Medication Summary
Antihypertensives
Several antihypertensive medications, including thiazide diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers, in principle, can be used as initial monotherapy in patients with hypertension. However, controversy regarding which drug to use as a first-line therapy continues partly due to the belief that antihypertensive medications have benefits beyond lowering of blood pressure (BP).
It is important to point out that regardless of which medication is chosen as the initial therapy, in the majority of patients monotherapy does not achieve adequate BP control. As shown in the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), more than 60% of patients required 2 or more therapies for BP control. Similar numbers were noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA), in which more than 50% of patients required combination therapy.
The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure VII (JNC VII) has recommended the following for uncomplicated hypertension:
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Therapy begins with lifestyle modification.
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If the BP goal is not achieved, thiazide-type diuretics should be used as initial therapy for most patients, either alone or in combination with one of the other classes (ie, ACE inhibitors, ARBs, beta-blockers, calcium channel blockers) that have also been shown to reduce one or more hypertensive complications in randomized controlled outcome trials. This recommendation is mainly based on the findings from the ALLHAT, which included more than 30,000 hypertensive patients; at the end, diuretics were found to be as effective at preventing major coronary events, or even superior in preventing heart failure, compared with calcium channel blockers or ACE inhibitors. In addition, diuretics are generally well tolerated and cheaper.
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Selection of one of these other agents as initial therapy is recommended when a diuretic cannot be used or when a compelling indication requires the use of a specific drug.
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More than two thirds of hypertensive individuals do not achieve adequate control on one drug and require 2 or more antihypertensive agents selected from different drug classes.
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The initiation of therapy with more than one drug increases the likelihood of achieving the BP goal faster. The use of multidrug combinations often produces greater BP reduction at lower doses of the component agents, resulting in fewer adverse effects.
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Hypertension may exist in association with other conditions with compelling indications for use of a particular treatment based on clinical trial data demonstrating benefits of such therapy on the natural history of the associated condition. Compelling indications for specific therapy involve high-risk conditions that can be direct sequelae of hypertension (eg, HF, ischemic heart disease, chronic kidney disease, recurrent stroke) or commonly associated with hypertension (eg, diabetes, high coronary disease risk). Therapeutic decisions in such individuals should be directed at both the compelling indication and lowering of BP.
Low-dose thiazides
Low-dose thiazides are now recognized as achieving maximal effects on BP with minimal adverse effects. Results from multiple treatment trials show the benefits of low-dose diuretics in preventing stroke, coronary events, congestive heart failure, and all-cause mortality.
ACE inhibitors
With the exception of ACE inhibitors in patients with diabetes, no data indicate the best way to treat patients with essential hypertension while preserving kidney function. However, results obtained with the use of different antihypertensive treatment in patients with chronic kidney failure and/or diabetes (in both animal and human studies) may be extrapolated to guide the treatment of patients with essential hypertension.
In animal models of chronic kidney failure and diabetes, control of hypertension with the use of ACE inhibitors has been clearly demonstrated, and ARBs can decrease proteinuria, reduce the severity of glomerulosclerosis and interstitial fibrosis, and slow the progression of kidney disease.
Human studies show that ACE inhibitors are capable of slowing the progression of kidney failure in all forms of nephropathy, except in patients with polycystic kidneys. Based on these and other results, ACE inhibitors have become the recommended initial therapy to treat hypertension in patients with diabetes.
This recommendation is also supported by the results of the Heart Outcomes Prevention Evaluation (HOPE) trial. According to this study, an ACE inhibitor administered once daily reduces cardiovascular events in patients without heart failure but with at least one cardiovascular risk factor, not including diabetes. Similarly, the Microalbuminuria, Cardiovascular, and Renal Outcomes (MICRO-HOPE) substudy of the HOPE trial randomized 3577 subjects with diabetes who had a prior cardiovascular event or at least one other cardiovascular risk factor and no clinical proteinuria to receive either ramipril (10 mg/d) or placebo. Treatment with ramipril resulted in a 24% risk reduction of overt nephropathy development after 4.5 years of follow-up care (independent of BP reduction).
