Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs, and Hypertension 

INTRODUCTION :

Acetaminophen is widely regarded as a safe therapy for pain and fever in patients with cardiovascular disease and those taking anticoagulants. However, recent studies report that acetaminophen, like most other nonsteroidal anti-inflammatory drugs, increases blood pressure, and a formulation containing sodium increases cardiovascular risk. Those findings call into question guidelines recommending acetaminophen for patients with cardiovascular disease and pain, and those taking anticoagulants. Acetaminophen has effects in common with nonsteroidal anti-inflammatory drugs, and its influence on coagulation via effects on vitamin K metabolism. Possible alternatives to acetaminophen for patients with pain . 

MECHANISMS OF ACTION OF ACETAMINOPHEN

 Acetaminophen shares with NSAIDs, such as ibuprofen and naproxen, a key analgesic mechanism of action: inhibition of prostaglandin biosynthesis. Prostaglandins, including PGE2, formed in response to tissue injury augment pain signaling by peripheral and central neurons. They promote the release of pain-producing mediators, increase the expression of and lower the activation threshold of pain-sensing ion channels in primary afferent nociceptors.

 Prostaglandins formed upon activation of pain-transmitting pathways in the central nervous system modulate neurotransmitter signaling to facilitate ascending excitatory and reduce descending inhibitory neurotransmission.

 Just like ibuprofen and naproxen, acetaminophen inhibits the first committed step in enzymatic prostaglandin biosynthesis catalyzed by the PGH2 synthases -1 and -2 (commonly called COXs [cyclooxygenases]), albeit with lower potency.

 The COXs have 2 functional sites, the cyclooxygenase site and the peroxidase site, which act sequentially on the substrate arachidonic acid to form PGH2. 

 Distinct isomerase enzymes transform PGH2 into various prostaglandins, prostacyclin (PGI2) and thromboxane. The lower potency of acetaminophen may relate in part to its unique molecular interaction with the target enzymes. While other COX inhibitors compete with arachidonic acid or cause allosteric inhibition through interactions with the arachidonic acid binding site, acetaminophen acts as a noncompetitive inhibitor of catalytic function at the peroxidase site of the enzyme. As a phenolic-reducing agent, it hinders the intramolecular electron transfer that is required for the removal of a hydrogen from arachidonic acid during prostaglandin synthesis. The weaker analgesic activity of acetaminophen (at commonly used therapeutic doses of 1000–1500 mg per day) in comparison to other NSAIDs is explained by its lower potency as an inhibitor of the COXs. At doses of 1000 mg, acetaminophen reversibly inhibits COX-1 and COX-2 by ≈ 50% for ~4 hours; this represents approximately half the effect of other drugs that are designated as NSAIDs.

 

EFFECT ON BLOOD PRESSURE 

In a study of effects of prescription drugs on blood pressure, “The most prevalent blood pressure (BP)-interfering prescription medications were NSAIDS, acetaminophens, and hormones.” In 2013, a systematic review concluded that the evidence regarding effects of acetaminophen on blood pressure was weak, and further studies were needed.

NSAIDs induce hypertension, sodium retention, and edema by inhibition of COXs in the kidney. The COXs are abundantly expressed in renal structures relevant to volume and pressure control. These include cortical and medullary collecting ducts, in the vasculature of the glomerulus, mesangial cells and the macula densa and medullary interstitial cells. Adverse effects of NSAIDs on blood pressure and cardiovascular outcomes have been reviewed.

One NSAID that is rarely prescribed, sulindac, may have a distinct blood pressure profile due to its specific pharmacokinetic characteristics. Sulindac is a prodrug, and its active metabolite is highly protein-bound, so very little is filtered into the renal tubule. That which does reach the renal tubule is re-oxidized back into the inactive prodrug. In 1984, Patrono’s group reported that in contrast to ibuprofen, sulindac did not reduce production of renal PGI2 or impair renal function, in patients with glomerular disease. In 1986, Wong et al, reported that in patients with hypertension stabilized on a beta-blocker and diuretic, naproxen and piroxicam significantly raised blood pressure compared with placebo, whereas sulindac lowered blood pressure significantly compared with placebo Although the study was small, its complete 4-way cross-over design minimizes the likelihood of bias. A meta-analysis by Pope et al, also reported that the effects of sulindac on blood pressure were minimal.

Acetaminophen is readily filtered in the kidney and a portion is excreted unchanged in the urine. Clinical studies with acetaminophen are consistent with a dose-dependent effect on blood pressure, particularly within the context of pre-existing hypertension.

 In 2010, Sudano et al, reported on a randomized double-blind controlled trial of acetaminophen (3000 mg per day) in patients with coronary artery disease. “Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mmHg, P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mmHg, P=0.02 versus placebo)”.

