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linical Pharmacology of Antihypertensive Therapyddison A. Taylor and James L. Pool

Adequate control of blood pressure poses challenges for hypertensive patients and theirphysicians. Success rates of greater than 80% in reducing blood pressure to target valuesamong high-risk hypertensive patients reported by several recent clinical trials argue thateffective medications currently are available. Yet, only 34% of hypertensive patients in theUnited States are at their goal blood pressure according to the most recent national survey.Rational selection of antihypertensive drugs that target both the patient’s blood pressureand comorbid conditions coupled with more frequent use of low-dose drug combinationsthat have additive efficacy and low adverse-effect profiles could improve significantly USblood pressure control rates and have a positive impact on hypertension-related cardio-vascular and renal mortality and morbidity. This article reviews the pharmacokinetic andpharmacodynamic principles that underlie the actions of drugs in each of the classes ofantihypertensive agents when used alone and in combination, provides practical pharma-cologic information about the drugs most frequently prescribed for treatment of hyperten-sion in the outpatient setting, and summarizes the current data influencing the selection ofdrugs that might be used most effectively in combination for the majority of hypertensivepatients whose blood pressures are not controlled adequately by single-drug therapy.Semin Nephrol 25:215-226 © 2005 Elsevier Inc. All rights reserved.

KEYWORDS antihypertensive drugs, angiotensin converting enzyme inhibitors, angiotensinreceptor blockers, calcium channel antagonists, beta blockers, diuretics, alpha-1 adrener-gic blockers, combination therapy

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ncontrolled hypertension is the most common treatablecause of cardiovascular and renal morbidity and mor-

ality. There currently are more than 200 different drugspproved by the US Food and Drug Administration that arevailable to physicians in the United States to treat hyperten-ive patients. Despite the introduction of newer drugs thatot only reduce cardiovascular mortality and morbidity buto so with fewer adverse effects than older antihypertensivegents, blood pressure is controlled to levels currently rec-mmended by the most recent national guidelines in onlyne third of patients with hypertension.1

Numerous clinical trials have documented that 2 or morerugs are needed to control blood pressure in a majority ofatients. One additional lesson learned from the Antihyper-ensive Lipid Lowering Heart Attack Trial2 (ALLHAT) washat even though blood pressure may be controlled initiallyn a single antihypertensive medication, additional medica-ions may need to be added over time to maintain goal blood

rom the Section on Hypertension and Clinical Pharmacology, Departmentof Medicine, Baylor College of Medicine, Houston, TX.

ddress reprint requests to Addison A. Taylor, MD, PhD, Section on Hyperten-sion and Clinical Pharmacology, Department of Medicine, Baylor College of

cMedicine, Houston, TX 77030. E-mail: [email protected].

270-9295/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.oi:10.1016/j.semnephrol.2005.02.006

ressure values.3 In the ALLHAT trial about 70% of patientsad achieved goal blood pressure values 6 months after ran-omization to single-drug therapy. After 5 years of follow-upvaluation, however, only about 30% of patients remainedontrolled on monotherapy and 70% required 2 or morerugs. Physicians often are reluctant to add medications to aatient’s therapeutic regimen for a variety of reasons. In ad-ition, a large minority of patients do not take their medica-ions as prescribed because of cost, adverse effects, socialtigmata, or other reasons. Thus, primary care physicians andpecialists alike must be familiar with both the actions andhe adverse effects of antihypertensive drug classes so theyan treat patients with the most therapeutically and cost-ffective drugs or drug combinations while minimizing ad-erse effects that may precipitate discontinuation of therapyy the patient. This article reviews the pharmacologic actionsnd adverse effects of the most commonly prescribed drugsor the treatment of hypertension in the outpatient setting. Aorking knowledge of this information allows clinicians toake rational choices of drugs or drug combinations both for

reatment of the uncomplicated hypertensive patient and forubgroups of the hypertensive population who pose unique
hallenges such as African Americans, the elderly, diabetics,
215

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216 A.A. Taylor and J.L. Pool

nd patients who already have experienced a stroke, myocar-ial infarction, renal damage, or congestive heart failure.