The beneficial effect of ACE inhibitors is attributed, at least in part, to their ability to reduce or suppress proteinuria. This is particularly important for patients with diabetes because the development of microalbuminuria is associated with an increased prevalence of cardiovascular complications. A few studies have suggested that microalbuminuria is an early marker of renal damage in patients with hypertension, and patients with microalbuminuria experience a faster decline in renal function. Ruilope et al (1994) reported a faster decline in creatinine clearance in patients who are hypertensive with microalbuminuria compared with patients who are hypertensive with normal albumin excretion (11 mL/min vs 2 mL/min). [48]
Similar findings were observed by Bianchi et al (1999). [49] In a few studies, ACE inhibitors, but not calcium channel blockers, reduced microalbuminuria in patients with essential hypertension. Other studies have also confirmed the ability of ACE inhibitors to reduce proteinuria in these patients.
Whether a reduction in microalbuminuria results in a decreased prevalence of ESRD in patients with hypertension remains to be determined.
ACE inhibitor and calcium channel blockers
While combining an ACE inhibitor with a calcium channel blocker has been shown to reduce cardiovascular events in clinical trials of hypertension, the renoprotective effects are less uniformly demonstrated. Different studies, including the Fosinopril versus Amlodipine Cardiac Events Trial (FACET), the HOT study, and the Systolic Hypertension in Europe (Syst-Eur) trial, have reported conflicting results in terms of both cardiovascular and renal outcomes.
In the FACET, combination therapy with ACE inhibitors and calcium channel blockers resulted in significantly lower BPs compared with other groups. Moreover, combination therapy also showed the best results in reducing the mortality rate. To date, in patients with established kidney failure (ie, serum creatinine > 1.4 mg/dL), none of the dihydropyridine calcium channel blockers available in the United States has been shown to slow kidney disease progression in the absence of an ACE inhibitor.
ACE inhibitor and ARB combination therapy
Data regarding the benefit of adding an ARB to an ACE inhibitor are controversial, and no consensus has been reached. Results from the single trial, the Combination Treatment of Angiotensin Receptor Blocker and Angiotensin Converting Enzyme Inhibitor in Nondiabetic Renal Disease (COOPERATE) trial, suggested combined therapy with losartan and trandolapril preserved kidney function better than monotherapy with either drug. These patients had nondiabetic proteinuric chronic kidney disease. However, since the publication of this trial, serious concerns about the quality of the data have been raised by Kunz et al. A meta-analysis by Kunz et al showed better reductions in proteinuria with combined therapy, although safety data were sparse. [50]
In 2008, Mann et al evaluated the effects of ACE inhibitors versus ARB versus combination therapy on renal outcomes in patients at high vascular risk from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). [51] More than 25,000 patients were enrolled in this study and were followed for more than 5 years. The primary goal was to evaluate whether combination therapy would result in better cardiovascular protection compared with ACE inhibitors. The primary renal outcome was the composite outcome of death, ESRD, and doubling of serum creatinine.
Even though the rate of microalbuminuria and macroalbuminuria was lower with the combination therapy, the rate of decline in estimated GFR (-6.1 mL/min/1.73 m2) was greater compared with the ACE inhibitor group (-2.8 mL/min/1.73 m2), which was statistically significant. In addition, the rate of acute dialysis was greater in the group receiving combination therapy. Note that the patients included in the ONTARGET were at low renal risk and cannot be generalized to include patients with overt nephropathy.
Because of the lack of conclusive data regarding the benefits of combined therapy and because of the ongoing concerns for increased adverse effects, dual ACE inhibitor-ARB therapy should be prescribed with caution.
ACE inhibitor and alpha-blocker combination
Alpha-adrenergic receptor blockers at low doses may be used as monotherapy in the treatment of hypertension. Alpha-adrenergic receptor blockers improve insulin sensitivity, improve urine flow, reduce total cholesterol and triglyceride levels, and increase high-density lipoprotein levels.
Combinations of alpha-blockers and ACE inhibitors have additive effects for lowering BP only in patients with a baseline pulse rate that is greater than 84 beats per minute. In terms of slowing kidney disease progression in patients with diabetes or impaired kidney function, alpha-blockers are of no additional benefit. Some patients may require an additional arteriolar vasodilator to control BP. Finally, ARBs, alone or in combination with other antihypertensive medications, offer a therapeutic alternative. ARBs have a favorable adverse effect profile and appear to share the same beneficial effects of ACE inhibitors; however, no conclusive human data on kidney disease progression are available for these agents.
