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
What are non-selective NSAIDs used for?
Analgesics for moderate pain of musculoskeletal and inflammatory origin (headaches, dysmenorrhea, osteoarthritis, rheumatoid arthritis, gout, surgical pain, tendonitis, bursitis)
Anti-inflammatory agents in conditions listed above and ulcerative colitis
Aspirin vs. Advil vs. Tylenol
Aspirin: acetylsalicylic acid (salicylate NSAID)
Advil: ibuprofen (NSAID)
Tylenol: acetaminophen
What drug is used for anti-platelet effects to prevent MI and stroke?
Aspirin, because it irreversibly inhibits COX in platelets, which do not have a nucleus and thus cannot synthesyze new COX molecules, thus TxA2 cannot be synthesized and you get less clotting activity
After administration of a single dose of aspirin, platelet aggregation is impaired for up to 4 days, until new platelets enter the circulation in sufficient numbers
All other NSAIDs inhibit COX competitively and thus their inhibitory effects on platelet aggregation depend on pharmacokinetics (half-life, etc)
Are NSAIDS or opioids more effective for pain associated with inflammation?
NSAIDs!
4 pharmacodynamic effects of NSAIDs
1) Antiplatelet: inhibit platelet aggregation, prolong bleeding time; have anticoagulant effects (Aspirin dose of <300 mg/day)
2) Analgesic: relief of pain by mechanism other than reduction of inflammation (ex: headache); NSAIDs have ceiling effect for analgesia (Aspirin dose of 300-2400 mg/day)
3) Antipyretic: reduce fever by lowering elevated body temperature by acting on hypothalamus (normal body temp not reduced) (Aspirin dose of 300-2400 mg/day)
4) Anti-inflammatory: treat inflammatory diseases and injuries, contributes to analgesic effect (lower inflammation –> lower perception of pain) (Aspirin dose of 2400-4000 mg/day)
How do NSAIDs reduce fever?
Fever occurs when set point in anterior hypothalamic regulatory center is elevated
Fever usually caused by increase in PGE2 due to bacterial endotoxins causing release of pyrogens (IL-1) which promote COX2 and production of PGE2
NSAIDs block COX so no more PGE2 produced
How is prostacyclin (PGI2) production by vascular endothelial cells affected by aspirin?
PGI2 produced in vascular endothelial cells, which DO have a nucleus so can just synthesize more COX, so even though aspirin irreversibly inhibits COX activity, the entire effect lasts only for a short time and then PGI2 levels are restored
Negative pharmacodynamic effects of NSAIDS
Remember, pharmacodynamic is what drug does to body
Gastric irritant, bleeding, decreased renal perfusion (prostaglandins dilate afferent arteriole)
Risk factors for NSAID induced GI toxicity
Higher NSAID doses
Older age
Concurrent steroid use
History of peptic ulcer disease
How do NSAIDs (including aspirin) damage GI cells?
NSAIDs and aspirin are acidic and exist in nonionized neutral lipophilic form in the gastric lumen which is at pH 2 (after you eat them) and can diffuse across plasma membranes into surface epithelial cells but when they get there and the pH gets to 7, they dissociate into ionized charged form and become ion trapped inside the cell
NSAIDs and adverse GI effects
Erosion is a microscopic discontinuity in the epithelium
No relationship between NSAID-associated dyspeptic symptoms and the presence of erosions
50% of patients taking nonselective NSAIDs have erosions
Up to 100% have subepithelial hemorrhage
20% have ulceration
Only 1-3% of patients have serious GI side effects while taking NSAIDs
How do you treat NSAID induced GI toxicity?
Discontinue NSAIDs
Take medication with a meal
Use other medicine: H2 antagonists (high doses of ranitidine), PPIs (omeprazole), PGE1 analog (misoprostol) to restore cytoprotective effect
Other adverse effects associated with NSAIDs
Cutaneous and hypersensitivity (urticaria, bronchospasm, anaphylaxis, erythema multiforme, skin reactions)
NSAID-induced hyperreactivity (in patients with aspirin allergy, NSAID exposure more likely to cause ocular and nasal congestion, severe bronchospasm and possible anaphylactic reaction, possibly bc AA shunted to lipoxygenase pathway and increases synthesis of bronchoconstrictor leukotrienes)
Samter’s triad (Aspirin allergy/hypersensitivity higher in patients with nasal polyps, bronchial asthma and rhinitis (sinusitis); occurs in 10% of asthmatics
Do NSAIDs affect renal function?
