NSAIDs (Week 2--Melega) Flashcards
3 broad classes of analgesics
Non-opioid
Opioid
Adjuvant analgesic (drugs with other indications but that are effective analgesics in certain circumstances)
NSAIDs
Non-steroidal anti-inflammatory drugs that reduce inflammation but are not structurally related to corticosteroids
Inhibit peripheral “pain” pathway by inhibiting prostaglandin synthesis (by blocking COX1/2)
Aspirin
Salicylates
Non-selective COX inhibitors
Selective COX-2 inhibitors
Acetaminophen
Non-opioid analgesic but not an NSAID because no anti-inflammatory activity
What is the main adverse side effect of NSAIDs?
Gastrointestinal injury
(ulcers due to too much acid secretion)
Physiologic and pathologic functions of prostaglandins
Physiologic: all cells can produce prostaglandins, they act locally; temperature homeostasis, bronchial tone, cytoprotection (gastric and renal mucosa), intestinal mobility, myometrial tone, semen viability (some, 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)
PGE2
Pain, hyperalgesia, heat, vasodilation, bronchoconstriction; can synergistically act with other pro-inflammatory mediators (histamine, complement, LTB4)
TxA2
Promotes platelet aggregation, vasoconstriction, bronchoconstriction
Pro-thrombotic
PGI2
Inhibits platelet aggregation, vasodilation, vascular permeability
Anti-thrombotic
Arachadonic acid as a precursor
Inflammatory stimuli –> phospholipase A2 cleaves AA from plasma membrane –> COX metabolizes AA to PGH2 –> PGD2, PGE2, PGF2alpha, PGI2, TxA2
Note: AA can also be metabolized to leukotrienes (LTB4, LTD4) by lipoxygenases, but only in neutrophils, eosinophils, monocytes, mast cells
Where do corticosteroids act?
Corticosteroids interfere with phospholipase A2 so you can’t maky any AA (and thus can’t make its downstream products like prostaglandins OR leukotrienes)
Where do NSAIDs act?
NSAIDs block cyclooxygenase (COX) so can’t make prostaglandins, TxA2, prostacyclin, but can still make leukotrienes
Do glucocorticoids affect COX activity?
They don’t directly affect basal COX activity, but they prevent IL-1 induced increases in COX activity
COX-1 vs COX-2
COX-1 and COX-2 catalyze same reaction but expression, functions, and properties are markedly different
COX-1: constitutive, found in platelets (converts AA –> TxA2), produces prostanoids that modulate physiologic functions (gastric cytoprotective, platelet aggregation, vascular homeostasis, renal function)
COX-2: inducible, NOT found in platelets, pro-inflammatory (produces prostanoids that result pain, fever, leukocyte proliferation, inducible by cytokines (IL-1, TNF-a), endotoxin, growth factors, reactive oxygen molecules
Do NSAIDs want to block COX-1 or COX-2?
The point is to block COX-2 because that’s the only way you get anti-inflammatory effect!
However, NSAIDs inhibit COX-1 and COX-2 and inhibition of COX-1 results in significant side effects (GI, platelet, renal)
NSAID pharmacodynamics
Aspirin covalently acetylates COX enzyme and irreversibly inhibits it
All other NSAIDs act as reversible, competitive COX inhibitors
Inhibition of COX-2/inhibition of COX-1 Ratio
All NSAIDs have a ratio of (COX2:1 inhibition) and the higher the ratio, the more specific the therapeutic effect and fewer GI or platelet effects
NSAIDs with 100:1 or 1000:1 are COX-2 selective
Do NSAIDs treat the problem?
No, NSAIDs usually do not treat the underlying pathophysioogy, they only provide symptomatic relief