Eicosanoids in Pain, Thermoregulation, Inflammation, and Coagulation

What are eicosanoids?

- Leukotrienes

- Prostaglandins

- Prostacyclin (PGI2)

- Thromboxane (TXA2)

What are the leukotriene antagonists?

- Zileuton

- Montelukast

- Zafirlukast

What drug classes are prostaglandin antagonists?

- Corticosteroids

- NSAIDs

What are eicosanoids derived from?

Arachidonic acid

What is arachidonic acid?

- Rapidly synthesized in response to specific stimuli

- Function as local hormones

- Rapidly degraded

What frees arachidonic acid from cell membrane phospholipids?

Phospholipase A2

What metabolizes arachidonic acid into epoxyeicosatrienoic acid?

CYP450

What are the metabolites when arachidonic acid is metabolized by lipoxygenases (LOX)?

- HETEs

- Leukotrienes

- Lipoxins

What are the metabolites when arachidonic acid is metabolized by cyclooxygenases (COX)?

Prostanoids

What enzyme turns arachidonic acid into TXA2?

Thromboxane synthase

What are the metabolites of arachidonic acid after action from prostaglandin isomerase?

- PGE2

- PGF2alpha

- PGD2

What turns arachidonic acid into PGI2?

Prostacyclin synthase

What are the intermediates in the COX pathway?

- PGG2

- PGH2

- PGF

What happens to PGE1 and PGE2 levels after birth and why?

Decrease, to close the patent ductus arteriosus

How is alprostadil used for patent ductus arteriosus?

- PGE1 analog

- Maintains patent ductus arteriosus

- Used 96 hours before corrective surgery

What are the PGE1 analogs?

- Alprostadil

- Misoprostol

- Misodel

What is alprostadil?

- Causes vasodilation in corpus cavernosum

- Treats erectile dysfunction

- Injection

- Cream

- PGE1 analog

What is misoprostol?

- Increases mucin and bicarbonate production

- PGE1 analog

- Prevents peptic ulcer disease

- Oral tablet

What is misodel?

- PGE1 analog

- Softens cervix for labor

- Used to induce labor

- Vaginal insert

What is dinoprostone?

- PGE2 analog

- Induces contraction of pregnant uterus

- Used for labor

- Vaginal insert

What is latanoprost?

- PGF2alpha analog

- Increases uveoscleral outflow

- Treats glaucoma

- Eye drops

What is epoprostenol?

- PGI2 analog

- Vasodilator

- Inhibits platelet aggregation

- Treats pulmonary hypertension

- Used in dialysis to prevent clotting

How do eicosanoids induce pain perception?

Sensitize nociceptors

By what is pain often accompanied?

- Allodynia

- Hyperalgesia

Allodynia

Perception of pain from normal stimulus caused by PGE2 production (touching a sunburn)

Hyperalgesia

Exaggerated response to pain stimulus (needle on a sunburn)

How do aspirin and NSAIDs produce analgesia?

Prevent production of PGE2

Central centralization

Enhanced spinal dorsal horn neuron excitability caused by PGE2 that augments pain intensity, widening the perception area and resulting in pain from innocuous stimuli

What does increased COX-2 in the periphery lead to?

Peripheral inflammation and inflammatory hyperalgesia

How does PGE2 cause fever?

Elevates set point of anterior hypothalamic regulatory center

What stimulates PGE2 synthesis?

- Interferons

- TNF

- Interleukins

- Pyrogens (cytokines)

What makes TXA2?

Platelets

What makes PGI2?

Endothelium

What makes PGE2?

Macrophages and mast cells

What are the effects of TXA2?

- Vasodilation

- Platelet activation

What are the effects of PGI2?

- Vasodilation

- Inhibits platelet aggregation

What are the effects of PGE2?

- Fever

- Diuresis

- Pain/hyperalgesia

- Vasodilation

What controls platelet aggregation (coagulation)?

Balance between TXA2 and PGI2

Why do COX-2 inhibitors increase cardiovascular disease risk?

Increased TXA2

What disease states are caused by eicosanoid-induced platelet aggregation?

- Deep vein thrombosis

- Stroke

- Myocardial infarction (heart attack)

How does aspirin work?

- Irreversibly inhibits COX-1 and COX-2

- Reduces TXA2 and PGI2 production

- Favors endothelial cell-mediated inhibition of coagulation

- Endothelial cells produce COX-2

How do NSAIDs work?

- Reversibly inhibits COX-1 and COX-2

- Inhibits aspirin

- Take 2 hours after aspirin