Term
| What is the arachidonic acid pathway? (4 steps) |
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Definition
| Damaged/activated endothelial cell with cell surface adhesion molecules>>phospholipase A2+phospholipids>>arachidonic acid>>eicosanoids |
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Term
| What are eicosanoids? (5 points) |
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Definition
| oxygenated polyunsaturated FAs, Wide range of biological activities, Short half-lives, Act in paracrine/autocrine manner, bind to specific receptors on cell membranes |
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Term
| What are 3 important arachidonic acid precursors? |
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Definition
| PGs, thromboxanes, leukotrienes |
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Term
| What are important prostanoids? (4 types) |
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Definition
| PGI2 (prostacyclin), TXA2 (thromboxane), PGE2, PGE1 |
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Term
| Function of PGI2? (7 points) |
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Definition
1. Synthesized by vascular endothelium
2. Vasodilation
3. Relaxation of respiratory smooth muscle
4. Inhibits platelet aggregation (counteracts TXA2)
5. Inflammation (via blood flow/leukocyte infiltration, edema)
6. Treatment of pulmonary hypertension (¯ resistance)
7. Protective function in gastric epithelium |
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Term
| What is the function of TXA2? (4 points) |
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Definition
1. Platelet aggregation (made from Platelet COX-1)
2. Vasoconstriction/Bronchoconstriction
3. Contraction of respiratory smooth muscle
4. Increased platelet/leukocyte interactions (inflammation) |
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Term
| What is PGE2 role in inflammation? 2 points |
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Definition
1. Increases body temperature (produced by COX-1&2 after interleukin-1 stimulation)
2. Inflammation (via increased blood flow/leukocyte infiltration, edema): Suppresses humoral antibody response |
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Term
| Other PGE2 functions (7 points) |
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Definition
3. Bronchodilation
4. Platelet function: increases aggregation (low conc), decreases (high conc)
5. Promotes uterine contractions
6. GI muscle contraction
7. Protective against peptic ulcers
8. Bone turnover
9. Promotes patency of fetal ductus (connection btw pulmonary artery and aorta) |
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Term
| Function of PGE1 (4 point) |
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Definition
1. Vasodilation
2. Smooth muscle relaxation
3. Misoprostol: analog of PGE1, prevents peptic ulcer, termination of early pregnancy
4. Treatment of erectile dysfunction |
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Term
| Important points about NSAIDs (3 points) |
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Definition
| All are antiinflammatory, inhibit COX enzymes by competitive and reversible active site inhibition, major biological effect is related to inhibition or prostaglandin synthesis |
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Term
| Differences in expression of COX 1 and COX 2 |
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Definition
| COX-1 is consistent and constant while COX-2 is induced according to stress, GFs, cytokines, and inflammatory mediators |
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Term
| Differences in function between COX-1 and COX-2 |
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Definition
| COX-1 synthesizes prostanoids for gastric protection, kidney function, and blood clotting while COX-2 is injury and stress mediated and is involved in tissue-specific effects, inflammation, and cancer |
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Term
| Differences in inhibition between COX-1 and COX-2 |
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Definition
| COX-1 inhibition leads to GI-related side effects while COX-2 inhibition leads to antipyretic, analgesic, and antiinflammatory action |
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Term
| What is the role of bradykinin? |
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Definition
| Sensitize pain receptors to stimuli and lead to release of PGs |
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Term
| What is the relationship between PGs and algesia? |
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Definition
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Term
| What is the role of PGE2 in fever? |
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Definition
| It is responsible for elevating the temperature set point in the hypothalamus |
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Term
| How are NSAIDs antipyretics? |
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Definition
| They block PG synthesis which stops the temperature set point in the hypothalamus from being elevated |
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Term
| Why are higher does needed for antiinflammatory responses? |
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Definition
| Inhibition of PG production requires higher plasma concentrations |
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Term
| Relationship between NSAIDs and Cancer |
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Definition
| COX-2 and its role in PGE2 and TXA2 have been linked to colon carcinogenesis in mice |
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Term
| GI adverse effects of ASA and NSAIDs (6) |
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Definition
| Pain, nausea, diarrhea, gastric ulcers/erosions, GI hemorrhage, perforation |
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Term
| Renal adverse effect of ASA and NSAIDs (7) |
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Definition
| renal insufficiency, renal failure, hyperkalemia, proteinuria, decreased effectiveness of HTN meds, decreased excretion (esp. aspirin), analgesic nephropathy |
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Term
| What is analgesic nephropathy |
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Definition
| slowly progressive renal failure, decreased concentrating capacity; associated with high doses of combinations of NSAID’s and frequent urinary tract infections |
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Term
| What is mechanism of platelet aggregate with NSAID use? |
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Definition
| PGI2 which protects vessel endothelium is inhibited without inhibiting TXA2 |
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Term
| Adverse effects of ASA and NSAIDs in pregnancy and lactation (3) |
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Definition
| prolonged gestation, inhibition of labor, may increase postpartum hemorrhage |
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Term
| Non-immunological HS adverse reactions with ASA and NSAIDS (7) |
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Definition
| vasomotor rhinitis, angioneurotic edema, asthma, urticaria, flushing, hypoTN, shock |
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Term
