Aspirin clearance

Probenecid is a uricosuric agent that blocks the tubular reabsorption of uric acid, increasing its excretion. Because of its mechanism of action, probenecid is contraindicated in patients with a history of uric acid stones or nephropathy. Probenecid loses its effectiveness as renal function declines and should be avoided when the creatinine clearance is 50 mL/minute or less. Its uricosuric effect is counteracted by low aspirin doses, which many patients receive for prophylaxis of coronary heart disease. 

Aspirin Aspirin is rapidly hydrolyzed in plasma to salicylic acid with a half-life of 20 minutes. Plasma levels of aspirin are essentially undetectable 2 to 2.5 hours after dosing, and peak salicylic acid concentration occurs 1 hour (range, 0.5 to 2 hours) after aspirin administration. Salicylic acid is primarily conjugated in the liver to form a number of minor metabolites. Salicylate metabolism is saturable and the total body clearance decreases at higher serum concentrations. 

Renal function impairment No changes were observed in the pharmacokinetics of dipyridamole or its glucuronide metabolite with creatinine clearances ranging from approximately 15 mL/min to more than 100 mL/min if data were corrected for differences in age. Avoid aspirin in patients with severe renal failure (glomerular filtration rate less than 10 mL/min). 

The arylpropionic acid derivatives are useful for the treatment of rheumatoid arthritis and osteoarthritis, for reduction of mild to moderate pain and fever, and for pain associated with dysmenorrhea. Side effects of the drugs are similar to but less severe than those described for the salicylates. Those who are sensitive to salicylates also may be sensitive to and have adverse reactions when taking ibuprofen and related drugs. Acute hypersensitivity to ibuprofen has been reported in patients with lupus. The hypersensitivity reaction to sulindac can be fatal. The use of sulindac has also been linked to cases of acute pancreatitis. The use of dimethylsulfoxide (DMSO) topically in combination with sulindac has been reported to induce severe neuropathies. The concurrent use of ibuprofen with aspirin reduces the antiinflammatory effects of both drugs. Ibuprofen is contraindicated in patients with aspirin sensitivity leading to bronchiolar constriction and in patients with an-gioedema. As with all NSAIDs, renal and liver function should be normal for adequate clearance of the drugs. 

Fenoprofen (Nalfon) is chemically and pharmacologically similar to ibuprofen and is used in the treatment of rheumatoid arthritis, osteoarthritis, and mild to moderate pain. GI effects such as dyspepsia and pain are most common, although dizziness, pruritus, and palpitations may occur. GI bleeding, sometimes severe, has been reported, and interstitial nephritis has been rarely associated with this drug. Concomitant administration of aspirin decreases the biological half-Ufe of fenoprofen by increasing the metabolic clearance of hydroxy-lated fenoprofen. Chronic administration of pheno-barbital also decreases the drug s half-life. 

Several drug interactions involving amantadine and rimantadine are clinically significant. Anticholinergic drugs can potentiate the toxicity of amantadine. Thiazide-triamterene, trimethoprim-sulfamethoxazole, quinine, and quinidine increase plasma amantadine levels. Cimetidine decreases rimantadine clearance, and aspirin and acetaminophen decrease rimantadine plasma levels. 

Renal clearance of lithium is reduced about 25% by diuretics (eg, thiazides), and doses may need to be reduced by a similar amount. A similar reduction in lithium clearance has been noted with several of the newer nonsteroidal anti-inflammatory drugs that block synthesis of prostaglandins. This interaction has not been reported for either aspirin or acetaminophen. All neuroleptics tested to date, with the possible exception of clozapine and the newer atypical antipsychotics, may produce more severe extrapyramidal syndromes when combined with lithium. 

The calculation of clearance using this equation is illustrated by the following example. Aspirin is metabolized primarily in the liver. Normal hepatic blood flow (Q) equals 1500 mL/min. If the blood entering the liver contains 200 fxg/mL of aspirin (Ci) and the blood leaving the liver contains 134 fxg/mL (Co), hepatic clearance of aspirin is calculated as follows ... 

This example illustrates that clearance is actually the amount of plasma that the drug can be totally removed from per unit time. As calculated here, the liver would be able to completely remove aspirin from 495 mL of blood each minute. Tetracycline, a common antibacterial drug, has a clearance equal to 130 mL/min, indicating that this drug would be completely removed from approximately 130 mL of plasma each minute. 

Drugs that alter the pH of urine can significantly affect the renal excretion of other drugs. Acid urine increases the effectiveness of mercurial diuretics. It also accelerates the excretion of basic drugs such as meperidine, tricyclic antidepressants, amphetamines, and antihistamines. Acidic drugs, such as aspirin, streptomycin, phenobarbital, sulfonamides, nalidixic acid, and nitrofurantoin have been shown to increase renal clearance in alkaline urine (61). The possible effects of urine pH on the renal excretion of drugs has been illustrated by the observation that if urine is rendered sufficiently alkaline, the excretion of amphetamine is markedly delayed and effective blood levels, after a single dose, can be maintained for several days (62). 

Concurrent administration of aspirin reduces ketoprofen protein binding and increases its clearance. Salicylate also reduces the metabohc conversion of ketoprofen to its conjugates and their renal elimination, and enhances its conversion to non-conjugated metabohtes (15). 

Aspirin and methotrexate compete for renal tubular secretion, and aspirin alters the systemic and renal clearances of intravenous methotrexate (131). However, the clinical relevance of this interaction is not clear. In one study, aspirin (mean dose 4.5 g) in 12 patients did not cause more toxicity than other NSAIDs taken by 22 other patients (132). 

Concomitant use of heparin and oral anticoagulants can increase the risk for bleeding due to the antiplatelet effect of aspirin. In addition, use with alcohol can increase the risk of Gl bleeding. / spirin displaces a number of drugs (e.g., tolbutamide, nonsteroidal anti-inflammatory drugs [NSAIDs], methotrexate, phenytoin, and probenecid) from protein binding sites in the blood. Corticosteroid use can reduce serum salicylate levels by increasing the clearance of aspirin. 

Antacids and food can delay and decrease the absorption of tolmetin. NSAIDS are known to decrease renal clearance of lithium carbonate, thus increasing lithium serum levels and risks of adverse effects. Concomitant use of tolmetin and aspirin may decrease plasma levels of tolmetin. 

Various NSAIDs, such as ibuprofen, indomethacin, ketoprofen, phenylbutazone, piroxicam, and oxyphenbutazone, can decrease renal creatinine and lithium clearance by their common inhibitory action on prostaglandin synthesis. Aspirin (acetylsalicylic acid) and sulindac have not been found to increase lithium plasma steady-state concentrations. ... 

Several NSAIDs, including aspirin, ibuprofen, and piroxicam, increase serum levels of methotrexate by interfering with its renal clearance. The adverse effects of methotrexate, including its hematotoxicity are predictably increased. The answer is (J). 

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