In this section we consider the principal drugs employed to treat chronic hypertension. Drugs for hypertensive emergen- cies and hypertensive disorders of pregnancy are considered separately.
Individual antihypertensive drugs and their classes are shown in Table 47.2. Combination products are shown in Table 47.3.
Diuretics
Diuretics are a mainstay of antihypertensive therapy. These drugs reduce BP when used alone, and they can enhance the only rarely. In the United States, reserpine is the only drug in
this class still on the market.
4—Beta1-Adrenergic Receptors on the Heart Blockade of cardiac beta1 receptors prevents sympathetic stimulation of the heart. As a result, heart rate and myocardial contractility decline.
5—Alpha1-Adrenergic Receptors on Blood Vessels Blockade of vascular alpha1 receptors promotes dilation of arterioles and veins. Arteriolar dilation reduces peripheral resistance. Venous dilation reduces venous return to the heart.
6—Vascular Smooth Muscle
Several antihypertensive drugs (see Fig. 47.2) act directly on vascular smooth muscle to cause relaxation. One of these agents—sodium nitroprusside—is used only for hypertensive emergencies. The rest are used for chronic hypertension.
7—Renal Tubules
Diuretics act on renal tubules to promote salt and water excre- tion. As a result, blood volume declines, causing BP to fall.
8—Components of the RAAS (8a to 8e)
8a—Beta1 Receptors on Juxtaglomerular Cells. Blockade of beta1 receptors on juxtaglomerular cells suppresses release of renin. The resultant decrease in angiotensin II levels has three effects: peripheral vasodilation, renal vasodilation, and suppression of aldosterone-mediated volume expansion.
Site of Drug Actiona Representative Drug Drug Effects
1. Brainstem Clonidine Suppression of sympathetic outflow decreases sympathetic stimulation of the heart and blood vessels.
2. Sympathetic ganglia Mecamylamineb Ganglionic blockade reduces sympathetic stimulation of the heart and blood vessels.
3. Adrenergic nerve
terminals Reserpine Reduced norepinephrine release decreases sympathetic stimulation of the heart and blood vessels.
4. Cardiac beta1 receptors Metoprolol Beta1 blockade decreases heart rate and myocardial contractility.
5. Vascular alpha1 receptors Prazosin Alpha1 blockade causes vasodilation.
6. Vascular smooth muscle Hydralazine Relaxation of vascular smooth muscle causes vasodilation.
7. Renal tubules Hydrochlorothiazide Promotion of diuresis decreases blood volume.
Components of the renin-angiotensin-aldosterone system (8a to 8e) 8a. Beta1 receptors on
juxtaglomerular cells Metoprolol Beta1 blockade suppresses renin release, resulting in (1) vasodilation secondary to reduced production of angiotensin II and (2) prevention of aldosterone-mediated volume expansion.
8b. Renin Aliskiren Inhibition of renin suppresses formation of angiotensin I, which in turn decreases formation of angiotensin II and thereby reduces (1) vasoconstriction and (2) aldosterone-mediated volume expansion.
8c. Angiotensin-converting
enzyme (ACE) Captopril Inhibition of ACE decreases formation of angiotensin II and thereby prevents (1) vasoconstriction and (2) aldosterone-mediated volume expansion.
8d. Angiotensin II receptors Losartan Blockade of angiotensin II receptors prevents angiotensin-mediated vasoconstriction and aldosterone-mediated volume expansion.
8e. Aldosterone receptors Eplerenone Blockade of aldosterone receptors in the kidney promotes excretion of sodium and water and thereby reduces blood volume.
TABLE 47.1 ■ Antihypertensive Effects Elicited by Drug Actions at Specific Sites
aSite numbers in this table correspond with site numbers in Fig. 47.2.
bNo longer available in the United States.
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: hypo- kalemia, 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 hypo- tensive effects. However, because of their ability to conserve potassium, these drugs can play an important role in an antihypertensive regimen. Specifically, they can balance potas- sium loss caused by thiazides or loop diuretics. The most significant adverse effect of the potassium-sparing agents is hyperkalemia. Because of the risk of 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, angiotensin II receptor blockers, or aldosterone antagonists, all of which promote significant hyperkalemia.
Sympatholytics (Antiadrenergic Drugs)
Sympatholytic drugs suppress the influence of the sympathetic nervous system on the heart, blood vessels, and other structures.
