Eicosanoids

Arachidonic Acid

Prostaglandins: PGE₁, PGE₂, PGF_2a, PGI₂

Thromboxane A₂

Drugs

NSAIDS – Aspirin, Indomethacin, Ibuprofen, Celecoxib

Prostin – PGE₁

Alprostadil – PGE₁

Misoprostol – PGE₁ derivative

Dinoprostone – PGE₂

Epoprostenol – PGI₂ (prostacyclin)

Iloprost – PGI_2a

Latanoprost – PGF_2a

Carboprost tromethamine – PGF_2a derivative

Leukotriene Modifiers

Zafirkulast

Zilueton

General

• specific cell stimulation, or shear-stress of blood flow, causes release of free arachidonic acid from membrane phospholipids
• COX-1 – GI tract, kidney
• COX-2 – expression induced at sites of inflammation by cytokines, growth factors, and prostacyclin
• Lipooxygenases – mast cells, eosinophils, basophils, neutrophils, macs, airway epithelium, and platelets; produce HPETEs and leukotrienes
• Epoxygenases – produce epoxides (EETs) and lipoxins (LX)

Prostaglandins

Ø  PGE₁ and PGE₂

• relax vascular smooth muscle causing vasodilation and increased blood flow in the kidney and the peripheral extremities
• stimulate gastric mucosal production of bicarbonate and mucus
• inhibit parietal cell acid secretion
• Oxytocic = contracts uterine smooth muscle

Ø  PGF_2a

• Vasoconstrictor
• Oxytocic = contracts uterine smooth muscle

Ø  PGI₂

• vasodilator in the coronary, systemic, and pulmonary circulation
• inhibits platelet aggregation

Thromboxane A­₂

• potent vasodilator
• stimulates the platelet release reaction

Pharmacology of the Eicosanoids

1.     Patency of the fetal ductus arteriosus – use PGE₁ (Prostin, Alprostadil)

Ø  normally the ductus begins to close within 1-2 hours after birth and usually closes within 1-2 weeks in full term neonates

Ø  Prostin – (PGE₁) used temporarily to maintain the patency until surgery can be performed

• must be rapidly infused because of rapid metabolism
• apnea is side affect in 10-12%

2.     Induction of erection – use PGE₁ (Caverject)

3.     1^st and 2^nd trimester abortions

• Carboprost tromethane- PGF_2a

Ø  stimulates uterine contractions

Ø  ong duration of action due to addition of methyl group

Ø  can also be used to control postpartum hemorrhage

Ø  can be given by i.m. injection

• Dinoprostone – PGE₂

Ø  actions and side effects similar to carboprost tromethane

Ø  also induces cervical ripening – cervical dilation

4.     Induction of Term labor

• Dinoprostone – PGE₂

Ø  stimulates myometrial contractions

Ø  cervical dilation

Ø  used before induction of labor by oxytocin or as an alternative to oxytocin

5.     Protection of NSAIDs-induced gastric and peptic ulcers

• Misoprostol – PGE₁ derivative (synthetic)

6.     Occlusive peripheral vascular diseases

• PGE₁ – Prostin, Alprostadil
• PGI₂ – Epoprostenol, Iloprost

Ø  currently in clinical trials becausing of vasodilation effects – Raynaud’s disease, arteriosclerosis obliterans

7.     Use during dialysis – PGI₂

• Epoprostenol, Iloprost – PGI₂

Ø  replacement for heparin

Ø  used because of lower t^1/2 than heparin (less side effects)

Ø  potent platelet inhibitor

Inhibitory Pharmacology of the Eicosanoids

Ibuprofen

• reversibly inhibits the enzyme required for prostaglandin and thromboxane formation -

PGH synthase (cyclooxygenase)

• Used to treat dysmenorrhea – blocks the increased production of PGE₂ and PGF_2a during menstruation that cause the painful contractions of the uterus

Indomethacin

• same MOA as ibuprofen
• used to close ductus arteriosus in premies

Celecoxib

• specific COX-2 inhibitor
• marked reduction in GI adverse effects
• as effective as other NSAIDS

Zileuton

• inhibits 5-lipooxygenase – reduces leukotriene biosynthesis
• used to treat mild persistent asthma
• oral administration
• P-450 metabolism – decrease metabolism of other drugs such as terfenadine and theophilline

Zafirkulast

• leukotriene LTD4 receptor antagonist
• oral administration
• used to treat mild persistent asthma as alternative to inhaled glucocorticoids

Aspirin – to control platelet aggregation

Tags: Arachidonic Acid, Aspirin, Celecoxib, cyclooxygenase, Ibuprofen, Indomethacin, NSAIDS, prostaglandins, Zafirkulast, Zilueton

This entry was posted on Wednesday, August 19th, 2009 at 5:00 am and is filed under Pharmacology. You can follow any responses to this entry through the RSS 2.0 feed. Responses are currently closed, but you can trackback from your own site.