Hypertension

REVIEW

Acetaminophen, Nonsteroidal Anti-Inflammatory

Drugs, and Hypertension
J. David Spence , Tilo Grosser , Garret A. FitzGerald

ABSTRACT: 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. We review evidence that 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 are discussed.

Key Words: acetaminophen ◼ blood pressure ◼ nonsteroidal anti-inflammatory drugs ◼ prostacyclin ◼ thromboxane

T
he impetus for this review was the recent publication
of 2 articles reporting that the analgesic acetamino-
phen (paracetamol) increases blood pressure,1 and
that sodium-containing acetaminophen is associated with
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augment pain signaling by peripheral and central neu-
rons. They promote the release of pain-producing media-
tors, increase the expression of and lower the activation
threshold of pain-sensing ion channels in primary affer-

an increased risk of adverse cardiovascular outcomes.2
These findings are of concern because the guidelines of
the American Heart Association recommend the use of
acetaminophen in patients with pain and hypertension.3
Acetaminophen is widely regarded as a safe alterna-
tive to nonsteroidal anti-inflammatory drugs (NSAIDs) in
patients at increased cardiovascular risk, including those
taking anticoagulants. Indeed, acetaminophen is com-
monly viewed as an analgesic that is mechanistically dis-
tinct from NSAIDs. However, those beliefs are on shaky
ground. In this narrative review, we focus on more recent
literature, and some that has been forgotten.
MECHANISMS OF ACTION OF
ACETAMINOPHEN
Acetaminophen shares with NSAIDs, such as ibupro-
fen and naproxen, a key analgesic mechanism of action:
inhibition of prostaglandin biosynthesis. Prostaglandins,
including PGE2, formed in response to tissue injury,
ent nociceptors.4 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.5
Just like ibuprofen and naproxen, acetaminophen
inhibits the first committed step in enzymatic prostaglan-
din biosynthesis catalyzed by the PGH2 synthases -1 and
-2 (commonly called COXs [cyclooxygenases]), albeit
with lower potency.6 The COXs have 2 functional sites,
the cyclooxygenase site and the peroxidase site, which
act sequentially on the substrate arachidonic acid to form
PGH2.7 Distinct isomerase enzymes transform PGH2 into
various prostaglandins, prostacyclin (PGI2) and throm-
boxane. The lower potency of acetaminophen may relate
in part to its unique molecular interaction with the target
enzymes. While other COX inhibitors compete with arachi-
donic acid or cause allosteric inhibition through interactions
with the arachidonic acid binding site,8 acetaminophen
acts as a noncompetitive inhibitor of catalytic function at

 
Correspondence to: J. David Spence, Department of Neurology & Clinical Pharmacology, Western University, Stroke Prevention & Atherosclerosis Research Centre,
Robarts Research Institute, 1400 Western Rd, London, ON, Canada N6G 2V4. Email dspence@robarts.ca
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/HYPERTENSIONAHA.122.19315.
For Sources of Funding and Disclosures, see page 1925.
© 2022 American Heart Association, Inc.
Hypertension is available at www.ahajournals.org/journal/hyp