In 2012, Sudano et al, reviewed the literature on acetaminophen, NSAIDs, and hypertension. They noted that prospective studies were inconsistent, with one study reporting an increase in mean blood pressure by 4 mmHg with acetaminophen (4000 mg per day). However,  population-based studies (The Nurses Health Study and the US Health Professionals study) reported increases in incident hypertension among persons taking acetaminophen. Incident hypertension was doubled among women taking acetaminophen, and among men the hazard ratio was 1.38, similar to that among men taking other NSAIDs.A retrospective, observational study published in 2013 reported that among 2754 hypertensive patients who received acetaminophen, BP rose slightly during the period of acetaminophen treatment when antihypertensive treatment was unchanged (change in systolic BP 1.6 [95% CI, 0.7–2.5] mmHg and change in diastolic BP 0.5 [95% CI, 0.1–1.0] mmHg)]. The prescribed acetaminophen doses were uncertain in this analysis of the UK General Practice Research Database and the authors suggested that “as needed” prescriptions might have been common.

BP fell when new antihypertensive medications were prescribed. These changes were not different from those in hypertensive patients not exposed to acetaminophen.

 A randomized trial in 2013 compared the effect of naproxen (500 mg per day) and acetaminophen (2000 mg per day) in 135 hypertensive patients whose blood pressure was normalized by randomly assigned treatment with ramipril, valsartan, or aliskiren for 8 weeks. Participants were randomized to receive naproxen or acetaminophen for 2 weeks. “Naproxen significantly increased clinic and ambulatory systolic/diastolic BP values in patients treated with ramipril (P<0.01) or valsartan (P<0.05) but did not affect aliskiren effects. 

Also, acetaminophen slightly but significantly affected clinic and ambulatory systolic BP/diastolic BP in all 3 groups and, surprisingly, it also produced a slight increase in HR (+3.1, +3.3, and +3.4 b/min day-time HR values, for ramipril, valsartan, and aliskiren, respectively; P<0.05). In 2018, a double-blind crossover study of effervescent acetaminophen, 3000 mg per day or matching placebo for 3 weeks, was carried out in 46 hypertensive patients. The authors reported an increase in 24-hour ambulatory systolic blood pressure with acetaminophen by 5.04 mmHg (95% CI, 1.80–8.28; P=0.004) in the per-protocol analysis. Some of this may have been due to the sodium content. The effervescent and soluble formulations of 0.5 g acetaminophen contain 0.44 and 0.39 g of sodium, respectively; thus, the intake of maximum daily dose (ie, 4 g/day) of sodium-containing acetaminophen corresponds to the ingestion of 3.5 and 3.1 g of sodium.

 It is possible that sodium content in other effervescent NSAIDS may have similar effects, little is known about that issue. 

A double-blind placebo-controlled crossover study in 103 individuals with hypertension reported in 2022 that acetaminophen increased blood pressure. Participants received 4000 mg daily, or matching placebo for 2 weeks, followed by a 2-week washout period and then crossing over to the alternative treatment. Ambulatory blood pressure was measured by a Spacelabs Healthcare 90207 Ambulatory BP recorder (Spacelabs, WA). Mean daytime systolic pressure was increased significantly by acetaminophen (132.8±10.5 to 136.5±10.1) compared with placebo (133.9±10.3 to 132.5±9.9, P<0.0001), with a placebo-corrected increase of 4.7 mmHg (95% CI, 2.9–6.6). Mean daytime diastolic pressure increased with acetaminophen from 81.2±8.0 to 82.1±7.8 mmHg, versus 81.7±7.9 to 80.9±7.8 mmHg with placebo, P=0.005. The placebo-corrected increase in diastolic pressure was 1.7 mmHg (95% CI, 0.5–2.7). Changes in clinic blood pressures were similar.  

SUMMARY

 A common misperception is that acetaminophen is distinct from other NSAIDs. In fact, it shares their primary mechanism of action—inhibition of COX-dependent prostaglandin formation. However, as it is a less potent inhibitor at commonly prescribed doses, it is less potent as an analgesic drug. Given at sufficient doses it assumes a risk profile similar to that of therapeutically administered conventional NSAIDs such as ibuprofen. This includes the GI adverse effect profile and the predisposition to hypertension, consistent with the recent reports in the literature. It seems that acetaminophen does indeed raise blood pressure, affect anticoagulation by warfarin through an effect on vitamin K metabolism, and may increase cardiovascular risk. However, the clinical trials that report comparative effects of NSAIDs on blood pressure and that aim to assess the cardiovascular outcomes from use of acetaminophen are small, and biobank approaches to assessing the comparative risks of prescribed drugs at scale may by confounded by non adherence or unrecorded over the counter consumption of NSAIDs. When an NSAID is prescribed (including acetaminophen) for a patient with hypertension, blood pressure should be monitored, and antihypertensive medication may require adjustment. Further study may be needed to determine if sulindac would be a better alternative to other NSAIDs for patients with hypertension.  

 

Acetaminophen, Nonsteroidal Anti-Inflammatory Drugs, and Hypertension 

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