Diclofenac adverse effects

For highly potent APIs, profound effects can occur at low ng levels, the adverse effect of ethynylestradiol on fish populations is one example [107]. Another example is the development of resistant bacterial strains induced by the release of antibiotics into the environment [112, 113]. Dome et al. [114] concluded that fluoxetine, ibuprofen, diclofenac, propranolol and metoprolol exhibit relatively high acute toxicity to aquatic species. In addition, due to the inherent properties of these chemicals, pharmacodynamic effects were observed in the heart rate of Daphnia magna for the (3-blockers propranolol and metoprolol. 

Pharmacotherapy. Acute relief of inflammatory symptoms can be achieved by prostaglandin synthase inhibitors nonsteroidal anti-inflammatory drugs, or NSAlDs, such as diclofenac, indomethacin, piroxicam, p. 200), and glucocorticoids (p. 248). The inevitably chronic use of NSAlDs is likely to cause adverse effects. Neither NSAlDs nor glucocorticoids can halt the progressive destruction of joints. 

Meloxicam is an enolcarboxamide related to piroxicam that preferentially inhibits COX-2 over COX-1, particularly at its lowest therapeutic dose of 7.5 mg/d. It is not as selective as celecoxib and may be considered "preferentially" selective rather than "highly" selective. The drug is popular in Europe and many other countries for the treatment of most rheumatic diseases and approved for treatment of osteoarthritis in the USA. It is associated with fewer clinical gastrointestinal symptoms and complications than piroxicam, diclofenac, and naproxen. Similarly, while meloxicam is known to inhibit synthesis of thromboxane A2, even at supratherapeutic doses its blockade of thromboxane A2 does not reach levels that result in decreased in vivo platelet function (see common adverse effects above). 

Gastrointestinal ulceration may occur less frequently than with some other NSAIDs. A preparation combining diclofenac and misoprostol decreases upper gastrointestinal ulceration but may result in diarrhea. Another combination of diclofenac and omeprazole was also effective with respect to the prevention of recurrent bleeding, but renal adverse effects were common in high-risk patients. Diclofenac, 150 mg/d, appears to impair renal blood flow and glomerular filtration rate. Elevation of serum aminotransferases occurs more commonly with this drug than with other NSAIDs. 

Rheumatoid arthritis is a disease that involves inflammation in joints and causes severe pain and immobility. The worldwide scenario indicates that the elderly population suffers the most from this disease. The drugs of choice for treatment of this condition are nonsteroidal antiinflammatory drugs (NSAIDs), which include acetylsalicylic acid, diclofenac sodium, piroxicam, nimesulide, celecoxib, and refecoxib. Therapeutic doses, adverse effects, and precautions are given in the foifowing pages. 

Clinical trial evidence in general appears to support the theory that COX-2 selective inhibitors are as effective as, but have fewer adverse effects than, non-COX-2 selective compounds for example meloxicam is better tolerated than diclofenac or piroxicam. The relative risk of serious gastrointestinal effects (bleeding peptic ulcers) due to rofecoxib (COX-2 selective) was 0.51 compared with conventional NSAIDs. COX-2 selective drugs are yet associated with significant dyspeptic symptoms (indigestion, heartburn), and these effects may result from inhibition of the (protective) constitutively expressed COX-2 in the stomach. 

Adverse effects may be severe with abdominal pain, vomiting and diarrhoea which may be bloody. Renal damage may result and rarely, blood disorders. Large doses cause muscle paralysis. Many patients are unable to tolerate colchicine and use NSAIDs such as indomethacin or diclofenac for an acute attack of gout some patients require oral corticosteroid. 

The incidence of adverse effects related to renal function in CLASS and VIGOR was low and similar (0.9% with celecoxib and 1.2% with rofecoxib). The incidence of increased creatinine and urea nitrogen concentrations was slightly lower in patients taking celecoxib than in those taking ibuprofen or diclofenac. Similar results have been documented in two other clinical trials. The... 

The overall incidence of adverse reactions to diclofenac is about 30%, but less than 1% of patients have to have treatment withdrawn for this reason. The manufacturers analysis of 1966 adverse effects in 987 patients over about 6 years, when over 30 million patients had been treated, provided some interesting quantitative data. Of the total number of adverse reactions, 34% were gastrointestinal and 16% hematological. Worldwide experience with diclofenac showed that the incidences of serious adverse drug reactions in phase III short-term trials (1227 patients) and long-term trials (1173 patients) in the USA were respectively as follows (1) ... 

The frequency of central nervous system adverse effects is 1-9%. Headache, dizziness, vertigo, insomnia, drowsiness, and agitation have been reported. Hallucinatory symptoms and generalized tonic-clonic seizures have also been described (SEDA-16, 109). Toxic encephalitis can be part of a general toxic reaction (2). Diclofenac provoked aseptic meningitis in patients with systemic lupus erythematosus (SEDA-17,109). 

