NSAIDs and acetaminophen: Effects on blood pressure and hypertension

INTRODUCTION — Nonsteroidal anti-inflammatory drugs (NSAIDs) have a variety of adverse effects. From a cardiovascular viewpoint, they can both raise blood pressure and affect overall cardiovascular risk.

The effect of NSAIDs and acetaminophen on blood pressure and the development of hypertension will be reviewed here. The cardiovascular effects of NSAIDs as well as their adverse effects in patients with chronic kidney disease are discussed separately. (See "NSAIDs: Adverse cardiovascular effects" and "NSAIDs: Acute kidney injury".)

EFFECT OF NSAIDS ON BLOOD PRESSURE — All NSAIDs in doses adequate to reduce inflammation and pain can increase blood pressure in both normotensive and hypertensive individuals [1]. The average rise in blood pressure is 3/2 mmHg but varies considerably [2-4]. These effects may contribute to the increase in cardiovascular risk associated with the selective cyclooxygenase 2 (COX-2) inhibitors [5]. (See "NSAIDs: Adverse cardiovascular effects".)

In addition, NSAID use may reduce the effect of all antihypertensive drugs except calcium channel blockers [6]. In addition, a small study of Japanese individuals initiating antihypertensive therapy suggested that the effect of NSAID use on beta-blocker efficacy might also be minimal [7]; in that study, the mean difference in systolic pressure reduction comparing NSAID users and nonusers among 364 patients taking beta blockers was only 0.4 mmHg.

The prohypertensive effect is dose dependent and probably involves inhibition of COX-2 in the kidneys, which reduces sodium excretion and increases intravascular volume [6]. Low-dose aspirin has no COX-2-inhibiting or prohypertensive effects. As an example, 75 mg/day of aspirin did not interfere with antihypertensive therapy, as compared with placebo, in 18,790 patients in the Hypertension Optimal Treatment (HOT) study [8]. However, these conclusions cannot be extended to larger doses of aspirin.

EFFECTS OF ACETAMINOPHEN ON BLOOD PRESSURE — Acetaminophen produces its analgesic effect by inhibiting the same cyclooxygenase (COX), prostaglandin H2 synthase, that is the target of NSAIDs and aspirin [9]. However, acetaminophen blocks this enzyme at its peroxidase catalytic rather than at the COX catalytic site. Therefore, the acetaminophen-mediated inhibition is sensitive to changes in the tissue peroxide levels; higher concentrations of peroxide in activated leukocytes and platelets block the effect of acetaminophen on inflammation and platelet thrombosis. However, acetaminophen is able to inhibit prostaglandins in the central nervous system, thus providing relief of pain and fever. Therefore, acetaminophen is not an NSAID or antithrombotic agent.

Some [10-14], but not all [15,16], studies have shown an increase in blood pressure with acetaminophen. As an example, in the Paracetamol in Hypertension-Blood Pressure trial, 110 people with hypertension were given acetaminophen (4 grams daily in divided doses) or placebo for four weeks and then, after a two-week wash out period, received the opposite therapy (crossover design). Ambulatory blood pressure monitoring (ABPM) was undertaken at baseline and repeated at the end of each of the two four-week periods of treatment [10]. During acetaminophen administration, ABPM (and office) pressures rose by 5/2 mmHg (systolic/diastolic). A second, smaller trial yielded similar results [14].

This degree of blood pressure elevation would be expected to confer an increase in cardiovascular risk; although there are no trials, several observational studies have found an association between chronic acetaminophen use and cardiovascular events [17-19].

The effect of intravenous acetaminophen on blood pressure seems to contrast with that of chronic oral acetaminophen. Specifically, intravenous acetaminophen may lower blood pressure, as was shown in both healthy individuals and in critically ill patients in the intensive care unit [20,21]. This decrease in blood pressure with intravenous acetaminophen among critically ill patients usually occurs within 30 minutes, lasts approximately one hour, and may be sufficiently severe to require interventions to raise the blood pressure [22].

The effects of acetaminophen on blood pressure may be smaller than the effects of NSAIDs. As an example, in one randomized trial of postpartum analgesia in previously preeclamptic females, the incidence of hypertension (defined as a pressure greater than or equal to 150 mmHg systolic or 90 mmHg diastolic) was significantly larger with ibuprofen compared with acetaminophen (63 versus 29 percent) [23]. However, other studies concluded that acetaminophen and NSAIDs have similar effects on blood pressure [24].