| Interactions between ASA and ibuprofen |
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Definition
| ibuprofen impairs ASA's ability to acetylate active sites removing its cardioprotective ability |
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Term
| NSAIDs, ACE inhibtors and hyperkalemia |
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Definition
| ACE inhibitors + NSAIDs can produced marked bradycardias>>syncope especially in the elderly and in patients with HTN, DM or ischemic heart disease |
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Term
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Definition
| both inhibit platelet function and warfarin and some NSAIDs are metabolized by CYP2C9 |
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Term
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Definition
| 1. Aspirin irreversibly acetylates Serine 530 in COX 1 and Serine 518 in COX2 – Aspirin is a suicide substrate for COX, Blocks access of arachidonic acid to the active site of the enzyme and prevents PG synthesis |
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Term
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Definition
| Contraindicated in children with fever to viral infections- potential to cause Reye’s syndrome |
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Term
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Definition
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Term
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Definition
| use diminished due to other drugs with better GI tolerance; standard by which other agents are judged |
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Term
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Definition
| prevent platelet aggregation, MI infarction-antiplatelet effects, low dose used – 80 mg or baby aspirin |
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Term
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Definition
| Mesalamine (aspirin) – local effects treating in treating IBD – poorly absorbed, useful in IBD especially UC |
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Term
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Definition
| Secreted by proximal tubule as well as glomerular filtration – Organic anion secretion-blocked by probenecid, Renal disease-dosage adjust, Urinary pH changes excretion- acidic urine- 2% excreted as free salicylate but in alkaline urine- 30% |
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Term
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Definition
| rapidly, partly from stomach but mostly from upper small intestine |
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Term
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Definition
| rapidly hydrolyzed to salicylate, which is conjugated to glycine (salicyluric acid) or glucuronic acid – at high doses the conjugation processes are saturated and metabolism becomes zero order |
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Term
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Definition
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Term
| ASA analgesic/antipyretic plasma levels |
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Definition
| 1-2 325 mg tablets, 20 mcg/mL or less of aspirin, 60 mcg/mL or less of salicylate |
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Term
| ASA antiinflammatory plasma levels |
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Definition
| 4-5 g/day, 120 350 mcg/mL (adverse effects can be seen at levels greater than 300 mcg/mL, tinnitus is indicator) |
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Term
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Definition
| a. Platelet effects last 4-7 days due to permanent inactivation of platelet COX’s; thromboxane synthesis prevented: Increased bleeding times, decreased myocardial infarction – 20-25% aspirin (low dose), 10% naproxen |
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Term
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Definition
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Term
| ASA and Acid-Base balance |
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Definition
| at therapeutic dose get a respiratory alkalosis followed by renal compensation and excretion of bicarb, Na, and K; at high doses get respiratory and metabolic acidosis due to accumulation of acid products |
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Term
|
Definition
| injury possible in patients taking high doses, usually reversible, use contraindicated in patients with chronic liver disease |
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Term
| ASA and metabolic effects |
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Definition
| uncouples oxidation-phosphorylation, inhibition of ATP generation, increase in O2 uptake and CO2 generation |
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Term
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Definition
| keratolytic effect is used form warts, corns, calluses |
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Term
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Definition
| no evidence for teratogenicity of moderate doses, use in 3rd trimester can lead to hemorrhage, prolonged gestation and complicated deliveries, treatment of women at high risk of preeclampsia |
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Term
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Definition
| uricosuric (excretion of uric acid, gout): at low doses decrease in urate excretion and elevation in plasma urate levels (1-2 g/day), at high doses induce uricouria and lower plasma levels – decreases urate reabsorption (5g/day or more) |
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Term
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Definition
| swelling of the eyes, face, lips, tongue, or throat; wheezing, difficulty breathing, hoarseness, or fast breathing; fast heartbeat; cold, clammy skin; hives, rash; bright red blood in stools or black, tarry stools; bloody vomit, vomit resembling coffee grounds, nausea, stomach pain, or heartburn; ringing in the ears or loss of hearing |
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Term
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Definition
| often in children; coma, convulsions, CV collapse; lethal dose: 10-30 g in adults although survival has occurred with ingestion of 130 g; Symptoms: mild-HA, dizziness, tinnitus, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting |
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Term
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Definition
| prevents synthesis of protective PGE/PGI2 for GI epithelial cells in stomach ling (increased acid secretion, COX-1 action), increased incidence of gastric and duodenal ulcers and GI hemorrhage, co-admin with PPI may ameliorate GI toxicity |
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Term
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Definition
| acute medical emergency, no specific antidote; maintain airway, breathing, circulation, decontaminate (activated charcoal), forced alkaline diuresis, maintain |
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Term
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Definition
