Drugs for Hypertension

Cardiac Output.

Cardiac output is influenced by four factors: (1) heart rate, (2) myocardial contractility (force of contraction), (3) blood volume, and (4) venous return of blood to the heart. An increase in any of these will increase cardiac output, thereby causing BP to rise. Conversely, a decrease in these factors will make BP fall. Hence, to reduce BP, we might give a beta blocker to reduce cardiac output, or a diuretic to reduce blood volume, or a venodilator to reduce venous return.

Peripheral Vascular Resistance.

Vascular resistance is increased by arteriolar constriction. Accordingly, we can reduce BP with drugs that promote arteriolar dilation.

Sympathetic Baroreceptor Reflex.

The sympathetic nervous system employs a reflex circuit—the baroreceptor reflex—to keep BP at a preset level. This circuit operates as follows:

The baroreceptor reflex frequently opposes our attempts to reduce BP with drugs. Opposition occurs because the “set point” of the baroreceptors is high in people with hypertension. That is, the baroreceptors are set to perceive excessively high BP as “normal” (i.e., appropriate). As a result, the system operates to maintain BP at pathologic levels. Consequently, when we attempt to lower BP using drugs, the reduced (healthier) pressure is interpreted by the baroreceptors as below what it should be, and, in response, signals are sent along sympathetic nerves to “correct” the reduction. These signals produce reflex tachycardia and vasoconstriction—responses that can counteract the hypotensive effects of drugs. Clearly, if treatment is to succeed, the regimen must compensate for the resistance offered by this reflex. Taking a beta blocker, which will block reflex tachycardia, can be an effective method of compensation. Fortunately, when BP has been suppressed with drugs for an extended time, the baroreceptors become reset at a lower level. Consequently, as therapy proceeds, sympathetic reflexes offer progressively less resistance to the hypotensive effects of medication.

Renin-Angiotensin-Aldosterone System.

The RAAS can elevate BP, negating the hypotensive effects of drugs. The RAAS is discussed in Chapter 36 and reviewed briefly here.

The RAAS elevates BP beginning with the release of renin from juxtaglomerular cells of the kidney. These cells release renin in response to reduced renal blood flow, reduced blood volume, reduced BP, and activation of beta₁-adrenergic receptors on the cell surface. After its release, renin catalyzes the conversion of angiotensinogen into angiotensin I, a weak vasoconstrictor. After this, angiotensin-converting enzyme (ACE) acts on angiotensin I to form angiotensin II, a compound that constricts systemic and renal blood vessels. Constriction of systemic blood vessels elevates BP by increasing peripheral resistance. Constriction of renal blood vessels elevates BP by reducing glomerular filtration, which causes retention of salt and water, which in turn increases blood volume and BP. In addition to causing vasoconstriction, angiotensin II causes release of aldosterone from the adrenal cortex. Aldosterone acts on the kidney to further increase retention of sodium and water.

Because drug-induced reductions in BP can activate the RAAS, this system can counteract the effect we are trying to achieve. We have five ways to cope with this problem. First, we can suppress renin release with beta blockers. Second, we can prevent conversion of angiotensinogen to angiotensin I with a direct renin inhibitor (DRI). Third, we can prevent the conversion of angiotensin I into angiotensin II with an ACE inhibitor. Fourth, we can block receptors for angiotensin II with an angiotensin II receptor blocker (ARB). And fifth, we can block receptors for aldosterone with an aldosterone antagonist.

Renal Regulation of Blood Pressure.

As discussed in Chapter 34, the kidney plays a central role in long-term regulation of BP. When BP falls, glomerular filtration rate (GFR) falls too, thereby promoting retention of sodium, chloride, and water. The resultant increase in blood volume increases venous return to the heart, causing an increase in cardiac output, which in turn increases arterial pressure. We can neutralize renal effects on BP with diuretics.

8b—Renin.

Inhibition of renin decreases conversion of angiotensinogen into angiotensin I and thereby suppresses the entire RAAS. The result is peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.

8c—Angiotensin-Converting Enzyme.

Inhibitors of ACE suppress formation of angiotensin II. The result is peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.

8d—Angiotensin II Receptors.

Blockade of angiotensin II receptors prevents the actions of angiotensin II. Hence blockade results in peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.

8e—Aldosterone Receptors.

Blockade of aldosterone receptors in the kidney promotes excretion of sodium and water and thereby reduces blood volume.

Thiazide Diuretics.

Thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone) are first-line drugs for hypertension. They reduce BP by two mechanisms: reduction of blood volume and reduction of arterial resistance. Reduced blood volume is responsible for initial antihypertensive effects. Reduced vascular resistance develops over time and is responsible for long-term antihypertensive effects. The mechanism by which thiazides reduce vascular resistance has not been determined.

