NSAIDs Flashcards
How do NSAIDs work?
inhibition of cyclo-oxygenase enzyme (COX)
What does COX enzyme do?
metabolizes arachidonic acid (fatty acid component of membranes) to ultimately prostanoids (PGD2, PGE2, PGF2a, PGI2, and TXA2)
What is COX-1?
found in stomach, colon, kidney, vascular smooth m, and platelets (involved in “housekeeping” functions of prostanoids
What is COX-2?
involved in inflammatory responses, fever, and algesia. also expressed in blood vessels, kidney, heart, and brain
What’s significant about the actions of prostanoids and leukotrienes?
tend to cause opposing effects (vasodilation/vasoconstriction, promotoe or inhibit platelet aggregation, etc)
What can the anti-inflammatory effects of NSAIDs be attributed to?
inhibition of COX-2
Which prostanoids have inflammatory effects?
all of them
How do NSAIDs combat inflammation?
reduce vasodilation, edema, and pain, ACUTE phase (vs, corticosteroids that inhibit all stages)
What sort of dosage do the anti-inflammatory effects of NSAIDs require?
significantly higher doses
What does the low pH of inflammatory milieu lead to?
increased intracellular concentrations of NSAIDs (ion trapping of an acidic drug)
What causes the analgesic effects of NSAIDs?
inhibition of COX-2 which prevents formation of prostaglandins (PGE2) at peripheral sites
What types of pain are NSAIDs effective vs?
chronic post-operative, pain from inflammation, integumental pain, PMS HA, myalgia) achieved with “ordinary” doses of NSAIDs
What don’t NSAIDs do?
not effective against some types of pain, don’t alter sensory perceptions, don’t cause physical dependence.
What are NSAIDs used in combo with?
opioids to achieve greater analgesic effect
Anti-pyresis?
COX-2, PGE2. NSAIDs reduce elevated body temp with “ordinary” doses
What do NSAIDs do to CV system?
inhibit platelet COX-1 derived TxA2 - inhibit platelet aggregation! also COX-2 derived PGI2
What’s unique about aspirin?
irreversibly inhibits platelet COX. achieved at very low dose. selective inhibition of COX-1 due to impact on platelets.. antagonized by reversible COX-1 inhibitors. Therefore therapeutic efficacy in stroke and MI.
What are two other CV considerations?
1) NSAIDs can elevate blood pressure via COX-2
2) COX-2 is upregulated in athersclerotic plaques, but role in athersclerosis is unclear
Which prostanoids act on kidneys and what do they do?
PGE2 and PGI2, COX-1 and COX-2 generated. increase and decrease sodium retention (natriuresis predominates)
What do NSAIDs do in the kidneys?
promote sodium retention and can therefore increase BP. can counteract effects of many anti-hypertensives.
Who is at risk of renal ischemia with NSAIDs?
elderly and volume depleted.
GI effects of NSAIDs?
COX-1 inhibition: gastric distress, gastric bleeding/ulcers, sudden acute hemorrhage. (prostaglandins PGE1 inhibit stomach acid secreation, enhance mucosal blood flow, and promote intestinal secretion of ctopreotective mucus)
effect on gestation?
prolong via COX-2 inhibition
effects on respiratory system?
COX-independent effects! increased CO2 production -> hyperventilation with high doses. even higher doses cause depression of respiration
What are the salicylates (2)?
Acetylsalicylic Acid, salicyclic acid
Acetylsalicyclic acid?
prototype non-selective NSAID. irreversible inhibition of COX
salicyclic acid?
reversible inhibition of COX
pharmacokinetics of ASA (4)?
1) rapid absorption mostly from upper small intestine.
2) wide distribution, bound to plasma protein
3) zero order metabolism (rapidly converted to salicylate)
4) excreted as metabolites and as free salicylate (enhanced by alkalinization)
Side effects of Salicylates (4)
1) GI distress and bleeding
2) prolongation of bleeding time (contraindicated in pts taking Warfarin)
3) Reye’s syndrome (contraindicated in kids with chicken pox or influenza)
4) salicylism: HA, dizziness, sweating, tinnitus-> CNS disturbances, acid-base disturbances, skin eruptions, fever, nausea
What are the non-selective/non-salicylate drugs?
Ibuprofen, Naproxen
what characterizes the non-selective/non-salicylate drugs?
structurally unrelated to salicylates, more potent but not more efficacious. NON-SELECTIVE COX-1 and COX-2 inhibitors.
What are the COX-2 selective inhibitors (1)? what about it?
Celecoxib. lack COX-1 side effects (GI, platelet). approved for rheumatoid arthritic, ostearthritis, acute pain.
what are the risks associated with COX-2 inhibitors?
CV risk! increased BP, oxidative stress, etc.
What is acetaminophen?
anti-pyretic, analgesic, but NOT anti-inflammatory!!
What is the mechanism of action of acetaminophen?
COX-independent effects and COX-dependent (but poor inhibitory of COX in presence of peroxides which are found at inflammatory sites)
What’s good about acetaminophen?
well tolerated, does not cause GI distress and does not effect platelet function.
where is acetaminophen metabolized? importance?
liver. high doses => hepatotoxicity!
what can be used to treat overdose of acetaminophen?
Acetylcysteine (replenished glutathione levels)
Why can NSAIDs and opioids be used in combo?
NSAIDs act peripherally, opioids act centrally.
Which NSAIDs can be used as therapy for rheumatoid arthritis (first-line treatment)? what other drugs?
high dose non-selective COX or COX-2 selective inhibitors (and corticosteroids). also disease modifying anti-rheumatic drugs (DMARDs)
What therapeutic strategies are used vs Gout?
1) acute therapy targets pain and inflammation
2) chronic therapy to increase excretion or decrease production of uric acid.
Which drugs are used for acute therapy of Gout?
NSAIDs: Indomethacin, ibuprofen, naproxen. do NOT use aspirin! (inhibits eric acid excretion). Also colchicine
Which drugs are used for chronic therapy of gout?
Allopurinol (inhibits production of uric acid), Probenicid (inhibits renal reabsorption of uric acid and therefore promotes excretion)
What are the drugs to know (9)?
acetylsalicyclic acid, ibuprofen, naproxen, celecoxib, acetaminophen, acytlcysteine, colchicine, allopurinol, probenicid
