1. Aspirin acetylates COX1 and COX2 at serine sites (irreversible action- acts as suicide substrate for COX)
2. leads to blocking access of arachadonic acid to active site of enzyme
3. prevents PG synthesis

In general more selective for COX2

1. reversible inhibition of COX1 and 2
2. prevents PG synthesis

In general, more selective than COX2

1. phospholipids to arachodonic acid via phospholipase A₂
   • the enzyme must have a stimulus
2. two pathways
   1. via lipooxygenases, form leukotrines
   2. via cyclooxygenases (COX1 and COX2), form prostaglandins

• COX1- induce by physiological stimulus (inh. at lower dose of NSAIDS)
  • platelets (blood clots)
  • PGE2 (kidney function)
  • PGI2 (for stomach production)
• COX2- induced by inflammatory stimulus  (inh. at higher doses of NSAIDS)
  • inflammatory PG's contribute to pain, heat, swelling

• antipyretic: lowers fever
• mild analgesic
• anti-inflammatory
• closure of patent ductus (PG's maintain open ductus arteriosus
  • use Indomethacin, other NSAIDS to close inappropriately open patent ductus
• cancer chemoprevention (frequent use of aspirin associated with 50% reduction in risk of colon cancer)

• can be additive with opoids
• most effective when pain due to inflam process
  • inflammatory mediators sensitize pain receptors to sitmuli and lead to release of PG's
  • PG's released can cause hyperalgesia

• temperature regulation of set point occurs in hypothalamus
  • elevated set point in fever
  • NSAID's promote return to normal by inhibiting PG synthesis
    • PGE2 elevated by cytokine release in and adjacent to preoptic nuclei triggering elevation of body temperature and decrease in heat loss
    • direct injuction of PGE2 into hypothalamus directly increase fever

• by inhibition of PG production, but need larger doses
  • Ibuprofen: 400-800 mg every 6-8 hrs
    • analgesia/antipyretic- 200-400 mg every 4-6 hrs
  • Aspirin: 4-5 g per day (plasma levels 120-350 mcg/mL)
    • analgesia/antipyretic- 325-650 mg every 4-6 hrs (plasma levels less than 60 mcg/mL)
• chief clinical application- pain and inflammation associated with musculoskeletal disorders
• ONLY symptomatic relief (do not arrest the disease)

• GI
• renal
• pregnancy/lactation
• hypersensitivity rxns
• CNS
• CV

• normally, PG's protect the stomach mucosa from acidic pH
• when you decrease PG's, leads to:
  • pain
  • nausea
  • diarrhea
  • gastric ulcers/erosions
  • GI hemorrhage
  • perforation

• salt/water retention, so CI in: 
  • CHF
  • chronic kidney disease
  • hypovolemia
  • any state where activation of RAAS occurs
• hyperkalemia
• edema
• decrease effectiveness of antihypertensive meds
• decreased urate excretion (esp. aspirin)
• analgesic nephropathy- slowly progressive renal failure, decreasing concentrating capacity
  • associated with high doses of combinations of NSAIDS
  • associated with frequent UTI's

• prolonged gestation
• inhibition of labor
• may increase risk of postpartum hemorrhage

• NOT immunologically based
• syndrome
  • vasomotor rhinitis
  • angioneurotic edema
  • asthma
  • uriticaria
  • flushing
  • hypotension
  • shock
• CI: aspirin intolerance/allergy (as well with any other NSAIDs)
• caution
  • nasal polyps
  • asthma
  • chronic urticaria

• headache
• vertigo
• dizziness
• confusion
• depression
• lowering seizure threshold

• platelets- inhibition of activation, increased propensity for bruising, increased risk for hemorrhage
• effect of cox 2 selective inhibitors- increase the risk of myocardial infarction and stroke esp. in patients at increased risk for CV disease

• NSAIDs concomitantly with low dose aspirin will lead to impairing aspirins ability to acetylate the active site
• w/ ACE inhibitors
  • w/hyperkalemia, ACE inh. + NSAIDs can produce marked bradycardia
    • esp. in elderly, HTN, DM, ischemic heart disease
    • can lead to syncopy
  • may attentuate effects of ACE inh.
• warfarin
  • NSAID's and aspirin inh. platelet function
    • so increase propensity for bleeding with warfarin
  • some NSAIDs can increase warfarin levels by inhibiting metabolism
  • dosage adjust to avoid toxicity

Classifications of NSAIDs

• Aspirin and friends- Aspirin, Dilunisal
• NSAIDs
  • COX1 and 2 inhibitors
    • Ibuprofen
    • Naproxen
    • Indomethacin
    • Sulindac
    • Piroxicam
  • COX2 selective inhibitors- Celecoxib
• DMARD- TNF alpha directed drugs, Methotrexate
• GI protective- Misoprostol, Omeprazol
• Analgesic and Antipyretic only- Acetaminophen