Of the thiazides available, hydrochlorothiazide is used most widely. In fact, hydrochlorothiazide is used more widely than any other antihypertensive drug. Nonetheless, other thiazides, especially chlorthalidone, may be more effective.

The principal adverse effect of thiazides is hypokalemia. This can be minimized by consuming potassium-rich foods and using potassium supplements or a potassium-sparing diuretic. Other side effects include dehydration, hyperglycemia, and hyperuricemia.

Thiazides are superior to calcium channel blockers (CCBs) and ACE inhibitors as monotherapy and therefore are preferred.

Loop Diuretics.

Loop diuretics (e.g., furosemide) produce much greater diuresis than the thiazides. For most individuals with chronic hypertension, the amount of fluid loss that loop diuretics can produce is greater than needed or desirable. Consequently, loop diuretics are not used routinely for hypertension. Rather, they are reserved for (1) patients who need greater diuresis than can be achieved with thiazides and (2) patients with a low GFR (because thiazides won’t work when GFR is low). Like the thiazides, the loop diuretics lower BP by reducing blood volume and promoting vasodilation.

Most adverse effects are like those of the thiazides: hypokalemia, dehydration, hyperglycemia, and hyperuricemia. In addition, loop diuretics can cause hearing loss.

Potassium-Sparing Diuretics.

The degree of diuresis induced by the potassium-sparing agents (e.g., spironolactone) is small. Consequently, these drugs have only modest hypotensive effects. However, because of their ability to conserve potassium, these drugs can play an important role in an antihypertensive regimen. Specifically, they can balance potassium loss caused by thiazides or loop diuretics. The most significant adverse effect of the potassium-sparing agents is hyperkalemia. Because of the risk for hyperkalemia, potassium-sparing diuretics must not be used in combination with one another or with potassium supplements. Also, they should not be used routinely with ACE inhibitors, ARBs, or aldosterone antagonists, all of which promote significant hyperkalemia.

Beta-Adrenergic Blockers.

Like the thiazides, beta blockers (e.g., metoprolol) are widely used antihypertensive drugs. However, despite their efficacy and frequent use, the exact mechanism by which they reduce BP is somewhat uncertain. Beta blockers are less effective in black people than in whites.

The beta blockers have at least four useful actions in hypertension. First, blockade of cardiac beta₁ receptors decreases heart rate and contractility, thereby causing cardiac output to decline. Second, beta blockers can suppress reflex tachycardia caused by vasodilators. Third, blockade of beta₁ receptors on juxtaglomerular cells of the kidney reduces release of renin and thereby reduces angiotensin II−mediated vasoconstriction and aldosterone-mediated volume expansion. Fourth, long-term use of beta blockers reduces peripheral vascular resistance—by a mechanism that is unknown. This action could readily account for most of their antihypertensive effects.

Three beta blockers have intrinsic sympathomimetic activity: pindolol, penbutolol, and acebutolol. That is, they can produce mild activation of beta receptors while blocking receptor activation by strong agonists (e.g., norepinephrine). As a result, heart rate at rest is slowed less than with other beta blockers. Accordingly, if a patient develops symptomatic bradycardia with another beta blocker, switching to one of these may help.

Beta blockers can produce several adverse effects. Blockade of cardiac beta₁ receptors can produce bradycardia, decreased atrioventricular (AV) conduction, and reduced contractility. Consequently, beta blockers should not be used by patients with sick sinus syndrome or second- or third-degree AV block—and must be used with care in patients with heart failure. Blockade of beta₂ receptors in the lung can promote bronchoconstriction. Accordingly, beta blockers should be used with caution in patients with asthma. If an asthmatic individual must use a beta blocker, a beta₁-selective agent (e.g., metoprolol) should be employed. Beta blockers can mask signs of hypoglycemia and therefore must be used with caution in patients with diabetes. Potential side effects of beta blockers include depression, insomnia, bizarre dreams, and sexual dysfunction; however, a review of older clinical trials has shown that the risk is small or nonexistent.

The basic pharmacology of the beta blockers is discussed in Chapter 14.

Alpha₁ Blockers.

The alpha₁ blockers (e.g., doxazosin, terazosin) prevent stimulation of alpha₁ receptors on arterioles and veins, thereby preventing sympathetically mediated vasoconstriction. The resultant vasodilation reduces both peripheral resistance and venous return to the heart.

The most disturbing side effect of alpha blockers is orthostatic hypotension. Hypotension can be especially severe with the initial dose. Significant hypotension continues with subsequent doses but is less profound.

