Journal of the American Society of Hypertension 8(12) (2014) 946–948
American Society of Hypertension Self-Assessment Guide
Secondary hypertension Drugs and herbal preparations that increase pressure Gary E. Sander, MD, PhD To purchase and complete the ASH Hypertension Self-Assessments please use the following link: https://secure.ptcny.com/webtest
Drugs may elevate blood pressure (BP) or impair responses to anti–hypertensive medications; it is imperative to consider the role of such drugs in the evaluation of hypertension, particularly resistant hypertension, as has been emphasized in the Joint National Committee (JNC) reports. The so–called ‘‘iceberg effect’’ refers to a very common situation in which a drug may significantly increase BP but the resultant BP still remains within the ‘‘normal range’’ by JNC 7 criteria. Clinical trial data and adverse drug reporting most often describe only new ‘‘hypertension’’; small but significant increases within the ‘‘normal range’’ elevate cardiovascular risk as has been demonstrated in a number of studies; an example of this is the increased cardiovascular risk between ‘‘high normal’’ and ‘‘optimal’’ BP groups. Accentuated BP responses are observed in the presence of older age and cardiovascular or renal disease. The more important drug classes and individual drugs that increase BP are listed in Table 1. Categorization of these drugs is sometimes difficult in that certain drugs may be represented in multiple classes; for example, sympathomimetic agents may be considered as decongestants, stimulants, and/or weight loss medications. Importantly, not all agents within a class have the same BP effects.
Nonsteroidal Anti–inflammatory Drugs (NSAIDs) Perhaps the best examples of drugs causing hypertension are the NSAIDs, including the cyclooxygenase–2 (COX–2) specific inhibitors. As early as 1994, a meta–analysis from 50 randomized trials demonstrated that NSAIDs elevated
supine mean BP by an average of 5.0 mm Hg. Among NSAIDs of the COX–1 class, piroxicam produced the most marked elevation in BP, whereas sulindac and aspirin had the least effect. The BP effects of NSAIDs presumably result from inhibition of renal PGE2 and PGI2 production with sodium and fluid retention. Age, diabetes, and chronic kidney disease (CKD) increase risk. NSAIDs and COX–2 agents also blunt the antihypertensive effects of diuretics, angiotensin–converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and b–blockers, an important factor in the assessment of resistant hypertension.
Sympathomimetic Amines (Decongestants/Stimulants/Diet Drugs) Sympathomimetics are vasoactive amines that activate the sympathetic nervous system. Pseudoephedrine, phenylpropanolamine, phenylephrine, oxymetazoline, and naphazoline increase systolic BP with variable effects on diastolic BP but with no effect on heart rate in controlled hypertensives as well as in normotensives. Stimulants are increasingly used in ADHD (attention–deficit/hyperactivity disorder), narcolepsy, fatigue due to depression, stroke, and traumatic brain injury. Placebo–controlled trials indicate that stimulants such as methylphenidate and amphetamine, as well as the non–stimulant atomoxetine, elevate systolic/ diastolic BP by 2–5/1–3 mm Hg. Sumatriptan, a serotonin (5–hydroxytryptamine) antagonist, can elevate BP by 4%–6% in both normotensive and hypertensive individuals.
Oral Contraceptives (OC) This article is part of the American Society of Hypertension Self-Assessment Guide series. For other articles in this series, visit the JASH home page at www.ashjournal.com. *Corresponding author: Dr Gary E. Sander, MD, PhD, Tulane Heart and Vascular Institute, 1415 Tulane Ave, New Orleans, LA 70112. Tel.: 504-458-5717; fax: 504-835-7019. E-mail: [email protected]
Estrogen–progestogen OC use may increase BP in normotensive women. A prospective study in of 68,297 normotensive nurses found an average increase in systolic BP of 7–8 mm Hg compared with non–users. Mildly hypertensive women taking low dosage estrogen–progestogen OC exhibited significantly higher daytime and nighttime
1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2014.10.006
G.E. Sander / Journal of the American Society of Hypertension 8(12) (2014) 946–948
947
Table 1 Oral agents that increase blood pressure Category
Examples
Anabolic steroids Anti–depressants Erythropoietin Herbal preparations Immunosuppressants Mineralocorticoids NSAIDs/COXIBs Oral contraceptives Stimulants
Norandrolone, oxymetholone, oxandrolone Venlafaxine, tricyclics (phenelzine, tranlcypromine), MAO inhibitors (phenelzine, tranlcypromine) rHuEPO, darbepoetin Ephedra Cyclosporin, tacrolimus Licorice (glycyrrhizic acid), carbenoxolone, fludrocortisone, 9a-fluoroprednisolone Ibuprofen, piroxicam, indomethacin Estrogen–containing methylphenidate, dexmethylphenidate, Dextroamphetamine, amphetamine, methamphetamine, modafinil, atomoxetine, dihydroergotamine, sumatriptan Glybenclamide Catecholamines and amine analogs such as phenylpropanolamine
Sulfonylureas Sympathomimetic amines
COXIBs, Cyclooxygenase–2 inhibitors; MAO, monoamine oxidase; NSAIDs, nonsteroidal anti–inflammatory drugs.
