Non-Steroid Anti Inflammation Drugs and Hypertension

dr. Riana Handayani, SpJP (K), FIHA

Department of Cardiology, RSUD Abdoel Moeloek, Bandar Lampung

[email protected]

Abstract

Non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are most widely prescribed drug on
the planet to treat pain, inflammation, and fever. However, NSAIDs have many different effects
on multiple organ including cardiovascular. Over the years, a large number of scientific reports
have associated NSAIDs with CVD risk. Approximately 15% of the general population redeem
one or more NSAID prescriptions annually and up to 5% of regular NSAID users can be expected
to develop hypertension. NSAIDs COX-2 inhibitors have also been found to produce a mean
increase in blood pressure of 2.0-5.0 mmHg. Among all of the reports, not many describe the
specific classification and how the NSAIDs work in causing hypertension. Most of them conclude
the COX-2 inhibitors have more significant effect on hypertension through the regulation of
prostanoids. This article provides a classification and mechanism of NSAIDS that may be helpful
to reduce adverse side effects while maximizing their benefit.

Keyword: NSAIDs, Prostaglandins, COX, CVD, Hypertension

Introduction

Cardiovascular diseases (CVD), including myocardial infarction (MI), hypertension, heart failure
(HF), and stroke are one of the major causes of morbidity and mortality across the world. 1 Based
on NHANES 2015-2018 data, the prevalence of CVD (comprising CHD, HF, stroke, and
hypertension) in adults ≥20 years of age is 49.2% overall (126.9 million in 2018) and increases
with age in both gender.2 While hypertension dominates the prevalence for 39,9% (102,91
million in 2018). From the combination of estimates from NHANES, REGARDS (Reasons for
Geographic and Racial Differences in Stroke), and randomized controlled trials for BP-lowering
treatments, it was estimated that achieving the 2017 American College of Cardiology/AHA BP
goals could prevent 3.0 million (uncertainty range, 1.1 million–5.1 million) CVD events (CHD,
stroke, and HF) compared with current BP levels. 2 During 2014–15, in the United States, the
estimated average annual expenses due to CVD and stroke was $351.2 billion which reconfirms
the severity of the disease and the economic burden on society. 2 Therefore, it would be highly
relevant to enquire the link between one of the leading causes of death globally i.e. CVD and
one of the most-prescribed-drugs on the planet i.e. NSAIDs. 1

Over the years, a large number of scientific reports have associated NSAIDs with CVD. Non-
aspirin non-steroidal anti-inflammatory drugs (NSAIDs) are usually used to treat pain,
inflammation, and fever.3 Approximately 15% of the general population redeem one or more
NSAID prescriptions annually and up to 5% of regular NSAID users can be expected to develop
hypertension.3 NSAIDs COX-2 inhibitors have also been found to produce a mean increase in
blood pressure of 2.0-5.0 mmHg.4 As hypertension is the leading risk factor for cardiovascular
disease (CVD), the well-described BP elevating effects of NSAIDs is likely to be a mechanism
contributing to increased CVD risk with their usage.5

Previously, NSAIDs is divided into two categories: traditional NSAIDs and newer cyclooxygenase
(COX)-2 inhibitors (Coxib). Distinct opposing roles of NSAIDs and blood pressure regulation have
been widely ascribed to the two COX isoforms, with inhibition of COX-1 being associated with
reductions in BP in angiotensin II-induced hypertension and COX-2 inhibition being shown to
elicit pressor effects.5 The pressor effects of NSAIDs have been primarily attributed to
deleterious effects on renal function. It has been suggested that the two COX isoforms have
opposing roles in renal function, with COX-1 inhibition enhancing natriuresis and lowering BP in
angiotensin II-induced hypertension, while COX-2 inhibition elevates BP and promotes sodium
retention. It has also been suggested that COX-2-derived prostaglandins are predominantly
vasodilators that maintain renal blood flow in the face of vasoconstrictor—such as angiotensin II
5
and norepinephrine—with a negligible role for COX-1 derived products. Thus, non selective
NSAIDs is more favorable than COX 2 selective NSAIDs. 3
Another research shows that NSAIDs clinically increase BP and interfere with the efficacy of ACE-
inhibitors. It is speculated that the antihypertensive effects of ACE inhibitors are partially
contingent on the production of vasodilatory prostaglandins. These effects are not found in
calcium-channel antagonists and diuretics. In this article we tried to provide overall idea about
NSAIDs classification, mechanism of action, impact on blood pressure as well as indicated the
possible strategies of using these drugs in a safer approach for clinicians prescribing NSAIDs. 3

