Harvard-MIT Division of Health Sciences and Technology HST.151: Principles of Pharmocology Instructor: Dr. Michael Weinblatt M. Weinblatt / HST-151 1 Anti-Inflammatory Drugs: NSAIDs, COX-2 Selective Inhibitors, Glucocorticoids and Anti-Cytokine Agents Michael E. Weinblatt, M.D. Overview Inflammation is mediated in part by prostaglandins produced by the cyclooxygenase pathway. NSAIDs inhibit this pathway and serve as combined anti-inflammatory, anti-pyretics, and analgesics. Because NSAIDs are generally nonspecific and exert numerous side effects, there is great interest in more specific therapeutics such as selective COX-2 inhibitors and anti-cytokine agents. Prostaglandins: Physiologic and Pathologic Functions All cells in the body have the capacity to synthesize prostaglandins. In response to inflammatory stimuli arachidonic acid (AA) is separated from plasma phospholipids by phospholipase A2. Cyclooxygenase metabolizes AA to the cycloendoperoxide prostaglandin H2 (PGH2), which is then converted to either PGD2, PGE2, PGF2α, PGI2 (prostacyclin) or TXA2 (thromboxane) by appropriate enzymes (i.e. thromboxane synthase in platelets, prostacyclin synthase in endothelial cells). The prostaglandins exert numerous physiologic and pathophysiologic functions :  Physiologic: temperature homeostasis, bronchial tone, cytoprotection (gastric and renal mucosa), intestinal mobility, myometrial tone, semen viability (some prostaglandins like PGE1 have anti-inflammatory effects), renin secretion  Pathologic: fever (aberrant hypothalamic thermoregulation), asthma (airway responsiveness and immune hyperreactivity), ulcers (loss of cytoprotection), diarrhea (intestinal mobility), dysmenorrhea (myometrial tone), inflammation, bone erosion, pain (thought to be caused by PGD2) Specific functions of prostaglandins in the context of inflammation include:  PGI2: inhibits platelet aggregation, vasodilatation, vascular permeability (edema)  PGE2: pain, hyperalgesia, heat, vasodilatation, bronchoconstriction, synergistically act with other pro-inflammatory mediators (histamine, complement, LTB4)  TXA2: promotes platelet aggregation, vasoconstriction, bronchoconstriction Cyclooxygenase There are two forms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Though COX-1 and COX-2 catalyze the same reaction, their expression, functions, and properties are markedly different.M. Weinblatt / HST-151 2 COX-1 COX-2 Constitutive (activated by Inducible by pro-inflammatory stimuli Expression physiologic stimuli) (LPS, TNFα, IL-2, IFNγ, etc) Ubiquitous Inflammatory and neoplastic sites (small Tissue amounts in kidney, uterus, ovary, CNS Localization [neocortex, hippocampus]) “Housekeeping” and Pro-inflammatory and mitogenic functions Role Maintenance (? Neuronal plasticity) COX-1 produces PGE2, PGI2, and TXA2 in platelets, GI mucosa, vascular endothelium, and the kidney. The housekeeping functions of these prostaglandins include maintaining renal and gastrointestinal blood flow (cytoprotection), regulation of vascular homeostasis, renal function, intestinal mucosal proliferation, and platelet function. Pro-inflammatory functions of COX-2 produced prostaglandins include pain, fever, leukocyte proliferation, and inflammation. COX-2 produces prostaglandins at sites of inflammation (in macrophages, in synovial tissue of rheumatoid arthritis joint). Mitogenic functions of COX-2 produced prostaglandin include renal genesis and reproduction. The goal of pharmacologic anti-inflammatory therapy has been to inhibit COX-2 produced prostaglandins. Non-specific inhibition of COX-1 results in gastrointestinal and platelet side effects. Recent data on the toxicity of COX-2 selective nsaids illustrate that this is an overly simplistic view. The magnitude of the COX-2 problem is still unclear at this writing, but it will be considered at various points in this discussion. (Note: There is an entire additional pathway of arachidonic acid metabolism by enzymes called lipoxygenases. 5-lipoxygenase is not present in all tissues but is limited to neutrophils, eosinophils, monocytes, and certain mast cell populations. Lipoxygenases produce leukotrienes (e.g. LTB4, LTD4), which are potent bronchoconstrictors and chemotactic agents. Leukotrienes have important roles in asthma, glomerulonephritis and inflammatory bowel disease. (Refer to the Asthma case.) NSAIDs (Non-steroidal anti-inflammatory drugs) Most NSAIDs are polycyclic carboxylic acid derivatives with relatively low pKa values. NSAIDs are often classified on the basis of their chemical structure (see Figure 1).  Salicylates: aspirin; diflunisal, 5-aminosalicylate, sodium salicylate, magnesium salicylate, sulfasalazine, olasalzine  Acetic acids: indomethacin, diclofenac, sulindac, etodolac, ketorolac, tolmetin  Propionic acids: ibuprofen, naproxen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin  Fenamic acids: meclofenamate, mefenamate  Enolic acids (oxicam class): piroxicam  Ketones: nabumetone (converted to 6-naphthylacetic acid in liver)M. Weinblatt / HST-151 3 NSAID General Pharmacodynamics All NSAIDs (except aspirin) act as reversible, competitive cyclooxygenase inhibitors. They block the hydrophobic channel by which the substrate arachidonic acid accesses the enzyme active site. Aspirin covalently modifies and destroys the cyclooxygenase enzyme. The ultimate function of the NSAID is to inhibit COX-2, preventing generation of proinflammatory eicosanoids, and thus limiting the extent of inflammation and adverse signs and symptoms.  All NSAIDs have a ratio of inhibition of COX-2 / inhibition of COX-1. The higher the ratio, the more specific the therapeutic effect and fewer GI or platelet effects. − NSAIDs with high ratio (100:1 to 1000:1) are COX-2 Selective (Coxib)  Despite the benefits of NSAIDs, they only provide symptomatic relief, as the underlying pathophysiology or injury generally is unaffected. NSAIDs have three primary therapeutic effects:  Analgesia  Anti-pyrexia (decreasing hypothalamic PGE2)  Anti-inflammatory NSAIDs are also used as anti-thrombotics. Since they impair platelet aggregation, they prolong bleeding time, and function as anticoagulants. The COX-2 specific inhibitors do not exert anti-thrombotic effects. Other functions of NSAIDs include inhibition of  Superoxide generation  Lymphocyte function  Lysosomal enzyme release 