NSAIDS and ACE-inhibitors - LECOM

NSAIDS and ACE-inhibitors

Monday, 21 January 2013

Kathryn Samai, PharmD, BCPS; Spencer Haslam, PharmD Candidate

The concomitant use of NSAIDs and ACE inhibitor (ACEI) has been associated with reducing the anti-hypertensive effects of the ACEI, as well as carrying the potential to inflict acute renal damage. The presumed mechanism of these effects on the kidneys and blood pressure stem from NSAIDs affect on prostaglandins (PG). These effects are typically not seen in normotensive patients or those with normal renal function, but occur more in patients with kidney or blood pressure pathologies.

Traditional NSAIDs target COX-1 and COX-2 for inhibition, while newer, more selective NSAIDs target just COX-2. COX-2 produces PG, which help regulate homeostasis within the kidneys. PGE2 is a tubular PG in the kidneys, where it regulates sodium, chloride, and water transport as well as renal medullary blood flow.1 PGI2 is typically more in the vasculature. The arterioles, tubules, medullary interstitial cells, and mesangial cells of the kidneys produce both PGE2 and PGI2. Because of NSAIDs COX-2 inhibition, both new and older NSAIDs have potential for causing renal adverse effects. These adverse affects, depending on the patient, can include sodium and potassium retention, reductions in GFR, urinary sodium excretion, urinary PGE2, and 6-keto-PGF1α excretion, especially in the elderly of renally insufficient.2,3 In patients with hypertension, COX-2 inhibition may cause worsening of hypertension and edema.1Clinically, there is study-derived data demonstrating the relationship between NSAIDs, ACE inhibitors and these cardiovascular effects. Several of these studies are described below. It is important to note that some of these studies looked at multiple NSAIDs interacting with multiple anti-hypertensive medications, but for the purpose of this article, the focus will be on NSAIDs and ACE inhibitors.

In a study by MacDonald, et al., a comparison of lumiracoxib 100 mg once daily and ibuprofen 600 mg three times daily showed both agents caused changes in mean systemic ambulatory blood pressure (MSABP) in patients receivingconcomitant blood pressure medications. For patients taking ACEI mono-therapy, lumiracoxib resulted in a fall of MSABP by 4.6 mmHg and ibuprofen showed an increase 3.7 mmHg. This was following 4 weeks of treatment with NSAIDs. This might suggest treatment with more selective NSAIDs may be beneficial in terms of blood pressure control.4

A cohort study of 1,204 subjects was conducted to investigate the systolic blood pressure effect of NSAIDs in patients taking various anti-hypertensive therapies. New antihypertensive therapy patients were identified using “The Antihypertensive Drug Database,” and were compared as either “User” receiving “NSAIDs other than low-dose aspirin and acetaminophen” or a “Non-user,” who were not. In the group taking ACEIs, the adjusted difference in systolic blood pressure reduction was 3.85 mmHg (95% CI: 1.16, 6.55) between “User” and “Non-user,” with “User” having a lesser reduction.5

A prospective trial looked at 88 hypertensive patients being treated with lisinopril/hydrochlorothiazide and amlodipine to see the blood pressure effect of concomitant use of ibuprofen, acetaminophen, or piroxicam over a 3-month period. With lisinopril/hydrochlorothiazide, there was a SBP increase of 7.7-9.9% (p<0.001) when ibuprofen and piroxicam was also used.6

A 7-day, randomized, parallel group study conducted by Rossat et al compared 40 salt-depleted men taking celecoxib 200 or 400 mg twice daily, naproxen 500 mg twice daily, or placebo. Celecoxib showed short-term transient decreases in GFR and renal blood flow on day 1 with the 400 mg BID dose. Celecoxib and naproxen both decreased UO, sodium, lithium, and potassium excretion, as well as decreased water excretion.7

In a report by Dixit et al, 15 inpatients (mean 15.2 ± 2.3 years old) were found to have NSAID-induced acute kidney injury from taking the reportedly recommended doses. Of the 15, only one patient had pre-existing renal diseases. From the AKI, the patients experienced one of more of the following: proteinuria, hematuria, elevations in serum creatinine (mean 4.09 ± 4.24 mg/dL), and a mean eGFR 8.2 ± 20.5 mL/min.8

