Atracurium Hofmann elimination

Atracurium besylate (Tracrium) is a benzylisoquinolin-ium compound like d-tubocurarine. Its actions are similar to those of d-tubocurarine, but its duration of action is shorter (45 minutes) because of spontaneous degradation of the molecule (Hofmann elimination). Because of this, atracurium is useful in patients with low or atypical plasma cholinesterase and in patients with renal or hepatic impairment. 

Atracurium is a synthetic bisquaternary benzylisoquinolinium compound with a novel method of metabolism, the Hofmann elimination reaction. This reaction takes place at a pH of 7.4 and a temperature of 37°C. It is thus metabolised at body temperature and pH, and has to be stored in a refrigerator. The usual intubating dose of atracurium is 0.5-0.75 mg-kg-1 (2-3xED95). The onset of action with this dose is 2-3 minutes and intubating conditions are acceptable in 90-120 seconds. Spontaneous recovery occurs reliably from an atracurium neuromuscular block, such that an intubating dose of about 0.5 mg-kg-1 can be expected to provide surgical muscle relaxation for 25-40 minutes in the normal healthy patient. Repeated administration of atracurium leads only to a small increase in the duration of action. 

The major metabolic pathway for cisatracurium is Hofmann elimination, although renal and other organ clearance accounts for some elimination. The pharmacokinetics of cisatracurium are independent of dose in healthy adult patients up to doses of 0.2 mg-kg-1 and its elimination half-life is similar to that of atracurium (Table 6.4). In contrast to atracurium, the clearance of cisatracurium is slightly reduced and recoveiy slightly slower in patients with renal failure. Much less laudanosine is produced as a metabolite of cisatracurium as compared with atracurium even when the drug is given by continuous infusion over a prolonged period of time. 

Atracurium is unique in that it is altered spontaneously in the body to an inactive form (t 30 min) by a passive chemical process (Hofmann elimination). The duration of action (15-35 min) is thus uninfluenced by the state of the circulation, the liver or the kidneys, a significant advantage in patients with hepatic or renal disease and in the aged. It has very little direct effect on the cardiovascular system... 

In contrast to other non-depolarizing drugs, atracurium is completely broken down at normal blood pH and temperature by Hofmann elimination, principally (although to disputed degrees) by nucleophilic substitution and enzymatic... 

Cisatracurium and atracurium share the same metabolic pathways, but Hofmann elimination may have a greater role in the elimination of cisatracurium than in atracurium (2,4-7). Spontaneous in vivo degradation accounts for 77 % of total body clearance of cisatracurium (6). Organ clearance is 23% of total body clearance. Major metabolites of cisatracurium are laudanosine and a monoquaternary acrylate. 

Fisher DM, CanfeU PC, Fahey MR, Rosen JI, Rupp SM, Sheiner LB, Miller RD. Elimination of atracurium in humans contribution of Hofmann elimination and ester hydrolysis versus organ-based elimination. Anesthesiology 1986 65(1) 6-12. 

Pharmacokinetics All agents are given parenterally. Drugs that are metabolized (eg, mivacurium, by plasma cholinesterase) or eliminated in the bile (eg, vecuronium) usually have shorter durations of action than those eliminated by the kidney (eg, doxacurium, pancuronium, tubocurarine). Atracurium clearance involves spontaneous breakdown (Hofmann elimination) to form laudanosine and other products is largely independent of hepatic or renal function. 

Atracurium (nondepolarizing) breaks down spontaneously in the plasma (Hofmann elimination) to form laudanosine, which has a long half-life. Since laudanosine enters the CNS and may cause seizures, prolonged administration of atracurium is usually avoided. The drug has no action on autonomic ganglia or muscarinic receptors. The answer is (C). 

Full neuromuscular block with atracurium is achieved in man with doses in the range 0.26-0.30 mg/kg the onset time is 1.7-3.0 mins., while the 90% twitch-strength recovery time is about 40 mins, for a 0.3 mg/kg dose. To permit the preparation of small volume injections for clinical use, the alkylating agent finally chosen for the quaternization was methyl benzenesulphonate —the drug is put up in 2.5- or 5-ml ampoules containing 10 mg/ml and the solution is stable for at least two years at the optimal pH of 3.5 (which inhibits possible occurrence of the Hofmann elimination) and storage at 5°C (504,527, 534, 536). 

A particular reaction of quaternary amines, the Hofmann elimination, was used to determine the design of atracurium, a muscle relaxant which falls apart spontaneously and thus does not require metabolic elimination. 

Draw the mechanism for the Hofmann elimination for the atracurium analogue doxacurium chloride. 

Atracurium has a duration of action similar to that of vecuroiuum and is eliminated by a rationally designed, purely chemical degradation mechanism via the Hofmann elimination (see Box 16.7) which occurs in an aqueous environment with the rate increasing with higher pH (Fig. 16.23). Atracurium is supplied as a sterile injection of 10 mg/mL. 

Figure 16.23 Hofmann elimination leading to the degradation of atracurium.

The main product of the Hofmann elimination of atracurium is laudanosine, an alpha-adrenoreceptor blocking agent which causes hypotension. Moreover, laudanosine crosses the blood-brain barrier (in contrast to the parent compound) and may cause excitement and seizure activity which leads to an increase in anaesthetic requirement by 30%. Accumulation and corresponding problems with laudanosine arise only in infants and with prolonged application in ICUs. ° Laudanosine-caused hypotension is enhanced by histamine released from tissue stores as a side effect of atracurium. 

R-cis R-cis isomer of atracurium. It is degraded by Hofmann elimination just like atracurium. However, plasma concentrations of laudanosine do not reach such high levels as in the case of atracurium, leading to fewer cardiac side effects. Cisatracurium also releases less histamine from tissue stores. The potency and duration of action are similar in both drugs. Cisatracurium besilate is provided in sterile injections with a concentration equivalent to 2 mg/mL of cisatracurium in 5- or 10-mL vials, or 10 mg/mL of cisatracurium in 20-mL vials intended for use in ICUs only. 

Atracurium (tracrium) Benzylisoquinoline Intermediate duration competitive 2-4 30-60 Hofmann degradation hydrolysis by plasma esterases renal elimination... 

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