The drug link behind secondary hypertension
Nonsteroidal anti-inflammatory drugs and oral contraceptives are among the agents that can cause otherwise inexplicable BP elevations.
Most patients with high BP have primary or essential hypertension, the cause of which is unknown. However, about 5%-10% of adults with hypertension have an identifiable or “secondary” cause of their elevated BP. Although relatively rare, the diagnosis of secondary hypertension is important because, depending on the source, it may be possible to cure the underlying condition or tailor therapy as a means to achieving optimal BP control.
Some of the features that aid clinicians in the diagnosis of secondary hypertension include onset of the condition before age 20 or after age 50 years; hypertension refractory to medical therapy and requiring the use of multiple antihypertensive medications from different classes; and specific body habitus and ancillary physical findings. For example, truncal obesity and purple striae occur with hypercortisolism, and exophthalmos is associated with hyperthyroidism. Biochemical tests may aid the diagnosis by revealing the presence of certain disorders, such as hypercalcemia in hyperparathyroidism and unprovoked hypokalemia in patients with renin-producing tumors.
A number of prescription and nonprescription drugs can cause transient or sustained increases in BP (Table 1). Nicotine in cigarettes, smokeless tobacco, and cigars causes transient increases in BP, although transdermal nicotine preparations do not appear to have this effect. Caffeine can raise BP acutely, but tolerance develops rapidly, and there appears to be no direct relationship between caffeine intake and chronic hypertension. Chronic overuse of alcohol is a potentially reversible cause of hypertension.
Nonsteroidal anti-inflammatory drugs (NSAIDs) decrease prostaglandin biosynthesis through inhibition of cyclooxygenase (COX), which exists as two isoforms, COX-1 and COX-2. NSAIDs and COX-2 inhibitors elevate BP via their antiprostaglandin effects on the kidneys.1 The cardiovascular consequences of COX-2 inhibition may include a shift in platelet aggregation balance toward thrombosis, notable increases in sodium and water retention, exacerbations of heart failure and hypertension, and loss of the protective effects of COX-2 upregulation in the setting of myocardial ischemia and infarction. A number of these effects are common with all NSAIDs.
NSAIDs may have deleterious effects on kidney function, especially with regard to solute homeostasis and maintenance of renal perfusion and glomerular filtration. The most clinically important adverse renal effects of NSAIDs are decreased sodium and potassium excretion and reductions in renal perfusion. Decreased sodium excretion can result in peripheral edema, BP elevations, and attenuation of the effects of antihypertensive agents.
The cardiovascular safety of COX-2 inhibitors has come under increased scrutiny since rofecoxib was withdrawn from the worldwide marketplace in September 2004 following reports of increased risks of MI and stroke. Studies published since then have reinforced the concerns about the cardiovascular risks of COX-2 inhibitors and have identified an increased cardiovascular risk even with nonselective NSAIDs, raising concerns about the safety of these drugs as well. The FDA requested and received a voluntary market withdrawal of another COX-2 inhibitor, valdecoxib, in April 2005.
The effects of NSAIDs on BP were examined in a meta-analysis of 38 randomized, placebo-controlled trials and 12 randomized but uncontrolled trials comparing two or more NSAIDs.2 Analysis of pooled data revealed that NSAIDs raised supine mean BP by 5.0 mm Hg but had no effect on other variables. NSAIDs antagonized the antihypertensive effect of beta blockers (BP elevation, 6.2 mm Hg) more than did vasodilators and diuretics. Among NSAIDs, piroxicam produced the most marked elevation in BP (6.2 mm Hg), whereas sulindac and aspirin had the least hypertensive effect.
It is unknown whether the relatively small BP increases associated with NSAIDs confer an increased risk of cardiovascular complications or if the increments in BP observed following NSAID administration are sustained over time. Risk factors for BP elevation during treatment with NSAIDs have not been documented. Some data suggest that elderly people and patients with pre-existing hypertension have an increased risk, particularly during antihypertensive treatment. Frequent measurement of BP may be warranted in select patients during the first few weeks of NSAID treatment.
Chronic use of oral contraceptives (OCs) results in a slight increase in BP in most women and overt hypertension in about 5%.3 The 5% reported incidence of hypertension in OC users, however, was documented in studies of high-dose OCs containing at least 50 µg of estrogen and 1-4 µg of progestin. Current OC preparations contain as little as 20% of the estrogen and progestin found in previous formulations.