However, this drug-drug interaction is not entirely one-sided. ACE inhibitors are also implicated in acute kidney injury and a potential cause of acute renal failure (ARF). Wynckel et al. found ACE inhibitors could cause ARF in many patients without renal artery stenosis, typically who were volume depleted, and accounted for 9% of all acute kidney injury requiring hospitalization. These acute effects were especially prominent in CHF and the elderly.9

While there is evidence suggesting NSAID’s potential to increase blood pressures of both hypertensive and normotensive patients, pain is also implicated in this issue. Pain causes a variety of stresses on the body, resulting in increased sympathetic activity and vascular resistance, heart rate, and consequently, blood pressure. Important things such as quality of life and sleep patterns are also affected by pain, which can be detrimental to a patient’s overall health outcome, especial in terms of acute care.10 This is important in weighing the risk vs. benefit of using NSAIDs for pain control. While there are other options for the management of pain (ie. acetaminophen, tramadol, opioid analgesics), some of these options carry their own adverse effects to be avoided (ie. addiction, tolerance, liver toxicity, CNS effects).

So who should be receiving combination NSAID and ACE inhibitor therapy? The above studies suggest that combination therapy has the potential to elevate blood pressure, with perhaps COX-2 selective agents having less of this effect. There is also evidence of acute kidney injury in both NSAID and ACE inhibitor. Patients at higher risk for elevation in blood pressure from NSAID use are those with pre-existing hypertension, while those at higher risk for renal adverse effects from NSAIDs include having liver dysfunction, renal dysfunction, CKD, salt depletion, hypovolemia, CHF, nephrotic syndrome, and those with pronounced proteinuria.1 Recommendations for this combination of therapy are as follows:

For controlled hypertensive patients with healthy renal function, the combined use of NSAIDs and ACE inhibitors can be recommended. If combination therapy is needed in patients with impaired renal function and/or in those with less-controlled hypertension, therapy can still be recommended, however, regular monitoring of serum creatinine, GFR, and blood pressure will be warranted under those circumstances. If negative changes in renal or BP parameters are seen after administration of NSAID therapy, discontinuation of the NSAIDs should be considered to see if the values normalize, then alternative therapies to NSAIDs should be considered.

  1. Hörl, Walter H. Nonsteroidal Anti-Inflammatory Drugs and the Kidney. Pharmaceuticals 2010; 3:2291-2321.
  2. Whelton, A.; Schulman, G.; Wallemark, C.; Drower, E.J.; Isakson, P.C.; Verburg, K.M.; Geis, G.S. Effects of celecoxib and naproxen on renal function in the elderly. Arch. Intern. Med. 2000; 160:1465–1470.
  3. Swan, S.K.; Rudy, D.W.; Lasseter, K.C.; Ryan, C.F.; Buechel, K.L.; Lambrecht, L.J.; Pinto, M.B.; Dilzer, S.C.; Obrda, O.; Sundblad, K.J.; et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann. Intern. Med. 2000; 133:1–9.
  4. MacDonald, TM; Richard, D; Lheritier, K; krammer, G. The effects of lumiracoxib 100 mg once daily vs. ibuprofen 600 mg three times daily on the blood pressure profiles of hypertensive osteoarthritis patients taking different classes of antihypertensive agents. Int J Clin Pract. 2010; 64:746–755.
  5. Ishiguro, C.; Fujita, T.; Omori, T; et al. Assessing the Effects of Non-steroidal Anti-inflammatory Drugs on Antihypertensive Drug Therapy Using Post-Marketing Surveillance Database. J Epidemiol2008; 18:119-124.
  6. Pavli evic , I; Kuzmanic , M; Rumboldt, M; et al. Interaction Between Antihypertensives and NSAIDs in Primary Care: A Controlled Trial. Can J Clin Pharmacol, 2008; 18:e372-e382
  7. Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects [abstract]. Clin Pharmacol Ther 1999; 66:76–84.
  8. Dixit, M; Doan, T; Kirschner, R; et al. Significant Acute Kidney Injury Due to Non-steroidal Anti- inflammatory Drugs: Inpatient Setting. Pharmaceuticals 2010; 3:1279-1285
  9. Wynckel A, Ebikili B, Melin JP, et al. Long-term follow-up of acute renal failure caused by angiotensin converting enzyme inhibitors. Am J Hypertens 1998; 11:1080–1086.
  10. Middleton, Carolyn. Understanding the physiological effects of unrelieved pain. NursingTimes.net, 2003; 99(37):28.