Obesity is common in patients with resistant hypertension. Data from the Hypertension and Diabetes Risk Screening and Awareness (HYDRA) study, a cross-sectional study of 45,125 primary care patients, showed that those with a body mass index >40 kg/m2 had a higher prevalence of hypertension, as well as a 5.3- and 3.2-fold higher probability of requiring 4 or 3 antihypertensive drugs, respectively, to achieve BP control compared with patients with normal weight (body mass index ≤25 kg/m2). Increased sodium and fluid retention, sympathetic activation, and stimulation of the renin-angiotensin-aldosterone system (RAAS) appear to contribute to high BP in obese persons.
Use of a variety of prescription drugs and other exogenous substances is commonly related to resistant hypertension (Table I), and a history of use of these agents should be queried in all patients with resistant hypertension. Withdrawal of these agents can reduce or even normalize BP in some patients.
Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase (COX) 2 inhibitors, are a common cause of uncontrolled BP and renal impairment in hypertensive patients. NSAIDs increase the BP through volume and sodium retention, likely due to inhibition of vasodilating prostaglandins in the kidney.
All NSAIDs appear to elevate mean BP (Figure 1) and antagonize the BP-lowering effects of antihypertensive drugs. The selective COX-2 inhibitors are also associated with BP elevation. A meta-analysis of 45,451 patients enrolled in 19 randomized controlled trials showed that COX-2 inhibitors elevate BP by an average of ≈4/1 mm Hg compared with placebo and by ≈3/1 compared with NSAIDs. The BP-elevating effects are dose-related, and some agents appear to have greater effects than others. For example, in the Multinational Etoricoxib and Diclofenac Arthritis Long-Term (MEDAL) program, which randomized 34,701 patients with osteoarthritis or rheumatoid arthritis to etoricoxib or diclofenac, patients assigned to etoricoxib discontinued the study due to hypertension more frequently than did those assigned to diclofenac. If analgesics are necessary in hypertensive patients, medications such as tramadol or hydrocodone and nerve block are useful alternatives. If NSAIDs or COX-2 inhibitors are needed, minimal effective doses should be prescribed. Providers must ask all hypertensive patients about use of pain control medications to avoid this form of iatrogenic resistant hypertension.
Figure 1. Effects of celecoxib, rofecoxib, and naproxen on changes in 24-hour mean systolic blood pressure after 6 weeks of therapy. From Sowers et al.13
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Oral contraceptives induce small increases in BP in the entire population of users, with frank hypertension occurring in fewer patients and resistant hypertension in very few patients. The Nurses' Health Study prospectively followed 68,297 normotensive premenopausal female nurses for development of hypertension for 4 years. Current oral contraceptive users had an 80% increased risk of developing hypertension compared with those who had never used them, but this increased risk resolved almost completely with withdrawal of the medication. Further, oral contraceptive use in persons with underlying hypertension is associated with uncontrolled BP. A cross-sectional study evaluating the association between oral contraceptives and BP control in 171 hypertensive women found that oral contraceptive users had poorer BP control and tended to have more severe hypertension than users of other contraceptive methods or nonusers. Combined (estrogen/progestin) oral contraceptives are more often associated with BP increases than progestin-only oral contraceptives.
Menopausal hormone therapy has minimal effects on BP and is not contraindicated in either normotensive or hypertensive women. Nevertheless, all hypertensive women treated with menopausal hormone therapy should have their BP measured initially and then at 3- to 6-month intervals depending on the difficulty of control.
Heavy alcohol ingestion increases the risk of uncontrolled hypertension, and its cessation promotes BP reduction and improves adherence to treatment. In a cross-sectional analysis, men with excessive alcohol intake (>4 drinks/d) had 50% higher probability of poor BP control. Moderation in alcohol consumption (<2 drinks/d) is recommended as a lifestyle modification in the general population, especially in patients with hypertension, and complete cessation should be advised in heavy drinkers.
Other exogenous substances that contribute to hypertension, such as corticosteroids, sympathomimetic agents, erythropoietin, and antidepressants, should be avoided in patients with high BP and discontinued if at all possible in those with uncontrolled BP. In persons for whom these substances are essential, more frequent BP evaluations and increased doses and/or numbers of antihypertensive medications may be required.