NSAIDS Flashcards

Question

What are the external applications for NSAIDS

Answer 1

✓ Salicylic acid is used topically to treat acne, corns, calluses, and warts. ✓ Methyl salicylate (“oil of wintergreen”) is used externally as a cutaneous counterirritant in liniments, such as arthritis creams and sports rubs. ✓ Diclofenac is available in topical formulations (gel or solution) for treatment of osteoarthritis in the knees or hands

Answer 2

✓ After oral administration, aspirin is rapidly deacetylated by esterases in the body, thereby producing salicylate. ✓ Unionized salicylates are passively absorbed mostly from the upper small intestine (dissolution of the tablets is favoured at the higher pH of the gut) ✓ Salicylates (except for diflunisal ) cross both the BBB and the placenta and are absorbed through intact skin (especially methyl salicylate). ✓ Salicylate is converted by the liver to water-soluble conjugates that are rapidly cleared by the kidney, resulting in first-order elimination and a serum half-life of 3.5 hours. ✓ At anti-inflammatory dosages (more than 4 g/day), the hepatic metabolic pathway becomes saturated, and zero-order kinetics are observed, leading to a half-life of 15 hours or more (Figure 36.11). ✓ Being an organic acid, salicylate is secreted into the urine and can affect uric acid excretion. ✓ Therefore, aspirin is avoided in gout or in patients taking probenecid

Answer 3

a. Gastrointestinal: ✓ The most common AEs of NSAIDs are GI related, ranging from dyspepsia to bleeding. Normally, PGI2 ↓ gastric acid secretion, and PGE2 and PGF2α ↑ mucus in both the stomach and small intestine. ✓ Agents that ↓COX-1 → ↓beneficial levels of these PGs→ ↑gastric acid secretion, ↓mucus protection, and ↑ risk for GI bleeding and ulceration. ✓ Agents with a higher relative selectivity for COX-1 may have a higher risk for GI events compared to those with a lower relative selectivity for COX-1. ✓ NSAIDs should be taken with food or fluids to diminish GI upset. ✓ If NSAIDs are used in patients with a high risk for GI events, PPI or misoprostol should be used concomitantly to prevent NSAID-induced ulcers b. Increased risk of bleeding (antiplatelet effect): ✓ TXA2 ↑platelet aggregation, whereas PGI2 ↓ it. ✓ Aspirin irreversibly ↓ COX-1–mediated TXA2 formation, while other NSAIDs reversibly inhibit the production of TXA2. ✓ Because platelets lack nuclei, they cannot synthesize new enzyme when inhibited by aspirin, and the lack of thromboxane persists for the lifetime of the platelet (3 to 7 days). ✓ Because of the decrease in TXA2 production, platelet aggregation (the first step in thrombus formation) is reduced, producing an antiplatelet effect with a prolonged bleeding time. ✓ For this reason, aspirin is often held, or not given, at least 1 week prior to surgery. ✓ NSAIDs other than aspirin are not utilized for their antiplatelet effect but can still prolong bleeding time. ✓ As agents become more COX-2 selective, they are expected to have less effect on platelet inhibition and bleeding time. ✓ NSAIDs can also block aspirin binding to COX when used concomitantly. ✓ Patients who take aspirin for cardio protection should avoid concomitant NSAID use if possible. c. Actions on the kidney: ✓ NSAIDs prevent the synthesis of PGE2 and PGI2, prostaglandins that are responsible for maintaining renal blood flow (Figure 36.12). ✓ ↓PGs → retention of Na+ /H2O → edema in some patients ✓ Patients with a history of HF or kidney disease are at particularly high risk. ✓ These effects can also mitigate (decrease) the beneficial effects of antihypertensive medication d. Cardiac effects: ✓ Aspirin, with a very high degree of COX-1 selectivity, has shown a cardiovascular protective effect due to a ↓TXA2. ✓ Agents with higher relative COX-2 selectivity have been associated with an ↑risk for cardiovascular events, possibly by ↓PGI2 production mediated by COX-2. ✓ All NSAIDs except aspirin→↑risk for cardiovascular events (MI & stroke). ✓ Use of NSAIDs, other than aspirin, is discouraged in patients with established cardiovascular disease. ✓ For patients with cardiovascular disease in whom NSAID treatment cannot be avoided, naproxen appears to be the least likely to be harmful. ✓ NSAID use should be limited to the lowest dose possible for the shortest duration.