Risk factors for susceptibility to the hypertensive effects of OCs were examined in a prospective cohort study of 68,297 women aged 25-42 years who were free of hypertension at baseline and followed for four years.4 Most of the OC users were taking a combination OC with low-to-medium estrogenic potency (≤50 µg ethinyl estradiol equivalents per day).
After adjustment for multiple risk factors, current OC users had an 80% greater risk of developing hypertension than did those who never used an OC. Past OC users had a slightly increased risk of hypertension compared with never-users. There were no important modifying effects of age, family history of hypertension, ethnicity, or BMI, and risk decreased quickly with cessation of OC use.
Hypertension among OC users usually develops within the first six months and occasionally is delayed for as long as six years. Evidence suggests that changes in BP related to OCs are reversible in a short time. Antihypertensive therapy is seldom needed as the hypertension that develops is generally mild and uncomplicated and rapidly reverses when OC use is discontinued.
Immunosuppression with cyclosporine has emerged as a major cause of hypertension after organ transplantation. The underlying pathophysiologic mechanisms of cyclosporine-induced hypertension include enhanced sympathetic nervous system activity, renal vasoconstriction, and sodium/water retention.5 In cardiac transplant recipients, cyclosporine-induced hypertension is associated with a loss of baroreflex function as a result of cardiac denervation-related uncoupling. Hypertension occurs in about 50% of kidney transplant patients receiving tacrolimus immunosuppression. Mild or moderate hypertension is more frequently reported than severe hypertension.
Tacrolimus is associated with an increased risk of hyperkalemia, so the use of potassium-sparing diuretics in patients with tacrolimus-related hypertension is not recommended. Calcium channel blockers are effective in treating tacrolimus-related hypertension but may interfere with tacrolimus metabolism. Insulin-dependent post-transplant diabetes mellitus occurs in about 20% of transplant patients with no prior history of diabetes who are treated with tacrolimus.
Recent data from multicenter trials and from cyclosporine-to-tacrolimus conversion studies suggest that renal transplant patients receiving tacrolimus-based immunosuppression experience less arterial hypertension than those treated with cyclosporine. In a study of 17 stable renal transplant recipients, mean daytime BP decreased from 149/95 mm Hg during cyclosporine treatment to 138/87 after switching to tacrolimus.6 Mean nighttime BP decreased from 140/86 to 132/79 after switching from cyclosporine to tacrolimus, and improvements in total and LDL cholesterol levels were also observed.
About 20%-30% of patients who receive IV erythropoietin for anemia associated with chronic renal failure experience an increase in diastolic BP ≥10 mm Hg.7 In contrast, BP levels are less likely to increase during treatment with subcutaneous erythropoietin. BP increases in patients treated with IV erythropoietin have been seen within the first 90 days of treatment.
The acute and chronic effects of erythropoietin administration on 24-hour ambulatory BP were examined in 30 erythropoietin-naïve patients receiving maintenance hemodialysis.8 After six months of treatment with erythropoietin, mean 24-hour ambulatory systolic and diastolic BP increased from 125 to 134 mm Hg and from 77 to 83 mm Hg, respectively. Echocardiographic examinations revealed increases in ejection fraction and decreases in fractional shortening, interventricular septum thickness, and left ventricular mass index after six months of erythropoietin treatment.
The pathophysiology of erythropoietin-induced hypertension is incompletely understood. Possible underlying mechanisms include contributory effects of the increases in hematocrit and erythrocyte mass, changes in production of or sensitivity to endogenous vasopressors, alterations in vascular smooth-muscle ionic milieu, dysregulation of production or responsiveness to endogenous vasodilatory factors, a direct vasopressor action of erythropoietin, and arterial remodeling through stimulation of vascular cell growth.9
Factors that may contribute to the hypertensive response in those treated with erythropoietin include high doses, rapid increases in hemoglobin and hematocrit, and large absolute elevations in hemoglobin and hematocrit. Prevention or correction of erythropoietin-related hypertension is accomplished by initiating therapy with a low-dose regimen that is slowly increased. Drug intervention, in combination with dialysis modification and restriction of dietary salt and fluid intake, may be useful. Discontinuation of erythropoietin therapy for patients with severe and uncontrollable hypertension is rarely necessary.
Dr. Weir is professor of medicine and head of nephrology at the University of Maryland Medical Center in Baltimore.
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9. Vaziri ND. Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis. 1999;33:821-828.