BPC 2001 summary

Chance, coincidence and atracurium

Looking at the early development of muscle relaxants for use in anaesthesia, Professor Stenlake said that in the mid-1930s Sir Henry Dale (a Hanbury medallist in 1943) showed that neuromuscular transmission was brought about by acetylcholine and that it was blocked by tubocurarine. Subsequent research led to the marketing of tubocurarine in 1946. Previously, adequate muscle relaxation required deep anaesthesia, which could be hazardous. Using a separate muscle relaxant allowed lighter anaesthesia, thus enhancing the margin of safety.

Tubocurarine is now known to have a monoquaternary structure, but research in the 1940s erroneously suggested a bisquaternary structure. That error fortuitously focused the attention of chemists on compounds with two or more quaternary centres, leading to the rapid appearance of gallamine, decamethonium and then suxamethonium.

Chance discussion

It was against that background that Professor Stenlake was drawn into muscle relaxant research in the early 1950s, shortly after arriving at Glasgow’s then Royal College of Science and Technology. A chance discussion led to the idea that intermediates he was preparing for other studies would also serve as intermediates in synthesising a new class of neuromuscular blocking agents.

In collaboration with John Lewis of Glasgow University, he spent a few years exploring structural factors that favour non-depolarising neuromuscular blockade. They edged their way towards a clinically useful replacement for suxamethonium, but when this work reached a dead end, Professor Stenlake turned to other ongoing fields of study — stereochemistry of neuromuscular blocking agents, drug metabolism and natural product chemistry, all of which were to play a part in the design of atracurium.

With tubocurarine still believed to have a bisquaternary structure, literature data on the relationship between its stereochemistry and potency was anomalous. Investigating this problem, the Glasgow team examined two simple monoquaternary compounds, l- and d-laudanosine methiodides, which are structurally related to the component moieties of the tubocurarine stereoisomers.

On his arrival in Glasgow in 1952, Professor Stenlake had been given responsibility for a project to isolate an alkaloid from the tubers of a Mediterranean plant. By a strange coincidence, the alkaloid was identified as a simple benzylisoquinoline quaternary salt closely related to the laudanosine methiodides. More significantly, the alkaloid was easily degraded in mild alkali at ambient temperature by the Hofmann elimination pathway — which usually requires strong alkali (pH 12–14) and high temperature (100C).

The alkaloid’s easy degradation triggered the idea of a new type of neuromuscular blocking agent, programmed by its chemical structure to undergo Hofmann elimination at physiological pH (7.4) and body temperature (37C). Its chemical structure would determine its breakdown rate and hence its duration of action. One advantage would be that, with a chemical rather than enzymic control, patients with plasma carboxyesterase deficiencies would be free from any risk of undesirably long muscle paralysis, as occurred after the use of suxamethonium.

The objective, then, was to synthesise a bisquaternary compound with competitive action (ie, capable of reversal by neostigmine), with high potency and selectivity, and with structural features to promote and control non-enzymic deactivation by Hofmann elimination at an appropriate rate. In their attempts to find such a drug, Stenlake’s team examined just four series of compounds. Problems with early contenders included inadequate potency and vagal blockade, but these drawbacks were finally overcome in the fourth series, which consisted of just five compounds. One of these was not only moderately potent but also showed a wide separation between neuromuscular and vagal blocking doses. This lead compound was just the 18th that they had prepared and tested.

Development of the breakthrough compound concentrated on modifying the ring substituents and the interquaternary chain. In the event, only chain extension was productive. Potency increased progressively as interonium spacing increased to 13–14 atom units, declining thereafter. Happily, the separation between vagal blocking and neuromuscular paralysing doses also increased, up to the pentamethylene compound. With this optimum combination of favourable properties, compound 33A74 became a potential candidate for clinical trial.

After encouraging studies in animals, an initial clinical evaluation of atracurium showed complete neuromuscular blockade at a dose level of 0.3mg/kg, with no effect on heart rate or arterial blood pressure at twice the full neuromuscular blocking dose. The rate of recovery was two to five times faster than with established muscle relaxants.

It was expected that atracurium would be metabolised by both Hofmann elimination and ester hydrolysis, but evidence for the dominance of Hofmann elimination was substantial — although it was years before it was confirmed as the rate determining step.

The industrial development of the compound was not straightforward: first, it had been designed to be labile; secondly, quaternary salts are difficult to purify and often hygroscopic; and thirdly, the ether used to isolate the product in the laboratory was unsafe on an industrial scale. But all these problems were overcome. The counter-ion was changed from iodide to besilate to increase solubility and, after seven years of development and clinical trials, 33A74 was transformed into atracurium besilate.

Atracurium’s non-enzymic, consistent breakdown rate accounts for many special clinical attributes. Recovery from single bolus doses is fast, and full blockade can be maintained for prolonged periods by small incremental doses, with recovery time unaffected by the number of such increments. It can also be administered by continuous infusion, without cumulative effect, and so is suitable for long surgical procedures.

Special place

Because its metabolism is independent of the liver and kidneys, atracurium has found a special place in operations on patients suffering from hepatic or renal failure and in organ transplant surgery. For the same reason, it is the agent of choice in intensive care: patients with problems such as severe head injuries or acute respiratory distress can be maintained in a passive state over prolonged periods to assist the healing process. Rapid recovery from muscle relaxation when administration is halted temporarily permits periodic assessment of the patient’s progress.

Atracurium is an unresolved mixture of 10 stereoisomers in unequal but constant proportions. When it eventually became possible to separate the individual isomers, their order of potency caused some surprises. But one isomer was found to have about twice the potency of the racemic drug, reducing the incidence of side effects, and also, fortuitously, a duration of action identical to that of atracurium. This isomer was eventually developed to become cisatracurium.

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