Content of the review

NSAIDs involve a large class of drugs with structural and functional diversity. Most NSAIDs are
weak organic acids. In terms of functional diversity, isoform-specific selectivity for COX
inhibition forms the basis of differentiation; while a third classification takes into account the
bioavailability of the NSAIDs in the serum, accounting for the pharmacokinetic aspects of NSAID
action in the systemic context. In the following section, a description about the classification of
NSAIDs is presented.6

Classification of NSAIDs

NSAIDs can be classified based on their structure, PGHS-specific inhibitory activity as well as half
life in serum. Structurally NSAIDs are divided into salicylates, aryl and heteroarylacetic acid
derivatives, indole/indene acetic acid derivatives, anthranilates and oxicams (enol acids). The
general structure of a typical NSAID consists of an acidic moiety (carboxylic acid, enols) attached
to a planar aromatic functional group. 6 Salicylates were the first NSAIDs which in the latter time,
replaced by acetylsalicylic acid (ASA) or aspirin. After salicylates, aryl derivatives such as
ibuprofen, fenoprofen, naproxen and oxaprozin comprise some of the most popular NSAIDs.
The next category of NSAIDs is indole including indomethacin and sulindac. Moving further,
anthranilates derivatives such as diclofenac, mefenamic acid and meclofenamic acid is invented.
Last, oxicams characterized by the presence of 4-hydroxybenzothiazine heterocycle, is
presented by piroxicam and meloxicam. 6
Fig.1 Classification of NSAIDs based on structure6

Classification of NSAIDs based on the type of PGHS also known as COX, are divided by their
selectivity. Bioconversion of arachidonic acid (AA) into inflammatory prostanoids
(prostaglandins and prostacyclin), is mediated by COX enzymes; mainly COX-1 and COX-2 which
are inhibited by NSAIDs. The potency of NSAIDs in inhibiting COX-1 and COX-2 are often
compared on the basis of their IC50 values (the concentration of NSAIDs that inhibits 50%
activity of the enzyme) in the in vitro assay system. It is known that NSAIDs is COX-1 selective (if
the ratio is <1), NSAIDs is non selective (if the ratio is =1), NSAIDs is COX-2 selective (if the ratio
is >1). 6

NSAIDs GI toxicity adverse effects are related to COX-1 inhibition. While therapeutic effect or
anti-inflammatory is correlated with COX-2 and often a high level of PG suppression is needed
for therapeutic effect. The extent to which COX-1 gets inhibited at the same concentration of
NSAID that is required for inhibiting of COX-2 activity is crucial. Diclofenac not only inhibits 80%
of COX-2 activity but also inhibit almost 70% of COX-1 activity. This indicates therapeutic dose
(80% inhibition of COX-2) can even lead to toxicity (70% inhibition of COX-1). Because of the
selectivity range, other variables that are important to be considered are consumed dose and
plasma half life. Piroxicam long plasma half life correlated with GI toxicity in vivo, without
notable COX-1 selectivity in the in vitro assay. The relative potency of NSAIDs vary with their
dose, concentration, plasma half life. Based on the potencies to inhibit COX isoforms, NSAIDs
are divided into four main categories (Table 1): (i) Nonselective, complete inhibitors of both
COX-1 and COX-2 (ii) complete inhibitors of COX-1 and COX-2, although with specific preference
for COX-2 (iii)strong inhibitors of COX-2, although with weak inhibiting action against COX-1 (iv)
weak inhibitors of both COX-1 and COX-2. In terms of pharmacokinetics, NSAID interactions with
both the COX isoforms can be classified as freely reversible interaction (ibuprofen), slowly
reversible interaction (indomethacin, diclofenac, celecoxib) and irreversible interaction
(aspirin).7