systolic BP as recorded by ABPM compared with controls, an average 8.3/6.1 mm Hg difference for daytime/nighttime. Newer progestins such as drospirenone have anti– mineralocorticoid diuretic effects and lower BP.
Anabolic Androgenic Steroids (AAS) AAS use elevates systolic and diastolic BP and with left ventricular hypertrophy that may persist for some time after drug cessation.
Erythropoietin Recombinant human erythropoietin (rHuEPO) can induce hypertension in chronic renal failure (CRF) patients receiving hemodialysis (HD). rHuEPO increased mean BP >10 mm Hg more commonly in HD than in predialysis CRF patients (27.0% vs. 5.5%). A correlation was found between endothelin–1 level and mean BP in HD but not in predialysis CRF.
Herbal Supplements Clinical information as to efficacy and safety of herbal products is clearly lacking. Herbal products, including areca, arnica, bitter orange, blue cohosh, dong quai, ephedra, ginkgo, ginseng, guarana, khat, kola, licorice, lobelia, mate, pennyroyal oil, Scotch broom, senna, southern bayberry, St. John’s wort, and yohimbine have been reported to cause hypertension. Of these, bitter orange, ephedra, caffeine, guarana, mate, kola, areca, lobelia, and khat appear to be the more common offenders, causing not only BP elevations but a variety of additional adverse cardiovascular effects as well. Significant prescription drug interactions may also occur; ginkgo biloba raises BP when combined with a thiazide. Ephedra alkaloids (ma– huang), particularly when combined with caffeine, appears to be particularly likely to increase systolic BP; even
hypertensive encephalopathy has been reported. Yohimbine, an alkaloid with stimulant and aphrodisiac effects, is an alpha2–adrenergic receptor antagonist that increases BP by increasing plasma norepinephrine release from sympathetic nerve terminals and epinephrine release from the adrenal. Licorice, present in candy, oral tobacco products, and a variety of herbal preparations, can raise BP by suppressing the metabolism of cortisol, thus increasing stimulation of the mineralocorticoid receptor. The licorice in question is true, unmodified licorice from the licorice plant, which contains glycyrrhizinic acid. Many popular candies labeled as ‘‘licorice’’ either contain no true licorice or have the glycyrrhizinic acid removed. Glycyrrhizic acid causes a mineralocorticoid excess syndrome that may result in hypertension; individuals with pre–existing hypertension and heart disease are more sensitive to this effect.
Anti–depressants Anti–depressant drugs act by altering brain catecholamine concentrations, the result of which may be an increase in BP that differs widely among classes. Tricyclics elevate BP and often cause stage 1 to stage 2 hypertension. Combined reuptake inhibitor and receptor blocker mirtazapine is 50% less likely to cause hypertension and tachycardia than the tricyclics; newer reversible monoamine oxidase inhibitors, including moclobemide and brofaromine, appear less problematic for BP than the older non– reversible inhibitors such as phenelzine and clorgyline. High doses of extended release venlafaxine cause hypertension in 12.5% of patients.