Not in people with normal kidneys, PGE2, and PGI2
But YES in people with renal failure, CHF, volume depletion, liver disease, those receiving diuretics –> renal insufficiency, acute renal failure
Prostaglandins vasodilate the afferent arteriole to increase renal blood flow and GFR
Mechanism of action of Aspirin
Aspirin binds and covalently (acetylation) and irreversibly modifies COX so that AA can’t bind it
What is the half life of Aspirin?
Short, only 20 minutes
What is Aspirin broken down into?
Aspirin –> salicylate –> filtered, secreted and reabsorbed
Salicylate is an active metabolite, can reversibly inhibit COX and reduce inflammation just as well as aspirin!
Salicylate is less effective than aspirin for analgesia though
Salicylate can build up and cause toxicity: first has first order kinetics with 3.5 hour half life but if >600mg in body, get zero order kinetics and half life increases to >15 hours (transporters in kidneys overwhelmed)
Dose-dependent effects of aspirin
Low: <300mg, blocks platelet aggregation for lifetime of platelet (10 days)
Intermediate: 300-2400mg/day; antipyretic and analgesic
High: 2400-4000mg/day; anti-inflammatory
Salicylism (toxicity at high doses) only a problem at REALLY high concentrations
Salicylism
Toxicity at high doses of aspirin due to buildup of salicylate
Early warning signs: tinnitus (ringing in ears), hyperventilation, dizziness
Reye’s Syndrome
Rare form of acute encephalopathy and fatty infiltration of the liver that tends to follow acute viral infection and using salicylates during the illness increases the risk of disease
Causal relationship hasn’t been confirmed but just in case, if kid has fever, chickenpox, flu, etc just give them Tylenol/acetaminophen instead!
Important NSAIDs and differences
Ibuprofen: 400mg; q 4-6h; half life 2h; available OTC
Naproxen: 250-500mg; q 12h; half life 14h; more potent than ibuprofen, long half-life (delayed effects)
Fenoprofen: 200mg; q 4-6h; contraindicated in renal disease
Indomethacin: 25-50mg; q 8h; GI side effects common; more potent anti-inflammatory than aspirin
Ketorolac: 15-60mg IM or IV; q 4-6h; available for parenteral use (IM, IV); short term management (5 days) of pain that requires analgesia at opioid level but not for minor or chronic painful conditions
Do NSAIDS (fenoprofen, ibuprofen, naproxen, aspirin) inhibit COX1 or COX2 more?
COX1! Even though we take then in order to inhibit the pro-inflammatory COX2
COX2 selective inhibitors
Only block COX2 because too bulky to access binding pocket of COX1 enzyme
Better treatment of arthritis
Fewer GI effects
Increased incidence of MI and stroke compared to naproxen or aspirin
Celecoxib is only COX2 inhibitor available in US
Acetaminophen (APAP)
Tylenol
Half life 2-4h
Analgesic, antipyretic
NOT anti-inflammatory (so not an NSAID)
No gastric irritation, no platelet function interference, not contraindicated for asthma, not associated with Reye’s syndrome
Selective inhibitor of COX2, but different mechanism of COX binding from NSAIDs (maybe scavenge free radicals needed for COX activity)
Note: weird that it is COX2 inhibitor and is NOT anti-inflammatory and does not have negative cardiovascular effects!
N-acetylcysteine
Give this drug IV to someone who has overdosed on acetaminophen (Tylenol + alcohol)
Aspirin compared to Tylenol
Aspirin and Tylenol (acetaminophen) have same potency for relieving mild/moderate pain and reducing fever
Aspirin is anti-inflammatory but Tylenol is not
Both used in combination with opioid analgesics for relief of severe pain
Major concern with acetaminophen is high doses cause liver toxicity!