eneral Principles ofntihypertensive Drug Therapy

any antihypertensive drugs exhibit a dose-response rela-ionship similar to that shown in Figure 1A. One character-stic of this relationship is a threshold dose below which theres no discernible effect of the drug. When a change in systolicr diastolic blood pressure is the measured response, theood and Drug Administration usually has required that theanufacturer define the lowest effective dose of the drug

Figure 1 Panel A depicts a typical sigmoid dose-responsethe % of maximum drug effect on the y-axis. The doseillustrated by the horizontal line. Adverse events (solid bthe drug dose is increased to well above the EC50. For thinear the maximum effect.Panel B illustrates the effect on the EC50 when a seconeffectiveness of the drug combination compared to thattwo drugs with little effect on the incidence of adverse ePanel C illustrates an effect of reducing the dose-dependadding a second drug which reduces the adverse eventsPanel D illustrates the effect of using two drugs that, wheincidence of adverse events.

nder consideration and this information is included in the t

rug’s product monograph. Once the dose is higher than thishreshold there usually is a relatively steep increase in theesponse when plotted against the logarithm of the dose untilurther dosage increases produce no additional response. Theose that produces a concentration of the drug which exerts0% of the maximum effect is the EC50. The EC50 is the dosehat produces 50% of the maximum effect. The characteris-ics of the dose-response relationship for a particular drug areefined not only by the dose of the drug but by the responsegainst which it is plotted. For example, the maximum anti-ypertensive effect of an angiotensin-converting enzyme in-ibitor (ACEI) or an angiotensin-receptor blocker (ARB) maye achieved at a dose that does not maximize the effect of

nship between [Drug] concentration on the x-axis andug which elicits 50% of the maximum effect (EC50) isne) typically are either absent or of low incidence untiln, it is preferable to avoid using doses of drug which are

is added to the first (light and dark gray areas). Thegle drug (dark gray) is increased by using low doses of

idence of adverse events attributable to the first drug byby the first drug.

bined, have not only greater efficacy but also a reduced

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Drug treatment of hypertension 217

an be made that the characteristics for the dose-responseelationship of ARBs and proteinuria is not known becausehe maximum effective dose of any ARB on proteinuria hasot been identified. This also may apply to actions of thesegents on the heart, vasculature, and brain related to but nototally linked to blood pressure.

As shown in Figure 1B, the dose versus adverse-effectelationship for most antihypertensive drugs is differentoth quantitatively and qualitatively from that for the doseersus response relationship. For most drugs, adversevents become apparent and begin to increase in fre-uency at doses higher than those at which a response first

s noted. One goal of therapy is to treat patients with dosesf drugs that maximize the desired effect but minimize therequency of adverse effects. An example of the applicationf this principle to practical therapeutics is the currentosing recommendations for thiazide diuretics comparedith the recommendations from 20 years ago. The resultsf clinical pharmacology trials have documented progres-ive reductions in blood pressure with daily doses of hy-rochlorothiazide from 3.125 to 25 mg that have few or nodverse metabolic or electrolyte consequences such as hy-okalemia, hypomagnesemia, hyperuricemia, dyslipide-ia, or hyperglycemia in the vast majority of patients. As

he dose was increased to greater than 25 mg daily, how-ver, there was little or no further decrease in blood pres-ure but an almost linear dose-dependent decrease in se-um potassium level and an increased frequency of othernwanted metabolic effects.6 In clinical trials, patientsho developed hypokalemia, even with low doses of di-retics, were at greater risk for cardiovascular events thanatients who remained normokalemic,7,8 particularly ifhey had electrocardiographic abnormalities at entry intohe trial.9

If a drug at any given dose is less than optimally effectiveut has a low adverse-effect profile, one option is to in-rease the dose of the drug. This approach, however, isikely to increase the number of adverse effects (Fig 1C).n alternative approach is to add a second drug at a lowose. It is desirable to select 2 drugs whose combinedfficacy is superior to either drug alone while maintaininglow frequency of adverse effects (Fig 1D). There are

umerous examples of this approach, the most frequenteing the addition of a low dose of a diuretic to an ACEI,RB, or �-adrenergic–receptor antagonist (�-blocker). In