| vasomotor rhinitis, angioneurotic edema, asthma, urticaria, flushing, hypoTN, shock; 10-25% of patients with nasal polyps, asthma, or chronic urticaria have hypersensitivity reactions – probably due to diversion of arachidonic acid to the leukotriene pathways; Aspirin intolerance/ allergy is contraindication for therapy with any other NSAID |
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Term
| Ibuprofen antiinflammatory dose |
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Definition
| 400-800 mg every 6-8 h (higher than analgesic/antipyretic); 2400 mg daily is equiv to ~4 g ASA |
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Term
| Ibuprofen for analgesic/antipyretic dose |
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Definition
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Term
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Definition
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Term
|
Definition
| closure of patent ductus (less renal effects compared to indomethacin, topical relief of osteoarthritis |
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Term
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Definition
| co-admin with ASA may decrease cardioprotective and antiinflammatory effects, 5-15% of patients experience GI effects (less than ASA) |
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Term
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Definition
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Term
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Definition
| closure of patent ductus, gout, ankylosing spondylitis, ophthalmic prep for conjunctival inflammation, oral rinse |
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Term
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Definition
| similar to other NSAIDs, high doses=GI effects sever and include pancreatitis, thrombocytopenia/aplastic anemia, drug interactions |
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Term
| Naproxen and number of enantiomers |
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Definition
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Term
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Definition
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Term
|
Definition
| free drug at higher levels in women |
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Term
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Definition
| RA, many formulations (oral/slow release, topical, ophthalmic) |
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Term
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Definition
| similar to other NSAIDs, 5-15% experience GI effects (higher than ibuprofen) |
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Term
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Definition
| prodrug so must be metabolized to active metabolite |
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Term
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Definition
| reabsorbed in intestine (enterohepatic cycling) |
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Term
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Definition
| anti-cancer: suppresses familial polyp formation, may decrease colon, prostate and breast cancer, decrease GI cancers in rodents |
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Term
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Definition
| Steven-Johnson epidermal necrolysis syndrome, thrombocytopenia, agranulocytosis, nephrotic syndrome, elevation or serum aminotransferases-liver damage |
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Term
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Definition
| inhibits migration at high doses |
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Term
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Definition
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Term
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Definition
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Term
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Definition
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Term
|
Definition
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Term
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Definition
| 20% patients get side effects (5% discontinue rate due to side effects), risk of peptic ulcer is 9.5x greater than other NSAIDs |
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Term
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Definition
| ii. Analgesic and antipyretic activity, but no antiinflammatory, CV, respiratory, platelet, coagulation, acid-base change, uricosuric, or GI effects |
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Term
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Definition
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Term
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Definition
| glucuronic acid and sulfate conjugates, small portion metabolized to a reactive metabolite, NAPQI – normally reacts with gluthione and rendered harmless, CYP dependent, large doses deplete GSH and liver toxicity ensues– as drug increases, there is an increase in covalent bonding with GSH |
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Term
| Acetaminophen hepatotoxicity |
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Definition
| single doses of 10-15 g causes serious heptatoxicity, 20-25 g are potentially fatal; induction of CYP2E1 increases risk of toxicity; Symptoms: nausea, abdominal pain, and anorexia; plasma transaminases elevated 12-36 h after ingestion; clinical indication of hepatic damage 2-4 d, liver enzymes peak 72-96 h after drug |
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Term
| Acetaminophen overdose management |
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Definition
| activated charcoal to reduce absorption; N-acetylcysteine (mucomyst): indicated for those at risk of injury, detoxifies NAPQI, adverse reactions to NAC include rash, nausea, vomiting, diarrhea and rare anaphylactoid reactions, loading doses given followed by maintenance doses; aggressive supportive care; renal failure possible |
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Term
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Definition
| COX-2, not absolute, less GI toxicity |
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Term
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Definition
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Term
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Definition
| CYP – substrate for CYP2C9, inhibits CYP2D6; significant drug interactions can occur with lithium and fluconazole |
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Term
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Definition
| not more so than non-selective inhibitors |
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Term
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Definition
| thrombosis, HTN, atherogenesis – avoid in patients prone to CV and cerebrovascular disease; use lowest possible dose for shortest time – not a first choice drug |
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Term
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Definition
| analog of PGE1, prevents peptic ulcer, termination of early pregnancy, prodrug, increases mucus/bicarb secretion, decreases ulcers to <3% and complications by 50%, GI toxicity limits usage, oxytocic/uterine contractions |
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