Table 1. NSAIDs categorization based on PGHS (COX) selective inibitory action 6

Categories COX isoform selectivity Representative NSAIDs

Category 1 COX-1 and COX-2 Indomethacin, Aspirin, Diclofenac, Naproxen,
Ibuprofen
Category 2 5-50 fold selectivity for COX-2 Meloxicam, Celecoxib, Nimesulide, Etodolac

Category 3 Greater than 50 fold NS-398

selectivity for COX-2

Category 4 Poor selectivity for COX-1 Sulfasalazine, Sodium salicylate, Nabumetone

and COX-2

2.3. Classification of NSAIDs on the basis of plasma half-life (t½)

NSAIDs are divided into short-acting (plasma t½ < 6 h) and long acting (plasma t½ approximately
>10 h drug. Short acting NSAIDs are as aspirin, diclofenac and ibuprofen while long-acting
NSAIDs are naproxen and celecoxib. Short acting NSAIDs like ibuprofen, show quick onset of
action and suitable for acute pain. On the other hand, naproxen has a longer half-life and
effective for treating chronic conditions and pain.8

Mechanism of action

Fig.2 Mechanism of action of prostanoids.9

During tissue injury, non neuronal cells release inflammatory mediators to sensitize nociceptors
and potentiate pain perception. These mediators are H+, 5HT, bradykinin, ATP, neurotrophins,
LTs, and PGs. Peripheral sensitization mainly by PGs, represents the basis for the peripheral
component of the analgesic activity of NSAIDs. The therapeutic effects of NSAIDs derive from
their ability to inhibit PG production. The first enzyme in the PG synthetic pathway is COX (PG
G/H synthase). It converts arachidonic acid to PGG2, PGH2 which later produce prostanoids,
TxA2, and a variety of PGs. COX-1 is the dominant source for homeostasis function, while COX-2
is the main source for inflammation and perhaps in cancer. COX-2 normally not present in most
tissue, but CNS and renal tissue. Prostanoid, PGI2 (prostacyclin) mostly found in vascular
endothelium causing vasodilatation and inhibition of platelet aggregation. Thromboxane (TXA2)
in contrast, causing vasoconstriction and platelet aggregation. PGE2 is mediator for the
inflammatory responses, fever, and pain.6

The Role of Prostanoids in Inflammation

In acute inflammation, PGI2 and PGE2 are generated by the local tissues and blood vessels. Both
prostanoids stimulating some responses and decreasing others in order to keep a balance
effect. The non selective inhibition of prostanoids explains most adverse reactions of NSAIDs.
Inhibition of COX-1 cause GI adverse events and bleeding because its dominant cytoprotective
isoform in gastric epithelial cells and forms TxA2 in platelets, amplifies platelet activation and
constricts blood vessels at the site of injury. Inhibition of COX-2 cause or exacerbate
hypertension and the likelihood of thrombotic events because its derived products play
important roles in BP regulation and as endogenous inhibitors of hemostasis.

Fig. 3 Cyclooxygenase pathway. AA under production of COX produces prostaglandins. COX-1

pathway functioning in GI mucosa, platelets, kidney and other organs. COX-2 induced by many
factors, causing inflammation, neoplasia and prostacyclin. Inhibition of COX-2 leads to a
decreased prostacyclin, causing vasoconstriction which later causing higher blood pressure and
platelet aggregation.10

