Drug-Induced Hypertension

US Pharm. 2008;33(9):HS11-HS20.

Pharmacists often receive inquiries about the effects of medications on blood pressure. For example, concerns about OTC cough and cold products still arise even though some ingredients, such as phenylpropanolamine, have been removed from the U.S. market. While only a few classes of drugs cause clinically significant increases in arterial pressure, pharmacists should be aware of drugs that may interfere with effective blood pressure control. A review of drug–drug interactions with antihypertensive agents is beyond the scope of this article. However, some of the more common examples of drug-induced hypertension will be discussed (TABLE 1). Drug-induced blood pressure elevations represent an important and modifiable cause of secondary hypertension; therefore, it is imperative that pharmacists recognize this causal relationship.

Sympathomimetic Agents
It is well established that sympathomimetic amines cause dose-related increases in blood pressure.^1-4 While sympathomimetic-induced hypertension may not be clinically significant in healthy patients, it can become hazardous in others.^1-4 Sympathomimetic amines include amphetamines and similar compounds, such as pseudoephedrine, phenylpropanolamine, and ephedrine. Historically, these compounds were contained in some OTC cough and cold preparations. Because phenylpropanolamine use was correlated with hypertension and stroke, the FDA banned it from the market in November 2000.^3,4

Pseudoephedrine: Pseudoephedrine is a bronchodilator and nasal vasoconstrictor that is generally innocuous when used in recommended doses. However, due to its potential for misuse, many retailers restrict its sale to behind the counter. Pseudoephedrine is commonly used to treat symptoms of rhinitis and rhinorrhea, but its effects on blood pressure and heart rate remain uncertain. Because of its pharmacologic similarity to ephedrine and phenylpropanolamine, use of pseudoephedrine has likewise been avoided in hypertensive patients.

Salerno et al assessed whether pseudoephedrine causes clinically meaningful elevations in blood pressure and heart rate.⁵ In this meta-analysis, the primary data extracted included systolic and diastolic blood pressure and heart rate. Twenty-four clinical trials had extractable vital sign information and included a total of 1,285 patients. This analysis demonstrated that pseudoephedrine causes a small mean increase in systolic blood pressure (approximately 1 mmHg), with no significant effect on diastolic blood pressure, and a slight increase in heart rate (about 3 beats per minute). Immediate-release formulations had a greater effect than sustained-releaseformulations, which would be expected based on pharmacokinetics. Among immediate-release formulations, there was a dose-related increase in all three cardiovascular variables. More substantial increases in both systolic and diastolic blood pressure were noted with increasing doses of pseudoephedrine. Women seemed to be slightly less susceptible to the cardiovascular effects than men. In patients whose hypertension was stable and controlled, pseudoephedrine therapy increased systolic blood pressure but had no effect on diastolic pressure. There was no effect on heart rate in treated hypertensive patients, though this may have been because many patients were receiving beta-blockers. There was no documentation of any clinically significant adverse outcomes, such as hypertensive emergencies, stroke, or arrhythmia. Other investigators have similarly concluded that when it is used at standard doses, pseudoephedrine does not have a clinically significant effect on systolic or diastolic blood pressure in patients with controlled hypertension.⁶

Pharmacists should counsel patients that pseudoephedrine may modestly increase blood pressure and heart rate. These effects are greatest with immediate-release formulations, higher doses, and short-term medication administration. Patients with stable, controlled hypertension do not seem to be at higher risk for blood pressure elevation compared to those without hypertension. However, one cannot predict how any individual patient will react. The risk-benefit ratio should be evaluated carefully before using any sympathomimetic agent in persons with hypertension. Pharmacists shouldinstruct patients with cardiovascular disease to monitor their blood pressures carefully after starting pseudoephedrine-containing medications. Sustained-release products would generally be preferred to avoid increases in blood pressure. Alternatively, intranasal decongestants such as oxymetazoline could be used, since they have not been shown to induce hypertension when used at recommended doses.⁷

Amphetamine Derivates: A variety of drugs used for narcolepsy and attention-deficit/hyperactivity disorder are chemically related to amphetamine. These central nervous system (CNS) stimulants include dextroamphetamine, methamphetamine, and methylphenidate. The FDA recently issued a warning for dextroamphetamine, stating that using CNS-stimulant treatment at usual doses in children and adolescents with serious heart problems and structural cardiac abnormalities has been associated with sudden death.⁸ However, adverse cardiovascular events induced by stimulants are not limited to children. Adults with known cardiac disease have also shown increased risk of sudden death with stimulant use at normal doses. As a general rule, amphetamine-related compounds (i.e., CNS stimulants) should be avoided in patients with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems that increase the risk of sudden death. Increases in both heart rate and blood pressure have been observed in children receiving drugs in this class.⁹ Thus, this potential cardiovascular risk should be balanced against the beneficial behavioral effects of these medications.