The American College of Cardiology (ACC) recommends that alpha blockers not be used as first-line therapy for hypertension. In a huge clinical trial known as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), in which doxazosin was compared with chlorthalidone (a thiazide diuretic), patients taking doxazosin experienced 25% more cardiovascular events and were twice as likely to be hospitalized for heart failure. It is not clear whether doxazosin increased cardiovascular risk or chlorthalidone decreased risk. Either way, the diuretic is clearly preferred to the alpha blocker.

The basic pharmacology of the alpha blockers is discussed in Chapter 14.

Alpha/Beta Blockers: Carvedilol and Labetalol.

Carvedilol and labetalol are unusual in that they can block alpha₁ receptors as well as beta receptors. Blood pressure reduction results from a combination of actions: (1) alpha₁ blockade promotes dilation of arterioles and veins, (2) blockade of cardiac beta₁ receptors reduces heart rate and contractility, and (3) blockade of beta₁ receptors on juxtaglomerular cells suppresses release of renin. Presumably, these drugs also share the ability of other beta blockers to reduce peripheral vascular resistance. Like other nonselective beta blockers, labetalol and carvedilol can exacerbate bradycardia, AV heart block, and asthma. Blockade of venous alpha₁ receptors can produce postural hypotension.

Centrally Acting Alpha₂ Agonists.

As discussed in Chapter 15 these drugs (e.g., clonidine, methyldopa) act within the brainstem to suppress sympathetic outflow to the heart and blood vessels. The result is vasodilation and reduced cardiac output, both of which help lower BP. All central alpha₂ agonists can cause dry mouth and sedation. In addition, clonidine can cause severe rebound hypertension if treatment is abruptly discontinued. Additional adverse effects of methyldopa are hemolytic anemia and liver disorders.

ACE Inhibitors.

The ACE inhibitors (e.g., captopril, enalapril) lower BP by preventing formation of angiotensin II and thereby prevent angiotensin II–mediated vasoconstriction and aldosterone-mediated volume expansion. In hypertensive diabetic patients with renal damage, these actions slow progression of kidney injury. Like the beta blockers, ACE inhibitors are less effective in blacks than in whites. Principal adverse effects are persistent cough, first-dose hypotension, angioedema, and hyperkalemia (secondary to suppression of aldosterone release). Because of the risk for hyperkalemia, combined use with potassium supplements or potassium-sparing diuretics is generally avoided.

Angiotensin II Receptor Blockers.

ARBs lower BP in much the same way as do ACE inhibitors. Like the ACE inhibitors, ARBs prevent angiotensin II–mediated vasoconstriction and release of aldosterone. The only difference is that ARBs do so by blocking the actions of angiotensin II, whereas ACE inhibitors block the formation of angiotensin II. Both groups lower BP to the same extent. In contrast to ACE inhibitors, ARBs have a low incidence of inducing cough or significant hyperkalemia, but they do cause angioedema.

Direct Renin Inhibitors.

DRIs act directly on renin to inhibit conversion of angiotensinogen into angiotensin I. As a result, DRIs can suppress the entire RAAS. At this time, only one DRI—aliskiren [Tekturna, Rasilez ]—is available. Antihypertensive effects equal those of ACE inhibitors, ARBs, and CCBs. Compared with ACE inhibitors, aliskiren causes less hyperkalemia, cough, or angioedema—but poses a similar risk for fetal harm. In addition, aliskiren causes diarrhea in 2.3% of patients. Also, in patients with type 2 diabetes mellitus, use of aliskiren has demonstrated an increased incidence of renal impairment, hypotension, and hyperkalemia. Because of these findings, use of aliskiren is contraindicated in patients with diabetes mellitus who are also taking an ACE inhibitor or ARB. There are conflicting data regarding reduction of stroke, kidney failure, or MI with use of Aliskiren. Accordingly, until experience with the drug is more extensive, other antihypertensives should be considered first.

Aldosterone Antagonists.

Aldosterone antagonists lower BP by promoting renal excretion of sodium and water. Only two agents are available: eplerenone and spironolactone. Both spironolactone and eplerenone promote renal retention of potassium and hence pose a risk for hyperkalemia. Accordingly, they should not be given to patients with existing hyperkalemia and should not be combined with potassium-sparing diuretics or potassium supplements. Combined use with ACE inhibitors, ARBs, and DRIs is permissible but must be done with caution. Spironolactone is discussed in Chapter 35, and eplerenone is discussed in Chapter 36.

Patients Without Compelling Indications.