1922   September 2022 Hypertension. 2022;79:1922–1926. DOI: 10.1161/HYPERTENSIONAHA.122.19315

 Spence et al
Nonstandard Abbreviations and Acronyms
BP blood pressure
COX cyclooxygenase
NSAID nonsteroidal anti-inflammatory drug
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.9 The weaker analge-
sic activity of acetaminophen (at commonly used thera-
peutic 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, acetamino-
phen 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.6 While the
analgesic effect of acetaminophen is dose dependent,10
dosing is limited by liver toxicity.
The modest anti-inflammatory activity and modest
and transient inhibition of platelet COX-1 with acet-
aminophen in comparison to other COX inhibitors can
be explained by its unique molecular interaction with the
enzyme. Inhibition of COX by the reducing action of acet-
aminophen can be antagonized by the elevated perox-
ide tone that returns the enzyme to its higher oxidation
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state.9 Inflamed tissues and the cytosol of platelets are
environments with high oxidant tone in which this func-
tional antagonism is facilitated.9
Several potential molecular mechanisms, in addition
to COX inhibition, have been suggested to amplify the
analgesic actions of acetaminophen based on experi-
mentation in cells and rodents. These include the for-
mation of endocannabinoid metabolites and inhibition of
fatty acid amide hydrolase.11 However, all COX inhibitors
have been hypothesized to modulate analgesic efficacy
through similar mechanisms,12 and the importance of
these pathways in the clinical efficacy of acetaminophen
remain to be shown.
Like other COX inhibitors, acetaminophen has ther-
apeutic efficacy in COX-dependent conditions other
than pain. For example, the antipyretic activity of acet-
aminophen is sufficiently explained by inhibition of the
formation of PGE2 in the thalamic site of the central
thermostat.13 Circulating cytokines, released during
inflammation, induce the formation of COX-2-dependent
PGE2 formation in endothelial cells in brain venules in
the median preoptic nucleolus, from where it crosses the
blood-brain barrier and disinhibits via its EPr3 receptor
on neurons to raise the central temperature setpoint.14
COX inhibitors, including acetaminophen, lower fever by
removing this PGE2 thermic signal.
COX-2-derived PGE2 is also critical in maintaining
intrauterine patency of the ductus arteriosus. Upon birth,
Hypertension. 2022;79:1922–1926. DOI: 10.1161/HYPERTENSIONAHA.122.19315
Acetaminophen and Blood Pressure
PGE2 metabolism in the lung is rapidly upregulated and
the removal of PGE2 signaling acts as the key stimulus
to cause closure of the ductus. Inhibition of COX-2 with
ibuprofen or indomethacin is routinely used to induce
Review
closure of a patent ductus arteriosus in neonates. More
recently, acetaminophen has been shown to be an effec-
tive and potentially safer alternative.15
COX inhibition is thought to be fundamental to
NSAID-associated gastrointestinal adverse effects such
as ulcer formation, because prostaglandins produced
in the GI wall play roles in epithelial mucus production,
microvascular mucosal perfusion, bicarbonate forma-
tion, and wound healing.16 Again consistent with its com-
mon mechanism of action, acetaminophen at doses that
approach the degree of COX inhibition achieved clinically
by ibuprofen and naproxen share their GI toxicity profile.17
EFFECT ON BLOOD PRESSURE
In a study of effects of prescription drugs on blood pres-
sure, Hwang et al18 stated that “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.19 We have focused on
the more recent studies.
NSAIDs induce hypertension, sodium retention, and
edema by inhibition of COXs in the kidney.20 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.21,22 Adverse effects of
NSAIDs on blood pressure and cardiovascular outcomes
have been reviewed.23 They largely reflect inhibition of
renal vasodilator prostanoids, such as PGE2 and PGI2,
formed predominantly by COX-2, under renoprival condi-
tions. 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 inac-
tive 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.24 In 1986, Wong et al25 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 pla-
cebo (Figure S1) Although the study was small, its com-
plete 4-way crossover design minimizes the likelihood of
bias. A meta-analysis by Pope et al26 also reported that
the effects of sulindac on blood pressure were minimal.
September 2022   1923
 Spence et al
Acetaminophen is readily filtered in the kidney and a por-
tion is excreted unchanged in the urine.27 Clinical studies
with acetaminophen are consistent with a dose-depen-
dent effect on blood pressure, particularly within the con-
Review
text of preexisting hypertension.
In 2010, Sudano et al28 reported on a randomized dou-
ble-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 mm Hg,
P=0.02 versus placebo) and diastolic (from 73.2±6.9 to
75.4±7.9 mm Hg, P=0.02 versus placebo)”.
In 2012, Sudano et al29 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 mm Hg with acetaminophen (4000 mg per day),
and 2 showing no or no reproducible increase. How-
ever, 2 population-based studies (The Nurses Health
Study and the US Health Professionals study) reported
increases in incident hypertension among persons
taking acetaminophen.30,31 Incident hypertension was
doubled among women taking acetaminophen,31 and
among men the hazard ratio was 1.38, similar to that