act, the actions of ACEIs and ARBs that ultimately reducehe production of aldosterone serve to lessen the incidencef hypokalemia and resultant metabolic consequencesroduced by diuretics. The addition of a second drug tolter the adverse effects of the first drug, even if the secondrug adds little to the efficacy of the combination, also isommon. Drug combinations that concurrently increasefficacy and reduce adverse effects include an ACEI and aiuretic, an ARB and a diuretic, an ACEI and a dihydro-yridine calcium channel antagonist (DCA). As noted ear-

ier, the incidence of hypokalemia is reduced when drugshat interdict the renin-angiotensin system are combined
ith potassium-loosing diuretics. When ACEIs are given r
ogether with a DCA, peripheral edema, the most commondverse effect of DCAs, is reduced. Sometimes drugs areombined because the actions of the second drug reducenwanted side effects of the first drug, even though theecond drug adds little to the overall efficacy of the com-ination. Preparations combining potassium-loosing andotassium-sparing diuretics have been available for manyears. The potassium-sparing component adds little to thentihypertensive efficacy of the potassium-decreasing di-retic but blunts the hypokalemia and selected other ad-erse metabolic consequences.Decisions about which drugs or drug combinations to se-

ect for individual patients should be based on known prop-rties of the drugs both for decreasing blood pressure and foreducing or preventing cardiovascular and renal target organamage, on medical information obtained by a thorough riskssessment, and on demographic and psychosocial charac-eristics of the patient.

ingle-Drugreatment of Hypertension

lthough a majority of patients with hypertension will re-uire more than 1 drug to control blood pressure to optimal

evels, some patients whose pretreatment blood pressures are0/10 mm Hg or less above their target value (140/90 mm Hgor uncomplicated stage 1 hypertension or 130/80 mm Hg forhose with diabetes or chronic kidney disease according touidelines published in the 7th Report of the Joint Nationalommittee on Prevention, Detection, Evaluation and Treat-ent of High Blood Pressure (JNC7) guidelines)) may be

andidates for single-drug therapy. All drugs approved by theS Food and Drug Administration for the treatment of hy-ertension have been shown to decrease blood pressure inost hypertensive patients compared with placebo. Clini-

ians can expect that most commonly used antihypertensiverugs will decrease systolic blood pressure, on average, 10m Hg and decrease diastolic blood pressure 5 mm Hg. Asith any generalization, there are some notable exceptions to

he 10/5 rule that influence the choice of drug class for thereatment of selected patient groups. African Americans as aroup do not experience as great a reduction in blood pres-ure with renin-angiotensin system–inhibitory drugs, theCEIs, and the ARBs, as they do with diuretics and DCAs. Onverage, a reduction of 6 to 8 mmHg systolic and 3 to 4mHg diastolic can be expected in this ethnic group with

ptimum doses of these drugs.10 In contrast, thiazide-typeiuretics and DCAs were among the most effective antihyper-ensive agents for controlling diastolic blood pressure inounger and older African-American men after 1 year of sin-le-drug therapy.11,12 Patients who achieve blood pressureontrol initially with a single drug should continue to bevaluated periodically because, as was observed in theLLHAT trial, blood pressure control with monotherapyay be lost over time and additional drug therapy may be

equired to maintain control.3,13

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iureticsiuretics not only decrease blood pressure by promoting the

enal excretion of salt and water, thereby reducing extracel-ular fluid volume and cardiac output, but they also reducentracellular sodium and calcium levels, leading to vasorelax-tion and a reduction in peripheral vascular resistance withong-term use.14 Thiazide-type diuretics are effective antihy-ertensive agents in patients with normal or modestly im-aired renal function as long as their dietary sodium intakeoes not exceed their renal sodium excretion. They become

neffective, however, in patients whose glomerular filtrationates are less than approximately 25 mL/min or their serumreatinine level is 2 mg/dL or greater. In these latter patients,ntense sodium reabsorption in the proximal tubule and loopf Henle leaves little sodium available for sodium-potassiumxchange in the distal tubule and a loop diuretic should berescribed instead of a thiazide. Numerous clinical trials havehown that thiazide-type diuretics reduce fatal and nonfatalardiovascular events in hypertensive patients.8,15