These drugs are used widely for hypertension.
effects of other hypotensive drugs. The basic pharmacology of the diuretics is discussed in Chapter 41.
Thiazide Diuretics. Thiazide diuretics (e.g., hydrochloro- thiazide, 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 (e.g., bananas, citrus fruits) and using potassium supplements or a potassium-sparing diuretic. Other side effects include dehydration, hyperglycemia, and hyperuricemia.
Thiazides are superior to calcium channel blockers 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
Diuretics Sympatholytics RAAS Suppressants Others
Thiazides and Related Diuretics Chlorothiazide
Chlorthalidone Hydrochlorothiazide Indapamide Methyclothiazide Metolazone Loop Diuretics Bumetanide Ethacrynic acid Furosemide Torsemide
Potassium-Sparing Diuretics Amiloride
Spironolactone Triamterene
Beta Blockers Acebutolol (has ISA) Atenolol
Betaxolol Bisoprolol Metoprolol Nadolol Nebivolol
Penbutolol (has ISA) Pindolol (has ISA) Propranolol Timolol Alpha1 Blockers Doxazosin Prazosin Terazosin
Alpha/Beta Blockers Carvedilol
Labetalol
Centrally Acting Alpha2
Agonists Clonidine Guanabenz Guanfacine Methyldopa
Adrenergic Neuron Blockers Reserpine
ACE Inhibitors Benazepril Captopril Enalapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril
Angiotensin II Receptor Blockers
Azilsartan Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan
Direct Renin Inhibitor Aliskiren
Aldosterone Antagonists Eplerenone
Spironolactone
Direct-Acting Vasodilators Hydralazine
Minoxidil
Calcium Channel Blockers Amlodipine
Diltiazem (non-DHP) Felodipine
Isradipine Nicardipine Nifedipine Nimodipine Nisoldipine
Verapamil (non-DHP) TABLE 47.2 ■ Drugs for Chronic Hypertension
DHP, Dihydropyridine; ISA, intrinsic sympathomimetic activity; RAAS, renin-angiotensin-aldosterone system.
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 they must be used with care in patients with heart failure.
Blockade of beta2 receptors in the lung can promote broncho- constriction. Accordingly, beta blockers should be avoided by patients with asthma. If an asthmatic individual absolutely must use a beta blocker, a beta1-selective agent (e.g., metoprolol) should be employed. Beta blockers can mask signs of hypo- glycemia; therefore, they 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 18.
As indicated in Table 47.2, there are five subcategories of sympatholytic drugs: (1) beta blockers, (2) alpha1 blockers, (3) alpha/beta blockers, (4) centrally acting alpha2 agonists, and (5) adrenergic neuron blockers.
Beta-Adrenergic Blockers. Like the thiazides, beta block- ers (e.g., propranolol, metoprolol) are widely used antihyper- tensive 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 African Americans 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 (see Table 47.2). That is, they can produce mild activation of
Generic Name Brand Name
TWO-DRUG COMBINATIONS Thiazide Plus a Beta Blocker
Hydrochlorothiazide + metoprolol Lopressor HCT Hydrochlorothiazide + bisoprolol Ziac
Hydrochlorothiazide + pindolol Viskazide
Bendroflumethiazide + nadolol Corzide
Chlorthalidone + atenolol Tenoretic
Thiazide Plus an ACE Inhibitor
Hydrochlorothiazide + captopril Generic only Hydrochlorothiazide + benazepril Lotensin HCT Hydrochlorothiazide + enalapril Vaseretic Hydrochlorothiazide + fosinopril Generic only Hydrochlorothiazide + lisinopril Zestoretic Hydrochlorothiazide + moexipril Generic only Hydrochlorothiazide + quinapril Accuretic
Indapamide + perindopril Coversyl Plus
Thiazide Plus an ARB
Hydrochlorothiazide + losartan Hyzaar
Hydrochlorothiazide + valsartan Diovan HCT
Hydrochlorothiazide + candesartan Atacand HCT Hydrochlorothiazide + eprosartan Teveten HCT Hydrochlorothiazide + irbesartan Avalide Hydrochlorothiazide + telmisartan Micardis HCT Hydrochlorothiazide + olmesartan Benicar HCT, Olmetec Plus
Generic Name Brand Name
Thiazide Plus a Potassium-Sparing Diuretic
Hydrochlorothiazide + spironolactone Aldactazide Hydrochlorothiazide + triamterene Dyazide, Maxzide Hydrochlorothiazide + amiloride Moduretic Thiazide Plus an Alpha2 Agonist
Chlorthalidone + clonidine Clorpres
Hydrochlorothiazide + methyldopa Generic only Thiazide Plus a Direct-Acting Vasodilator
