NSAIDs and GI Study Guide for IDM1-Lymperopoulos-3(2).docx

The MOA of NSAIDs is cyclooxygenase (COX) inhibition. COX converts arachidonic acid to prostaglandins (PGs) and thromboxanes (TXs) (together known as prostanoids). Two functional COX isoforms in humans: COX1 is the constitutive and "good" COX isoform, i.e. housekeeping and GI-protective. In contrast...

The MOA of NSAIDs is cyclooxygenase (COX) inhibition. COX converts arachidonic acid to prostaglandins (PGs) and thromboxanes (TXs) (together known as prostanoids). Two functional COX isoforms in humans: COX1 is the constitutive and "good" COX isoform, i.e. housekeeping and GI-protective. In contrast, COX2 is the inducible (by toxins, infectious agents, etc.) and "bad" isoform, i.e. pro-inflammatory. All eicosanoids come from arachidonic acid. NSAIDs block synthesis of all PGs (including prostacyclin, which is also called PGI2) & TXs (prostaglandins + thromboxanes = prostanoids) but not of leukotrienes or other eicosanoids. Chemistry-Nomenclature: All PGs and TXs have 20 carbon atoms (eicosanoids) and are carboxylic acids (arachidonic acid derivatives) with one or more double bonds and at least one ring. The number of double bonds is indicated as subscript next to the letter of the series of the eicosanoid: for example, PGE1: one double bond, PGE2: two double bonds. If the ring consists of carbon atoms only, then it is a PG. If the ring is heterocyclic (contains oxygen atoms also), then the eicosanoid is a TX. Prostacyclin (PGI2) is a special PG, because: a) it is the only PG with a bicyclic system consisting of carbon atoms only; and b) it is the only PG with beneficial (rather than pro-inflammatory) actions, esp. in the cardiovascular system. It mediates venodilatation by furosemide, inhibits platelets, and lowers pulmonary arterial pressure (itself and its analogs are used in pulmonary arterial hypertension, PAH). All NSAIDs (including coxibs) cause renal problems because they can block synthesis of the beneficial and functionally important for the kidney PGE2 and PGI2, produced by both COX1 and COX2. NSAIDs divert arachidonic acid metabolism to leukotriene synthesis in the airways (since the COX pathway for arachidonic acid metabolism is blocked), thereby increasing the risk of bronchospasm and asthma-related inflammation (leukotrienes are important mediators of airway inflammation underlying asthma). All NSAIDs are analgesic and antipyretic (PGE2 is responsible for setting the hypothalamic temperature set point higher, which presumable helps the immune system fight infection). At higher doses, they are also anti-inflammatory (except for acetaminophen, which is only analgesic and antipyretic at all doses). Aspirin (acetylsalicylic acid) is contraindicated for fever in children/adolescents due to Reye`s syndrome. At very low doses (below those needed for analgesic or antipyretic activity), aspirin (and only aspirin) has anti-platelet/cardio-protective activity via thromboxane TXA2 synthesis inhibition in platelets. All NSAIDs help close patent ductus arteriosus in preterm infants, with ibuprofen & indomethacin being the NSAIDs of choice. The GI protection afforded by COX1 is mainly due to synthesis of PGE1 and PGE2, two prostaglandins that protect and nourish gastric mucosa and epithelia. Misoprostol is a PGE1 synthetic analog, co-prescribed with an NSAID for gastric protection (to prevent peptic ulcers). Alternatively, a histaminergic H2 receptor antagonist or a proton pump inhibitor can be co-prescribed (or an antacid that does NOT contain salicylate/NSAID, i.e., other than Pepto-Bismol). Misoprostol is also used as abortifacient, together with mifepristone (RU-486, a steroid progesterone receptor antagonist) or (more rarely) methotrexate (an anti-folate used in rheumatoid arthritis), in medical abortions. Synthetic PGE2 (dinoprostone) is also used as a drug for uterine bleeding post-labor. Synthetic PGE1 (alprostadil) is a medication used (injected directly into the corpus cavernosum of the penis) for erectile dysfunction (induces penile vasodilation, now largely supplanted by PDE5 inhibitors). Indomethacin or ibuprofen are administered to assist with the closing of ductus arteriosus in the newborn, while alprostadil or dinoprostone are administered to keep the vessel open until surgery can be performed (PGE1 & PGE2 are the main PGs responsible for keeping this vessel open). Coxibs or selective COX2 inhibitors: Celecoxib is the only agent still on the market in the US (all the others, starting with rofecoxib and valdecoxib ~20 years ago, have been withdrawn from the market). COX2 selectivity is due to their sulfonamide moiety that binds a hydrophilic side pocket in COX2 active site (absent in COX1). Thus, all coxibs are contraindicated in people with sulfonamide allergy. Celecoxib has very little GI toxicity, since COX1 is the gastro-protective COX isoform, but is as nephrotoxic as the traditional (non-selective) NSAIDs (since both COX1 and COX2 produce nephro-protective PGs) and can cause cardiovascular problems (vascular COX2 is the main isoform responsible for cardio-protective prostacyclin synthesis).