Anti-Inflammatories Flashcards
What characterizes each of the following three phases of the inflammatory response? 1. acute, transient; 2. delayed, subacute; 3. chronic proliferative
- local vasodilation, increased capillary permeability
- infiltration of leukocytes and phagocytic cells
- tissue degeneration and necrosis
Name the four classes of the major inflammatory mediators.
histamine, kinins, cytokines, eicosanoids
Actions of histamine in the inflammatory response?
capillary dilation, increases post-capillary venule permeability, itching from sensitizing primary sensory neurons
Effects of the kinins? Are there drugs to counter act these effects?
acute pain from excitation of sensory neurons; chronic effects due to capillary dilation, permeability, stimulation of PLA2 to release arachidonic acid
no drugs!!
Effects of IL-1?
produced mostly by macrophages; increases eicosanoid synthesizing enzymes, collagenase, and adhesion molecule expression; regulates B and T cells; induces fever
Effects of IL-8 and chemokines?
chemotaxis
Effects of TNF?
regulates production of other cytokines; induces fibrosis and tissue catabolism
What molecules are derived from arachidonic acid? What types of enzymes mediate this?
lipoxygenase - leukotrienes
cyclooxygenase - prostaglandins, prostacyclins, thromboxanes
COX-1 is produced constitutively. What is it involved in?
gastric cytoprotection, platelet aggregation, renal blood flow autoregulation, initiation of parturition
When is COX-2 induced?
During inflammation - produce prostaglandins locally
Source and actions of PGE2?
macrophages; protection of gastric mucosa, vasodilation, hyperalgesia
Source and action of PGD2?
mast cells; vasodilation, inhibition of platelet activation
Action of PGF2alpha?
bronchoconstriction
Source and action of PGI2 (prostacyclin)?
endothelial cells; vasodilation, inhibitions of platelet activation
Source and action of TXA2?
platelets; vasoconstriction, bronchoconstriction, platelet aggregation
Is aspirin reversible or irreversible? What enzymes does it act on?
irreversible inhibitor (via acetylation) of COX-1 and COX-2
How is aspirin metabolized? What does its major metabolic product do?
metabolized in liver to salicylic acid (and then others that are excreted in urine); salicylic acid cannot acetylate but can reversibly inhibit COX-1&2
What are the major four effects of aspirin? Which occurs at the lowest dose?
anti-platelet (lowest dose), anti-inflammatory (highest dose), analgesic, antipyretic
How does aspirin act as an analgesic? What is it therefore not helpful with?
inhibits eicosanoid sensitization of pain receptors; not effective in alleviating visceral pain
What are the potential adverse effects of aspirin?
GI irritation (lose cytoprotection), nephrotoxicity (decreases renal blood flow), bleeding and anemia (prolongs bleeding time), hepatotoxicity, hypersensitivity reactions, salicylate toxicity
Action and use of diflunisal?
competitive COX-1/2 inhibitor; analgesic and weak antipyretic effects, longer half-life, fewer GI side effects and less effect on platelets
OA, cancer bone pain, pain post dental extraction, postepisiotomy pain
What are the major effects of acetaminophen?
analgesic and anti-pyretic mainly; weak anti-inflammatory (poor inhibition ability in presence of peroxides at inflammatory site, disproportionate effect in brain?)
How is acetaminophen metabolized? What threat does this pose?
major - conjugation with sulfate and glucuronide
minor - P450 with toxic intermediate; this pathway becomes important in setting of overdose - potentially fatal hepatic necrosis
What can be used to treat acetaminophen overdose?
acetylcysteine (MUCOMYST)