Gastrointestinal adverse effects are particularly frequent, and affect some 14-25% of patients the incidence of the most serious, peptic ulcer and bleeding were 0.16-0.34% and 0.16-0.17%, respectively (1). A prospective 12-week endoscopic study documented better gastrointestinal tolerability with diclofenac than naproxen (SEDA-20, 92). Upper gastrointestinal hemorrhage has been associated with transdermal application of diclofenac, with massive bleeding in two of four patients (SEDA-21, 104). 

Lonazolac, an arylacetic acid derivative, causes adverse effects like those of other NSAIDs. Gastrointestinal disturbances are followed in frequency by nervous system and skin reactions. The extent of gastrointestinal blood loss is similar to that with diclofenac (1). Cholestatic hepatitis has also been reported (SEDA-8, 106). 

Widespread use of naproxen, sulindac, diclofenac, and diflunisal probably explains why they were the most frequently rmphcated, rather than because they have a greater tendency to cause these adverse effects. NSAIDs differ in their ability to cause adverse skin reactions in terms of both frequency and severity pyrazolones, butazones, and oxicams are most often blamed, and among the arylalkanoic acid derivatives fenbufen and carprofen are most often incriminated. 

The adverse effects profile of suppositories, soluble tablet formulations, and standard capsules are similar (SEDA-13, 83). A parenteral formulation of piroxicam caused somnolence more often than diclofenac in a doubleblind study, but diclofenac provoked more gastric discomfort and nausea than piroxicam. Local adverse effects of both drugs were pain, burning, and induration at the site of injection (SEDA-15, 103). 

Aside from consideration of the relatively uncommon but serious GI adverse effects described above, fewer overall GI complaints from patients are found for COX-2 inhibitors compared to nonspecific NSAIDs. Moreover, celecoxib use was associated with decreased outpatient physician claims for upper GI symptoms compared with other prescription nonspecific NSAIDs. Finally, celecoxib was comparable to a combination of diclofenac and misoprostol in reducing the risk of recurrent GI bleeding in patients who had a prior GI bleed. ... 

In the recent 8000-patient celecoxib long-term arthritis safety study [123], significantly more patients receiving traditional NSAlDs (ibuprofen or diclofenac) experienced clinically significant elevations in serum creatinine and/or serum urea nitrogen levels when compared to celecoxib. In an equally large gastrointestinal safety trial with rofecoxib, the incidence of adverse effects related to renal function for rofecoxib was similar to naproxen (1.2% versus 0.9%, respectively) [124]. When rofecoxib and celecoxib were directly evaluated in elderly hypertensive OA patients who manifested "normal" serum creatinine at the time of study recruitment, the overall incidence of clinically... 

Misoprostol increases the incidence of abdominal pain and diarrhoea when used with diclofenac or indometacin. Isolated cases of neurological adverse effects have been seen with naproxen or phenylbutazone given with misoprostol. However, no important pharmacokinetic interactions seem to occur between aspirin, diclofenac, ibuprofen or indometacin and misoprostol. NSAIDs are reported not to affect the abortive effects of intravaginal misoprostol. 

A higher incidence of abdominal pain, diarrhoea, nausea and dyspepsia occurred when diclofenac was combined with misoprostol. Concurrent use of indometacin and misoprostol also resulted in an increase in frequency and severity of abdominal symptoms, frequency of bowel movements and a decrease in faecal consistency. The most frequent adverse effect of misoprostol alone is diarrhoea, and this may limit the dose tolerated. When using misoprostol with NSAIDs, warn patients about the possibility of increased stomach pain and diarrhoea. Preparations combining diclofenac or naproxen with misoprostol are available. 

Ketoprofen reduced morphine-associated respiratory depression, and did not alter morphine pharmacokinetics. Similarly, diclofenac did not alter morphine pharmacokinetics in one study. Improved pain relief and reduced adverse effects have been found when morphine was given with lomoxicam, ketoprofen, or ketorolac. However, in another, diclofenac slightly increased respiratory depression despite reducing morphine use, possibly because of persistent levels of an active metabolite of morphine. Diclofenac did not affect the pharmacokinetics or analgesic effects of codeine in healthy subjects. Intramuscular diclofenac did not affect the pharmacokinetics of methadone solution in cancer patients. Ibuprofen did not appear to interact... 

One patient taking fenbufen 800 mg had involuntary movements of the neck and upper extremities after taking ofloxacin 600 mg. The pharmacokinetics of ofloxacin 200 mg twice daily were unchanged by ketopro-fen 100 mg daily for 3 days in 10 healthy subjects. The incidence of psychotic adverse effects (euphoria, hysteria, psychosis) in 151 patients on ofloxacin were not increased by the concurrent use of NSAIDs (aspirin, diclofenac, indometacin, dipyrone)."... 

Takeuchi K, Abe K, Yasujima M, Sato M, Tanno M, Sato K, YoidtinagaK. No adverse effect of non-steroidal anti-inflammatory drugs, sulindac and diclofenac sodium, on blood pressure control with a calcium antagonist, nifedipine, in elderly hypertensive patients. TchokuJExp Med (1991) 165, 201-Z... 

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