Steroids and Immunosuppressants Glucocorticoids, particularly those with the strongest mineralocorticoid effect, induce sodium and water retention that can in turn result in BP increases that are further
948
G.E. Sander / Journal of the American Society of Hypertension 8(12) (2014) 946–948
augmented by concomitant immunosuppressive therapy. Tacrolimus, like cyclosporine, has a significant effect on BP but the incidence of tacrolimus–induced hypertension (35%) is less than that of cyclosporine (50%). Mechanisms include altered vascular endothelial function, reduced levels of vasodilators (PGI2 and nitric oxide), increased vasoconstrictors including endothelin, and increased insulin resistance.
Conclusions Hypertensive patients as well as patients with observed BP increases within the normal range should be carefully questioned as to the use of over–the–counter drugs as well as herbal preparations. A small increase in BP even within the normal range may be difficult to detect, but any increase in BP increases cardiovascular risk and should be evaluated on a risk–benefit basis.
Suggested References 1. Achar S, Rostamian A, Narayan SM. Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm. Am J Cardiol 2010;106:893–901. 2. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood pressure Research. Hypertension 2008;51:1403–19.
3. JNC 7 Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure: the JNC 7 report. JAMA 2003;289:2560–72. 4. Cohen PA, Ernst E. Safety of herbal supplements: a guide for cardiologists. Cardiovasc Ther 2010;28:246–53. 5. Grossman E, Messerli FH. Secondary hypertension: interfering substances. J Clin Hypertens 2008;10:556–66. 6. Grossman E, Messerli FH. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med 2012;125:14–22. 7. Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011;306:2673–83. 8. Jalili J, Askeroglu U, Alleyne B, Guyuron B. Herbal products that may contribute to hypertension. Plast Reconstr Surg 2013;131:168–73. 9. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:289–300. 10. Licht CM, de Geus EJ, Seldenrijk A, van Hout HP, Zitman FG, van Dyck R, et al. Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension 2009;53:631–8. 11. Shufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease. J Am Coll Cardiol 2009;53:221–31. 12. Vora CK, Mansoor GA. Herbs and alternative therapies: relevance to hypertension and cardiovascular diseases. Curr Hypertens Rep 2005;7:275–80.
American Society of Hypertension Self-Assessment Guide
Secondary hypertension Drugs and herbal preparations that increase pressure Gary E. Sander, MD, PhD To purchase and complete the ASH Hypertension Self-Assessments please use the following link: https://secure.ptcny.com/webtest
Drugs may elevate blood pressure (BP) or impair responses to anti–hypertensive medications; it is imperative to consider the role of such drugs in the evaluation of hypertension, particularly resistant hypertension, as has been emphasized in the Joint National Committee (JNC) reports. The so–called ‘‘iceberg effect’’ refers to a very common situation in which a drug may significantly increase BP but the resultant BP still remains within the ‘‘normal range’’ by JNC 7 criteria. Clinical trial data and adverse drug reporting most often describe only new ‘‘hypertension’’; small but significant increases within the ‘‘normal range’’ elevate cardiovascular risk as has been demonstrated in a number of studies; an example of this is the increased cardiovascular risk between ‘‘high normal’’ and ‘‘optimal’’ BP groups. Accentuated BP responses are observed in the presence of older age and cardiovascular or renal disease. The more important drug classes and individual drugs that increase BP are listed in Table 1. Categorization of these drugs is sometimes difficult in that certain drugs may be represented in multiple classes; for example, sympathomimetic agents may be considered as decongestants, stimulants, and/or weight loss medications. Importantly, not all agents within a class have the same BP effects.
Nonsteroidal Anti–inflammatory Drugs (NSAIDs) Perhaps the best examples of drugs causing hypertension are the NSAIDs, including the cyclooxygenase–2 (COX–2) specific inhibitors. As early as 1994, a meta–analysis from 50 randomized trials demonstrated that NSAIDs elevated
supine mean BP by an average of 5.0 mm Hg. Among NSAIDs of the COX–1 class, piroxicam produced the most marked elevation in BP, whereas sulindac and aspirin had the least effect. The BP effects of NSAIDs presumably result from inhibition of renal PGE2 and PGI2 production with sodium and fluid retention. Age, diabetes, and chronic kidney disease (CKD) increase risk. NSAIDs and COX–2 agents also blunt the antihypertensive effects of diuretics, angiotensin–converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and b–blockers, an important factor in the assessment of resistant hypertension.