Answer 4

f. Drug interactions: ✓ Salicylate is roughly 80%-90% plasma protein bound (albumin) and can be displaced from protein binding sites →↑conc. of free salicylate. ✓ Alternatively, aspirin can displace other highly protein-bound drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of these agents (Figure 36.13). g. Toxicity: ✓ Salicylate intoxication may be mild or severe. ✓ The mild form is called salicylism and is characterized by nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus (ringing or roaring in the ears). When large doses of salicylate are administered, severe salicylate intoxication may result (Figure 36.9). Restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure may occur. ✓ Children are particularly prone to salicylate intoxication. Ingestion of as little as 10 g of aspirin can cause death in children.

Answer 5

✓ Celecoxib, a selective COX-2 inhibitor, is significantly more selective for inhibition of COX-2 than COX-1 (Figure 36.14). ✓ Unlike the inhibition of COX-1 by aspirin (which is rapid and irreversible), the inhibition of COX-2 is reversible. 1. Therapeutic uses: ✓ Celecoxib is approved for the treatment of RA, osteoarthritis, and acute mild to moderate pain. ✓ Celecoxib has similar efficacy to NSAIDs in the treatment of pain. 2. Pharmacokinetics: ✓ Celecoxib is readily absorbed after oral administration. It is extensively metabolized in the liver by cytochrome P450 (CYP2C9) and is excreted in feces and urine. ✓ The half-life is about 11 hours, and the drug may be dosed once or twice daily. ✓ The dosage should be reduced in those with moderate hepatic impairment, and celecoxib should be avoided in patients with severe hepatic or renal disease. 3. Adverse effects: ✓ Headache, dyspepsia, diarrhea, and abdominal pain are the most common adverse effects. ✓ Celecoxib, when used without concomitant aspirin therapy, is associated with less GI bleeding and dyspepsia than other NSAIDs. However, this benefit is lost when aspirin is added to celecoxib therapy. 3. Adverse effects: ✓ Patients who are at high risk of ulcers and require aspirin for cardiovascular prevention should avoid the use of celecoxib. ✓ Like other NSAIDs, the drug has a similar risk for cardiovascular events. ✓ Celecoxib should be used with caution in patients who are allergic to sulfonamides.?? ✓ Patients who have had anaphylactoid reactions to aspirin or nonselective NSAIDs may be at risk for similar effects with celecoxib. ✓ Inhibitors of CYP2C9, such as fluconazole , may increase serum levels of celecoxib.

Answer 6

Acetaminophen (paracetamol) ↓PGs synthesis in the CNS. ✓ This explains its antipyretic and analgesic properties. ✓ Acetaminophen has less effect on COX in peripheral tissues (due to peripheral inactivation), which accounts for its weak anti-inflammatory activity. ✓ Acetaminophen does NOT affect platelet function or ↑ bleeding time. ✓ It is NOT considered to be an NSAID. A. Therapeutic uses ✓ Acetaminophen is a suitable substitute for the analgesic and antipyretic effects of NSAIDs for those patients: ✓ with gastric complaints/ risks, ✓ in those whom a prolongation of bleeding time is not desirable, ✓ as well as those who do not require the anti-inflammatory action of NSAIDs Acetaminophen is the analgesic/antipyretic of choice for children with viral infections or chickenpox (due to the risk of Reye syndrome with aspirin). B. Pharmacokinetics ✓ Acetaminophen is rapidly absorbed from the GI tract. A significant firstpass metabolism occurs in the luminal cells of the intestine and in the hepatocytes. ✓ Under normal circumstances, acetaminophen is conjugated in the liver to form inactive glucuronidated or sulfated metabolites. ✓ A portion of acetaminophen is hydroxylated to form N-acetyl-pbenzoquinoneimine, or NAPQI, a highly reactive metabolite that can react with sulfhydryl groups and cause liver damage. At normal doses of acetaminophen, NAPQI reacts with the sulfhydryl group of glutathione, which is produced by the liver, forming a nontoxic substance (Figure 36.16). ✓ Acetaminophen and its metabolites are excreted in urine. The drug is also available in intravenous and rectal formulations. C. Adverse effects ✓ At normal therapeutic doses??, acetaminophen is virtually free of significant adverse effects. ✓ With large doses of acetaminophen, the available glutathione in the liver becomes depleted, and NAPQI reacts with the sulfhydryl groups of hepatic proteins, forming covalent bonds ✓ Hepatic necrosis, a very serious and potentially life threatening condition, can result ✓ Patients with hepatic disease, viral hepatitis, ✓ or a history of alcoholism are at higher risk of acetaminophen induced hepatotoxicity. ✓ [Note: N-acetylcysteine, which contains sulfhydryl groups to which the toxic metabolite can bind, is an antidote in cases of overdose] ✓ Acetaminophen should be avoided in patients with severe hepatic impairment.

NSAIDS Flashcards

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