Prostaglandins, Leukotrienes, and Essential Fatty Acids
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Prostaglandins and leukotrienes
Termed eicosanoids Derived from arachidonic acid Released by phospholipase (PLA2) in response to traumatic event
2 different routes for eicosanoid biosynthesis
Cyclooxygenase pathway (synthesis of prostaglandins and thromboxane) Lipoxygenase pathway (synthesis of leukotrienes)
Initial precursor of all other prostaglandins
PGH2
NSAIDs
Inhibit PGH-synthase Reversible competitive inhibition of arachidonic acid oxygenation by cyclooxygenase
Acetominophen
Weak inhibitor of arachidonic acid oxygenation Used to stop cyclooxygenase in brain where peroxide levels are lower than in peripheral joints
COX-2 inhibitors
Show selectivity for the inducible form of cyclooxygenase Reduce side effects of gastric irritation and ulceration
Design of eicosanoid drugs
Hard to do: chemical complexity and instability, rapid degradation, and likelihood to affect many tissues Structural analogs resist degradation and keep biological activity, but side effects are much worse due to longer half life Can be used to induce miscarriage
Eicosanoid receptor classes
Relaxant (DP, EP2, EP4, IP): smooth muscle relaxation due to increased levels of cAMP Contractile (EP1, FP, TP): smooth muscle contraction due to Ca ion mobilization Inhibitory (EP3): prevents contraction by lowering cAMP levels
Ophthalmic use of eicosanoids
Treat glaucoma or ocular hypertension Lower eye pressure
Focuses of clinical development of prostaglandin-related drugs
Lots of work still to be done: drugs are metabolized quickly and are very potent Work needs to be done on developing specificity of these drugs and controlling their clearance