Sympathomimetic Amines (Decongestants/Stimulants/Diet Drugs) Sympathomimetics are vasoactive amines that activate the sympathetic nervous system. Pseudoephedrine, phenylpropanolamine, phenylephrine, oxymetazoline, and naphazoline increase systolic BP with variable effects on diastolic BP but with no effect on heart rate in controlled hypertensives as well as in normotensives. Stimulants are increasingly used in ADHD (attention–deficit/hyperactivity disorder), narcolepsy, fatigue due to depression, stroke, and traumatic brain injury. Placebo–controlled trials indicate that stimulants such as methylphenidate and amphetamine, as well as the non–stimulant atomoxetine, elevate systolic/ diastolic BP by 2–5/1–3 mm Hg. Sumatriptan, a serotonin (5–hydroxytryptamine) antagonist, can elevate BP by 4%–6% in both normotensive and hypertensive individuals.
Oral Contraceptives (OC) This article is part of the American Society of Hypertension Self-Assessment Guide series. For other articles in this series, visit the JASH home page at www.ashjournal.com. *Corresponding author: Dr Gary E. Sander, MD, PhD, Tulane Heart and Vascular Institute, 1415 Tulane Ave, New Orleans, LA 70112. Tel.: 504-458-5717; fax: 504-835-7019. E-mail: [email protected]
Estrogen–progestogen OC use may increase BP in normotensive women. A prospective study in of 68,297 normotensive nurses found an average increase in systolic BP of 7–8 mm Hg compared with non–users. Mildly hypertensive women taking low dosage estrogen–progestogen OC exhibited significantly higher daytime and nighttime
1933-1711/$ - see front matter Ó 2014 American Society of Hypertension. All rights reserved. http://dx.doi.org/10.1016/j.jash.2014.10.006
G.E. Sander / Journal of the American Society of Hypertension 8(12) (2014) 946–948
947
Table 1 Oral agents that increase blood pressure Category
Examples
Anabolic steroids Anti–depressants Erythropoietin Herbal preparations Immunosuppressants Mineralocorticoids NSAIDs/COXIBs Oral contraceptives Stimulants
Norandrolone, oxymetholone, oxandrolone Venlafaxine, tricyclics (phenelzine, tranlcypromine), MAO inhibitors (phenelzine, tranlcypromine) rHuEPO, darbepoetin Ephedra Cyclosporin, tacrolimus Licorice (glycyrrhizic acid), carbenoxolone, fludrocortisone, 9a-fluoroprednisolone Ibuprofen, piroxicam, indomethacin Estrogen–containing methylphenidate, dexmethylphenidate, Dextroamphetamine, amphetamine, methamphetamine, modafinil, atomoxetine, dihydroergotamine, sumatriptan Glybenclamide Catecholamines and amine analogs such as phenylpropanolamine
Sulfonylureas Sympathomimetic amines
COXIBs, Cyclooxygenase–2 inhibitors; MAO, monoamine oxidase; NSAIDs, nonsteroidal anti–inflammatory drugs.
systolic BP as recorded by ABPM compared with controls, an average 8.3/6.1 mm Hg difference for daytime/nighttime. Newer progestins such as drospirenone have anti– mineralocorticoid diuretic effects and lower BP.
Anabolic Androgenic Steroids (AAS) AAS use elevates systolic and diastolic BP and with left ventricular hypertrophy that may persist for some time after drug cessation.
Erythropoietin Recombinant human erythropoietin (rHuEPO) can induce hypertension in chronic renal failure (CRF) patients receiving hemodialysis (HD). rHuEPO increased mean BP >10 mm Hg more commonly in HD than in predialysis CRF patients (27.0% vs. 5.5%). A correlation was found between endothelin–1 level and mean BP in HD but not in predialysis CRF.
