Hypertensive Crisis: The Causative Effects of Nonsteroidal Anti- Inflammatory Drugs

Abstract

62-year-old female presents with hypertensive urgency while taking daily NSAIDs. This case demonstrates the effect of NSAIDs on BP, an often overlooked etiology of secondary hypertension. The detrimental effects of NSAIDs upon blood pressure have been well documented. The report reiterates and reviews the severity of the problem. We will review the existing literature and discuss the importance of small increases in blood pressure. This paper has not been submitted elsewhere, is not under review, or published previously and all of the authorship are aware of and approve the manuscript being submitted to this journal. 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 (Figure 1). She had started taking OTC ibuprofen 3200 mg to 4000 mg daily for three weeks due to cervical-spine radicular pain. Her clinical course is outlined in detail in Table 1. Physical exam revealed flushing and mild non-pitting edema of the digits. Ophthalmologic and cardiac exams were normal as was the ECG. Initial work-up revealed a normal renal function with 2+ proteinuria on urinalysis, mild hypokalaemia that resolved spontaneously, and a CT head that was negative for haemorrhage. She initially received 0.2 mg of clonidine and the ibuprofen was discontinued. When she 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 as again indicated in Table 1. It does appear that she had pre-existing hypertension prior to her acute episode. Discussion NSAID-induced hypertension 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 [1]. 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 overlooked etiology of secondary hypertension. We will review the existing literature and discuss the importance of small increases in blood pressure. The mechanism of action of NSAIDs involves blocking the conversion of arachidonic acid to the inflammatory prostaglandins (PG) and thromboxane A [2]. Found in the renal cortex, PGI2 functions as a vasodilator and promotes sodium excretion. PGE2, excreted in the renal medulla, also promotes vasodilation, inhibits sodium resorption, as well as inhibits free water resorption by blunting the effect of antidiuretic hormone (ADH). Therefore, the net effect of these inflammatory agents is vasodilation and excretion of sodium and water. When these prostaglandins are inhibited, the opposite effect occurs-retention of 4 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 [2,3]. Patients who are particularly vulnerable to these effects include elderly, those with chronic kidney disease (CKD), and diabetes. 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 [3,4-6]. 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 (95% CI 1.2 mmHg to 8.7 mmHg) [7,8]. 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 inhibitors [8]. Also in 2005, the APPROVE trial investigators reported that 19% of patients on naproxen developed hypertension, although this result did not reach statistical significance [9]. 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. Additionally, 5 these studies utilized retrospective survey analysis, allowing for considerable recall bias [2] Significant increases in BP have also been reported in trials that