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Chapter: Basic & Clinical Pharmacology : Antihypertensive Agents

Outpatient Therapy of Hypertension

The initial step in treating hypertension may be nonpharmaco-logic. As discussed previously, sodium restriction may be effective treatment for many patients with mild hypertension.


The initial step in treating hypertension may be nonpharmaco-logic. As discussed previously, sodium restriction may be effective treatment for many patients with mild hypertension. The average American diet contains about 200 mEq of sodium per day. A reasonable dietary goal in treating hypertension is 70–100 mEq of sodium per day, which can be achieved by not salting food during or after cooking and by avoiding processed foods that contain large amounts of sodium. Eating a diet rich in fruits, vegetables, and low-fat dairy products with a reduced content of saturated and total fat, and moderation of alcohol intake (no more than two drinks per day) also lower blood pressure.

Weight reduction even without sodium restriction has been shown to normalize blood pressure in up to 75% of overweight patients with mild to moderate hypertension. Regular exercise has been shown in some but not all studies to lower blood pressure in hypertensive patients.

For pharmacologic management of mild hypertension, blood pressure can be normalized in many patients with a single drug. However, most patients with hypertension require two or more antihypertensive medications (see Box: Resistant Hypertension & Polypharmacy). Thiazide diuretics, β blockers, ACE inhibitors, angiotensin receptor blockers, and calcium channel blockers have all been shown to reduce complications of hypertension and may be used for initial drug therapy. There has been concern that diuretics, by adversely affecting the serum lipid profile or impairing

glucose tolerance, may add to the risk of coronary disease, thereby offsetting the benefit of blood pressure reduction. However, a recent large clinical trial comparing different classes of antihyper-tensive mediations for initial therapy found that chlorthalidone (a thiazide diuretic) was as effective as other agents in reducing coro-nary heart disease death and nonfatal myocardial infarction, and was superior to amlodipine in preventing heart failure and superior to lisinopril in preventing stroke.

The presence of concomitant disease should influence selection of antihypertensive drugs because two diseases may benefit from a single drug. For example, drugs that inhibit the renin-angiotensin system are particularly useful in patients with diabetes or evidence of chronic kidney disease with proteinuria. Beta blockers or cal-cium channel blockers are useful in patients who also have angina; diuretics, ACE inhibitors, angiotensin receptor blockers, β blockers or hydralazine combined with nitrates in patients who also have heart failure; and α1 blockers in men who have benign prostatic hyperplasia. Race may also affect drug selection: African Americans respond better on average to diuretics and calcium channel block-ers than to β blockers and ACE inhibitors. Ethnic Chinese patients are more sensitive to the effects of β blockers and may require lower doses.

If a single drug does not adequately control blood pressure, drugs with different sites of action can be combined to effectively lower blood pressure while minimizing toxicity (“stepped care”). If a diuretic is not used initially, it is often selected as the second drug. If three drugs are required, combining a diuretic, a sym-pathoplegic agent or an ACE inhibitor, and a direct vasodilator (eg, hydralazine or a calcium channel blocker) is often effective. In the USA, fixed-dose drug combinations containing a β blocker, an ACE inhibitor, or an angiotensin receptor blocker plus a thiazide, and a calcium channel blocker plus an ACE inhibitor are available. Fixed-dose combinations have the drawback of not allowing for titration of individual drug doses but have the advantage of allow-ing fewer pills to be taken, potentially enhancing compliance.

Assessment of blood pressure during office visits should include measurement of recumbent, sitting, and standing pressures. An attempt should be made to normalize blood pressure in the pos-ture or activity level that is customary for the patient. The large Hypertension Optimal Treatment study suggests that the optimal blood pressure end point is 138/83 mm Hg. Lowering blood pres-sure below this level produces no further benefit. In diabetic patients, however, there is a continued reduction of event rates with progressively lower blood pressures. Systolic hypertension (> 140 mm Hg in the presence of normal diastolic blood pressure) is a strong cardiovascular risk factor in people older than 50 years of age and should be treated.

In addition to noncompliance with medication, causes of failure to respond to drug therapy include excessive sodium intake and inadequate diuretic therapy with excessive blood volume, and drugs such as tricyclic antidepressants, nonsteroidal anti-inflammatory drugs, over-the-counter sympathomimetics, abuse of stimulants (amphetamine or cocaine), or excessive doses of caffeine and oral contraceptives that can interfere with actions of some antihyper-tensive drugs or directly raise blood pressure.

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