All corticosteroid drugs, including prednisone, can cause sodium retention, resulting in dose-related fluid retention. Corticosteroids with strong mineralocorticoid effects, such as fludrocortisone and hydrocortisone, produce the greatest amount of fluid retention. However, some corticosteroids that lack significant mineralocorticoid activity (e.g., dexamethasone, triamcinolone, betamethasone) may produce minor fluid retention. Corticosteroid-induced fluid retention can be severe enough to cause hypertension, and patients with preexisting hypertension may develop a worsening of blood pressure control when these drugs are initiated. The principal mechanism of corticosteroid- induced hypertension is the overstimula- tion of the mineralocorticoid receptor, resulting in sodium retention in the kidney. This results in volume expansion and a subsequent increase in blood pressure. Corticosteroid-induced hypertension may respond to diuretic therapy. The smallest effective dose and shortest duration of steroid therapy should be used in order to decrease the development of this adverse effect.
Fludrocortisone causes significant blood pressure increases and, thus, is useful in treating patients with postural hypotension. In a study of 64 elderly patients receiving an average dose of 75 mcg of fludrocortisone for approximately five months, four patients had to withdraw because of druginduced hypertension. The study investigators concluded that fludrocortisone therapy was poorly tolerated in elderly patients, even at low doses.Caffeine
The effects of caffeine on blood pressure control are not well defined. A meta-analysis of randomized controlled trials analyzing the effect of either coffee or caffeine alone on blood pressure levels was recently published. A total of 16 studies with randomized, controlled designs were selected for review, representing 1,010 subjects. An increase of 2.04 mmHg in systolic blood pressure and of 0.73 mmHg in diastolic blood pressure was found after pooling these trials. When the coffee and caffeine trials were analyzed separately, the blood pressure elevations induced were larger with caffeine (410 mg/day) than with coffee (725 mL/day). The effects of coffee and caffeine on heart rate were not significant.Estrogens and Progestins
Chronic use of oral contraceptives may slightly raise blood pressure in certain women and may have other adverse effects on cardiovascular risk. Early epidemiologic studies using high-dose estrogen found mean elevations in blood pressure of 3 to 6 mmHg systolic and 2 to 5 mmHg diastolic, with approximately 5% of women developing new hypertension. This was more likely to occur in patients who had previously developed hypertension during a pregnancy or in those with a family history of hypertension. Although the rise in blood pressure is usually mild, malignant hypertension can occur. The main concern with an oral contraceptive-induced rise in blood pressure is the development of persistent hypertension and subsequent premature cardiovascular disease, especially in women who smoke. Cessation of therapy typically leads to a return to baseline blood pressure within two to 12 months, but proteinuria may persist.[25,26]
The mechanisms responsible for the hypertensive effect of oral contraceptives are poorly understood. The renin-angiotensin system may be involved, since estrogen stimulates the hepatic production of the renin substrate angiotensinogen. Both estrogen and progesterone appear to contribute in a dose-dependent fashion. The often-quoted 5% incidence of hypertension associated with estrogen is derived from studies of highdose therapy in which the estrogen dose was at least 50 mcg and the progestin dose was 1 to 4 mg. However, current preparations contain as little as 20% of the amount of estrogen and progestin used in previous preparations. A report from the Nurses' Health Study prospectively evaluated almost 70,000 female nurses, aged 25 to 42 years. After adjustment for age, weight, smoking, family history, and other risk factors, the relative risk of hypertension in the nurses compared to women who never used oral contraceptives was 1.8 for current users and 1.2 for previous users. Overall, only 41.5 cases of hypertension per 10,000 person-years could be attributed to oral contraceptive use, and this number rapidly declined with cessation of therapy. In a meta-analysis of 14 studies published between 1980 and 2003, the relative risk of stroke and heart attack increased twofold in current users of oral contraceptives (<50 mcg of ethinyl estradiol daily).
Postmenopausal estrogen replacement therapy (ERT), or hormone replacement therapy (HRT) when combined with progestin, consists of much lower estrogen doses than those in oral contraceptives. ERT and HRT appear to have a neutral effect on blood pressure as illustrated by the following observations from two large randomized trials. The Women's Health Initiative (WHI) is the largest (N = 16,000) randomized, placebo-controlled trial that has evaluated the effect of estrogen-progestin replacement on outcomes in postmenopausal women. At 5.2 years, HRT produced only a small increase (1.5 mmHg) in systolic pressure compared to placebo. Similar findings were noted in the PEPI trial in which ERT, with or without progestins, did not affect blood pressure at three years.