NSAIDs and COX-2 Inhibitors
Nonsteroidal anti-inflammatory drugs (NSAIDs) have potentially adverse effects on blood pressure.^10,11 NSAIDs block both cyclooxygenase-1 (COX-1) and COX-2 enzymes, which leads to a reduction in prostaglandin formation. These drugs can have widespread beneficial and harmful effects, depending on the patient context. Drug-induced hypertension associated with NSAIDs is due to the renal effects of these drugs. Specifically, NSAIDs cause dose-related increases in sodium and water retention. This effect is also seen with COX-2 selective agents, such as celecoxib.¹¹

The COX-1 and COX-2 isoforms are both expressed within the normal adult kidney, with COX-1 in the glomerulus and afferent arteriole and COX-2 in the afferent arteriole, the podocytes, and macula densa.¹² The specific location of each of these isoenzymes in the kidney translates into notably different effects on renal function. The prostaglandins produced by COX-1 primarily affect renal homeostasis by promoting vasodilation in the renal vascular bed, reducing renal vascular resistance, and consequently increasing renal perfusion. Prostaglandins produced by the COX-2 isoenzyme have diuretic and natriuretic effects.^12,13 In patients who are hemodynamically compromised, the effects of the two isoenzymes are essential for the maintenance of renal perfusion because of their vasodilatory effects. Because NSAIDs block the production of the COX-1 and COX-2 prostaglandins, renal side effects are not uncommon, occurring in approximately 1% to 5% of NSAID users.¹³

By inhibiting COX-2's natriuretic effect, thereby increasing sodium retention, all NSAIDs carry with them the consequent risk of increased fluid retention.¹⁴ Additionally, the inhibition of vasodilating prostaglandins and the production of vasoconstricting factors, namely endothelin-1, can contribute to the induction of hypertension in a normotensive and/or controlled hypertensive patient.¹⁴

In a comparison of celecoxib with diclofenac conducted in 287 patients with arthritis, cardiovascular and renal side effects were seen in 79 patients (27.8%), with hypertension being the most common (16.6%).¹⁴ There was no statistical difference in the incidence of hypertension between the traditional NSAID and COX-2 groups. This initiation of hypertension by NSAIDs is especially important in the discussion of COX-2 safety in light of the fact that hypertensive status is a key risk factor in the progression of virtually all cardiovascular diseases including stroke, myocardial infarction, and congestive heart failure.¹⁵

A recent meta-analysis of COX-2 inhibitors and their effects on blood pressure was published.¹⁶ Data were collected in 45,451 patients from 19 clinical trials. Interestingly, there appeared to be a somewhat greater blood pressure elevation with COX-2 inhibitors compared with placebo and nonselective NSAIDs (e.g., ibuprofen and diclofenac). Rofecoxib appeared to confer a greater risk of developing clinically important elevations in both systolic and diastolic pressures in comparison to celecoxib. However, rofecoxib was voluntarily pulled from the market in 2004 due to concerns about increased risk of heart attack and stroke.¹⁷

Because of the widespread availability of NSAIDs without a prescription, many patients with hypertension may be at risk for aggravated blood pressure effects caused by these drugs. Pharmacists should take a careful medication history and specifically inquire about OTC use of NSAIDs. Patients with hypertension should be more closely monitored for blood pressure elevations when using NSAIDs. Patients should be counseled that this adverse effect tends to be dose related, but it is not always predictable. The adverse effect of all NSAIDs and COX-2 inhibitors on blood pressure may have the most clinical significance in the elderly, in whom the prevalence of arthritis, hypertension, and NSAID use is high.¹⁸

Corticosteroids
All corticosteroid drugs, including prednisone, can cause sodium retention, resulting in dose-related fluid retention.¹⁹ 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.²⁰ 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 overstimulation 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.²¹ 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 drug-induced hypertension.²² 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.²³ 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 dia­ stolic 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.²⁴ 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.²⁵ 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.²⁷ 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 high-dose therapy in which the estrogen dose was at least 50 mcg and the progestin dose was 1 to 4 mg.²⁴ 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.²⁸ 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 two-fold in current users of oral contraceptives (<50 mcg of ethinyl estradiol daily).²⁹

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.³⁰ 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.³¹

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.³⁴ 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.³⁵

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.³⁶ 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.³⁷ 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 Inhibitors
Venlafaxine: 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.³⁸ The extended-release formulation of venlafaxine increases blood pressure in approximately 3% of patients when normal doses (75-150 mg) are used.³⁸ 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.³⁹ 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.⁴⁰

Sibutramine: The clinical significance of sibutramine-induced 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.⁴¹ 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.⁴² 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.

Immunosuppressants
Cyclosporine: The adverse effect of cyclosporine on blood pressure is well known.⁴⁵ 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.⁴⁸ 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.⁴⁵ 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%.⁴⁸ 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%).⁴⁹ The mechanism of tacrolimus-induced hypertension is postulated to be similar to cyclosporine's, as previously discussed.⁵⁰ Modifications similar to those listed for cyclosporine-induced hypertension, whether pharmacologic or nonpharmacologic, may be required to treat the blood pressure elevations associated with tacrolimus therapy.⁵¹ 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.

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