Although these agents are being recommended by some asnitial therapy for all uncomplicated hypertensive pa-ients,1,2,16 they do have adverse effects that must be consid-red when deciding to prescribe one of the drugs in this classo a specific hypertensive patient. Of particular concern is theevelopment of hypokalemia, which is linked closely to theresence of impaired glucose tolerance and to insulin resis-ance.17 The development of these adverse effects may play aart in the higher rate of discontinuation of drugs in this classhan with drugs in the ARB or ACEI class.18 As noted earlier,dverse effects can be minimized by treating with low ratherhan high doses of diuretics. For those individuals at risk forevelopment of metabolic syndrome or overt diabetes be-ause of obesity, a strong family history or 2 but not 3 com-onents of the metabolic syndrome such as hypertension andyslipidemia (coexistent in an estimated 27 million Ameri-ans) or hypertension and obesity, therapy with a diuretichould be initiated with some caution. The results of thentihypertensive Treatment and Lipid Profile in a North ofweden Efficacy Evaluation (ALPINE) trial study suggestedhat that adverse metabolic consequence in northern Euro-ean patients treated with a diuretic to which a �-blockerould be added were substantially more common than thosen patients treated with an ARB to which a DCA could bedded for blood pressure control if needed.19

In the ALLHAT trial the incidence of new-onset diabetesas 11.6% in the group randomized to chlorthalidone com-ared with 9.8% in the amlodipine group and 8.1% in the

isinopril group.2 This association of a higher rate of new-nset diabetes with thiazide-type diuretics compared withCAs and ACEIs is of particular concern in light of the recent

eport by Verdecchia et al20 in which, after a median fol-ow-up period of 6 years, the cardiovascular risk for patientsho developed diabetes after starting antihypertensive ther-

py was 2.9 times higher than patients who did not developiabetes and was only slightly less than patients who alreadyad diabetes (3.6-fold higher) when therapy was started. For
more thorough review of the electrolyte and metabolic ef- d
ects of diuretics the reader is referred to a recent excellenteview of this topic by Sica.21

The similarities and differences between chlorthalidonend hydrochlorothiazide have received considerable atten-ion recently22 after the publication of the ALLHAT trial re-ults in which chlorthalidone was found to be equivalent toither a DCA (amlodipine) or an ACEI (lisinopril) in its effectsn the combined primary end point of coronary heart diseaseortality and morbidity.2 Most physicians in this country do

ot prescribe chlorthalidone but instead prescribe hydro-hlorothiazide (HCTZ). There are differences in the pharma-okinetic properties of the 2 drugs of which the prescribinglinician should be aware. Chlorthalidone is estimated to be0% to 75% more potent than HCTZ and has a much longeralf-life (45-60 hours after repeated dosing) than HCTZ8-15 hours after repeated dosing). The duration of action ofoth drugs, however, is much longer than predicted by thealf-life and once-daily dosing with either drug appears torovide effective blood pressure control over 24 hours.

-Blockers-adrenergic–receptor antagonists or �-blockers have an im-ortant role in the therapy of a variety of cardiovascular con-itions including ischemic heart disease, cardiac arrhyth-ias, congestive heart failure, and hypertension. Theharmacologic effects of �-receptor blockers are caused byultiple factors including the chemical characteristics of spe-

ific �-blockers (some are lipophilic and some are hydro-hilic); the relative affinity of a particular drug for �1 versus

2 receptors and the tissue distribution of those receptors;he capacity of a drug to activate partially as well as to inhibit-receptors (partial agonist action or intrinsic sympathomi-etic activity); the inhibitory actions of a drug on receptors

ther than �-receptors such as combined �- and �-receptorntagonists like carvediolol and labetolol; and the drug’sharmacokinetic characteristics such as bioavailability, renalersus hepatic metabolism, and the extent of first-pass me-abolism by the liver. Lipophilic �-blockers such as timolol,ropranolol, and metoprolol penetrate the blood-brain bar-ier more readily than do the hydrophilic �-blockers such astenolol and esmolol; this characteristic might explain theigher frequency of central nervous system adverse effects inatients taking lipophilic �-blockers. Some �-blockers ex-ibit greater selectivity for �1 than �2 receptors and are re-

erred to as cardioselective. This term, however, is relativeecause the blockade of both �1 and �2 receptors occurs atigher doses. Although the survival benefit of both cardiose-

ective and nonselective �-blockers after myocardial infarc-ion is well established, the results of 2 meta-analyses haveuggested that �-blockers with intrinsic sympathomimeticctivity do not provide the same cardiovascular outcomesenefit as do �-blockers without this property.23,24

