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Dr. Pham is a Pharmacy Practice Resident at UCLA Medical Center in Los Angeles, California.

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Hypertension affects approximately 60 million adults in the United States and is one of the most common chronic reasons for physician office visits.¹ Data from the National Health and Nutrition Examination Survey census bureau show that only 34% of patients with hypertension have adequate blood-pressure (BP) control²; the result is that hypertensive emergencies present in roughly 27.5% of emergency room visits.³ Long-term effects of hypertension also are significant risk factors for hospitalization.^4-6

Essential hypertension is the term used for elevated BP of unknown origin. These elevations have been classified into stages, according to the most recent report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), based on the average of ≥2 properly measured BP readings on separate health care visits (Table).²

Improper management of hypertension is a major risk factor for cardiovascular disease (CVD), such as left ventricular hypertrophy, angina, myocardial infarction, and heart failure,^4-6 and can lead to other end-organ damage, such as stroke, retinopathy, chronic kidney disease, and peripheral arterial disease. Benefits of treating hypertension with medication have been demonstrated in numerous clinical trials.^7,8

Patient Evaluation

Thorough patient evaluation for essential hypertension is key² and should begin with a complete history to assess the course of BP levels, the extent of organ damage, the presence of other risk factors for CVD (eg, obesity, dyslipidemia, diabetes mellitus, cigarette smoking), and other comorbidities. Other evaluation recommendations include a physical examination, observing signs of organ damage; laboratory tests, including urinalysis, blood glucose, hematocrit and lipid panel, serum potassium, creatinine, and calcium; an electrocardiogram, monitoring cardiac activity; and accurate vital-sign assessment, determining BP, heart rate, and respiratory rate.

Table

Nonpharmacologic Treatment

Treating essential hypertension usually begins with lifestyle modifications.² In the PREMIER trial, sponsored by the National Heart, Lung, and Blood Institute, patients experienced a lower prevalence of hypertension and required less use of antihypertensive medications after 18 months of nonpharmacologic therapy.⁹ Health care providers should outline a specific plan per patient.

A reduced-sodium diet (6 g of salt daily) has been shown to lower systolic BP (SBP) by about 2 to 8 mm Hg.Weight reduction (maintaining a healthy body weight index of 18.5-24.9 kg/m²) can lead to SBP reductions of roughly 5 to 20 mm Hg. Patients are encouraged to adopt the eating plan, Dietary Approaches to Stop Hypertension (DASH diet), which is rich in fruits, vegetables, and low-fat dairy products, with reduced saturated and total fat, and can lower SBP by 8 to 14 mm Hg.

Aerobic physical activity at least 30 minutes per day, most days of the week, can reduce SBP by 4 to 9 mm Hg. Moderation of alcohol consumption (men <2 drinks daily, women <1 drink daily) also can slightly reduce SBP. All patients are encouraged to stop smoking.²

Pharmacologic Treatment

Pharmacologic treatment of essential hypertension is usually initiated for patients who do not achieve their BP goals (BP <140/90 mm Hg or BP <130/80 mm Hg in patients with diabetes or chronic kidney disease) through lifestyle modifications.² Initial drug choice is based on the presence or absence of other compelling factors. Based on outcomes from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the JNC 7 guidelines recommend a low-dose thiazide diuretic for patients with uncomplicated hypertension.¹⁰ Results have shown benefits of diuretics in patients with heart failure, previous myocardial infarction (spironolactone), and diabetes, and for stroke prevention.

If BP goals are not reached with a thiazide diuretic, the addition of an angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker (ARB), beta-blocker (BB), calcium channel blocker (CCB), or a combination of these agents should be considered. Patients initially diagnosed with stage 2 hypertension may need to start with a combination of the above antihypertensives (usually diuretic + ACE inhibitor for synergy).¹¹

Although thiazide diuretics are considered the initial drug choice for uncomplicated hypertension, specific compelling indications are used for other antihypertensives. ACE inhibitors are considered first-line options for patients who have heart failure, previous myocardial infarctions, stroke, diabetes, systolic dysfunction, or chronic kidney disease.² This is due to the suggested cardiac and renal protective effects of inhibiting the reninangiotensin-aldosterone system. ARBs are likely to have similar indications and are usually substituted if patients do not tolerate an ACE inhibitor (eg, cough).

Combination therapy with an ACE inhibitor and an ARB appears to be beneficial in patients with heart failure and chronic renal failure.¹² The newly approved direct renin inhibitor (aliskiren) also may be useful when used alone or in combination with other antihypertensive agents.¹³ All medications that block the renin-angiotensin system should be used with extreme caution in the 1st trimester (category C) and are contraindicated in the 2nd and 3rd trimesters (category D) of pregnancy due to fetal injury.¹⁴

BBs are primarily indicated for essential hypertension in patients with previous myocardial infarction, stable heart failure, and diabetes. BBs also are useful for patients with atrial fibrillation, angina, and migraine headaches. Although no absolute indications for CCBs exist, they can offer added benefit for patients with atrial fibrillation or angina and may be preferred in patients with chronic obstructive airway disease.

