Arachidonic Acid (AA) is a C20:4 FA derived from phosphotidylinositol, a component of cell membrane. Upon stimulus (hormones, Ca2+, heat, trauma, etc) it is released by cleavage with Phospholipase A2 (PLA2). All cells have AA and PLA2
AA is then metabolized by all cells (except RBCs) into different AUTACOIDS, including: Prostanoids/Prostaglandins by the PGH synthase pathway, and Leukotrienes by the Lipoxygenase pathway.
AUTACOIDS are neurohormones that are not stored, are synthesized and released on demand, and are used locally without entering the circulation.
Inhibition of AA metabolism affects each tissue differently.
PGI (Prostacyclin) – vascular endothelium, coronary arteries, stomach and microvessels of circulation.
TXA/TXB (Thromboxanes) – platelets, brain, larger airway passages of lung.
LTB (Leukotriene) – Constricts blood vessels
LTC/LTD (Leukotrienes) – white cells, mast cells, particularly mast cells of lung. Anaphylactic shock, asthma.
Inhibition of Biosynthesis
Two classes of compounds exist that inhibit AA metabolism:
(1) Glucocorticoids
– Cortisone/prednisone (aka steroids) inhibit PLA2 in all cells! so they block AA production.
Þ no prostanoid production. (Acetaminophen/Tylenol is not an NSAID! Does nothing for inflammation!)
In humans there are two forms of prostaglandin synthases:
COX-1 – Normal gene found in all tissues, always expressed.
COX-2 – Found in monocyte lineage only, and some other cells. Activated in response to inflammation or other cytokines.
NSAIDs like
Naproxen have a x10,000 fold specificity for COX-1 rather than COX-2 receptors. As such, in order to achieve the desired anti-inflammatory results, a proportionally huge amount of drug would have to be used thus possibly resulting in deleterious from the COX-1 inhibition.
New NSAIDs like Celebrix and Celcoxib better target COX-2. Unfortunately they only have a x5 to x10 fold specificity for COX-2, so COX-1 is still affected.
Physiology of Prostanoids
Platelet/Endothelium Interactions in Clotting
Upon vessel injury the exposed basement membrane (collagen) and muscle stimulate platelet aggregation, clot initiation, and vessel constriction. How? Platelet stimulation releases AA which is used by enzymes on both the platelets and endothelial cells. The platelets use AA to make TXA (thromboxane) which causes vasoconstriction and platelet aggregation, while the endothelial cells use AA to make PGI (prostacycline) which causes vasoconstriction and platelet disaggregation. This is a homeostatic relationship!
The release of PGI by endothelium plays an important physiological role in lung microvessels and coronary arteries. While most endothelium has little PLA2 of its own, these vessels have a high intrinsic PLA2 which is regulated by pO2. A decreased pO2stimulates PLA2 activity Þ Ý PGI synthesis/release Þ dissolves microclots and vasodilation.
Atherosclerotic patients have an increased level of PGI metabolites (20 fold)!, as a response to injury
Role of ASA
: Can ASA help vasodilation? Taking a large dose of ASA will lead to inhibition of all prostanoid production (both TXA and PGI). This would be bad. Taking a small dose of ASA will lead to inhibition of ONLY the platelets Þ no TXA production Þ no vasoconstriction Þ vasodilation by remaining PGI !!!
How does this work
? After ASA is absorbed from the intestine it enters the hepatic circulation and is metabolized in the liver. While a large dose would not completely be metabolized and thus enter the systemic circulation, a small dose ("Baby Aspirin" 80-160 mg) would interact with the platelets circulating in the hepatic circulation but would not reach systemic circulation due to hepatic breakdown!!! Because ASA’s affect on the platelets is permanent the small dose is only needed once per day, with new production of platelets.
Neonatal Cardiovascular System
the stimulus for keeping the ductus arteriosus open in the fetus is PGE. The increased pO2 once the baby begins to breath is the stimulus to shut down PGE synthesis which closes the ductus arteriosus
Kidney
Angiotensin II and NE are major vasoconstrictive agents acting on blood flow and distribution between the medulla and cortex of the kidney. AII directly stimulates production of PGE and PGI to provide a counteractive vasodilatory effect. Intrarenal PGE stimulates renin release thus increasing circulating AII levels
In hypertension or increased Na load, ADH is increased resulting in increased water permeability and thus increased water retention and increased volume. PGE blocks the effect of ADH on water permeability and thus increases water excretion
Inhibition of PGE/PGI synthesis with an NSAID in a normal person does little since the AII/NE regulation is not the dominant factor in perfusion. But in hypertension or increased Na load, inhibition of PGE/PGI synthesis will cause poor perfusion, increased renal perfusion pressure and ischemia in the medulla (renal nephropathy snydrome)
Reproductive System
During labor, PGF2
a is markedly increased in blood and amniotic fluid. Administration of PGF2a induces rhythmic contractions in uterine smooth muscle and can induce labor. This is the method of choice for 2nd trimester induction of abortion
NSAIDs increase average length of gestation and increases the mean duration of spontaneous labor
During endometrial breakdown at the end of the menstrual cycle, PGF2
a production is increased greatly and can constrict the uterus so as to cause ischemia of the myometrium and therefore cramps and pain. The amount of PGF2a synthesized and released can be so high that it gains access to the systemic circulation. Once there it acts on other PGF2a receptors to generate the other systemic symptoms associated with dysmenorrhea such as headache, NV, and syncope. Symptoms can be reproduced in women (and in men) by IV infusion of PGF2a
Inflammation and Pain
Local release of prostaglandins (PGs) causes edema, vasodilation and is a major component of the inflammatory process, hence their use in inflammatory disease.
Local release of PGs do not cause pain. Local release of PGs sensitizes nerve endings to other molecules in the environment (bradykinins, etc). The PGs have their effects by binding EP3 receptors on nerve endings; Drug companies are currently working to manufacture drugs that will block these receptors.
GI Tract
PGE/PGI in the stomach inhibits H+ secretion via parietal cell H+,K+-ATPase stimulated by any known cause (histamine, gastrin, food, Ca2+, etc.) They also increase mucin production. These are apparently mechanisms for preventing overproduction of H+.
NSAIDs knock out the PGE/I control system on acid secretion. This leads to increased and prolonged acid secretion and a diminution of mucin production. In this setting the lining of the stomach is ripe for irritation and erosion from acid, leading to the most common adverse effect of PGE/I, GI distress and eventually peptic ulceration. (from syllabus)
Something interesting: a certain type of frog lays eggs
Þ get fertilized Þ swallows them Þ eggs secrete PGE which blocks stomach acid production Þ baby frogs grow in mom’s stomach Þ mom pukes them out when they are mature.
Bronchoconstriction/Anaphylaxis
under certain conditions (immune mediated responses), the lung synthesizes large amounts of TxA and leukotrienes which mediate the reactions of anaphylaxis and asthma. In sensitive persons, even small doses of aspirin and other NSAIDs can shift sufficient AA to lipoxygenase / TxA pathways, giving aspirin/NSAID-induced asthma or anaphylaxis