Hydrochlorothiazide + hydralazine Generic only CCB Plus an ACE Inhibitor
Amlodipine + benazepril Lotrel
Felodipine + enalapril Generic only
Verapamil + trandolapril Tarka
CCB Plus an ARB
Amlodipine + olmesartan Azor
Amlodipine + valsartan Exforge
Amlodipine + telmisartan Twynsta
Aliskiren (a DRI) Plus Another Drug
Aliskiren + amlodipine Tekamlo
Aliskiren + hydrochlorothiazide Tekturna HCT, Rasilez HCT THREE-DRUG COMBINATIONS
Hydrochlorothiazide + amlodipine + valsartan Exforge HCT Hydrochlorothiazide + amlodipine + olmesartan Tribenzor Hydrochlorothiazide + amlodipine + aliskiren Amturnide TABLE 47.3 ■ Combination Products for Chronic Hypertension
ACE, Angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; CCB, calcium channel blocker; DRI, direct renin inhibitor.
hypotension is low. With both drugs, the lowering of BP may be followed by reflex tachycardia, renin release, and fluid retention.
Reflex tachycardia and release of renin can be prevented with a beta blocker. Fluid retention can be prevented with a diuretic.
The most disturbing adverse effect of hydralazine is a syndrome resembling systemic lupus erythematosus (SLE).
Fortunately, this reaction is rare at recommended doses. If an SLE-like reaction occurs, hydralazine should be withdrawn.
Hydralazine is considered a third-line drug for chronic hypertension.
Minoxidil is potentially more harmful than hydralazine. By causing fluid retention, minoxidil can promote pericardial effusion (accumulation of fluid beneath the myocardium) that in some cases progresses to cardiac tamponade (compression of the heart). A less serious effect is hypertrichosis (excessive hair growth). Because of its capacity for significant side effects, minoxidil is not used routinely for chronic hypertension. Instead, the drug is reserved for patients with severe hypertension that has not responded to safer drugs.
The basic pharmacology of hydralazine and minoxidil is discussed in Chapter 46.
Calcium Channel Blockers
The calcium channel blockers (CCBs) fall into two groups:
dihydropyridines (e.g., nifedipine) and nondihydropyridines (e.g., verapamil and diltiazem). Drugs in both groups promote dilation of arterioles. In addition, verapamil and diltiazem have direct suppressant effects on the heart.
Like other vasodilators, CCBs can cause reflex tachycardia.
This reaction is greatest with the dihydropyridines and minimal with verapamil and diltiazem. Reflex tachycardia is low with verapamil and diltiazem because of cardiosuppression. Since dihydropyridines do not block cardiac calcium channels, reflex tachycardia with these drugs can be substantial.
Because of their ability to compromise cardiac performance, verapamil and diltiazem must be used cautiously in patients with bradycardia, heart failure, or AV heart block. These precau- tions do not apply to dihydropyridines.
The immediate-release formulation of nifedipine has been associated with increased mortality in patients with MI and unstable angina. Thus the National Heart, Lung, and Blood Institute has recommended that the use of immediate-release nifedipine be discontinued for treatment of hypertensive emergency.
The basic pharmacology of the CCBs is discussed in Chapter 45.
Drugs That Suppress the RAAS
Because the RAAS plays an important role in controlling BP, drugs that suppress the system—especially the ACE inhibitors—
have a significant role in controlling hypertension. The basic pharmacology of these drugs is discussed in Chapter 44.
ACE Inhibitors. The ACE inhibitors (e.g., captopril, enalapril) lower BP by preventing the formation of angiotensin II and thereby preventing angiotensin II–mediated vasoconstric- tion and aldosterone-mediated volume expansion. In hyper- tensive diabetic patients with renal damage, these actions slow the progression of kidney injury. Like the beta blockers, ACE inhibitors are less effective in African Americans 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 of Alpha1 Blockers. The alpha1 blockers (e.g., doxazosin,
terazosin) prevent stimulation of alpha1 receptors on arterioles and veins, thereby preventing sympathetically mediated vaso- constriction. The resultant vasodilation reduces both peripheral resistance and venous return to the heart.