The combination of different classes of antihypertensive medications often is needed to adequately control BP. A BP >20/10-mm Hg above goal is generally an indication to start an additional medication.² Diuretics are thought to have a synergistic effect with ACE inhibitors, ARBs, and BBs by minimizing volume expansion. Combinations can be derived based on this or other factors (eg, cost, patient tolerability). Some combinations should be used with caution because of possible potentiating side effects (ACE inhibitor + ARB can increase serum potassium levels; BB + CCB can potentiate heart block).

Although age and race are not considered compelling indications, they can be used to predict response from hypertensive patients. Young and white patients tend to respond better to ACE inhibitors (and probably ARBs) and BBs.¹⁵ These responses may be related to theoretical elevated baseline plasma renin activity levels in these patients.¹⁶ Elderly and black patients have been shown to respond better to diuretics and CCBs.¹⁷

Alpha-blockers (doxazosin, terazosin) are not considered initial treatment options in essential hypertension unless the patient has concomitant benign prostatic hypertrophy. A central alpha-agonist (clonidine) is used primarily for refractory hypertension that is not otherwise controlled. The transdermal formulation may be an attractive option for patients who do not tolerate pills. Direct arterial vasodilators (hydralazine, minoxidil) also are considered 2nd- or 3rd-line agents. Nitrates (isosorbide mononitrate and dinitrate) are usually used in patients who are resistant to other antihypertensive therapy; however, a nitrate-free period (12 hours daily) is necessary to avoid tolerance.

Formulary Considerations

With regard to essential hypertension in a health system, it is strongly recommended that each institution consider JNC 7 guidelines when adding medication classes to its formulary. Diuretics (thiazide and loop), BBs (specific ß1 without intrinsic sympathomimetic activity), ACE inhibitors (short- and long-acting), ARBs, and CCBs (dihydropyridines and nondihydropyridines) are all standard antihypertensive medications that should be part of a complete health system drug formulary. Agents used for refractory hypertension (eg, clonidine, hydralazine, nitrates) should be available for resistant patients.

References

1. Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44:398-404.
2. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA. 2003;289:2560-2572.
3. Kitiyakara C, Guzman NJ. Malignant hypertension and hypertensive emergencies. J Am Soc Nephrol. 1998;9:133-142.
4. Psaty BM, Furberg CD, Kuller LH, et al. Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. Arch Intern Med. 2001;161:1183-1192.
5. Levy D, Larson MG, Vasan RS, Kannel WB, Ho KK. The progression from hypertension to congestive heart failure. JAMA. 1996;275:1557-1562.
6. Coresh J, Wei L, McQuillan G, et al. Prevalence of high blood pressure and elevated serum creatinine level in the United States: findings from the third National Health and Nutrition Examination Study (1998-1994). Arch Intern Med. 2001;161:1207-1216.
7. Neal B, MacMahon S, Chapman N; Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists, and other blood pressure lowering drugs. Lancet. 2000;356:1955-1964.
8. Wong ND, Thakral G, Franklin SS, et al. Preventing heart disease by controlling hypertension: impact of hypertensive subtype, stage, age, and sex. Am Heart J. 2003;145:888-895.
9. Appel LJ, Champagne CM, Harsha DW, et al. Effects of comprehensive lifestyle modification on blood pressure control: main results of the PREMIER clinical trial. JAMA. 2003;289:2083-2093.
10. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs. diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997.
11. Neutel JM, Black HR, Weber MA. Combination therapy with diuretics: an evolution of understanding. Am J Med. 1996;101:61S-70S.
12. Lip GY, Frison L, Grind M. Angiotensin converting enzyme inhibitor and angiotensin receptor blockade use in relation to outcomes in anticoagulated patients with atrial fibrillation. J Intern Med. 2007;261:577-586.
13. Tekturna [package insert]. East Hanover, NJ: Novartis; 2007.
14. United States Food and Drug Administration. Center for Drug Evaluation and Research. www.fda.gov/cder/index.html. Accessed January 18, 2008.
15. Dickerson JEC, Hingorani AD, Ashby MJ, Palmer CR, Brown MJ. Optimization of antihypertensive treatment by crossover rotation of four major classes. Lancet. 1999;353:2008-2013.
16. Blaufox MD, Lee HB, Davis B, et al. Renin predicts the blood pressure response to nonpharmacologic and pharmacologic therapy. JAMA. 1992;267:1221-1225.
17. Morgan TO, Anderson AI, MacInnis RJ. ACE inhibitors, beta-blockers, calcium blockers, and diuretics for the control of systolic hypertension. Am J Hypertens. 2001;14:241-247