Additional studies involving fewer women have found a reduction of ambulatory blood pressure and a greater decline of nocturnal pressure in ERT users.[32,33] It is possible that HRT may slow the rise in systolic pressure over a longer period of treatment. However, because of the significant increases in coronary, stroke, and venous thromboembolic risk demonstrated in the WHI, HRT is no longer recommended for cardiovascular protection.Dietary Supplements
Ginseng is generally recognized as safe and has been associated with few serious side effects. Because it can have a mild stimulant effect, use with other stimulants in patients with cardiovascular disease should be cautioned. A type of ginseng abuse syndrome, characterized by diarrhea, hypertension, nervousness, dermatologic eruptions, and insomnia, has been described. This syndrome may be exhibited after single high doses or prolonged periods of use. Other supplements that may increase arterial pressure include natural licorice and yohimbine. Generally, all patients with hypertension should discuss use of dietary supplements with their pharmacist or physician beforehand. The effects of most supplements on blood pressure have not been adequately characterized.
Serotonin-norepinephrine Reuptake InhibitorsVenlafaxine
Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI) used in the treatment of depression and anxiety disorders. The likely mechanism of venlafaxine-induced hypertension is the increase in levels of norepinephrine and the subsequent potentiation of noradrenergic neurotransmission. The extended-release formulation of venlafaxine increases blood pressure in approximately 3% of patients when normal doses (75-150 mg) are used. The majority of these blood pressure elevations, however, were considered minor. Doses ≥300 mg of extended-release venlafaxine demonstrated clinically significant elevations in 13% of patients, with the majority of blood pressure increases between 10 and 15 mmHg. However, it is important to note that dosing 300 mg or more is not common, and the risk of venlafaxine-induced hypertension will usually not warrant the discontinuation of this drug.Sibutramine
The clinical significance of sibutramineinduced hypertension is not well defined. Sibutramine is an SNRI and is chemically similar to amphetamine. Sibutramine's likely mechanism of blood pressure elevation in both normotensive and hypertensive patients is the elevated amount of norepinephrine present in the body. A clinical trial evaluating the adverse reactions induced by sibutramine demonstrated a mean elevation of systolic and diastolic blood pressures of 2 mmHg in previously normotensive patients receiving 10 to 15 mg sibutramine daily. Interestingly, an elevation of 7 mmHg was demonstrated in hypertensive patients receiving similar doses. Other trials have demonstrated similar findings.[43,44] Patients with established hypertension receiving sibutramine experienced significantly higher elevations in blood pressure than patients who had normal blood pressure before medication initiation. Sibutramine treatment should probably be limited to patients who do not have cardiovascular disease, including hypertension, functional abnormalities, and coronary artery disease.
The adverse effect of cyclosporine on blood pressure is well known. The exact mechanism of cyclosporine-induced hypertension is uncertain, but several hypotheses have been proposed, including increased prostaglandin synthesis and decreased water, sodium, and potassium excretion.[46,47] Up to 50% of renal transplant patients receiving cyclosporine treatment have reported elevated blood pressure, and most of these cases required treatment for hypertension. Because of the adverse effects of cyclosporine withdrawal in transplant patients and in patients with autoimmune disease, cyclosporine is rarely discontinued for elevated hypertension. Treatment of cyclosporine-induced hypertension may be pharmacologic, consisting possibly of calcium channel blockers, diuretics, beta-blockers, or ACE inhibitors, or nonpharmacologic, consisting of reduced sodium intake. In 1999, a consensus statement was released, stating that if systolic blood pressure rose above 140 mmHg or diastolic pressure rose above 90 mmHg on two consecutive occasions, then the cyclosporine dose should be decreased by 25%. Blood pressure should be monitored every two weeks for the first three months of cyclosporine therapy in order to monitor for any changes.Tacrolimus
In patients with severe, treatment-refractory cyclosporine-induced hypertension, switching to tacrolimus may be an option. Tacrolimus, like cyclosporine, has been shown to have a significant effect on blood pressure. However, the incidence of tacrolimus-induced hypertension (35%) is less than that of cyclosporine (50%). The mechanism of tacrolimus-induced hypertension is postulated to be similar to cyclosporine's, as previously discussed. Modifications similar to those listed for cyclosporineinduced hypertension, whether pharmacologic or nonpharmacologic, may be required to treat the blood pressure elevations associated with tacrolimus therapy. Careful blood pressure monitoring is warranted during therapy with either tacrolimus or cyclosporine.Summary
Pharmacists should maintain an awareness of the major drug classes that may increase blood pressure and/or interfere with effective blood pressure control. Examples include sympathomimetics, NSAIDs, estrogens, corticosteroids, cyclosporine, and some natural products (e.g., ginseng). Pharmacists should screen for medications that raise blood pressure and should provide feedback to patients and medical providers to decrease this potential cause of secondary hypertension. Generally, all patients with hypertension should be monitored more closely anytime additional medications are prescribed, especially when drugs known to raise blood pressure are added.
Table 1. Drugs Commonly Linked to Hypertension
Table 1. Drugs Commonly Linked to Hypertension
CNS = central nervous system; NSAID = nonsteroidal anti-inflammatory drug; COX = cyclooxygenase; ERT/HRT = estrogen replacement therapy/hormone replacement therapy; SNRI = serotonin-norepinephrine reuptake inhibitor.