Probenecid with salicylates

Exacerbation of gout Exacerbation of gout following therapy with probenecid may occur in such cases, colchicine or other appropriate therapy is advisable. Salicylates Use of salicylates is contraindicated in patients on probenecid therapy. Salicylates antagonize probenecid s uricosuric action. 

In connection with the uric acid retaining property of diuretics. It Is significant to note that several of the thiazides and also ethacrynlc acid, when administered Intravenously, first elicit a uricosuric response of brief duration followed by uric acid retention. However, after oral administration, only the retention Is observed. This two-phase response Is presumably related to the blood concentration of the drugs presented to the kidney. It will be recalled that certain uricosuric drugs that are not natriuretic, particularly probenecid and salicylic acid, at low levels, show a uric acid retention dille higher levels produce uric acid excretion. Further, certain compounds, particularly of the pyrazolldlne-dlone series, have some actions that are the opposite of the diuretics. 

There is an increased risk of toxicity of MTX when administered with the NSAIDs, salicylates, oral antidiabetic drugs, phenytoin, tetracycline, and probenecid. There is an additive bone marrow depressant effect when administered with other drug known to depress the bone marrow or with radiation therapy. There is an increased risk for nephrotoxicity when MTX is administered with other drug that cause nephrotoxicity. When penicillamine is administered with digoxin, decreased blood levels of digoxin may occur. There is a decreased absorption of penicillamine when the dmg is administered with food, iron preparations, and antacids. 

Probenecid can impair the renal active secretion of a variety of acidic compounds, including sulfinpyrazone, sulfonylureas, indomethacin, penicillin, sulfonamides, and 17-ketosteroids. If these agents are to be given concomitantly with probenecid, their dosage should be modified appropriately. Salicylates interfere with the clinical effects of both sulfinpyrazone and probenecid and should be avoided in patients treated with uricosuric agents. Uricosuric agents also can influence the volume of distribution and hepatic metabolism of a number of drugs. 

Salicylates [P] Decreased uricosuric effect of probenecid (interaction unlikely with less than 1.5 g of salicylate daily). 

Other compounds producing some inhibition of ZDV conjugation were oxazepam, salicylic acid, and acetylsalicyclic acid. More recently, Trapnell et al. examined the inhibition of ZDV at a more relevant concentration of 20 pM in bovine serum albumin (BSA)-activated microsomes by atovaquone, methadone, fluconazole, and valproic acid at therapeutically relevant concentrations (127). Both fluconazole and valproic acid inhibited ZDV glucuronidation by more than 50% at therapeutic concentrations. Clinical interaction studies have been conducted with methadone, fluconazole, naproxen, probenecid, rifampicin, and valproic acid (see Table 10). 

Aminosalycylic Acid Dose forms should be freshly prepared, since aqueous solutions are unstable. Aminosalicylate acid interacts with other salicylates, such as probenecid and procaine. 

Aspirin, salicylates, and thiazide diuretics should not be used with allopurinol. The dose of mercaptopurine should be reduced one-third or one-fourth when used with allopurinol. Acute poisoning of colchicine should be treated with gastric lavage and activated charcoal administration. Supportive maintenance measures for blood pressure and respiration should be provided. Probenecid is used by athletes to inhibit the urinary excretion of banned anabolic steroids.85... 

In low dosages (up to 2 g/day), aspirin reduces urate excretion and blocks the effects of probenecid and other uricosuric agents (116). However, in 11 patients with gout, aspirin 325 mg/day had no effect on the uricosuric action of probenecid (117). In higher dosages (over 5 g/day), salicylates increase urate excretion and inhibit the effects... 

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. 

Clinically important, potentially hazardous interactions with aspirin, buprenorphine, methotrexate, probenecid, salicylates... 

Clinically important, potentially hazardous interactions with acitretin, aldesleukin, aminoglycosides, amiodarone, amoxicillin, ampicillin, aspirin, bacampicillin, bismuth, carbenicillin, chloroquine, cisplatin, cloxacillin, co-trimoxazole, dapsone, demeclocycline, dexamethasone, diclofenac, dicloxacillin, etodolac, etoricoxib, etretinate, fenoprofen, flurbiprofen, folic acid antagonists, haloperidol, hydrocortisone, ibuprofen, indomethacin, influenza vaccines, ketoprofen, ketorolac, lithium, magnesium trisalicylate, meclofenamate, mefenamic acid, methicillin, mezlocillin, minocycline, nabumetone, nafcillin, naproxen, NSAIDs, omeprazole, oxacillin, oxaprozin, oxytetracycline, paromomycin, penicillin G, penicillin V, penicillins, phenylbutazone, piperacillin, piroxicam, polypeptide antibiotics, prednisolone, prednisone, probenecid, procarbazine, rofecoxib, salicylates, salsalate, sapropterin, sulfadiazine, sulfamethoxazole, sulfapyridine, sulfasalazine, sulfisoxazole, sulindac, tazobactum, tenoxicam, tetracycline, ticarcillin, tolmetin, trimethoprim, vaccines... 

Clinically important, potentially hazardous interactions with ACE inhibitors, amikacin, aminoglycosides, aminophylline, anti-diabetics, antihypertensives, cephalosporinss, cisplatin, gentamicin, indomethacin, kanamycin, neomycin, probenecid, salicylates, streptomycin, tobramycin... 

Concomitant use with anticoagulants may increase plasma levels of both drugs and, after continued therapy, may reduce the plasma levels of anticoagulant effects. Use with chloramphenicol, guanethidine, insulin, monoamine oxidase inhibitors, probenecid, salicylates, or sulfonamides may enhance the hypoglycemic effect by displacing tolazamide from its protein-binding sites. 

Note. The simultaneous administration of drugs like probenecid, salicylate and other NSAIDs etc., directly interfere with its secretion and hence, should be avoided as far as possible. 

Interactions with the following drugs may increase the risk of hypoglycemia other hypoglycemics, sulfonamides, propranolol, salicylates, clofibrate, probenecid, pentamidine, valproic acid, dicumarol, cimetidine, MAO inhibitors, and alcohol. In addition, co-ingestion of alcohol may occasionally produce a disulfiram-like interaction (see p 186). 

The uricosuric effects of high doses of aspirin or other salicylates and probenecid are not additive as might be expected but are mutually antagonistic. Low dose, enteric-coated aspirin appears not to interact with probenecid. 

A three to fourfold increase in serum methotrexate levels at 24 hours was also seen in 4 patients given probenecid. Pretreatment with probenecid (500 mg every 6 hours for 5 doses) doubled the serum methotrexate levels of another 4 patients. Severe and life-threatening pancytopenia occurred when a woman taking low-dose methotrexate 7.5 mg weekly for rheumatoid arthritis was given probenecid. She also had renal impairment, hy-poalbuminaemia and was taking salsalate (a salicylic acid derivative). ... 

Neither probenecid nor pyrazinamide significantly altered uric acid excretion when administered to patients with serum salicylate levels above 14 mg%. 

Let s now study the titrations of the carboxylic acids that are too poorly soluble in water and therefore necessitate the use of mixtures of water and organic solvents. The most commonly used mixtures are the hydroalcoholic ones. Ethanol must be neutralized by a sodium hydroxide solution before being mixed with water. Benzoic, undecyienic, etacrinic, and salicylic acids as well as probenecid (Fig. 11.4) are titrated according to this methodology. 

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