Indomethacin toxicity

Nonsteroidal antiinflammatory drugs (NSAIDs) are the mainstay of therapy because of their excellent efficacy and minimal toxicity with shortterm use. There is little evidence to support one NSAID as more efficacious than another, and three drugs (indomethacin, naproxen, and sulindac) have FDA approval for this indication (Table 1-1). 

In Sect. 8.2.3, we have discussed 1-alkyl-l-azacycloalkan-2-ones (8.32, n = 1 or 2 m = 3, 4, 5 or 6) as a group of amidoalkyl esters, taking prodrugs of indomethacin (8.9, R = OH) and naproxen (8.26) as examples [43a,b]. For both compounds, the prodrugs in the series n = 1 were rapidly hydrolyzed (tm ca. 0.5-1 h in pH 7.4 buffer at 32°). Furthermore, the carbinolamides liberated were not fully stable and broke down by hydrolysis to produce the toxic formaldehyde (Fig. 8.3) [62], Thus, the half-life of decomposition of A-(hydroxymethyl)benzamide (HOCH2-NH-CO-C6H5), a pro-moiety of 8.56 discussed below, was 160 h at pH 7.4 and 37° [69]. This means that a small amount of formaldehyde may be formed in vivo. 

T. Ogiso, M. Iwaki, T. Tanino, T. Nagai, Y. Ueda, O. Muraoka, G. Tanabe, Pharmacokinetics of Indomethacin Ester Prodrugs Gastrointestinal and Hepatic Toxicity and the Hydrolytic Capacity of Various Tissues in Rats , Biol. Pharm. Bull. 1996, 19, 1178 — 1183. 

Acetyls alley lie acid was shown to prevent cirrhosis under certain experimental conditions [125]. Naproxen and indomethacin partially protected against LPS and D-galactosamine-in-duced hepatotoxicity [126] Acetylsalicylic acid and ibuprofen were also protective in endo-toxic shock [127]. Endotoxaemia is one of the complications in cirrhotic patients [128] and is probably caused by an impaired ability of the liver to take up and detoxify gut-derived LPS [116]. The presence of portosystemic shunts in cirrhotic patients may also contribute to this spill-over of LPS into the systemic circulation [129]. NSAIDs, however, are also reported to provoke deleterious effects on renal function in cirrhosis [130], and can therefore not be used in cirrhotic patients. Cell-specific delivery of NSAIDs to SECs and/or KCs may make application of these drugs in cirrhosis feasible by circumventing the renal side-effects. 

Lithium intoxication can be precipitated by the use of diuretics, particularly thiazides and metola-zone, and ACE inhibitors. NSAIDs can also precipitate lithium toxicity, mainly due to NSAID inhibition of prostaglandin-dependent renal excretion mechanisms. NSAIDs also impair renal function and cause sodium and water retention, effects which can predispose to interactions. Many case reports describe the antagonistic effects of NSAIDs on diuretics and antihypertensive drugs. The combination of triamterene and indomethacin appears particularly hazardous as it may result in acute renal failure. NSAIDs may also interfere with the beneficial effects of diuretics and ACE inhibitors in heart failure. It is not unusual to see patients whose heart failure has deteriorated in spite of increased doses of frusemide who are also concurrently taking an NSAID. 

Many interactions with lithium have been described. Thiazide and loop diuretics decrease lithium excretion predisposing to serious lithium toxicity. Also non-steroidal anti-inflammatory agents, especially indomethacin can increase the risks for lithium toxicity due to decreased renal excretion. 

Apart from the salicylates NSAIDs include several classes of weak acids like propionic acid derivatives such as ibuprofen, carprofen, fenbufen, fenoprofen, flurbiprofen, ketorolac, loxoprofen, naproxen, oxaprozin, tiaprofenic acid and suprofen. Phenylbutazone is the most important representative of the pyrazolon derivatives which have a bad reputation for their risk of potentially fatal bone-marrow toxicity. To the acetic acid derivatives belong in-domethacin, diclofenac and sulindac. Sulindac is a pro-drug with less toxicity than indomethacin. The enolic acids include piroxicam, droxicam and tenoxicam. Meloxicam is an analog of piroxicam and has a high selectivity for COX-2. 

Indomethacin (Indocin) is used in the treatment of acute gouty arthritis, rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. It is not recommended for use as a simple analgesic or antipyretic because of its potential for toxicity. While indomethacin inhibits both COX-1 and COX-2, it is moderately selective for COX-1. It produces more CNS side effects than most of the other NSAIDs. Severe headache occurs in 25 to 50% of patients vertigo, confusion, and psychological disturbances occur with some regularity. GI symptoms also are more frequent and severe than with most other... 

Thus, NSAIDs tend to be differentiated on the basis of toxicity and cost-effectiveness. For example, the gastrointestinal and renal side effects of ketorolac limit its use. Some surveys suggest that indomethacin or tolmetin are the NSAIDs associated with the greatest toxicity, while salsalate, aspirin, and ibuprofen are least toxic. The selective COX-2 inhibitors were not included in these analyses. 

Although colchicine is more specific in gout than the NSAIDs, NSAIDs (eg, indomethacin and other NSAIDs [except aspirin]) have replaced it in the treatment of acute gout because of the troublesome diarrhea sometimes associated with colchicine therapy. Colchicine is now used for the prophylaxis of recurrent episodes of gouty arthritis, is effective in preventing attacks of acute Mediterranean fever, and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Although it can be given intravenously, this route should be used cautiously because of increased bone marrow toxicity. 

The use of indomethacin to block benzene toxicity has led to data that indicate that myelotoxicity may involve the destruction of stromal macrophages that produce IL-1, a cytokine essential for hematopoiesis (Renz and Kalf 1991). External administration of recombinant IL-1 to mice prior to benzene administration prevents the myelotoxicity, presumably by providing a source of the cytokine (Renz and... 

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