The mechanisms of blood pressure reduction by �-block-rs is attributed primarily to decreased cardiac output result-ng from a slowing of heart rate and, to a much lesser extent,

decrease in contractility. Peripheral resistance also is re-
uced by a �2-receptor–mediated reduction in renin release

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ith consequent reduction in angiotensin II concentrations.sympatholytic effect also occurs by blocking �2-receptor–ediated increases in norepinephrine release from sympa-

hetic nerve terminals. These mechanisms of action have im-lications for the effectiveness of �-blockers in Africanmericans and in the elderly. Because African Americans

end to have low-renin and salt-sensitive hypertension, it isot surprising that �-blockers reduce blood pressure much

ess in this ethnic group than in Caucasian hypertensive pa-ients.25 African Americans with heart failure, however, ex-erience the same reduction in mortality and morbidity with-blockers as do Caucasian patients.26 The elderly tend notnly to have a higher incidence of low-renin hypertensionhan younger individuals but also to exhibit blunted �-recep-or–mediated responses to �-agonists.27 These differencesay explain why the elderly derive less survival benefit from-blockers than do their younger counterparts.28

A concern has been expressed in the literature about using-blockers in patients with cardiovascular disease who haveoncomitant reactive airway disease. �-blockers, especiallyhose with a high affinity for the �2 receptor, are relativelyontraindicated in patients with asthma and chronic lungisease with a significant bronchospastic component.29 Theesults of a recent meta-analysis of studies that have exploredhe use of cardioselective �-blockers in these patients suggesthat cardioselective �-blockers not only are safe but actuallyay enhance sensitivity to inhaled �-agonists because of re-

eptor activation.30,31

Although �-blockers have been used extensively in hyper-ension and related disorders for a number of years, a recentxtensive re-analysis of various trials suggested that atenololxerts no therapeutic benefits whatsoever.32 The investiga-ors surveyed the major trials in hypertension that usedtenolol and concluded that it was no better than a placebond significantly inferior to other antihypertensive drugs.

hether these findings are applicable to other �-blockers isnclear. Nevertheless, this provocative re-appraisal of ateno-

ol casts doubt on the relative use of �-blocker therapy inatients with hypertension. Much debate can be expected asresult of this observation from atenolol-based studies. Someredence to these observations is gained by the demonstra-ion of reduced benefits from atenolol therapy comparedith losartan in the Losartan Intervention for Endpoint Re-uction in Hypertension (LIFE) study.33 In this trial, losar-an-based treatment compared with an atenolol-based regi-en at equivalent blood pressure levels decreased the risk for

atal and nonfatal strokes in a high-risk population. Thus,ne could argue for angiotensin-receptor blockade over-blockade for superior target organ protection in patientsith hypertension, at least in those older patients with leftentricular hypertrophy.

alcium-Channel Blockershe class of drugs called calcium-channel blockers (CCBs)an be separated into 3 groups on the basis of their chemicaltructures: the phenylalkylamines (verapamil-like), the ben-
othiazepines (diltiazem-like), and the dihydropyridines d
nifedipine-like). All of the drugs in this class that currentlyre available commercially in the United States bind to andnhibit L-type but not P-, N-, or T-type calcium channels.rugs in each of the 3 groups bind at different adjacent sitesn the polypeptide chain that comprises the pore-forming

1c subunit of the L-type calcium channel,34 suggesting thathey could have complementary effects when given togethern a clinical setting.35 The actions of the CCBs are based onegional differences in the expression of L-type calcium chan-els, the affinity of a specific CCB for the channel in a partic-lar tissue, and on the varied biochemical pathways thatediate the response to different agonists which modulate

