Prostaglandins and Other Eicosanoids

Core Concepts

The arachidonate cascade: release and conversion

Eicosanoids are not stored; they are made on demand. The sequence: a stimulus (injury, infection, hormone) activates phospholipase A₂, which cleaves arachidonic acid from membrane phospholipids at position 2. Free arachidonate is then a substrate for two competing enzyme systems:

• Cyclooxygenase (COX-1, COX-2) → prostaglandins (PGG₂, PGH₂ intermediates) and thromboxanes
• Lipoxygenase (LOX) → leukotrienes

Because both pathways compete for the same substrate, blocking COX with an NSAID shunts more arachidonate toward leukotriene synthesis in some tissues — one reason NSAID side effects are complex.

Prostaglandin structure: the prostanoic acid skeleton

All prostaglandins share the prostanoic acid skeleton: a cyclopentane ring with two side chains — one ending in a carboxylic acid (7 carbons from the ring) and one ending in a methyl group (8 carbons). The letters and subscripts encode the functional groups:

• PGE: a ketone (E = "ether-soluble" fraction) on the ring
• PGF: two hydroxyls on the ring (F = "phosphate/fat-soluble" fraction); the α subscript marks stereochemistry
• PGI₂ (prostacyclin): an extra oxygen bridged ring

The subscript number counts double bonds in the side chains. PGE₂ and PGF₂α are the best-studied: PGE₂ dilates blood vessels and causes fever; PGF₂α contracts uterine and bronchial smooth muscle. The same skeleton with different ring substituents produces opposite physiology.

Thromboxanes and leukotrienes

Thromboxane A₂ (TXA₂), made in platelets, has a six-membered oxane ring and is a potent promoter of platelet aggregation and vasoconstriction — it is why a cut seals. Prostacyclin (PGI₂), made by blood-vessel endothelium, does the opposite: it inhibits platelet aggregation and dilates vessels. The balance between TXA₂ and PGI₂ controls normal clotting; low-dose aspirin tips that balance by irreversibly inhibiting COX in platelets (which cannot make new enzyme). Leukotrienes (LTC₄, LTD₄, LTE₄) are made by leukocytes; they constrict airways and recruit immune cells, and they are central to asthma. Both families illustrate the general rule: eicosanoids are local, short-lived, and tissue-specific.

Biosynthesis in one line

Arachidonic acid (20:4) → COX → PGG₂ → PGH₂ → (tissue-specific isomerases) → PGE₂, PGF₂α, PGI₂, TXA₂. The committed step is the COX-catalyzed addition of two oxygens; aspirin blocks exactly this step, and COX-2-selective drugs (celecoxib) were designed to preserve stomach-protective COX-1 while blocking inflammatory COX-2 — though cardiovascular risk from selective COX-2 inhibition later complicated that story, a reminder that pathway selectivity is never complete.

Prostaglandins as local hormones: a contrast

Unlike insulin or thyroxine (endocrine, blood-borne), prostaglandins act on the cell that made them or its immediate neighbors (autocrine/paracrine). They are rapidly inactivated (half-lives of seconds to a few minutes in blood), so their effects stay local. This is why the same molecule can mean different things in different tissues, and why systemic drug effects (stomach erosion, bleeding risk) reflect COX inhibition everywhere at once.

How It Works / Step-by-Step Process

Following the arachidonate cascade:

1. Stimulus (injury, cytokine, hormone) activates phospholipase A₂.
2. Arachidonic acid is cleaved from membrane phospholipids.
3. COX oxygenates arachidonate to PGG₂, then PGH₂.
4. Tissue-specific enzymes convert PGH₂ to PGE₂, PGF₂α, PGI₂, or TXA₂ (or LOX makes leukotrienes).
5. Eicosanoids bind nearby receptors, trigger responses, and are rapidly inactivated.

Reading a prostaglandin name: PGE₂ = prostaglandin (cyclopentane ring), E = ring ketone, ₂ = two double bonds in the side chains; PGF₂α = ring diols, α = the hydroxyl stereochemistry below the ring plane.

Common Confusions