For initial therapy in the absence of a compelling indication, a thiazide diuretic is currently recommended for most patients. This preference is based on long-term controlled trials showing conclusively that thiazides can reduce morbidity and mortality in hypertensive patients and are well tolerated and inexpensive too. Other options for initial therapy—ACE inhibitors, ARBs, and CCBs—equal diuretics in their ability to lower BP. However, they may not be as effective at reducing morbidity and mortality. Accordingly, these drugs should be reserved for special indications and for patients who have not responded to thiazides. Certain other alternatives—centrally acting sympatholytics and direct-acting vasodilators—are associated with a high incidence of adverse effects and hence are not well suited for initial monotherapy. One last alternative—alpha₁ blockers—is no longer recommended as first-line therapy. As noted, when the alpha blocker doxazosin was compared with the diuretic chlorthalidone, doxazosin was associated with a much higher incidence of adverse cardiovascular events.

Patients With Compelling Indications.

For patients with hypertension plus certain comorbid conditions (e.g., heart failure, diabetes), there is strong evidence that specific antihypertensive drugs can reduce morbidity and mortality. Drugs shown to improve outcomes for six comorbid conditions are indicated in Table 39.3. Clearly, these drugs should be used for initial therapy. If needed, other antihypertensive agents can be added to the regimen. Management of hypertension in patients with diabetes and renal disease—two specific comorbid conditions—is discussed further under “Individualizing Therapy.”

Benefits of Multidrug Therapy.

Treatment with multiple drugs offers significant benefits. First, by employing drugs that have different mechanisms, we can increase the chance of success: targeting BP control at several sites is likely to be more effective than targeting at one site. Second, when drugs are used in combination, each can be administered in a lower dosage than would be possible if it were used alone. As a result, both the frequency and the intensity of side effects are reduced. Third, when proper combinations are selected, one agent can offset the adverse effects of another. For example, if a vasodilator is used alone, reflex tachycardia is likely. However, if a vasodilator is combined with a beta blocker, reflex tachycardia will be minimal.

Children and Adolescents.

The incidence of secondary hypertension in children is much higher than in adults. Accordingly, efforts to diagnose and treat an underlying cause should be especially diligent. For children with primary hypertension, treatment is the same as for adults—although doses are lower and should be adjusted with care. Because ACE inhibitors and ARBs can cause fetal harm, they should be avoided in girls who are sexually active or pregnant.

Older Adults.

By age 65 years, most Americans have hypertension. Furthermore, high BP in this group almost always presents as isolated systolic hypertension; DBP is usually normal or low. The good news, as shown in the Hypertension in the Very Elderly Trial (HYVET), is that treatment can reduce the incidence of heart failure, fatal stroke, and all-cause mortality. The bad news is that most older people are not treated.

The new 2014 guidelines advocate for a target BP of less than 150/90 mm Hg in patients 60 years and older. This differs from the 2011 ACC/American Heart Association (AHA) expert consensus document on treatment of hypertension in people 65 years and older, for whom the target systolic pressure is below 140 mm Hg (for patients ages 65–79 years) and below 145 mm Hg (for patients 80 years and older). Data supported improved outcomes with tighter BP control in the older adult population are lacking—hence the likely reason for the change in philosophy. Although the newer guidelines may be more lax, they do not serve as a substitute for clinical judgment.

Because cardiovascular reflexes are blunted in older adults, treatment carries a significant risk of orthostatic hypotension. Accordingly, initial doses should be low—about one-half those used for younger adults—and dosage escalation should be done slowly. Drugs that are especially likely to cause orthostatic hypotension (e.g., alpha₁ blockers, alpha/beta blockers) should be used with caution.

Minimize Side Effects.

If we expect patients to comply with long-term treatment, we must keep adverse effects to a minimum. As discussed earlier, adverse effects can be minimized by (1) encouraging patients to report side effects, (2) discontinuing objectionable drugs and substituting more acceptable ones, (3) avoiding drugs that can exacerbate comorbid conditions, and (4) using doses that are low initially and then gradually increased.

Establish a Collaborative Relationship.

The patient who feels like a collaborative partner in the treatment program is more likely to comply than is the patient who feels that treatment is being imposed. Collaboration allows the patient to help set treatment goals, create the treatment program, and evaluate progress. In addition, a collaborative relationship facilitates communication about side effects.

Simplify the Regimen.

Antihypertensive regimens may consist of several drugs taken multiple times a day. Such complex regimens deter adherence. Therefore, to promote adherence, the dosing schedule should be as simple as possible. After an effective regimen has been established, dosing just once or twice daily should be tried. If an appropriate combination product is available (e.g., a fixed-dose combination of a thiazide diuretic plus an ACE inhibitor), the combination product may be substituted for its components.

Other Measures.

Adherence can be promoted by giving positive reinforcement when therapeutic goals are achieved. Involvement of family members can be helpful. Also, adherence can be promoted by scheduling office visits at convenient times and by following up when appointments are missed. For many patients, antihypertensive therapy represents a significant economic burden; devising a regimen that is effective but inexpensive will help.