hannel activity. The pharmacodynamics of verapamil andiltiazem are similar to each other and both are distinct fromhose of the dihydropyridines. Verapamil and diltiazem oftenre called nondihydropyridine calcium antagonists (NDCAs) toistinguish their actions from those of the DCAs. The NDCAseduce the sino-atrial node firing rate and the atrioventricularonduction rate because they bind more avidly to the L-typealcium channels in those cardiac cells than do the DCAs atherapeutic concentrations. Accordingly, they are consideredo be rate-control CCBs. These properties provide the ratio-ale for their use in the treatment of atrial fibrillation, atrialutter, and nodal re-entrant tachycardias without accessoryonducting pathways. These drugs also reduce cardiac con-ractility whereas DCAs do not have this effect at doses usedlinically. In general, the DCAs, especially nifedipine, areore potent arterial vasodilators than the NDCAs; they have

ar less effect on venous dilation, a property that accounts forhe significant incidence of peripheral edema. Because oftudies showing that the rapid, potent, and unpredictableypotensive effect of native nifedipine increases the risk forngina and myocardial infarction in susceptible individuals,his drug is not recommended for the treatment of hyperten-ive urgencies or emergencies.36

After oral administration, most of the CCBs undergo ex-ensive first-pass metabolism that contributes to the relativehort half-life of verapamil, diltiazem, and nifedipine, andequires they be taken 2 or 3 times daily to maintain 24-hourfficacy. The availability of extended-release formulations ofhese 3 drugs allows them to maintain more constant bloodevels for 24 hours when given once daily. DCAs such asmlodipine and felodipine that are subject to less extensiveepatic metabolism have a substantially longer duration ofction and the native drugs are effective when given onlynce daily. With the exception of nifedipine and diltiazem,he CCBs are formulated as racemic mixtures. It is the�enantiomer of the CCB that binds to the L-type calciumhannel. Recent studies indicate that the R� enantiomer ofmlodipine is responsible for the activation of nitric oxideynthase by this dihydropyridine CCB, an effect not sharedith diltiazem or nifedipine.37,38 This amlodipine enantio-er also potentiates the nitric oxide synthase–stimulatory

ffect of the ACEI, ramiprilat.39 It is not known if stereoiso-ers of other CCBs have biological effects.All of the CCBs are metabolized to less-active or inactiveetabolites by the cytochrome P450 family of enzymes, pre-
ominantly by CYP3A. Concurrent administration of CCBs

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ith either inducers or inhibitors of the CYP3A enzyme canesult in drug-drug interactions of which the clinician shoulde aware. Co-administration of digoxin with either verapamilr diltiazem results in a 40% to 90% increase in serumigoxin concentrations. Rifampin and phenytoin, both in-ucers of CYP3A4, decrease verapamil and diltiazem concen-rations whereas cimetidine, a CYP3A4 inhibitor, has the op-osite effect. The CCBs all increase cyclosporine blood levels

n organ transplant patients taking this immunosuppressiverug. For a more thorough review of the clinical pharmacol-gy of the CCBs with extensive references, the reader is re-erred to an excellent review of this drug class by Abernethynd Schwartz.40

CEIsince captopril, the first orally active nonpeptide inhibitor ofCEIs, was approved in 1986, it has become increasinglyvident that blockade of the renin-angiotensin-aldosteroneystem not only decreases blood pressure in hypertensiveatients but also reduces injury to the heart, kidney, brain,nd blood vessels. The ACEIs have been shown in random-zed, controlled, clinical trials to decrease mortality and mor-idity in congestive heart failure after recent and remoteyocardial infarction, blunt the decline in glomerular filtra-

ion rate, reduce incidence of stroke, produce greater regres-ion of left ventricular hypertrophy than non–RAAS-block-ng therapies, reduce albuminuria, delay the onset of newiabetes, and improve endothelial function (see Cushman41

or review). This last effect is thought to occur because of annhibition of angiotensin-dependent increase in oxidativetress and the resulting decrease in nitric oxide activity andoncurrent increase in inflammatory cytokines and chemo-ines.42

