History of Alfaxalone
The anesthetic properties of steroids have been known for more than 70 years. In the 1940s, the Hungarian-born endocrinologist Hans Selye showed that reversible unconsciousness could be produced in rats administered intraperitoneal injections of large quantities of steroid hormones.4 Of the steroids injected, pregnanedione was the most potent and devoid of hormonal acivity.5
In 1955, P’an and colleagues reported that a close structural analog of pregnaendione, hydroxydione, was more potent and safer than the thiobarbiturate, thiopentone.6 However, hydroxydione was not an ideal anesthetic induction agent as it produced a delayed induction of up to three minutes and had to be solubilized in an alkaline pH causing venous thrombosis. Further research on the structure/activity relationship of neurosteroids showed that manipulation of the 3 and 21 carbon positions altered anesthetic potency.7,8
Eventually, the active molecule 3α-hydroxy-5α-pregnane-11, 20-dione [alfaxalone] was discovered by the Glaxo UK Pharmacology Department. Similar to the barbiturates, benzodiazepines, propofol and isoflurane, it is thought that alfaxalone’s main mechanism of action is through the gamma-aminobutyric acid type A [GABAA] receptor, which belongs to a superfamily of ligand-gated, pentameric, ion-pore-forming, cell surface receptors found in neurones and other excitable cells [see Figure 3].9