Calcium channel blockers
Dihydropyridines are effective BP medications that can be used as monotherapy for BP control. They may also have benefit when used in combination with ACE inhibitors.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) compared the effect of a calcium channel blockers (amlodipine) with an ACE inhibitor (perindopril) added as needed to a beta-blocker (atenolol) with thiazide (bendroflumethiazide) added as needed in preventing nonfatal myocardial infarction and fatal coronary heart disease. [52] The study was conducted in British and Scandinavian countries and enrolled more than 19,000 patients with hypertension and at least 3 cardiovascular risk factors (type 2 diabetes mellitus, left ventricular hypertrophy, peripheral vascular disease, microalbuminuria, prior stroke or transient ischemic attack) and followed them for more than 5 years.
Even though the primary outcome (nonfatal myocardial infarction and fatal coronary heart disease) did not reach significance when comparing the 2 groups, the calcium channel blockers plus ACE inhibitors was found to be superior to beta-blockers plus thiazide in preventing fatal and nonfatal strokes, all-cause mortality, and total cardiovascular events and in lowering the rate of kidney failure and diabetes.
The lack of reaching statistical significance in primary outcome has been attributed to the premature termination of trial, which was done because of significant overall mortality reduction in the group receiving calcium channel blocker plus ACE inhibitor therapy. Note, however, that the group receiving combination therapy with a calcium channel blocker plus an ACE inhibitor had lower BP (2.7/1.9 mm Hg) compared with the group receiving a beta-blocker plus thiazide, and the benefits noted from the combination therapy with a calcium channel blocker plus an ACE inhibitor may be partly related to the differential BP control.
More recently, the Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial compared a calcium channel blocker (amlodipine) combined with an ACE inhibitor (benazepril) to hydrochlorothiazide combined with benazepril. [53] The ACCOMPLISH trail was a multicenter trial in 5 countries, including the United States, that enrolled patients with hypertension and high cardiovascular disease risk (history of coronary artery disease, myocardial infarction, revascularization, stroke, kidney failure, peripheral vascular disease, left ventricular hypertrophy, and diabetes mellitus). More than 11,000 patients were enrolled and followed for a median of 36 months.
The study was terminated early as the difference between the 2 groups exceeded the boundary of the prespecified stopping rule. The primary endpoint was the time to the first event defined as the composite of a cardiovascular event and death from cardiovascular causes. By the end of the study, 9.6% in the calcium channel blocker plus ACE inhibitor group, compared with 11.8% in the diuretic plus ACE inhibitor group, had a primary outcome event. Individuals receiving calcium channel blockers plus ACE inhibitors also had fewer fatal and nonfatal myocardial infarctions and fewer coronary revascularizations. These results suggest that the combination of a calcium channel blocker with an ACE inhibitor may be a great choice for treatment of patients with hypertension and cardiovascular risk factors.
Diuretics
Class Summary
Induce natriuresis, reduce target organ damage and mortality rates in patients with hypertension, achieve maximal BP-lowering effects at low doses (12.5-25 mg/d), and potentiate antihypertensive effects of other BP medications. Antihypertensive effect of these agents is observed in all demographic groups. Thiazides induce vasodilation and are superior to loop diuretics as antihypertensive agents.
Hydrochlorothiazide (Microzide)
Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium, water, potassium, and hydrogen ions.
Angiotensin-converting enzyme inhibitors
Class Summary
Reduce proteinuria, have specific renal protective effects in both diabetic and nondiabetic renal impairment, and reduce morbidity and mortality rates in congestive heart failure. Less effective as monotherapy if patient >50 y. Black patients require increased doses. Inhibit or blunt all adverse metabolic effects of thiazides, and reduce left ventricular hypertrophy.
Fosinopril
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Ramipril (Altace)
Prevents conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Angiotensin II receptor antagonists
Class Summary
Indicated in patients intolerant of ACE inhibitors because they do not interfere with the breakdown of bradykinin or cause cough. Reduce left ventricular hypertrophy and thirst similarly to ACE inhibitors and reduce proteinuria.
Losartan (Cozaar)
Blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.
Angiotensin II receptor blockers reduce BP and proteinuria, protecting renal function and delaying onset of ESRD.
