Medicines NSAIDs

Commission on Human Medicines. NSAIDs letter to healthcare professionals Safety of selective and non-selective NSAIDs. October 2006. Available at htty //www.mhia.gov.uk/ home/idcplg IdcService=SS GET PAGE nodeId=227 (accessed 16/08/07). 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

G. Weissmann, NSAIDs Aspirin and Aspirin-Like Drugs, in Cecil Textbook of Medicine, 19th ed., ed. J. B. Wyngarden, L. H. Smith, J. C. Bennett (Philadelphia W. B. Saunders, 1988), 114. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed medicines. Although these compounds represent a very effective class of drugs, their use is associ-... 

These drugs are the most prescribed medicines in the world. For certain NSAIDs, ibuprofen and indomethacin, there has been shown a dose response relation for renal failure risk. For individual NSAIDs, those with longer half lives than 12 hours have proved to be more dangerous. There has not been shown any clear advantages for selective cox-2-inhibition to the more unselective in this aspect. 

Sultan, M., Stecher, G., Stoggl, W. M., Bakry, R., Zahorski, P, Huck, C. W., El Kousy, N. M., and Bonn, G. K., Sample pretreatment and determination of non steroidal anti-inflammatory drugs (NSAIDs) in pharmaceutical formulations and biological samples (blood, plasma, erythrocytes) by HPLC-UV-MS and micro-HPLC, Current Medicinal Chemistry 12(5), 573-588, 2005. 

Table 2. Medicines used in nociceptive pain conditions — paracetamol and NSAID ...

The authors reported that two other cases of metformin-associated lactic acidosis with concurrent NSAID therapy have been reported to the Committee on Safety of Medicines in the UK. Indometacin can impair kidney function and may have done so in this case. Phenformin can cause tubular damage and oliguria in animals (145) and so it is conceivable that metformin-induced renal damage may also have contributed. 

The development of aspirin was a significant landmark in the history of medicine because it stimulated the development of a family of medicines, collectively known as the nonsteroidal antiinflammatory drugs (NSAIDs). NSAIDs such as ibuprofen, naproxen, and sulindac are valuable drugs used for the alleviation of pain, inflammation, and fever, and they are commonly prescribed for the treatment of rheumatoid disorders such as arthritis. The world market for NSAIDs now exceeds 6 billion (Vainio and Morgan, 1997). 

NSAIDs are the most widely used analgesics in human and veterinary medicine, and all have some toxic potential. NSAIDs cause an acute reduction in renal function, which leads to nephrotoxic acute renal failure. The abnormalities related to renal function associated with NS AID... 

Several NSAIDs such as ibuprofen, phenylbutazone, and mefenamic acid have been reported to be a contaminant in several alternative medicine preparations and these compounds cause renal toxicity as described before (Saper et al, 2004 Gabardi et al., 2007). 

Piroxicam (84, Feldene in the US), a non-selective COX inhibitor with both analgesic and antipyretic properties, is one of the most used NSAIDs and serves as prototype of the oxicam family. This drug is utilized to relieve the symptoms of arthritis, menstrual pains or cramps and fever. It is also used in veterinary medicine to treat certain neoplasias expressing COX receptors, such as bladder, colon and prostate cancers. Variation on the structure of piroxicam has produced several other analogues with the benzene ring replaced by a thiophene ring and/or derivatives of the amide moiety, including meloxicam (85, a thiazole amide), isoxicam (86, an isoxazole amide), tenoxicam (87a, a thiophene derivative) and lornoxicam (87b, a chlorothiophene derivative). 

Many medicines affect performance, not only psychotropic drugs (amongst which sedative antidepressants, benzodiazepines, hypnotics and antipsychotics are the most obvious examples) but also antihistctrnines, antimuscaiinics, analgesics including some NSAIDs, (e.g. indomethacin), antiepileptics, antidiabetics (hypoglycaemia) and some antihypertensives. Alcohol and caimabis are discussed on pages 178 and 190. 

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). 

Advanced age is one of the most important risk factors for AKI. Feest and colleagues performed a prospective 2-year study of450,000 patients and found that more than 70% of AKI cases occurred in patients age > 70 years [70]. In those patients aged 80-89 years, the risk of AKI was 56-foId higher than the reference population of those aged < 50 years. Certainly, much of this risk is attributable to co-morbidities seen in the elderly (impaired renal reserve due to chronic kidney disease, impaired left ventricular dysfunction, diabetes meUitus, concomitant medicine use such as non-steroidal anti-inflammatory agents (NSAIDS), etc). 

The discovery and commercialization of asprin over 100 years ago, and the introduction of other non-steroidal anti-inflammatory drugs (NSAIDs) have had a profound impact on the practice of medicine and the treatment of the inflammatory conditions. Widespread access and over-the-counter availabihty of these agents has lead to the impression... 

Johnsen SP, Larsson H,Tarone RE etal. Riskof hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs a population-based case-control study. Archives of Internal Medicine 2005 65 978-984. 

LeeTA, Bartle B, Weiss KB, LeeTA, Bartle B, Weiss KB. Impact of NSAIDS on mortality and the effect of preexisting coronary artery disease in US veterans. American Journal of Medicine 2007,120 98-16. 

HeerdinkER, Leufkens HG, Herings RMet al. NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Archivesof Internal Medicine 1998,158 1108-1112. 

Page J, Henry D, Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients an underrecognized public health problem.. Archivesof Internal Medicine 2000,160 777-784. 

Of particular importance to lithium patients is a well-documented interaction with nonsteroidal antiinflammatory drugs (NSAIDs). These drugs may increase serum lithium concentrations by as much as 60% because of their effect of reducing renal lithium clearance. The risk of lithium toxicity is of major clinical importance due to the widespread use of NSAIDs by general practitioners who may not be aware of the problem, and even as over-the-counter medicines. Careful monitoring of serum lithium concentrations is essential when these drugs are combined (193). 

Hawkey C J, Karrasch J A, SzczepanskI L et al 1998 Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. New England Journal of Medicine 338 727-734 Henninger R W, Horst J 1997 Magnesium toxicosis in two horses. Journal of the American Veterinary Medical Association 211 82-85... 

Furthermore, there is evidence that NSAIDs may work synergistically with opiates to induce analgesia. Therefore, NSAIDs will continue to be one of the most commonly prescribed classes of drugs in veterinary medicine. 

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