Hepatotoxicity NSAIDs

HCQ cimetidine increases serum levels absorption decreased when taken with kaolin and magnesium trisilicate MTX decreases effect of phenytoin concomitant use with other hepatotoxic drugs can increase risk of hepatotoxicity. NSAIDs can increase half-life and prolong excretion of MTX however, low doses of MTX with NSAIDs for RA are allowed with close monitoring. 

Acetaminophen is usually well tolerated, but potentially fatal hepatotoxicity with overdose is well documented. It should be used with caution in patients with liver disease and those who chronically abuse alcohol. Chronic alcohol users (three or more drinks daily) should be warned about an increased risk of liver damage or GI bleeding with acetaminophen. Other individuals do not appear to be at increased risk for GI bleeding. Renal toxicity occurs less frequently than with NSAIDs. 

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. 

The first major new drug to be approved and withdrawn from the market by the CSD was ibufenac, the first of the non-steroidal antiinflammatory drugs (NSAID) to be marketed. Ibufenac was a precursor of ibuprofen and its use in the United Kingdom was associated with serious and frequent hepatotoxicity. Two other drug withdrawals (also approved during their tenure by CSD) were chlormadinone and fenclozic acid. 

Methefrexate (Rheumatrex Dose Pack, Trexall) [Antineeplastic/ Antirheumatic (DMARDs), Immunosuppressant/ Antimetabolite] warning Administration only by experienced healthcare provider do not use in women of childbearing age unless absolutely necessary (teratogenic) impaired elimination w/ impaired renal Fxn, ascites, pleural effusion severe myelosuppression if used w/ NSAIDs hepatotox can induce lung Dz ... 

Uses AML, ALL, CML Action Purine-based antimetabolite (substitutes for natural purines interfering w/ nucleotide synth) Dose 2-3 mg/kg/d X in severe renal/hepatic impair Caution [D, -] Contra Resistance to mercaptopurine Disp Tabs SE X BM (leucopenia/thrombocytopenia), NA /D, anorexia, stomatitis, rash, hyperuricemia, rare hepatotox Interactions t Bleeding W/ anticoagulants, NSAIDs, salicylates, thrombolytics EMS t Effects of anticoagulants/salicylates/ NSAIDs T risk of Infxn OD May cause NA, hypotension, and diaphoresis symptomatic and supportive... 

Aspirin, 325-650 mg every 4-6 hours Bayer Aspirin, Ecotrin, Bufferin, various generic children who cannot chew or swallow tablets. Do not exceed a total daily acetaminophen dose of 4 g (2 g/d in regular alcohol users). Aspirin should be used cautiously in certain individuals (see text). Use of OTC products containing aspirin, other salicylates, acetaminophen, ibuprofen, or naproxen may increase the risk of hepatotoxicity and gastrointestinal hemorrhage in individuals who consume 3 or more alcoholic drinks daily. Long-term continuous use of NSAIDs may increase the risk of heart attack or stroke. 

Polypharmacy For example, NSAIDs if used with other hepatotoxic drugs increase the risk of hepatotoxicity. Isoniazid with rifampicin or pyrazinamide... 

Hepatotoxicity is an extremely rare but unpredictable side effect associated with most NSAIDs. There is some suggestion that diclofenac and sulindac have the highest risk, whereas ibuprofen has the lowest risk. 

Although NSAID-induced hepatotoxicity can occur at any time, it usually occurs within six to 12 weeks of the start of treatment [28]. Effects range from asymptomatic rises in LFTs to, rarely, fulminant hepatic necrosis resulting in death or the need for transplantation [30]. Mortality has been estimated at <1/100 000 patient-years of exposure... 

The mechanism for most NSAID-induced hepatotoxic reactions is idiosyncratic, either immunological (hypersensitivity) or metabolic in type [29]. 