Of the 10 ACEIs for oral administration currently mar-eted in the United States (benazepril, quinapril, ramipril,oexipril, perindopril, trandolapril, fosinopril, enalapril, lis-

nopril, and captopril), all except lisinopril and captopril arerodrugs that require hydrolysis by esterases in the liver or

ntestine to the active dicarboxylic acid form. Although theharmacokinetic properties of the drugs in this class varyomewhat, these differences usually are not critical in thehoice of a specific ACEI because all of the drugs in this class,ith the exception of captopril,43 usually exhibit little or noose-limiting toxicity. Doses of captopril greater than 225g/d have been associated with agranulocytosis and protein-ria, thought to be related to the sulfhydryl side chain of therug. The drugs that are highly lipophilic such as quinaprilnd ramipril bind to ACE in tissue membranes in vitro morevidly than the more hydrophilic agents such as captopril.lthough the mechanistic importance of inhibiting angioten-in II formation and facilitating nitric oxide bioavailability innjured tissues such as the heart, kidney, brain, and arteries isndisputed, the clinical significance of tissue ACE inhibitionemains unknown.44

There are several pharmacokinetic and pharmacodynamicharacteristics of ACEIs with which the clinician should be
amiliar when prescribing drugs in this class. As mentioned o
reviously, the response of blood pressure to increasingoses of all ACEIs is relative flat whereas the dose-responseelationships for other markers of tissue injury such as albu-inuria, inflammatory cell activation, and left ventricularypertrophy are not established clearly. Those drugs thatrovide 24-hour blood pressure reduction with once-dailyosing are preferred over drugs such as captopril and enala-ril, which usually must be taken 2 or 3 times daily to pro-ide similar blood pressure control. Compliance with takingedications that require multiple doses per day is less thanith those that can be administered once daily.45 Drugs that

re metabolized by the liver have higher peak plasma con-entrations and areas under the curve (AUC) in patients withoderate hepatic cirrhosis; the starting dose of an ACEI in

hose patients should be reduced and dose incrementshould be made with careful monitoring of the blood pres-ure. The same approach applies to administration of ACEIsliminated predominantly by the kidney for patients withenal impairment, particularly those with glomerular filtra-ion rates less than 30 mL/min. Increases of the serum creat-nine level are to be expected in patients with chronic kidneyisease, but usually do not exceed 150% of pretreatmentalues over a 4-week period46 unless the patient has under-ying bilateral renal artery stenosis or stenosis of the renalrtery to a single kidney. Therefore, modest changes in theerum creatinine level should not deter the physician fromontinuing ACEI therapy. Patients who are fluid volume de-leted because of diuretic therapy or gastrointestinal fluid

oss are often more susceptible to hypotension and ACEIherapy should be initiated with a reduced starting dose.atients of African descent exhibit a smaller reduction inlood pressure than those of Northern European descent.47

The most irritating but least worrisome adverse effect ofCE inhibitor is nonproductive cough.48 This adverse effectccurs in 5% to 20% of patients taking ACEIs, is thought toe mediated by bradykinin or substance P,49 is a class effectnd therefore will not likely resolve if one ACEI is substitutedor another, and has not been linked to any specific pulmo-ary functional changes or bronchial reactivity.50 Althoughar less frequent but more potentially life-threatening is an-ioedema. The incidence of angioedema is about 0.3% inarge clinical trial populations51; is more common in those offrican descent51,52; may present initially as minimal to mod-st swelling of the lips, tongue, and throat, and then becomesore severe over time. It may occur only in the intestine,resenting as intermittent abdominal pain and diarrhea.53

Treatment of women with either ACEIs or ARBs during theecond or third trimesters of pregnancy is contraindicatedecause of the high risk for fetal hypotension, acute renalailure, oligohydramnios, calvarial and pulmonary hypopla-ia, and limb deformities, all of which appear to be conse-uences of maternal/placental hypotension and/or interfer-nce with the fetal renin-angiotensin system.54,55

Recent reports of an increase in cardiovascular events inatients treated with cyclooxygenase-2 inhibitors versus pla-ebo have resulted in valdecoxib being withdrawn from thearket. Although the clinical trial in which this outcome was

bserved was not designed specifically to gather information

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bout potential mechanisms, studies before the initiation ofhese trials showed a greater increase in blood pressure withaldecoxib than with celecoxib in hypertensive patients whoad stable controlled blood pressure on ACEI therapy.56 In aore recent investigation it was observed that diclofenac pro-uced a greater increase in the 24-hour mean blood pressurend a greater decrease in glomerular filtration rate than didelecoxib in ACEI-treated African Americans and Hispan-cs.57 Collectively, these findings suggest that inhibitors of theyclooxygenase enzyme either should be avoided or usedith caution in hypertensive patients being treated withCEIs.

