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A 62-year-old white female
with no documented past medical history of hypertension or any other chronic
disease state presented to the Emergency Department with severe occipital
headache and was found to have hypertensive urgency, with initial blood
pressure (BP) of 225/110 mmHg. She had started taking OTC ibuprofen 3200-4000
mg daily for three weeks due to cervical-spine radicular pain. She initially
received 0.2 mg of clonidine and the ibuprofen was discontinued.
What could be the major cause for Hypertensive urgency here?
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the
most frequently used medications in the USA; more than 29 million adults are
reported to be regular users of NSAIDs. Often thought of as benign
medications, NSAIDs have been shown to have a number of serious side effects
including hypertension, renal failure, gastrointestinal bleeding, bronchospasm,
and severe cardiovascular complications such as myocardial infarction, stroke,
and congestive heart failure. This case demonstrates the effect of NSAIDs on
BP, an often over-looked aetiology of secondary hypertension.
A female patient presented with hypertensive urgency with
the blood pressure of 225/110 mm Hg. Thorough examination revealed daily
administration of NSAIDs as the cause of the hypertensive crisis. Ibuprofen was
discontinued, and anti-hypertensives were initiated.
The patient had a history of hypertension, which was treated with
angiotensin II receptor blockers. She had no other past medical history. At
presentation, she was not taking any herbal preparations or anticoagulants. She
had no family history of bleeding tendency.
Physical exam revealed flushing and mild non-pitting edema
of the digits. Ophthalmologic and cardiac exams were normal as was the
electrocardiogram (ECG). Initial work-up revealed a normal renal function with
2+ proteinuria on urinalysis, mild hypokalemia that resolved spontaneously, and
a CT head that was negative for hemorrhage.
When the patient saw her
primary care physician the following day, BP was 170/100 mmHg; she was started
on 100/25 mg of losartan/HCT, an angiotensin-receptor blocker/thiazide
combination and 5 mg of amlodipine, a calcium channel blocker, for Stage II
hypertension. The patient was then seen by a hypertension specialist; 5 mg
nebivolol, a β1 cardioselective vasodilating β-blocker, was added and home BP
measurements were initiated. Home BP documented that BPs soon decreased to
<120/80 mmHg, after which amlodipine and losartan/HCT were tapered off and
nebivolol alone continued. The patient was noted to have a white-coat
hypertension pattern, but on continued follow up has done very well. It does
appear that she had pre-existing hypertension prior to her acute episode.
The mechanism of action of NSAIDs involves blocking the conversion of arachidonic acid to the inflammatory prostaglandins (PG) and thromboxane A. The overall effect of these inflammatory agents is vasodilation and excretion of sodium and water. When these prostaglandins are inhibited, the opposite effect occurs-retention of sodium and water and relative vasoconstriction. Additionally, PG may have direct effects on the vasculature. PG may inhibit endothelin-1,a known vasoconstrictor. This is the postulated mechanism for NSAID-induced hypertension. Further, it has been established that NSAIDs may blunt the effects of other anti-hypertensive drugs such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, ARBs, and beta blockers, leading to resistant hypertension.
Many studies throughout the years have attempted to characterize the exact effect of NSAIDs on hypertension. In a large meta-analysis published in 1994 including 38 randomized, placebo-controlled trials (as well as 12 randomized non-placebo controlled trials), supine mean BP was increased by 5 mmHg with NSAID use. Another meta-analysis from 2005 showed an increase in systolic/ diastolic BP of 2.83/1.34 mmHg in patients using nonselective NSAIDs when compared to cyclooxygenase-2 inhibitors8. Also in 2005, the APPROVE trial investigators reported that 19% of patients on naproxen developed hypertension, although this result did not reach statistical significance. In fact, numerous trials have demonstrated a non-statistically significant, modest increase in BP related to NSAID use. Much of the existing research on this topic is limited by data that was underpowered to assess for changes in BP, did not use standardized BP data acquisition protocols, were not placebo-controlled, or involved various NSAIDs at various dosages. Hypertensive adults in the TARGET trial showed an increase in systolic/diastolic BP of 2.1/0.5 mmHg in patients using naproxen and ibuprofen when compared to lumiracoxib, however, no placebo was used2,10. A meta-analysis in 1993 with1324 patients, 92% of which were hypertensive, demonstrated statistically significant changes in blood pressure observed only in the hypertensive patient group11. Though various NSAIDS were analyzed, indomethacin and naproxen had the largest mean arterial pressure increases of 3.59 mmHg and 3.74 mmHg, respectively.
In above studies, hypertensive patients on ACE-inhibitors
and beta-blockers specifically had more severe elevations in BP while taking
NSAIDs. The significance of these modest increases in BP due to NSAID use is
related to the severe cardiovascular sequelae of elevated BPs. There is a known
linear correlation between increasing BP and ischemic heart disease and stroke
mortality even in patients with no history of vascular disease. Further, a
decrease in systolic BPs by only 2 mmHg can decrease the risk of ischemic heart
disease mortality by 7% and decrease stroke mortality by 10%. The development
of individual increases in BP that fall below threshold of 140/90 definition is
called the iceberg effect, and implies that the problem of elevated BPs from
baseline is often unrecognized. In fact, even when below the JNC 7 cutoff for
hypertension, a prospective meta-analysis of one million patients showed that
increases of systolic/ diastolic BPs of 20/10 mmHg led to a two-fold increase
in cardiovascular event rates. In summary, lower BPs (at least down to 115/75
mmHg) are associated with fewer cardiovascular events.
As this case demonstrates, NSAIDs have associated
cardiovascular risks with their use even though the public often consider them
benign. Widely prescribed and taken over-the-counter especially in the elderly,
NSAIDs have the ability to cause resistant hypertension by causing sodium and
water retention as well as limiting the vasodilator effects of the systemic
vasculature. While often only modest increases in BP have been observed,
continuing evidence demonstrate this may increase patients’ cardiovascular risk
and mortality. These BP increases may be more pronounced in the elderly,
diabetics, CKD patients, and in previously hypertensive patients on
anti-hypertensive regimens. Further randomized controlled trials powered for BP
changes are necessary to further assess specific BP effects from NSAIDs and
their clinical outcomes. When patients are taking NSAIDs, it is important to monitor
home BPs and inform patients of the cardiovascular risks of elevated BPs in an
effort to promote informed decision-making. If elevated BPs occur,
discontinuation of NSAIDs is a necessary first-line approach.
J Clin Case Rep 6: 838. doi:10.4172/2165-7920.1000838
Hypertensive Crisis: The Causative Effects of Nonsteroidal AntiInflammatory Drugs
Kevin Landefeld et al.
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