Given the potential hepatotoxicity of NSAIDs, some have suggested that raised transaminase levels are an early indicator of reversible liver toxicity during prolonged NSAID courses, and therefore should be monitored reasonably closely [31]. However, it should be noted that minor subclinical abnormalities in LFTs rarely represent acute liver injury [32, 33]. 

Given the rare but potential hepatotoxic risk with NSAIDs, patients should be instructed to be aware of the symptoms of hepatotoxicity and to report fatigue, malaise, anorexia, nausea and vomiting. 

Many centres prefer to avoid using NSAIDs in any patient with liver disease because of their side-effect profile. However, if the liver disorder is purely cholestatic in origin and the disease has not progressed to cirrhosis and portal hypertension, NSAIDs may be an option. Any risk-benefit assessment should consider the potential risk of hepatotox-icity, albeit rare. There are no specific contraindications in this patient because they are not cirrhotic, do not have deranged clotting, and are unlikely to be at increased risk of deteriorating renal function. If deemed necessary an NSAID could be used cautiously. 

While the pattern of alclofenac toxicity resembles that of other NSAIDs, the frequency of adverse effects differs widely. Allergic reactions have been reported more frequently and skin rashes have been particularly common. Hypersensitivity reactions, including anaphylactic shock, severe generalized vasculitis, hepatotoxicity, and nephrotoxicity, have been observed. Alclofenac has therefore been withdrawn in several countries (1). Blood dyscrasias and neurological symptoms are rare. 

About 5% of patients have itching, rashes, or erythema multiforme (3). Circulating immune complexes have been found (4). The UK s Committee on Safety of Medicines issued a warning about the high rate of cutaneous adverse reactions with fenbufen and noted that some are followed by severe illnesses (SEDA-13,72) (SEDA-14, 94) (SEDA-15, 100). Toxic epidermal necrolysis, a life-threatening reaction, has also been reported (SEDA-6, 96) (SEDA-8, 106) and a 1981-85 review on its incidence in France identified fenbufen as the third most common NSAID, after isoxicam and oxyphenbutazone, as a causal factor (5). Another severe skin reaction with laboratory evidence of hepatotoxicity has been described (SEDA-22,115). 

Boelsterli UA. Mechanisms of NSAID-induced hepatotoxicity focus on nimesulide. Drug Saf 2002 25(9) 633-48. 

Because of hepatotoxicity, particularly problematic in the elderly, benoxaprofen was withdrawn from the market in 1982, and ibufenac is not on sale for the same reason. Serious hepatocellular reactions have been well-documented with phenylbutazone and the death rate is high (143). Hepatotoxicity has been reported with all of the structural classes of NSAIDs. 

Nearly all NSAIDs have the potential to induce hepatic injury, although this effect has not been documented in the horse. In other species, hepatic injury associated with most NSAIDs is an idiosyncratic reaction with a low incidence of occurrence. The hepatotoxicity of carprofen in dogs, for example, was not observed until the NSAID was in widespread use in the USA (MacPhail et al 1998). The heptatoxicity of a few compounds, such as aspirin and acetaminophen (paracetamol), however, is a dose-dependent side-effect that is well described (Fry Seeff 1995). 

Although the horse appears to be refractory to the hepatic effects of most NSAIDs, their hepato-toxic potential should be considered, especially when they are concomitantly administered with other potentially hepatotoxic agents, such as fluoroquinolones, potentiated sulfonamides or anabolic steroids. In addition, many herbal preparations are potential hepatotoxic agents and clients may administer these compounds concurrently with prescribed NSAIDs without consulting their veterinarian. Echinacea and kava kava products, for example, are reported to be potential hepatotoxins and both are used in herbal remedy products that claim to produce calming or sedating effects in horses (Abebe 2002). 

Goldkind L, Laine L. A systematic review of NSAIDs withdrawn from the market due to hepatotoxicity Lessons learned from the bromfenac experience. Pharmacoepidemiol DrugSaf. 2006 15(4) 213-220. 

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