Flashcards: Eicosanoids

• Eicosanoids description

20 carbon atoms.

• Eicosanoids categories

Prostanoids (prostaglandins (PGs), thromboxanes (TXs)), leukotrienes (LTs), lipoxins.

• Eicosanoids function

Important mediators of inflammation and allergy.

• Main source of eicosanoids

Arachidonic acid.

• Arachidonic acid description

A 20-carbon unsaturated fatty acid.

• Eicosanoid biosynthesis initial step

Membrane phospholipid converted to arachidonic acid by phospholipase A2 (activated by chemical and mechanical stimuli).

• Arachidonic acid metabolism pathways

Cyclooxygenase and Lipoxygenase.

• Cyclooxygenase pathway products

PGG2, PGH2, which are then converted to PGE2, PGD2, PGF2α, PGI2, TXA2.

• Lipoxygenase pathway products

12-HPETE, 12-HETE, 5-HPETE, 5-HETE, LTA4, LTB4, LTC4, LTD4, LTE4, LTF4.

• Prostanoids (PGs & TXs)

PGI2 (prostacyclin) and TXA2 (thromboxane A2) are examples.

• PGI2 (prostacyclin) location

Located predominantly in vascular endothelium.

• PGI2 main effects

Vasodilation, inhibition of platelet aggregation.

• TXA2 location

Found in the platelets.

• TXA2 main effects

Platelet aggregation, vasoconstriction.

• Cyclooxygenase (COX) location

Found bound to the endoplasmic reticulum.

• Cyclooxygenase isoforms

COX exists in 3 isoforms

• COX-1 (constitutive)

Acts in physiological conditions, known as a "housekeeping" enzyme.

• COX-1 locations

Stomach, kidney, platelets, endothelium.

• COX-1 physiological functions

Secretion of mucus for protection of gastric mucosa, hemostasis, maintenance of renal function.

• COX-1 products/effects

TXA2, PGI2, PGE2 for gastrointestinal mucosal integrity, platelet aggregation, renal function.

• COX-2 (inducible)

Induced in inflammatory cells by pathological stimulus.

• COX-2 locations

Macrophages, leukocytes, fibroblasts, endothelium.

• COX-2 inducers

Cytokines, growth factors, and other stimuli during inflammatory response.

• COX-2 participation

Participates in inflammation.

• COX-2 constitutive presence

Constitutively present in kidney and brain.

• COX-2 products/effects

PGI2, PGE2 for inflammation, mitogenesis, bone formation, and other functions.

• COX-3 location

In brain.

• Inhibition of COX products synthesis

Can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs).

• Aspirin COX inhibition

Acetylates COX and causes irreversible inhibition.

• Other NSAIDs COX inhibition

Competitive and reversible inhibitors.

• Most NSAIDs selectivity

Nonselective COX-1 and COX-2 inhibitors.

• Selective COX-2 inhibitors examples

Celecoxib, Etoricoxib.

• Aspirin-like drugs primary inhibition

Inhibit mainly COX-1.

• Aspirin-like drugs side effects

Can cause peptic ulcer, GI bleeding, bronchial asthma, and nephrotoxicity.

• COX inhibitors categories

Nonselective (aspirin-like, COX-1/COX-2 inhibitors), COX-2 inhibitors (selective - coxibs, preferential), Selective COX-3 inhibitors.

• Selective COX-3 inhibitors function

Antipyretic analgesics.

• Aspirin effects

NSAID with analgesic, antipyretic, & anti-inflammatory effects.

• Aspirin antiplatelet effect

Inhibits platelet aggregation & used to prevent and treat arterial thromboembolic disorders.

• Aspirin effect on PGI2

Inhibits PGI2 (prostacyclin), which is produced by vascular endothelium and inhibits platelet aggregation.

• Aspirin effect on TXA2

Inhibits TXA2 (thromboxane A2), which is produced by platelets and promotes platelet aggregation.

• Low doses of aspirin

Selectively inhibit TXA2 synthase.

• Higher doses of aspirin

Inhibit the synthesis of both TXA2 and PGI2.

• Aspirin as irreversible inhibitor

Aspirin is an irreversible inhibitor of COX.

• Aspirin and platelet aggregation net effect

After some time, endothelial cells produce new COX enzyme (contain nucleus), whereas platelets (due to lack of nucleus) cannot produce TXA2, resulting in a net platelet anti-aggregatory activity.

• Aspirin in MI prophylaxis

Aspirin is the only NSAID in MI prophylaxis.

• Natural PGs examples

Dinoprostone (PGE2), Gemeprost, Dinoprost (PGF2α), Alprostadil (PGE1), Prostacyclin (PGI2).

• PG analogues examples

Carboprost, Misoprostol, Latanoprost, Bimatoprost.

• PGE2 (dinoprostone) use

Low doses of PGE2 applied in cervical canal/vagina make the cervix soft and more compliant for delivery/abortion (cervical priming/ripening).

• Carboprost (15-methyl PGF2α) use

I.V is an alternative drug to Ergometrine or Oxytocin for postpartum hemorrhage (PPH).

• Misoprostol (PGE1 analogue) use

Can be used for healing NSAID associated peptic ulcer.

• Topical PGF2α analogues use

Latanoprost, Travoprost, Bimatoprost are the first choice drugs in wide angle glaucoma.