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24 Cards in this Set
- Front
- Back
NSAIDS
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Non-Steroidal Anti-inflammatory Drugs, aka COX inhibitors
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Pharmacological Effects/Mechanism of Action
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most of the actions of NSAIDS can be attributed to inhibition of the enzyme cyclo-oxygenase (COX). This enzyme metabolizes arachidonic acid to the endoperoxide intermediates and ultimately to the formation of the prostaglandins
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COX-1
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A constitutive enzyme found in a variety of tissues including stomach and colon, kidney, vascular smooth muscle, and platelets (involved in many “housekeeping” functions of prostaglandins).
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COX-2
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Involved in inflammatory responses, fever, and algesia (typically induced). Also expressed in blood vessels, kidney, heart, and brain.
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Actions of Prostaglandins
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PGE2, PGI2 (Prostacyclin), PGF2, PGD2, TXA2 (Thromboxane)
Vasodilation, Vasoconstriction, Increase capillary permeability Contracts other smooth muscle (uterine, GI, bronchial)/relax bronchial smooth muscle Promote or inhibit platelet aggregation Inhibit mast cell secretion Decrease intestinal secretion of gastric acid Stimulate Na and water excretion from kidney (increase Na retention) Stimulate mucus secretion and cytoprotection Pyrogenic Sensitize nerve endings to other analgesic mediators |
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Actions of Leukotrienes
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LATB4, LTC4, LTD4
Chemoattractant for polymorphonuclear leukocytes Long-lasting bronchial constriction Increase capillary permeability |
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NSAIDS
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reduce vasodilation, edema and pain assoc. with inflammation (acute phase, as compared to corticosteroids that inhibit all stages of inflamamtion)
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Anti-inflammatory effects of NSAIDS
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require significantly higher doses (4-6g of aspirin per day)
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Analgesia
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Inhibition of COX-2 prevents formation of prostaglandins at peripheral sites. Prostaglandins sensitize nociceptive receptors to algesic mediators such as bradykinin
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Mild analgesics
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treat chronic post-op pain, pain from inflammation, integumental pain, PMS headaches, myalgia. Ordinary doses of NSAIDS (650 aspirin, or 400mg ibuprofen)
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Anti-pyresis
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Centrally mediated effect via resetting of the tep control center in hypothalmus. NSAIDS inhibit COX-2 and ultimate production of prostaglandins in brain.
NSAIDS effectively reduce elevated body temp (fever). This effect is achieved with ordinary doses. |
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Aspirin (acetylsalicylic acid)
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covalently modifies and irreversibly inhibits platelet cyclo-oxygenase. Enzyme is inhibited for the lifetime of the platelet (8-11 days). Low dose.
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Cardiovascular: Platelets
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inhibition of platelet COX-1 derived TxA2 with the net effect of increasing bleeding time (inhibition of platelet aggregation)
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Atherosclerosis
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inhibition of COX-2 can destabilize atherosclerotic plaques
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Blood vessels/smooth muscle
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COX-2 derived PGI2 can antagonize catecholamine and Angiotensin II-induced vasoconstriction (NSAIDS can elevate blood pressure)
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Renal
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COX-1 and COX-2 generated prostaglandins can both increase and decrease sodium retention.
NSAIDS tend to promote sodium retention and can therefore increase BP. Can counteract effects of many anti-hypertensives (diuretics, ACE inhibitors and beta-AR antagonists). Patients (elderly and volume depleted) are at risk of renal ischemia with NSAIDS |
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GI
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NSAIDS with COX-1 inhibitory activity will produce gastric distress, gastric bleeding, and sudden acute hemorrhage
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Acetylsalicylic Acid (Aspirin)
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prototype NSAID.
Irreversible inhibition of COX aspirin binds to pocket that leaves behind the acetyl group on serine and that’s how the enzyme inhibits |
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Salicylic Acid
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reversible inhibition of COX
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Salicylates
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non-selective COX inhibitors
absorption is rapid Distribution is widely, bound to plasma protein |
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Ibuprofen, Naproxen (Aleve)
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like salicylates, non-selective COX inhibitors
longer half-life than aspirin, only need 1-2 aleves per day to relieve pain |
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Celecoxib (Celebrex)
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COX-2 selective inhibitor
Virtually without COX-1 side effects (GI, platelet) |
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Cardiovascular risk of COX-2 inhibitors
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inhibition of anti-thrombogenic prostaglandins (PGI2)
Increased BP destabilization of atherosclerotic plaques COX-2 helps to stabilize the plaques, so an inhibitor will make plaque less stable and it could burst |
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Acetaminophen (Tylenol)
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1. Anti-pyretic and Analgesic
2. Does not have anti-inflammatory effects 3. Does not cause GI distress and does not affect platelet function 4. High doses cause hepatotoxicity 5. Overdose can be treated with sulfhydryl reagent such as Acetylcysteine. |