• respiration- increase respiration (uncoupling of oxidative phosphorylation)
• acid base balance
• CV- at low doses, prevent platelet aggregation
• GI effects
• hepatic effects (usually in high doses)- usually reversible (CI: chronic liver disease)
• metabolic effects (uncouple oxidative-phosphorylation, leading to inh. ATP generation and increase in oxygen uptake and carbon dioxide generation)
• skin (keratolytic- used for warts, corns, calluses)
• renal
• pregnancy

• therapeutic doses- get respiratory alkalosis followed by renal compensation via increased excretion of bicarb, Na, K
• toxic doses- resp., metabolic acidosis due to accumulation of acid products

• cardioprotective at low doses, prevent platelet aggregation
  • platelet effects last 4-7 days due to permanent inactivation of platelet COX's (no thromboxane synthesis)
  • increased bleeding times

• prevent GI synthesis of protective PGE for stomach lining
• leads to increase incidence of gastric and duodenal ulcers, GI hemorrhage

• no evidence for teratogenicity in moderate doses
• use in third trimester can lead to hemorrhage, prolonged gestation, complicated deliveries
• some evidence for tx of women with high risk of preeclampsia

• uricosuric effects
  • low dose- decrease urate excretion and elevation in plasma urate levels (caution: gout)
  • high doses- induce uricosuria and lower plasma urate levels (decrease urate reabsorption)
    • small doses of aspirin block effects of probenecid to prevent urate reabsorption at lower doses

• absorbed rapidly, partly from stomach, but mostly from the upper small intestines
• distributed to most tissues and fluids
• metabolism- aspirin is rapidly hydrolyzed to salicylate
  • salicylate conjugated to glycine or glucuronic acid
    • at high doses, conjugation processes are saturated and metabolism becomes zero order
• excretion
  • metabolism to conjugates
  • renal excretion
    • secreted by PCT as well as glomerular filtration (organic anion secretion blocked by probenecid)
    • dosage adjust for renal disease
  • urinary pH changes excretion
    • acidic urine: 2% excreted as free salicylate
    • alkaline urine: 30% excreted as free salicylate
• dose dependent kinetics

• at low doses, you have a linear dose time relationships
• at higher doses, you begin to saturate your conjugation pathways
  • this leads to a "bend" in the dose time curve

• analgesia, antipyretic
  • 1-2 tablets (325 mg/tablet)
  • plasma levels of aspirin 20 mcg/mL or less
  • plasma levels of salicylate 60 mcg/mL or less
• anti-inflammatory
  • 4-5 g/day
  • plasma levels of salicylate of 120-350 mcg/mL
  • adverse effects seen at levels greater than 300 mcg/mL
  • tinnitus is indicative of us exceeding acceptable plasma levels

• antipyresis
  • CI: children with fever and viral diseases (association with development of Reye's syndrome)
• analgesia (minor aches, pains)
• rheumatoid arthritis
  • use diminished due to other drugs with better GI tolerance
• CV disease
  • prevent platelet aggregation
  • MI (antiplatelet effects)
  • low doses used (80 mg or baby aspirin)
• IBD (mesalamine- local effects in tx IBD)
  • poor absorption
  • useful in IBD esp. ulcerative colitis

• often in children (hence childproof containers)
• manifestation- coma, convulsions, CV collapse
• lethal dose
  • 10-30 g in adults (has been survival at 130 g)
  • methylsalicylate- oil of wintergreen (smells like mint), as little as 4 mL is lethal
• symptoms of mild toxicity: salicylism
  • headache
  • dizziness
  • tinnitus
  • drowsiness
  • sweating
  • thirst
  • hyperventilation
  • nausea
  • vomitting

• CNS- stimulation followed by CNS depression
  • confusion, dizziness, tinnitus, high tone deafness, delirium, stupor, coma, hyperthermia
• respiration- stimulate respiration (increased CO₂ production and direct stimulation of respiratory center
  • increase rate and depth, causing respiratory alkalosis
  • prolonged exposure to high doses leads to respiratory depression of medulla (resp. acidosis ensues), circulatory collapse due to vasomotor depression)

• this is an acute medical emergency
• no specific antidote
• maintain airway, breathing, curculation, decontaminate (activated charcoal)
  • forced alkaline diuresis
  • maintain pH 7.5-7.55 (pH urine at or above 8)

• vasomotor rhinitis, angioedema, urticaria, bronchial asthma
• laryngeal edema, bronchoconstriction, flushing, hypotension, shock
  • often nasal polyps
  • rxn not immunological
  • provoked by low doses
  • mechanism- diversion of AA to the leukotrine pathway
• cross sensitive for all NSAIDs

• anorexia, nausea, dyspepsia, abdominal pain, diarrhea
• some have duodenal ulcers (superficial erosion to full perforation)
• combine low dose aspirin with other NSAIDs increase risk for GI adverse effects
• increase risk of GI bleed

prevent with misoprostol or omeprazole to prevent ulceration

• slowly progressive renal failure
• decrease concentrating functionof renal tubule
• risk factors: chronic use, recurrent UTI
• tx: early recognition and discontinuation of NSAIDs