Herbal Supplements Clinical information as to efficacy and safety of herbal products is clearly lacking. Herbal products, including areca, arnica, bitter orange, blue cohosh, dong quai, ephedra, ginkgo, ginseng, guarana, khat, kola, licorice, lobelia, mate, pennyroyal oil, Scotch broom, senna, southern bayberry, St. John’s wort, and yohimbine have been reported to cause hypertension. Of these, bitter orange, ephedra, caffeine, guarana, mate, kola, areca, lobelia, and khat appear to be the more common offenders, causing not only BP elevations but a variety of additional adverse cardiovascular effects as well. Significant prescription drug interactions may also occur; ginkgo biloba raises BP when combined with a thiazide. Ephedra alkaloids (ma– huang), particularly when combined with caffeine, appears to be particularly likely to increase systolic BP; even
hypertensive encephalopathy has been reported. Yohimbine, an alkaloid with stimulant and aphrodisiac effects, is an alpha2–adrenergic receptor antagonist that increases BP by increasing plasma norepinephrine release from sympathetic nerve terminals and epinephrine release from the adrenal. Licorice, present in candy, oral tobacco products, and a variety of herbal preparations, can raise BP by suppressing the metabolism of cortisol, thus increasing stimulation of the mineralocorticoid receptor. The licorice in question is true, unmodified licorice from the licorice plant, which contains glycyrrhizinic acid. Many popular candies labeled as ‘‘licorice’’ either contain no true licorice or have the glycyrrhizinic acid removed. Glycyrrhizic acid causes a mineralocorticoid excess syndrome that may result in hypertension; individuals with pre–existing hypertension and heart disease are more sensitive to this effect.
Anti–depressants Anti–depressant drugs act by altering brain catecholamine concentrations, the result of which may be an increase in BP that differs widely among classes. Tricyclics elevate BP and often cause stage 1 to stage 2 hypertension. Combined reuptake inhibitor and receptor blocker mirtazapine is 50% less likely to cause hypertension and tachycardia than the tricyclics; newer reversible monoamine oxidase inhibitors, including moclobemide and brofaromine, appear less problematic for BP than the older non– reversible inhibitors such as phenelzine and clorgyline. High doses of extended release venlafaxine cause hypertension in 12.5% of patients.
Steroids and Immunosuppressants Glucocorticoids, particularly those with the strongest mineralocorticoid effect, induce sodium and water retention that can in turn result in BP increases that are further
948
G.E. Sander / Journal of the American Society of Hypertension 8(12) (2014) 946–948
augmented by concomitant immunosuppressive therapy. Tacrolimus, like cyclosporine, has a significant effect on BP but the incidence of tacrolimus–induced hypertension (35%) is less than that of cyclosporine (50%). Mechanisms include altered vascular endothelial function, reduced levels of vasodilators (PGI2 and nitric oxide), increased vasoconstrictors including endothelin, and increased insulin resistance.
Conclusions Hypertensive patients as well as patients with observed BP increases within the normal range should be carefully questioned as to the use of over–the–counter drugs as well as herbal preparations. A small increase in BP even within the normal range may be difficult to detect, but any increase in BP increases cardiovascular risk and should be evaluated on a risk–benefit basis.
Suggested References 1. Achar S, Rostamian A, Narayan SM. Cardiac and metabolic effects of anabolic-androgenic steroid abuse on lipids, blood pressure, left ventricular dimensions, and rhythm. Am J Cardiol 2010;106:893–901. 2. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood pressure Research. Hypertension 2008;51:1403–19.
3. JNC 7 Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood pressure: the JNC 7 report. JAMA 2003;289:2560–72. 4. Cohen PA, Ernst E. Safety of herbal supplements: a guide for cardiologists. Cardiovasc Ther 2010;28:246–53. 5. Grossman E, Messerli FH. Secondary hypertension: interfering substances. J Clin Hypertens 2008;10:556–66. 6. Grossman E, Messerli FH. Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med 2012;125:14–22. 7. Habel LA, Cooper WO, Sox CM, Chan KA, Fireman BH, Arbogast PG, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA 2011;306:2673–83. 8. Jalili J, Askeroglu U, Alleyne B, Guyuron B. Herbal products that may contribute to hypertension. Plast Reconstr Surg 2013;131:168–73. 9. Johnson AG, Nguyen TV, Day RO. Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994;121:289–300. 10. Licht CM, de Geus EJ, Seldenrijk A, van Hout HP, Zitman FG, van Dyck R, et al. Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension 2009;53:631–8. 11. Shufelt CL, Bairey Merz CN. Contraceptive hormone use and cardiovascular disease. J Am Coll Cardiol 2009;53:221–31. 12. Vora CK, Mansoor GA. Herbs and alternative therapies: relevance to hypertension and cardiovascular diseases. Curr Hypertens Rep 2005;7:275–80.