Furthermore, prostanoids play an important role in modulating blood pressure. Under basal
conditions, both COX1 and COX2 pathways are responsible for the biosynthesis of these
prostanoids. In the angiotensin II–stimulated kidney, PGE2 and PGI2 are generated mainly via
the COX2 pathway. Selective inhibitors of COX-2 were developed to afford efficacy similar to
traditional NSAIDs with better GI tolerability. Six such COX-2 inhibitors, The Coxibs (celecoxib,
rofecoxib, valdecoxib and its prodrug parecoxib, etoricoxib, and lumiracoxib). Unfortunately,
most coxibs have been either restricted in their use in view of their adverse cardiovascular risk
profile. Celecoxib currently is the only COX-2 inhibitor licensed for use in the US.
Fig 3. Effect of NSAIDs on different target organs. The effect of NSAIDs mediated through PGHS-
dependent prostanoid and mitochondrial integrity. 6

Effects of NSAIDs on Cardiovascular profile

COX-2 inhibitors depress formation of PGI2 but do not inhibit the COX-1–catalyzed formation of
platelet TxA2. PGI2 inhibits platelet aggregation and constrains the effect of prothrombotic and
atherogenic stimuli by TxA2. When selective or dominant COX-2 NSAIDs is given, PGI2 decrease
while TxA2 still in the same amount, this causing vasoconstriction and platelet aggregation.
Tissue-specific genetic deletion of COX-2 in the vasculature, accelerates the response to
thrombotic stimuli and raises blood pressure. These mechanisms would be expected to alter the
cardiovascular risk of humans, as COX-2 inhibition in humans depresses PGI2 synthesis.10

Clinical trials—with celecoxib, valdecoxib (withdrawn), and rofecoxib (withdrawn)—revealed an

increase in the incidence of myocardial infarction, stroke, and vascular death by approximately
1.4 fold. COX-2–selective should be reserved for patients at high risk for GI complications. The
CV risk appears to be conditioned by factors influencing drug exposure, such as dose, plasma
half-life, degree of COX-2 selectivity, potency, and treatment duration. 9,10

Blood Pressure and Renal Adverse Events

All NSAIDs have been associated with renal and renovascular adverse events. In renal, PGI2 &
PGE2 formed by COX-2 contribute to arterial pressure homeostasis. In situations that challenge
the regulatory systems (dehydration, hypovolemia, CHF, hepatic cirrhosis, CKD and other states
of activation of the sympathoadrenal or RAA systems) regulation of renal function by PG
formation becomes crucial. NSAIDs impair the PG-induced inhibition of both the reabsorption of
Cl– and the action of antidiuretic hormone, which may result in the retention of salt and water.
NSAIDs also promote reabsorption of K+ as a result of decreased availability of Na+ at distal
tubular sites and suppression of the PG-induced secretion of renin. Inhibition of COX-2–derived
PGs that contribute to the regulation of renal medullary blood flow may lead to a rise in blood
pressure, increasing the risk of CV thrombotic events and HF.11,12

Genetic deletion of the PGI2 receptor, IP, in mice augments the thrombotic response to
endothelial injury, accelerates experimental atherogenesis, increases vascular proliferation, and
adds to the effect of hypertensive stimuli. Up to 5% of regular NSAID users can be expected to
develop hypertension. Clinical studies suggest that hypertensive complications occur more
commonly in patients treated with COX-2–selective than with nonselective NSAIDs.10

Conclusions

Recent research from meta-analysis to systematic review has shown the effect of NSAID on
cardiovascular disease, especially hypertension. Approximately 15% of the general population
annually redeem one or more NSAID prescriptions and up to 5% of regular NSAID users can be
expected to develop hypertension. The side effects of NSAIDs on cardiovascular risk depends on
the their dose, selectivity, and plasma half-life. It is well accepted that COX-2 selective NSAIDs is
more suitable for people with high risk GI toxicity and bleeding, but it cause adverse effect on
blood pressure. NSAIDs use may result in the retention of salt and water, suppression of the PG-
induced secretion of renin and impair the regulation of renal medullary blood flow may lead to a
rise in blood pressure and have also been found to produce a mean increase in blood pressure.
Hypertensive complications occur more commonly in patients treated with COX-2–selective
than with nonselective NSAIDs. However, the studies regarding cardiovascular risk remain about
the dose and duration of NSAID use associated with hypertension still need to be investigated.
Thus, the lowest possible dose should be prescribed for the shortest possible period.

Acknowledgement and affiliations

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