Drugs for the Treatment of Respiratory Diseases: Drugs affecting the synthesis and action of leukotrienes

Introduction In 1938, Feldberg and Kellaway reported an activity in the perfusate of guinea pigs' lungs stimulated with cobra venom, which caused slow onset, but very sustained, contraction of smooth muscle. The time course of the contraction was subsequently demonstrated to be distinct from histamine and Kellaway and Trethewie named the mediator Slow Reacting Substance of Anaphylaxis (SRS-A). In 1960, Brocklehurst reported that SRS-A was released from lung fragments from an asthmatic subject, when these fragments were exposed to allergen. This raised the possibility that SRS-A was important in causing symptoms in allergic asthmatics after allergen inhalation, because of its ability to contract airway smooth muscle with a much longer duration of action than other smooth muscle constrictors. Subsequent studies demonstrated the potency of SRS-A as a bronchoconstrictor agonist in animals. In the late 1970s, the identity of the component molecules of SRS-A was reported to consist of the cysteinyl leukotrienes C 4 , D 4 and E. Synthetic pathways of the leukotrienes The leukotrienes are derived from the ubiquitous membrane constituent arachidonic acid and are members of a larger group of biomolecules known as eicosanoids. Arachidonic acid-(5,8,11,14- cis -eicosatetraenoic acid), is found esterified, in the sn - 2 position, to cell-membrane phospholipids in a wide variety of mammalian cells. The synthesis of leukotrienes is initiated by the action of phospholipase A 2 , which selectively cleaves arachidonic acid from cell membranes.