Phenytoin Aspirin

Multiple drug interactions can occur with the TCA drugs. Because of their high degree of binding to plasma proteins, competition for binding sites can exist between TCAs and phenytoin, aspirin, phenothiazines. 

Information seems to be limited to these studies, whieh await confirmation. A similar interaction with phenytoin has been reported with phenylbutazone, which has a very close chemical relationship with sulfinpyiazone (see Phenytoin + Aspirin or NSAIDs , p.551). Thus what is known suggests that concuncnt use should be monitored and suitable phenytoin dosage reductions made where necessary. 

Distribution - protein-bound drugs (e.g. phenytoin, aspirin) may displace each other resulting in an increased unbound (i.e. active) fraction of drug in plasma. 

Allopurinol, aspirin, carbamazepine, chlorpropamide, clomipramine, clozapine, colchicine, desipramine, gold salts, imipramine, levodopa, penicillamine, phenothiazines, phenytoin, propylthiouracil, and sulfonylureas... 

Acetazolamide, allopurinol, aspirin, captopril, carbamazepine, chloramphenicol, chlorpromazine, dapsone, felbamate, gold salts, metronidazole, methimazole, penicillamine, pentoxifylline, phenothiazines, phenytoin, propylthiouracil, quinidine, sulfonamide antimicrobials, sulfonylureas, and ticlopidine... 

CH, a 42-year-old man, comes into the emergency department after his sister discovered him seizing at home. He has a history of hypertension, diabetes, epilepsy, and rheumatoid arthritis. His medications include hydrochlorothiazide, gly-buride, phenytoin, and aspirin. He smokes one pack per day, drinks heavily on the weekends, and has a history of cocaine use. Upon further discussion with his sister, you discover that he stopped taking his phenytoin 4 days ago due to failure to obtain a refill from his doctor. He is currently unarousable since his last seizure 10 minutes ago. 

Drugs that may interact include antacids, cimetidine, aspirin, digoxin, phenytoin, and theophylline. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

In adults, TCAs are highly protein-bound medications. At any one time 75%-95% of the drug in the body will be bound to circulating ttj glycoprotein. Competition for binding sites on ttj glycoprotein by drugs such as aspirin, phenytoin, and some phenothiazines... 

Substance which remain in the stomach for a long time Barbital, aspirin, iron, alcohol, cholinergic blockers, narcotic drugs, phenytoin, antidepressants. 

Substances which have a long half-life when present in large amounts Theophylline, aspirin, alcohol, phenytoin, chloral hydrate, acetaminophen. 

Paxton JW. Effects of aspirin on salivary and serum phenytoin kinetics in healthy subjects. Clin Phannacol Ther 1980 27 170-178. 

Zero-order kinetics With a few drugs, such as aspirin (see p. 407), ethanol and phenytoin (see p. 146), the doses are very large, so the [C] is much greater than Km, and the velocity equation becomes ... 

ASPIRIN ANTI EPILEPTICS Possible t levels of phenytoin and valproate Possibly t unbound phenytoin or valproate fraction in the blood Monitor phenytoin or valproate levels when co-administering high-dose aspirin... 

Antiepileptics - aspirin may cause an elevation and even toxic effects of phenytoin and valproate. 

For a displacement interaction to become clinically important, a second mechanism usually operates sodium valproate can cause phenytoin toxicity because it both displaces phenytoin from its binding site on plasma albumin and inhibits its metabolism. Similarly aspirin and probenecid (and possibly other nonsteroidal anti-inflammatory drugs) displace the folic acid antagonist methotrexate from its protein-binding site and reduce its rate of active secretion by the renal tubules the result is serious methotrexate toxicity. 

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. 

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