NSAIDs Flashcards
USES OF NSAIDS
Integumentary pain or that associated with inflammation. Poor for visceral or neurogenic pain.(analgesic); Blocks IL-1 action during illness. No effect on hyperthermia from exercise, ambient conditions. (antipyretic); Reduces erythema, edema, hyperalgesia (antiinflammatory)
NSAIDs act largely by inhibiting ________. Prostaglandins do not directly activate ________, but instead sensitize the dorsal gray of the spinal cord to nociceptive input. Prostaglandins applied to the skin do not evoke pain. NSAIDs may also block the _______ on nociceptors.
prostaglandin synthesis; nociceptors; acid sensing ion channels
The endogenous pyrogen is __. It causes elevation of the ________ during infection. This is mediated by increased ______ synthesis. NSAIDs are very effective in blocking hyperthermia due to IL-1, but ineffective if fever results from exercise or elevated ambient temperature.
IL-1; body temperature set point; prostaglandin
Rank order potency in models of inflammation corresponds to rank order potency for inhibition of
prostaglandin synthesis.
Cyclo-oxygenase (COX) is the enzyme inhibited by _____ in the pathway leading to prostaglandin production. __________ in membrane lipids is the starting material. Note arachidonate also leads to leukotriene synthesis
NSAIDs; Arachidonic acid
COX-1 regulates production of several physiological effectors such as ______ and _______. Adverse effects of NSAIDs are largely due to inhibiting this enzyme
thromboxane (platelet adhesion) and prostacyclin (GI track, renal)
COX-2 is normally made at low levels in most tissues. However, it contributes to renal prostaglandins and endothelial cell prostacyclin (decreases cell adhesion) Structurally very similar to COX-1. COX-2 is induced _______ and is responsible for _________.
locally at sites of inflammation; many of the problems associated with chronic inflammation.
In general, ________ doses of NSAIDs are higher than antipyretic or analgesic doses
anti-inflammatory
Activation of the transcription factor ______ by some NSAIDs can antagonize NFKB and reduce inflammatory cytokine (IL-1, IL-6, TNF-alpha) synthesis
PPAR-gamma
Nociceptors have ________ that can be blocked by some NSAIDs.
acid-sensing ion channels (ASIC receptors)
Some NSAIDs modify ______ activity and reduce Aß amyloid production
gamma secretase
NSAID adverse effects
GI Tract bleeding is major problem. Due to reduced blood supply caused by vasoconstriction and increased endothelial adhesion
Hypertension due to renal actions is a second common adverse effect
Excess bleeding and inhibition of smooth muscle contraction contraindicate use during labor
Hypersensitivity (allergic) reactions CAN BE FATAL. Common in pts with adult onset asthma and nasal polyps
Prostaglandins largely counteract the effects of ______ in regulating renal function. Inhibiting PG synthesis will have effects similar to excess ___ resulting in ______
angiotensin II; A-II; hypertension
Aspirin is the only NSAID which _______. Makes it effective for anti-platelet therapy at low doses. Only NSAID that _______.
irreversibly inhibits COX; increases bleeding for days after use
Aspirin has a generally good _______, but overdose is not uncommon, especially in children and some using aspirin as an anti-inflammatory (arthritis)
therapeutic index
_____ is a good indicator that the patient is approaching toxic doses of the drug For severe overdose treat the hyperthermia and dehydration and provide respiratory support. Alkalinize the urine. No sedatives. Pump stomach if ingestion is within 4 hours
development of tinnitus
Aspirin is the prototypical chemopreventive drug
Dozens of studies find daily aspirin reduces risk of _______
cardiovascular disease
Aspirin works because it is an ________. Requires synthesis of _______ to relieve inhibition. Platelet half-life is 14 d and has no protein synthesis
irreversible COX inhibitor; new enzyme
Also appears to reduce ______ risk (and other cancers) Chemopreventive dose is below that needed for other uses (80 mg daily; 325 mg every other day). Men 45-80 Women 55-80.
colon cancer
Acetaminophen
Possesses antipyretic and analgesic actions of NSAIDs, but not anti-inflammatory actions (ergo, not a true NSAID)
Low COX inhibition
Delayed hepatotoxicity at high doses, particularly in combination with ethanol consumption. Normal metabolism is nontoxic (sulfation, glucuronidation). Overflow into CYP450 oxidation produces toxic metabolite that is neutralized by glutathione. Low glutathione or CYP450
CYP450 induction contribute sto hepatotoxicity. Treat with oral charcoal and N-acetylcysteine (restores glutathione)
Significant problem with combination medicines (Cotylenol, Vicodin etc). Patients take more than prescribed dose not realizing they are overdosing on acetaminophen
Propionic Acids (ibuprofen)
Less GI toxicity than aspirin
Reversible antagonist. May interfere with chemopreventive aspirin therapy by transiently occupying active site. Take aspirin before ibuprofen to avoid the problem.
PPARγ agonist (like oral antidiabetic drugs)
________ can be given once daily in patients where multiple dosing regimens are difficult
Oxaprozin (Daypro)
Indomethacin
Reportedly more efficacious against inflammation than other NSAIDs
Also more GI toxicity
Useful in closing a patent ductus arteriosus in newborns
PPARγ agonist,
Ketorolac (Toradol)
Highly effective as postoperative analgesic (equal to 12 mg morphine). Only use short term (
Arthrotec (diclofenac and misoprostol)
has reduced GI tract toxicity due to the addition of the prostaglandin to replace GI tract prostacyclin
Celecoxib
COX-2 selective drugs. These drugs have little inhibition of COX-1. The are active in assays of inflammation. No anti-platelet activity (safe with anticoagulants). Seem as effective as other NSAIDs in arthritis.
Celecoxib adverse effects
Recent trial data suggest doubling of cardiovascular infarction risk.
Increased thrombosis due to failure to inhibit platelet thromboxane (COX-1) combined with inhibition of endothelial prostacyclin (COX-2). Rofecoxib withdrawn; others prescribed with caution
