The discovery of non-steroidal anti-inflammatory drugs (NSAIDs) was one of the most soothing discoveries in the history of drug development. It was nearly 33 years ago, when mechanism of action of these NSAIDs was discovered and since then hundreds of NSAIDs were clinically developed for human kind's one of the most suffered 'pain'. Vane J.R. in 1971 first discovered NSAIDs inhibit the key enzyme of prostaglandin biosynthesis, cyclooxygenase (COX).
Prostaglandins are responsible for inflammatory changes at various sites in the human body, as well as having other functions relating to platelets, renal tissue and the gastrointestinal mucosa. COX is a pharmacologically important enzyme that has a role in blood clotting, inflammation etc. In the past years, with the advancement of genetic engineering and increasing understanding genetic make up of the COX enzymes, two isoforms of COX (COX-l and COX-2) have been discovered. Further it lead to defining their respective roles in the functionalization in the normal human physiology as well as in the altered physiological conditions like inflammation. The relationship between these two major forms and their products, however, has been largely undefined.
Studies on COX-1 enzymes expressed its role in the gastrointestinal tract, kidneys and platelets. COX-1 enzyme was referred as "Housekeeping" which maintains homeostasis.
Its regulation is constitutive and is found in all tissues. COX-2 enzyme expressed its role in inflammation. One of the most important functions of COX-2 is that it mediates inflammation. It was found expressed in brain, renal cortex, and medullary interstitial cells. Major sites of inflammation were found to be macrophages, monocytes, synovial cells, leukocytes and fibroblasts. One of the noted facts about the COX-2 enzyme is, it is inducible. It gets rapidly induced (within 1-3 hours) in sites of inflammation by cytokines, growth factors, endotoxins etc.
With these defined roles, search was begun for specific inhibitors of COX-2 as traditional NSAIDs inhibit prostaglandin synthesis by nonselectively blocking both COX-1 and COX-2, resulting in therapeutic as well as toxic effects, particularly gastric ulcers and bleeding.
Selectivity related issues:
Based on selectivity, the NSAIDs were reclassified as
I) COX-1-Specific Inhibitors like Low-dose aspirin (Target COX-1 without measurable effects on COX-2)
II) COX Nonspecific Inhibitors like Ibuprofen, Naproxen etc (Demonstrate no meaningful differences in inhibition of COX-1 versus COX-2)
III) COX-2 Preferential like Meloxicam, Nimesulide etc (some analgesic or anti-inflammatory activity; at higher doses, inhibition of COX-1 may be seen)
IV) COX-2-Specific Inhibitors like Celecoxib, Rofecoxib, Valdicoxib etc (Spare COX-1).
The launch of the COX-2 selective NSAIDs was based on two distinct facts. The first states the advantage over major adverse effects limiting the usefulness of nonselective NSAIDs such as gastrointestinal symptoms, ulcers, ulcer complications and ulcer complications leading to death. The second is, COX-2 selective NSAIDs are associated with less gastrointestinal toxicity than nonselective NSAIDs. At the time of the launch of COX-2 selective NSAIDs neither of these facts were proven.
Potential problems of COX-2 selective NSAIDs
Design of the specific COX-2 selective NSAIDs was based on reducing the adverse effects related to non-specific NSAIDs so as to achieve the better clinical outcome. The major limitations or adverse effects of conventional NSAIDs are Gastrointestinal like Nausea, dyspepsia, ulceration, enteropathy, strictures, bleeding, perforations, Renal like Sodium/ fluid retention, hypertension, hyperkalemia, acute renal failure, Platelet related like inhibition of aggregation leading to bleeding potential, Respiratory like bronchospasm with aspirin, triad hypersensitivity with or without nasal polyposis, bronchospasm, rhinitis, asthma, rash etc.
Renal toxicity and selective COX-2 inhibitors:
Traditional NSAIDs have problems with respect to solute homeostasis, maintenance of renal perfusion and glomerular filtration. It is now well known that COX-2 is very well expressed in the renal tissues. In particular, human nephrectomy and autopsy specimens have shown presence of COX-2 enzyme at glomerular podocytes, afferent arterioles, and the endothelial cells of arteries and veins. It clearly suggests its role in renal hemodynamics, at the macula densa, thick loops of Henle, and medullary interstitial cells, thus have important role in salt and water balance.
The treatment with selective COX-2 NSAIDs thus might compromise renal function, and thus raising the question of safety over nonselective COX inhibitors. Many clinical studies have been published in relation to the limitations of COX-2 inhibitors for the their renal safety. In a randomized clinical trial, 36 healthy elderly persons received the COX-2 inhibitor rofecoxib at 50 mg/day, the nonspecific NSAID indomethacin at 50 mg tid or placebo for two weeks. All subjects were maintained on a high-sodium diet (200 mmol/day). Both rofecoxib and indomethacin induced a significant decrease in urinary sodium excretion, which returned to baseline after approximately the third day of drug therapy. Many clinical studies show that both rofecoxib and celecoxib produce qualitative changes in urinary prostaglandin excretion, glomerular filtration rate and sodium retention similar to those caused by nonselective NSAIDs.