The effects of acetaminophen on blood pressure may also be due to its sodium content, as certain formulations, particularly effervescent and soluble forms, may contain substantial amounts of sodium. Patients using acetaminophen on a regular basis should review labels for sodium content. In a survey of patients with hypertension in the United Kingdom, those who initiated therapy with sodium-containing acetaminophen preparations had more adverse events (mortality, nonfatal stroke, nonfatal myocardial infarction, or heart failure) than those who took an acetaminophen preparation without sodium (5.6 versus 4.6 percent); the dose of acetaminophen used was similar between the groups [25]. Analogous findings were reported among those without hypertension (4.4 versus 3.7 percent).

MANAGEMENT OF HYPERTENSIVE PATIENTS TAKING NSAIDS AND ACETAMINOPHEN — Many hypertensive patients require chronic analgesic therapy with NSAIDs or acetaminophen in order to treat chronic pain (eg, due to osteoarthritis). In one large cohort, for example, more than 50 percent of hypertensive patients were prescribed NSAIDs or acetaminophen [26]. Overall, management of hypertension in such patients is similar to the management in patients who do not chronically use these medications. However, attention should be paid to the following aspects of care:

●With the possible exception of calcium channel blockers, NSAIDs can inhibit the effectiveness of most antihypertensive drugs. Thus, use of a dihydropyridine calcium channel blocker (eg, amlodipine), which is acceptable first-line therapy in the treatment of hypertension, may simplify the management of such patients. Amlodipine, a dihydropyridine calcium channel blocker, is available in a single-pill combination with celecoxib (an NSAID) and has a blood pressure-lowering effect that is similar to amlodipine alone [27,28]. (See "Choice of drug therapy in primary (essential) hypertension".)

●NSAIDs increase blood pressure at least in part by reducing sodium excretion by the kidney. Thus, it is important to remind hypertensive patients taking chronic NSAID therapy to limit their sodium intake. (See "Salt intake and hypertension".)

●More frequent monitoring of blood pressure, including home monitoring, may be required, particularly if patients change analgesics or analgesic doses.

●NSAIDs can cause an acute deterioration in glomerular filtration rate; no single NSAID appears safer than the others. Patients taking antihypertensive medications who initiate NSAID therapy should have their serum creatinine monitored at two- to four-week intervals until it is certain that it is stable. Most kidney effects of NSAIDs should be apparent in the first month. Thereafter, we monitor the serum creatinine every 6 to 12 months or if there is a change in the dose of NSAID therapy. (See "NSAIDs: Acute kidney injury".)

SUMMARY AND RECOMMENDATIONS

●Effects of NSAIDS on blood pressure – Nonsteroidal anti-inflammatory drugs (NSAIDs), given in doses adequate to reduce inflammation and pain, can increase blood pressure and diminish the antihypertensive efficacy of antihypertensive drugs.

Aspirin, in the low dose that is used as an antithrombotic agent, does not affect blood pressure or interfere with the efficacy of antihypertensive drugs. (See 'Effect of NSAIDs on blood pressure' above.)

●Effects of acetaminophen on blood pressure – Acetaminophen may also increase blood pressure at doses commonly used for pain relief (see 'Effect of NSAIDs on blood pressure' above and 'Effects of acetaminophen on blood pressure' above). Patients using acetaminophen on a regular basis should review labels for sodium content, as certain formulations may contain substantial amounts of sodium.

●Management of hypertensive patients taking NSAIDS and acetaminophen – Overall, management of hypertension in patients who require chronic therapy with NSAIDs is similar to the management in patients who do not chronically use these medications. However, it is important that such patients limit their sodium intake (because NSAIDs increase blood pressure in part by reducing sodium excretion), monitor their blood pressure frequently (eg, with home monitoring), and monitor their kidney function after NSAIDs are initiated and with any increase in NSAID dose. (See 'Management of hypertensive patients taking NSAIDs and acetaminophen' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Norman M Kaplan, MD, who contributed to an earlier version of this topic review.