among men taking other NSAIDs.30
A retrospective, observational study published in
201332 reported that among 2754 hypertensive patients
who received acetaminophen, BP rose slightly during the
period of acetaminophen treatment when antihyperten-
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sive treatment was unchanged (change in systolic BP
1.6 [95% CI, 0.7–2.5] mm Hg and change in diastolic
BP 0.5 [95% CI, 0.1–1.0] mm Hg)]. 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 201333 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 treat-
ment 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 val-
sartan (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 efferves-
cent acetaminophen, 3000 mg per day or matching
1924   September 2022 Hypertension. 2022;79:1922–1926. DOI: 10.1161/HYPERTENSIONAHA.122.19315
Acetaminophen and Blood Pressure
placebo for 3 weeks, was carried out in 46 hypertensive
patients.34 The authors reported an increase in 24-hour
ambulatory systolic blood pressure with acetaminophen
by 5.04 mm Hg (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 maxi-
mum daily dose (ie, 4 g/day) of sodium-containing acet-
aminophen corresponds to the ingestion of 3.5 and 3.1
g of sodium.2 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 hypertension1 reported in 2022
that acetaminophen increased blood pressure. Partici-
pants 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 Health-
care 90207 Ambulatory BP recorder (Spacelabs, WA).
Mean daytime systolic pressure was increased signifi-
cantly 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
mm Hg (95% CI, 2.9–6.6). Mean daytime diastolic pres-
sure increased with acetaminophen from 81.2±8.0 to
82.1±7.8 mm Hg, versus 81.7±7.9 to 80.9±7.8 mm Hg
with placebo, P=0.005. The placebo-corrected increase
in diastolic pressure was 1.7 mm Hg (95% CI, 0.5–2.7).
Changes in clinic blood pressures were similar.
EFFECT ON CARDIOVASCULAR
OUTCOMES
In 2016, Roberts et al35 reported on a systematic review
and meta-analysis of observational studies of acet-
aminophen and cardiovascular risk. They found a dose-
response increase in cardiovascular disease and decline
of renal function with use of acetaminophen.
In 2018, Girard et al36 reported that among 2239
residents of nursing homes in France followed for 1.5
years, consumption of acetaminophen (2352±993 mg
of acetaminophen daily) did not increase cardiovascular
risk in the overall study population. However among par-
ticipants with diabetes the odds ratio for stroke was 3.19
([95% CI, 1.25–8.18]; P=0.0157).
In 2022, Zeng et al2 reported on the cardiovascular
risk of sodium-containing acetaminophen versus acet-
aminophen that did not contain sodium, over a 1-year
follow up. The estimate of sodium intake from a maxi-
mal dose of acetaminophen (4000 mg per day) was 3.5
to 3.1 mg/day. This probably represents an important
increase in sodium intake; average daily sodium intake
in China decreased from ~6.5 to 4.5 mg/day between
1991 and 2009,37 though it may have increased recently.
 Spence et al
The outcomes were incident CVD (myocardial
infarction, stroke, and heart failure) and all-cause mor-
tality. Among participants with hypertension (mean
age: 73.4 years), the average weighted hazard ratio
was 1.59 (95% CI, 1.32–1.92) among 4532 who took
sodium containing acetaminophen, versus 146 866
persons who took nonsodium-containing acetamino-
phen. Among individuals without hypertension (mean
age: 71.0 years), the average weighted HR was 1.45
(95% CI, 1.18–1.79) in 5351 persons who took
sodium-containing acetaminophen versus 141  948
who took nonsodium-containing acetaminophen.
Unfortunately, effect of acetaminophen was not com-
pared with no intake of acetaminophen.
EFFECT OF ACETAMINOPHEN IN
PATIENTS TAKING WARFARIN
Although acetaminophen is often regarded as safe
in patients taking warfarin, there is an important
interaction, not with metabolism of warfarin, but with
vitamin K metabolism, that can increase the interna-
tional normalized ratio to clinically important levels.
This appears to be because of a toxic metabolite of
acetaminophen, N-acetyl-para-benzoquinoneimine
(NAPQI), even in patients without hepatoxicity from
acetaminophen.38,39
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CONCLUSIONS
A common misperception is that acetaminophen is
distinct from other NSAIDs. In fact, it shares their pri-
mary mechanism of action—inhibition of COX-depen-
dent 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 pre-
disposition 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 car-
diovascular 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 unre-
corded 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
Hypertension. 2022;79:1922–1926. DOI: 10.1161/HYPERTENSIONAHA.122.19315
Acetaminophen and Blood Pressure
if sulindac would be a better alternative to other NSAIDs
for patients with hypertension.
Review
ARTICLE INFORMATION
Affiliations
Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Insti-
tute, Western University, London, Ontario, Canada (J.D.S.). Institute for Transla-
tional Medicine and Therapeutics, Department of Systems Pharmacology and
Translational Therapeutics, University of Pennsylvania Perelman School of Medi-
cine, Philadelphia (T.G., G.A.F.). Department of Translational Pharmacology, Medi-
cal School EWL, Bielefeld University, Germany (T.G.).
Sources of funding
None.
Disclosures
None.
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