Drug Combination: Potential Serious Consequences of the Combination - Essay Example

POTENTIAL SERIOUS CONSEQUENCES OF THE COMBINATION OF THE DRUGS USED IN THE TABLE Best combination: Aspirin given before Ibuprofen, the mean % inhibition of platelet aggregation is 100% at the end of 2 hr and there is no considerable decrease at the intervals of 4, 6, 12 and 24 hrs. At the end of 24 hrs the mean % inhibition of platelet aggregation falls only up to 97.9%.This is appears to the safest combinations as there is no considerable fall in the platelet aggregation and hence the anti platelet activity of aspirin is not lost. Moderate Combinations: The other combinations like Aspirin before Rofecoxib, Rofecoxib before aspirin and Diclofenac before aspirin2x daily are similar in sense that as all of the three have good mean % inhibition of platelet aggregation (99.8%, 97.3 and 97.8% respectively) at 2 hr starting point; however there is slow increase at the intervals 4, 8, 12 and 24 hr (almost 100% for three). There is no risk for cardiac patients as the cardio-protective effect of aspirin is not lost in all three combinations, in fact its effect have been increase with intervals. Risky Combination: Residual two combinations Ibuprofen before Aspirin and Aspirin before ibuprofen 3x daily, they are similar in the sense both demonstrate very low mean % of inhibition of platelet aggregation at the end of 24 hr interval (3.9 and 11.7%). A cardiac patient appears at high risk as the cardio-protective effect of the Aspirin is lost due to combination with ibuprofen before aspirin and aspirin before ibuprofen 3x daily. EXPLANATION OF RESULTS ON THE BASIS OF INTERACTIONS OF NSAIDS WITH COX AND ITS ISOENZYMES: As we know cyclooxygenase enzyme is represented by two isoform i.e. COX-1 and COX-2. The COX-1 enzyme is relatively ubiquitous in the body and is the only isoform present in platelets, where it converts arachidonic acid to TxA2 (FitzGerald et al, 2000). COX-1 is also the main COX isoform in gastric mucosa, where it is the predominant source of cytoprotective PGs (Warner TD et al, 1999). Where as COX-2 isoform is expressed mainly during pathophysiological conditions. NSAIDS acts on both isoform of COX enzymes COX-1 and C0X-2. Best combination: Aspirin given before Ibuprofen is safest as discussed earlier due to the retained aspirin action in spite of Ibuprofen (Anthony, 2002). Aspirin given before Ibuprofen, acts as an irreversible inhibitor of platelet aggregation, hence aspirin is able to maintain its irreversible binding property irrespective of ibuprofen as it has access the site of action prior to the Ibuprofen, hence can be considered to be the safest combination. Moderate Combinations: Combinations like Aspirin before Rofecoxib, Rofecoxib before aspirin and Diclofenac before aspirin2x daily are similar in results as discussed earlier. However there mode of actions vary. Aspirin before Rofecoxib and Rofecoxib before aspirin combinations indicate that Rofecoxib has no effect on COX-1, hence Aspirin given before or after the Rofecoxib show no decline in the % of inhibition of platelet aggregation. Rofecoxib did not influence the effects of aspirin. Cyclooxygenase-2 inhibitors bind to a side pocket that is present in the hydrophobic channel of cyclooxygenase-2 but not in that of cyclooxygenase-1 (Luong et al, 1996). Diclofenac before aspirin2x daily act in different manner, though diclofenac has an action on the cox-1 but the irreversibility property of aspirin is not lost, may be due to diclofenac inability to block the aspirin entry into the site of action. This lack of interaction may reflect the lower potency and shorter duration of action of the diclofenac regimen (Catella-Lawson et al, 2001). Risky Combination: Remaining two combinations Ibuprofen before aspirin and Aspirin before ibuprofen 3x daily, they are similar in the sense both show very low % of inhibition of platelet aggregation. This has led the patient at risk of stroke and other serious complications. Ibuprofen before aspirin, as we know ibuprofen has the binding sites on the cox-1 similar to that of aspirin and it binds reversibly denying access to the aspirin, resulting in a decline in mean % of inhibition after a period of time. Aspirin before ibuprofen also demonstrate decline in mean % of inhibition even though aspirin is administered before Ibuprofen, this may be due to prolong administration of ibuprofen, which has competitively taken away the effect of aspirin. Thus, the inhibitory effects of daily low-dose aspirin on platelets are competitively inhibited by the prolonged use of multiple daily doses of ibuprofen, even when aspirin is administered before the first dose of the NSAIDs (Catella-Lawson et al, 1996). These results are consistent with competitive inhibition by NSAIDs of the access of aspirin to the acetylation site in plateletcyclooxygenase-1 (Loll et al, 1995) MECHANISM UNDERLYING THE REPORTED HIGH RISK OF ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS TREATED WITH COX2 INHIBITORS FOR ACUTE INFLAMMATION CAUSED BY ARTHRITIS: Cyclooxygenase-1 is constitutively expressed in cultured endothelial and vascular smooth-muscle cells. In Rheumatoid Arthritis, COX-2 inhibition will serve the purpose of treating inflammation and pain. Increased expression of COX-2, but not of COX-1, has been demonstrated in rheumatoid synovial tissues in vivo (Crofford et al, 1994). The expression of cyclooxygenase-2 is increased by cytokines, growth factors, phorbol esters, and lipopolysaccharide in both types of cells and by injury to smooth-muscle cells (FitzGerald et al, 2001). TABLE 2: Ibuprofen as expected has superior mean % of inhibition of platelet aggregation than that of celecoxib due its ability to inhibit both TxA2 & TxB2. This was expected as Ibuprofen being a non-selective inhibitor of COX has much better mean % of inhibition than that of celecoxib, However celecoxib has some extent of inhibition of platelet aggregation which is attributed to its action on TxB2 as it has both COX-1 & COX-2 sites and hence a healthier mean % of inhibition than that of placebo. Nonetheless, it does not modify TxA2-dependent platelet aggregation, reflective of its modest inhibitory effect on COX-1 (McAdam et al, 1999). COX2 inhibition was associated with decreased Ang II-stimulated renal PGE2 and PGI2 production (Zhonghua et al, 2002 ). Prostacyclin is the major product of endothelial cell cyclooxygenases (Moncada et al, 1981). Urinary excretion data of PGI-M (PGI2) indicates that celecoxib interferes with the excretion of PGI-M which in turn will lead to series of chain reactions and finally ending up with increase blood pressure. By blocking PGE2 and PGI2 synthesis, COX2 inhibitors simultaneously enhance epithelial salt absorption and further constrict vascular resistance beds. These events could conspire to result in hypertension and edema in humans (Zhonghua et al, 2002). FitzGerald & Patrono (2001) suggests that despite the potential difference in COX-2 specificity, both agents induce similar selective suppression of systemic prostacyclin without a concomitant inhibition of platelet aggregation (cited by Anthony N, 2002). In summary, coxibs interact with vascular physiology by inhibiting synthesis of prostacyclin by vascular endothelial cells. This effect is seen with traditional NSAIDs as well, but nonspecific COX inhibitors additionally suppress COX-1-mediated platelet production of TxA2 (Anthony N, 2002). The most compelling evidence regarding the cardiovascular risks of rofecoxib was provided by another randomized, double-blind, placebo-controlled clinical trial that assessed the role of rofecoxib (rofecoxib 25 mg daily vs placebo) in adenomatous polyposis prevention (Bresalier et al, 2005). Panagiotis et al (2005) states that: "multiple lines of evidence indicate that COX-2 inhibitors are associated with an increased risk of adverse cardiovascular outcomes, which is mostly evident in patients with established atherogenic disease". Wallberg-Jonsson et al (1999) suggests that the reasons for increased cardiovascular risk in this patient population seem to include inflammation as the underlying pathophysiology for both RA and atherosclerosis (cited by Doggen et al, 2000). CONCLUSION: In terms of combination it is very obvious that Ibuprofen is interacting with the Aspirin where as diclofenac and Rofecoxib combinations with Aspirin are not showing such interactions. But COX-2 inhibitors have its own reservations when used alone as it appears to have considerable cardio-vascular risk, however further studies may help to establish these out of contention. Rofecoxib (COX-2) combination with Aspirin doesn't seem to have any interaction in terms of mean % of inhibition of platelet aggregation but the risk of its interference with PGI-M (PGI2) when used alone which in turn may lead to Hypertension & Atherosclerosis. Risk of GI bleeding when used in combination with Aspirin should exclude it from the first choice of therapy, a part from its cost of therapy. The best possible choice of therapy as of now appears to be use of Aspirin 2hr before Ibuprofen as this combination is overcoming all the interactions and also serving there foremost purpose of anti-inflammatory and cardio-protective properties. The second choice of therapy is diclofenac before aspirin 2x daily as the diclofenac doesn't appear to interact with Aspirin. If no other combination be considered due to any reasons then COX-2 and Aspirin combination can also be considered. REFERENCES Anthony N (2002). DeMaria NSAIDs, Coxibs, and Cardio-Renal Physiology: A Mechanism-Based Evaluation. [online].Available from: [Accessed 13, Nov 2005] Bresalier RS, Sandler RS, Quan H. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352: 1092-1102. Catella-Lawson, F., Reilly, M.P., Kapoor, S.C., Cucciara, A.J., Marco, S., Tournier B., Vyas, S.N. and Fitzgerald, G.A. (2001). 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