The most disturbing side effect of alpha blockers is ortho- static hypotension. Hypotension can be especially severe with the initial dose. Significant hypotension continues with sub- sequent doses but is less profound.
The American College of Cardiology 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 thia- zide 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 18.
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 19, 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 (accompanied by a positive direct Coombs’
test) and liver disorders.
Adrenergic Neuron Blockers. Reserpine—the only adrenergic neuron blocker still available—depletes norepineph- rine from postganglionic sympathetic nerve terminals, reducing sympathetic stimulation of the heart and blood vessels. The result is a drop in cardiac output and blood pressure. In addition to its peripheral effects, reserpine depletes serotonin and catecholamines from neurons in the central nervous system, causing deep emotional depression. Accordingly, reserpine is absolutely contraindicated for patients with a history of depres- sive illness. Because reserpine can cause depression and because more desirable antihypertensive drugs are available, reserpine is not a preferred agent for treating hypertension. The basic pharmacology of reserpine is discussed in Chapter 19.
Direct-Acting Vasodilators: Hydralazine and Minoxidil
Hydralazine and minoxidil reduce BP by promoting dilation of arterioles. Neither drug causes significant dilation of veins.
Because venous dilation is minimal, the risk of orthostatic
As shown in the algorithm at this link, lifestyle changes should be instituted first. If these fail to lower BP enough, drug therapy should be started, and the lifestyle changes should continue.
Treatment often begins with a single drug. If needed, another drug may be added (if the initial drug was well tolerated but inadequate) or substituted (if the initial drug was poorly toler- ated). However, before another drug is considered, possible reasons for failure of the initial drug should be assessed. Among these are insufficient dosage, poor adherence, excessive salt intake, and the presence of secondary hypertension. If treatment with two drugs is unsuccessful, a third and even fourth may be added.
Initial Drug Selection
Initial drug selection is determined by the presence or absence of a compelling indication, defined as a comorbid condition for which a specific class of antihypertensive drugs has been shown to improve outcomes. Initial drugs for patients with and without compelling indications are discussed in the sections that follow.
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 inexpen- sive 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, adrenergic neuron blockers, 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 recom- mended 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 47.4. 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.
Adding Drugs to the Regimen
Rationale for Drug Selection. When using two or more drugs to treat hypertension, each drug should come from a different class. That is, each drug should have a different mechanism of action. In accord with this guide- line, it would be appropriate to combine a beta blocker, a diuretic, and a vasodilator, since each lowers BP by a dif- ferent mechanism. In contrast, it would be inappropriate to combine two thiazide diuretics or two beta blockers or two vasodilators.
hyperkalemia, combined use with potassium supplements or potassium-sparing diuretics is generally avoided. ACE inhibitors can cause serious fetal harm, especially during the second and third trimesters of pregnancy, and hence must not be given to pregnant women. ACE inhibitors—along with angiotensin receptor blockers (ARBs) and direct renin inhibitors (DRIs)—are the only antihypertensive drugs specifically contraindicated during pregnancy.
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 vasoconstric- tion 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. Like the ACE inhibitors, ARBs can cause fetal harm and must not be used during pregnancy. 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 of fetal harm. In addition, aliskiren causes diarrhea in 2.3% of patients. Also, in patients with type 2 diabetes mellitus, the use of aliskiren has demonstrated an increased incidence of renal impairment, hypotension, and hyperkalemia. Because of these findings, the use of aliskiren is contraindicated in patients with diabetes mellitus who are also taking an ACE inhibitor or ARB. Although we know that aliskiren can lower BP, we don’t yet know if it reduces adverse outcomes (e.g., stroke, kidney failure, MI). 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. (In case you’re confused about spironolactone, yes, it’s the same drug we discussed earlier under potassium-sparing diuretics.
We’re discussing it here because it produces diuresis through aldosterone receptor blockade.) Both spironolactone and eplerenone promote renal retention of potassium, and hence pose a risk of 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. Spirono- lactone is discussed in Chapter 41, and eplerenone is discussed in Chapter 44.