Valsartan (Diovan)
Prodrug that produces direct antagonism of angiotensin II receptors. Displaces angiotensin II from AT1 receptor and may lower BP by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water intake, and hypertrophic responses. May induce more complete inhibition of renin-angiotensin system than ACE inhibitors, does not affect response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.
Renin inhibitor
Class Summary
This is a new class of renin-angiotensin-aldosterone system (RAAS) inhibitors that works by inhibiting renin activity. They are long-acting and can be used for treatment of hypertension with once daily dosing.
Aliskiren (Tekturna)
Aliskiren directly inhibits renin, which results in a reduction in plasma renin activity and thereby a decrease in the conversion of angiotensinogen to angiotensin I.
Calcium channel blockers
Class Summary
Effective as monotherapy in black patients and elderly patients. Potentiate ACE inhibitor effects. Renal protection is not proven, but reduce morbidity and mortality rates in congestive heart failure. Indicated in patients with diastolic dysfunction.
Verapamil (Calan, Verelan)
During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.
Amlodipine (Norvasc)
Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Benefits nonpregnant patients with systolic dysfunction, hypertension, or arrhythmias. Can be used during pregnancy if clinically indicated.
Felodipine
Relaxes coronary smooth muscle and produces coronary vasodilation, which, in turn, improves myocardial oxygen delivery.
Beta-adrenergic blocking agents
Class Summary
Suppress renin secretion. Monotherapy less effective in black patients. Reduce morbidity and mortality rates after myocardial infarction. Not considered a first-line therapy in the absence of a compelling indication (eg, coronary artery disease). [47]
Labetalol
Blocks beta1-, alpha-, and beta2-adrenergic receptor sites, decreasing BP.
Vasodilators, direct-acting
Class Summary
Cause arteriolar dilation by blocking arterial wall calcium uptake. Effective in severe hypertension (minoxidil more effective than hydralazine). Best if used in combination with a diuretic plus a beta-blocker.
Minoxidil
Most potent vasodilator available for oral use.
Relaxes arteriolar smooth muscle, causing vasodilation, which, in turn, may reduce BP.
Hydralazine
Decreases systemic resistance through direct vasodilation of arterioles.
Alpha 2-adrenergic agonists
Class Summary
Central alpha-agonists lower BP by stimulating alpha2-adrenergic receptors in the brainstem and activate inhibitory neurons, causing decreased vasomotor tone and heart rate. This class of drugs may cause dry mouth or sedation.
Methyldopa
DOC in pregnancy. Mechanism of action is likely due to drug's metabolism to alpha-methyl norepinephrine, which lowers arterial pressure by stimulating central inhibitory alpha-adrenergic receptors, false neurotransmission, or reducing plasma renin activity.
Clonidine (Catapres, Kapvay)
Stimulates alpha-2 adrenoreceptors in brain stem, activating an inhibitory neuron, which results in reduced sympathetic outflow. Decreases vasomotor tone and heart rates. Used in hypertensive emergency. Useful when patient has a migraine in association with hypertension.
Alpha-1 Blockers
Class Summary
Peripheral alpha-antagonists inhibit postsynaptic alpha 1-adrenergic receptors, resulting in vasodilation of veins and arterioles and decreasing total peripheral resistance and BP. These drugs often cause marked hypotension after the first dose. High doses are likely to cause postural hypotension.
Doxazosin (Cardura, Cardura XL)
Inhibits postsynaptic alpha-adrenergic receptors, resulting in vasodilation of veins and arterioles and decrease in total peripheral resistance and BP.
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Nephrosclerosis. The glomerular tuft is shrunken, with wrinkling of the capillary walls (asterisk), global glomerular sclerosis (arrow), and complete obliteration of the capillary loops and glomerular ischemia (periodic acid-Schiff stain at 250X magnification).
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Nephrosclerosis. Glomerulus with wrinkling of glomerular basement membranes accompanied by reduction of capillary lumen diameter (silver stain at 400X magnification).
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Nephrosclerosis. Hyaline arteriosclerosis with hyaline deposits (arrows) (trichrome stain at 250X magnification).
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Nephrosclerosis. Fibrointimal proliferation of the arcuate artery (periodic acid-Schiff stain at 150X magnification).
