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Transcript
Drug Question New Height Clinic Pharmacy Ted Williams 2008 Introduction New Height Clinic does not provide opioid analgesics for pain. We rely heavily on NSAIDS, particularly ibuprofen to manage pain. COX-2 inhibitors like Vyoxx and Celebrex have been derided for increasing the risk of cardiovascular events. To what extent do other non-opioid analgesics introduce cardiovascular risks? Pathophysiology Non-steroidal anti-inflammatory (NSAID) medications block the activity of cyclooxygenase (COX) enzymes. Isoenzymes COX-1 and COX-2 have differing effects, with COX-2 being the more inducible form and COX-1 more active at a basal level. Therapeutic effects of analgesia, antipyresia, and anti-inflammation are attributable to both COX-1 and COX-2.1 Most side effects of NSAIDs and COX inhibition are associated with inhibition of COX-1, including platelet aggregation, Gastrointestinal (GI) side effects, renal function changes, and hypersensitivity reactions. GI and renal effects are primarily due to the inhibition of prostaglandin and prostacycline production. Prostaglandins are responsive for regulating GFR, Choloride ion reabsorption in the renal tubules, vasopressin release, and Endothelin-1 release.2 Prostaglandins regulate afferent arteriole tone and thereby regulate GFR. Increases in prostaglandin synthesis produce afferent arteriole smooth muscle relaxation and subsequent vasodilation, leading to increased GFR. In otherwise healthy adults, prostaglandin inhibition is compensated for by the renin-angiotensin system, which also regulates GFR in the renal arterioles.3 In the hypertensive patient, the rennin-angiotensin system is either compromised or its compensatory capacity is compromised. Most antihypertensive medication also work either in the renal tubules (diuretics), on the reninFigure 1. Prostaglandin Cascade angiotensin system (ACE Inhibitors, Angiotensin II affecting hemodynamics Receptor Blockers, Beta Blockers), or affect vascular smooth muscle (non-dihydropyridine calcium channel blockers), further limiting compensatory mechanisms of maintaining GFR. Trials and Studies The Vyoxx debacle gave a bad name to COX-2 selective inhibitors due to their increased risk of cardiovascular events.4 Non-selective COX inhibitors continue to be used widely in patients with and without hypertension. Interestingly, at least one study demonstrated that non-selective COX inhibitors (naproxen) and selective COX-2 inhibitors (celecoxib) have similar effects on prostaglandin levels.2 In normotensive patients, NSAIDs do not cause a clinically or statistically significant increase in blood pressure at doses of 1200mg of ibuprofen daily for 8 days.3 Drug Question New Height Clinic Pharmacy Ted Williams 2008 In hypertensive patients, risk of hypertension due to NSAID use appears to be associated with frequency and duration of therapy and somewhat with dose.3 The Nurses Health Study (NHS) I and II evaluated the use of NSAIDs in women with hypertension from age 31-50years. Relative risk ratio increased in both studies when frequency exceeded 5 days per month and plateaued after 2 weeks of therapy.5,6 These increases were seen with doses as low as 400mg/day. Two seminal meta-analyses by Pope et al7 and Johnson et al8 found that in patients with well controlled hypertension, on low sodium diets, NSAID increased blood pressure by 3.2mmHg. Other studies have reported increases as high as 10mmHg and 12mmHg.3 Although these increase are small, sustained changes of 56mmHg over several years can increase the risk of stroke 67% and CAD 15%. 9 It is important to note that comparable changes in blood pressure are found with other commonly used medications like oral contraceptives (5mmHg).3 Acute renal failure is also a concern when taking NSAIDs, due to selective inhibition of efferent arteriole vasodilation. One large scale nested case-control study from the UK evaluated the effects of prescription NSAID use and the risks of ARF.10 Relative risk of ARF while using NSAIDs is 3.2. This increases with the concurrent use of diuretics (11.6RR), CCB (7.8). Patients with HF and HTN taking NSAID saw an increase in risk of ARF (7.63RR, 6.12RR) when taking NSAIDs vs. HF and HTN patients not taking NSAIDS (2.82RR, 2.09RR). Although most research has been focused on COX-2 seletive inhibitors and NSAIDs, acetaminophen is also a COX inhibitor. Acetaminophen’s effects on renal function have been demonstrated to be similar to other NSAIDs.11 In a study simiar to the NHS design, the hypertensive effects of acetaminophen, NSAIDs, and Asprin were evaluated in otherwise healthy men.12 The results were similar to the NHS results, showing a significant increased risk of hypertension with increasing frequency of use of NSAIDs. Importantly, these risks also increased with the use of NSAIDs and Acetaminophen.. Conclusions Non-opioid and non-steroidal analgesics all work by inhibition of COX enzymes. This shared mechanism leads to similar analgesic effects and side effects for NSAIDs and APAP. Blood pressure is not significantly changed in normotensive patients, but there are statistically and clinically significant changes in patient with hypertension. The risk of ARF is increased in all patients using NSAIDs, with the greatest increases in patients with Heart Failure, Hypertension, and on medications treating hypertension. Patients requiring a non-steroidal, non-opioid analgesic should be monitored carefully when taking either NSAIDs or APAP for fluid retention, increases in blood pressure, and renal function. 1 Goodman and Gilman Chapter 26 Burke, A., Smyth, E., and FitzGerald, G.A., ANALGESICANTIPYRETIC AGENTS; PHARMACOTHERAPY OF GOUT. 2 Gaziano, JM. Nonnarcotic Analgesics and Hypertension. American Journal of Cardiology 2006;97 Suppliment 10E-16E. 3 Wilson, S, Poulter, N. The effects of non-steroidal anti-inflammatory drugs and other commonly used non-narcotic analgesics on blood pressure level in adults. Journal of Hypertension 2006:24:1457-1469 Drug Question New Height Clinic Pharmacy Ted Williams 2008 4 Sequence of Events with VIOXX, since opening of IND http://www.fda.gov/OHRMS/DOCKETS/AC/05/briefing/2005-4090B1_04_E-FDA-TAB-C.htm 5 Dieder, J, et al. Nonnarcotic analgesic use and the risk of hypertension in US women. Hypertension 2002:604-608 6 CurhanGC, Willett WC, Rosner, B, Stampfer, MJ. Frequency of Analgesic Use and Risk of Hypertension in Younger Women. Archives of Internal Medicine 2002;162:2207 7 Pope, JE, Anderson, JJ, Felson, DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Archive of Internal Medicine 1993; 153:477-484 8 Johnson AG, Nguyen TV, Day RO. DO nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Annals of Internal Medicine 1994;121:289-300 9 MacMahon, S, Peto, R, Culter, J, Collins, R, Sorlie, P, NEaton, J et al. Blood pressure, stroke, and coronary heart disease. Part 1. Prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990; 335:765-74 10 Huerta, C, Castellsague, J, Varas-Lorenzo, C, Rodrigues, LAG, Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population. 11 Fored, CM, et al. Acetaminophen, Aspirin, And Chronic Renal Failure. New England Journal of Medicine. 2001;345:25 12 Forman, JP, Rimm, EB, Curhan, GC. Frequency of Analgesic Use and Risk of Hypertension Among Men. Archives of Internal Medicine. 2007;167:394-399