Toews: NSAIDS and Other RA Drugs- Pt. II-X Flashcards
Aspirin is the prototype of the A)___-__________ _______-________ drugs and of the B) ___-_____ _________ _____ (which largely overlap); it is the drug by which all others are judged
A) non-steroidal anti-inflammatoryB) non-opioid analgesic drugs
Aspirin is ______-________ acid, but it is rapidly hydrolyzed to salicylic acid
A) acetyl-salicylic
Most (but not all) of the therapeutic effects of aspirin are mediated by its A)__________ __________, effects shared with all other salicylate NSAIDs.
A) salicylate metabolite
Aspirin is different from other NSAIDs because it can A)___________ inactivate COXs in some tissues and cells by covalently B)___________ the enzyme
A) irreversiblyB) acetylating
Binding of salicylate to COX can _______ COX activity. Acetylation of COX can _______ COX activity also.
Inhibit
What needs to happen to terminate the covalent acetylation component of aspirin action?
Degradation of acetylated COX and synthesis of new COX enzyme molecules is required.
Other NSAIDs (NOT ASPIRIN), including other salicylate agents, are A)__________ and B)_________ COX inhibitors.
A) reversibleB) Competitive
ASPIRIN is: 1. Well ________ orally 2. ___________ throughout the body, including to the CNS (for fever and pain) 3. _______% protein-bound in plasma; drug interactions from displacing warfarin, methotrexate, sulfonamides 4. Rapidly __________ to salicylic acid
- Absorbed2. Distributed3. 80-90%4. hydrolyzed
At low to moderate doses, salicylate is metabolized how?
in the liver by conjugation, with first-order kinetics and saturable.
At higher doses, salicylate is excreted how?
unmetabolized via the kidneys, with zero- order kinetics and a half-life that increases with increasing dose NOTE: These higher doses that saturate the liver metabolism are required for aspirin to achieve therapeutic levels for inhibition of COX-2 and inflammation, which also takes a longer time to achieve
Typical NSAID effects and therapeutic uses of aspirin at 650-1000 mg / 4 hrs are: (2)
- ANALGESIA- For mild to moderate pain, Headache, arthritis, dysmenorrhea, neuralgia, myalgia. NOTE: PGs particularly contribute to pain of inflammation, in part by sensitizing receptors for pain-related peptide mediators (bradykinin, substance P, others). This makes NSAIDs particularly beneficial in inflammation-related pain. (aka pain reliever)2) ANTIPYRESIS- Action in hypothalamus to return thermoregulatory set-point to normal. (aka reduce fever)
Typical NSAID effects and therapeutic uses of aspirin at 1300 mg+ / 4 hr are: (1)
Anti-inflammatory effects- Acute rheumatic fever, rheumatoid arthritis, others.
A unique effect of aspirin ONLY to prevent thrombus formation and prolong bleeding time is due to…
its ability to acetylate COXs for both irreversible and prolonged action.
What drug is a major current use to prevent (reduce risk) of MI and stroke?
ASPIRIN!!!!
Aspirin has what effect on platelets?
A unique effect on platelets, because of their inability to make new COX and their long lifetime; platelet effects of aspirin persist for about 7 days.
A)_________ and B)________ ___________ cells near the site of absorption are perhaps the only cells that are exposed to acetyl-salicylic acid, due to its rapid hydrolysis before reaching most other cellular targets and tissues.
A) PlateletsB) Vascular endothelial
Other cells and tissues experience only the __________ COX inhibition by salicylate
Reversible
Aspirin has what effects on TX (Thromboxins)?
1) Prolonged inhibition of platelet COX leads to reduced TX FORMATION, the major COX product from platelets. 2) Decreased TXs reduces platelet AGGREGATION, decreasing the likelihood of clotting and thrombotic events (for better or worse!)
What is the current recommendation for preventive use of aspirin – “aspirin regimen”?
1) For reducing MI in men 45-79 and ischemic stroke in women 55-79, use aspirin 75-81 mg/day, if potential benefit of reduced disease risk outweighs potential harm of increased GI hemorrhage. This aspirin dose was called “baby aspirin” when aspirin was still used in children, prior to the Reye’s Syndrome connection.2) Men younger than 45 and women younger than 55 not recommended. Over 80 not recommended.
What are 2 miscellaneous uses of aspirin?
- Colorectal cancer, especially with familial adenomatous polyposis (FAP). NOTE: Many cancers have elevated COX2, and epidemiology studies suggest a benefit, but still an emerging story 2. Alzheimer’s Disease – possible benefit, evidence not strong.
What are other salicylate NSAIDs and their characteristics?
A. Sodium salicylate, methyl salicylate, diflunisal, salsalate, olsalazine, sulfasalazine B. Share analgesic, anti-pyretic, and anti-inflammatory effects and uses with aspirin C. DO NOT share platelet-related anti-thrombotic effects and uses, because they are NOT irreversible inhibitors like aspirin so do not have long-lasting effects on platelets
Describe GI adverse effects of salicylates, both aspirin and others
NOTE: Because PGs are major GI mucosa protectors 1. Gastric irritation and mild bleeding 2. Gastric ulceration and hemorrhage 3. Exacerbation of peptic ulcers 4. The most common complaint and responsible for many deaths 5. Effects can be moderated with PG analog misoprostol [Cytotec] or proton pump inhibitor omeprazole
Describe Cardiovascular adverse effects of salicylates, both aspirin and others
- No important effects with therapeutic doses 2. Dilation of peripheral vessels by large doses 3. Toxic levels (80 mg%) can cause central vasomotor paralysis 4. Avoid aspirin in patients with blood-clotting deficiencies; not a problem with other salicylates or other NSAIDs)
Describe ACID BASE BALANCE adverse effects of salicylates, both aspirin and others at LOW, HIGHER, and TOXIC doses.
- Low therapeutic doses increase CO2 production via uncoupling oxidative phosphorylation in skeletal muscle 2. At higher doses (40 mg%+), compensation for respiratory alkalosis by bicarbonate excretion 3. Toxic doses (80 mg%+) lead to metabolic acidosis and disturbances in potassium balance (hypokalemia)