Thrombosis and selective COX-2 inhibitors
From the physiology of COX-2 enzyme, the problems in thrombosis can be well thought. Unlike conventional nonspecific NSAIDs, specific COX-2 inhibitors do not inhibit platelet activation. However, these agents significantly reduce systemic production of prostacyclin. Prostacyclin, which inhibits platelet function and causes vasodilatation, is synthesized by the action of COX-2. On the other hand production of thromboxane A2, a promoter of platelet aggregation & vasoconstriction, is regulated by COX-1.
Patients suffering from connective tissue diseases (CTD), are susceptible to vasculopathy and thrombosis. These patients often have symptoms of arthritis, inflammation or pain, which requires treatment with anti-inflammatory drugs. Studies with selective COX-2 inhibitors in these types of patients have shown that, patients are at risk of thrombosis and needs to be monitored. In one of the published study reports, the relative risk of developing a thrombotic cardiovascular event (e.g. myocardial infarction, unstable angina, sudden cardiac death, ischemic stroke, transient ischemic attack) was more in the rofecoxib as compared to naproxen treatment.
Inhibiting both COX-1 and COX-2 likely retains the balance. Creating an imbalance of prostanoids in the kidney by selectively inhibiting the COX-2 isoenzyme may result in a greater potential for salt and water retention, hypertension and exacerbation of congestive heart failure that non-specific inhibition.
COX-2 inhibitors and healing process
Human body in response to injury or inflammation produces COX-2 enzyme. The effects of selective COX-inhibitors on healing are published very recently. In June 2002, two scientific articles triggered widespread controversy over the use of COX-2 inhibitors during fracture repair. Researchers at Stanford University Medical Center have found that selective COX-2 inhibitors interfere with the healing process after a bone fracture or cementless joint implant surgery. In another study in rats showed that NSAIDs can noticeably interfere with fracture healing; where this effect was more with the COX-2 selective NSAIDs rofecoxib and celecoxib than with the nonselective NSAID like indomethacin.
COX-2 inhibitors and blood pressure
It is reported that newer COX-2 inhibitors may be an important cause of secondary hypertension. In European United League Against Rheumatism Congress (EULAR), it is reported that osteoarthritis patients taking specific COX-2 inhibitors experienced significant increases in edema and systolic blood pressure. Approximately 800 hypertensive, osteoarthritic patients participated in the six-week, multi-center, randomized, double-blind, parallel study. By the end of the study, approximately 60 percent more patients treated with these drugs exhibited systolic blood pressure elevations.
No doubt COX-2 selective inhibitors shown clear-cut advantages with regard to gastrointestinal side effects as compared to non-specific NSAIDs but many issues with these drugs have to be addressed carefully. In long-term diseases like osteoarthritis, treatment with NSAIDs is life long. Selective COX-2 inhibitors exhibit more cost as being new drugs with so shown 'selectivity' advantage. The major look out should be followed in terms of the patient's safety that going behind the brand of the 'selectivity'.
By looking in to these issues, the question to be answered, therefore, is whether the benefits of these newer selective COX-2 inhibitors are sufficiently great to justify a large increase in the cost of treatment.
The sales of the COX-2 selective drugs all over the world have shown remarkable growth because of hypothesis-based marketing of the pharma companies. But the scientific backgrounds behind the advantages and the disadvantages have to be titrated before being used in the patients. In the treatment with the selective drugs, patient's background and the associated illness have to be assessed properly by taking in to consideration risk benefit ratio.
Patient's economic background has to be considered at priority as many a times non-specific NSAIDs can also benefit with metered adverse reactions. It can also be suggested that traditional NSAIDs could be co-prescribed with a proton pump inhibitor (e.g. omeprazole), with the same clinical effect as a COX-1-sparing drug in many clinical conditions.
One of the important thing, which is known in case of selectivity issue is, in the activity of NSAIDs is ratio of selectivity for COX 1 and COX-2. This relative difference in the selectivity could be of great importance. Development of balanced COX inhibitors could be a new option in the therapeutic regimen where 'relatively selective' with respect to COX-1 and COX-2 enzymes, molecules can be tailor made for many clinical conditions. The invention of this class of drugs could open a new era in the management of pain and inflammatory responses for the human beings.
-- The authors are with Pharmacy Group, Birla Institute of Technology and Science, Pilani, Rajasthan