thiopental, injected immediately beforehand, is also said to have some effect, as is giving the suxamethonium slowly. 

Edmondson L, Lindsay SL, Lanigan LP, Woods M, Chew HE. Intra-ocular pressure changes during rapid sequence induction of anaesthesia. A comparison between thiopentone and suxamethonium and thiopentone and atracurium. Anaesthesia 1988 43(12) 1005-10. 

Scott RP, Norman J. Effect of suxamethonium given during recovery from atracurium. Br J Anaesth 1988 61(3) 292-6. 

Skeletal muscle relaxants fall into three major categories those that reduce spasticity, those that cause neuromuscular blockade and those that work at the cellular level. Spasmolytic agents (e.g. metho-carbamol, guaifenesin) act centrally whereas neuromuscular blockers (e.g. succinylcholine (suxamethonium), pancuronium, atracurium) act at the neuromuscular end plate to produce muscular relaxation. Dantrolene falls into the third category and acts within the muscle cell itself to produce relaxation. 

The design of atracurium (Fig. 11.40) was based on the structures of tubocurarine and suxamethonium. It is superior to both since it lacks cardiac side-effects and is rapidly broken down in blood. This rapid breakdown allows the drug to be administered as an intravenous drip. 

The inhalational anaesthetics increase the effects of the neuromuscular blockers to differing extents, but nitrous oxide appears not to interact significantly. Ketamine has been reported to potentiate the effects of atracurium. Propofol does not appear to interact with mivacurium or vecuronium. Xenon is reported not to interact with mivacurium or rocuronium, and has less effect than sevoflurane on vecuronium neuromuscular blockade. Bradycardia has been seen in patients given vecuronium with eto-midate or thiopental. Propofol can cause serious bradycardia if it is given with suxamethonium (succinylcholine) without adequate antimuscarinic premedication, and asystole has been seen when fentanyl, propofol and suxamethonium were given sequentially. 

Ketamine prolonged the duration of neuromuscular blockade induced by atracurium, but did not influence suxamethonium (succinylcholine)-induced neuromuscular blockade. However, the UK manufacturers of suxamethonium still warn of a possible interaction because they say that ketamine may reduce normal plasma cholinesterase activity. ... 

An in vitro study found that the acute neuromuscular effects of carbamazepine reduced the concentrations required for 50% paralysis with both a depolarising neuromuscular blocker (suxamethonium (succinylcholine)) and a competitive neuromuscular blocker (atracurium) by about 30%. ... 

In other studies diazepam was found to have no significant effect on the neuromuscular blockade due to alcuronium, atracurium, gaiiamine, pancuronium, suxamethonium " or tubocurarine. " " Lo-razepam and lormetazepam have been reported to have little or no effects on atracurium or vecuronium, and midazolam has been reported to have no eftect on suxamethonium or pancuronium. ... 

An isoiated case report describes potentiation of tubocurarine and pancuronium by orai verapamii. However, long-term oral nifedipine did not aiter vecuronium or atracurium effects, and iong-term therapy with various caicium-channel blockers did not interact with rocuronium. Caicium-channei blockers do not increase the piasma potassium rise due to suxamethonium (succi-nyichoiine). 

One report suggests that recovery from the neuromuscular blocking effects of suxamethonium (succinyichoiine) is prolonged by ci-metidine, but this may possibiy have been due to the presence of metociopramide. Four other reports say that no interaction occurs between suxamethonium and either cimetidine, famotidine or ranitidine. Cimetidine, but not ranitidine, has been reported to increase the effects of vecuronium. Cimetidine does not aiter the effects of atracurium or rocuronium and ranitidine does not aiter the effects of atracurium. 

Information seems to be limited to the reports cited. The most likely explanation for the discord between the cimetidine/suxamethonium results is that in the one study reporting increased suxamethonium effects some of the patients were also given metoclopramide, which can inhibit plasma cholinesterase and prolong the effects of suxamethonium (see also Neuromuscular blockers + Metoclopramide , p.l27). In four other studies, cimetidine and other H2-receptor antagonists did not alter suxamethonium effects. Therefore, it seems unlikely that an interaction exists. There is some evidence that cimetidine may slightly prolong the effects of vecuronium, but ranitidine appears not to interact. Atracurium and rocuro-nium appear not to be affected. Overall these possible interactions seem to be of little clinical significance. 

For reports of bradycardia occurring with atracurium or suxamethonium used with propofol and fentanyl, see Anaesthetics, general + Neuromuscular blockers , p.lOl. 

The reasoning that led to the development of Atracurium (Tracrium ) has been discussed in several publications (533-536) and need not be repeated in detail here. Suffice it to note that deficiencies were recognized in the drugs developed in the 1960/70s slower onset and longer duration of action than suxamethonium, lack of specificity, i.e. freedom from cardiovascular effects, and undue prolongation of muscle relaxation in patients with renal or hepatic impairment. 

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). 

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