RBSRBs inhibit the actions of angiotensin II at the tissue level byompeting with this potent vasoconstrictor for binding to thengiotensin AT1-subtype receptor, the receptor that mediateshe well-documented cardiovascular and renal actions attrib-ted to angiotensin II. Some of these drugs, as the corner-tone of a multidrug therapeutic regimen, have exhibitedardioprotective or renoprotective benefits in patients with aariety of chronic kidney disease or proteinuria. A thoroughiscussion, however, of these clinical trial results is beyondhe scope of this article.

Structural differences in the 7 compounds (candesartan,prosartan, irbesartan, losartan, olmesartan, telmisartan, andalsartan) currently marketed in the United States likely ac-ount for the observed differences in bioavailability, metab-lism, potency, and duration of action of these drugs.58,59

espite these differences, the ARBs as a class are well toler-ted over a broad range of doses. In blinded, placebo-con-rolled, clinical trials the reported incidence of adverse effectsf these drugs is low and often indistinguishable from thosescribed to placebo.

Each of the 7 drugs in this class marketed in the Unitedtates bind to the AT1 receptor with high affinity comparedith their binding to other angiotensin receptors. Losartan,alsartan, and eprosartan showed competitive or surmount-ble receptor binding whereas olmesartan, irbesartan, cande-artan, telmisartan, and the major active metabolite of losar-an, EXP3174, exhibit noncompetitive or insurmountableinding. Candesartan cilexitil and olmesartan medoxomil arerodrugs that are hydrolyzed to the active moieties by hydro-

ysis in the gastrointestinal mucosa. Losartan is metabolizedxtensively in the liver, in part by the cytochrome P450soenzymes, 3A4 and 2C9. About 15% of the dose is con-erted to the more potent EXP3174 metabolite. The durationf action of all of these drugs, or in the case of losartan itsctive metabolite, is sufficiently long that they maintain 24-our efficacy when administered once daily. Although theioavailability of valsartan (40%) and losartan (10%) are re-uced if administered with food and the bioavailability ofprosartan (55%) is increased, dosage adjustments almostever are necessary. The drugs in this class generally are wellolerated, in part because they exhibit few interactions withther drugs. Exceptions include losartan, whose half-life is
ecreased by rifampin and increased by phenytoin,58 and s
elmisartan, which may increase digoxin AUC by about5%.60 ARBs, such as ACEIs, should not be taken duringregnancy because of the fetopathy caused by interruption ofhe fetal renin-angiotensin system. The reader is referred toeveral comprehensive reviews for more detailed informationbout the pharmacodynamics and pharmacokinetics of theRBs.58,59,61,62

1-Adrenergic–Receptorntagonists

elective �1-blockers promote vascular smooth muscle relax-tion by antagonizing the binding of norepinephrine to the1-adrenergic receptor in this tissue. Drugs in this class (pra-osin, terazosin, and doxazosin) have a similar effect onmooth muscle in the prostate and therefore are indicated foroth hypertension and prostatic hypertrophy with symptomsf lower urinary tract outlet obstruction. The principal targetopulation for which monotherapy with these drugs mighte considered is elderly men with both hypertension androstatic hypertrophy.63 An added benefit of selective-blocker therapy in older patients at increased risk for cor-nary artery disease–related events is a modest reduction inow-density lipoprotein cholesterol and triglyceride levels ac-ompanied by a slight increase in high-density lipoproteinholesterol levels.64 However, there is concern about an in-reased incidence of first-dose orthostatic hypotension in thisame patient population because older individuals have di-inished autonomic nervous system compensatory re-

ponses to hypotensive stimuli.65

ther Drugsirect-Acting Vasodilatorsydralazine and minoxidil are drugs that act directly on vas-

ular smooth muscle cells to promote vasorelaxation al-hough the cellular mechanisms by which this is accom-lished differ. These potent hypotensive agents usually arerescribed as part of a therapeutic regimen for the patienthose hypertension is refractory to multidrug therapy.66 Hy-ralazine also has been used effectively as part of a multidrugegimen in the management of heart failure. Recently, hydral-zine combined with isosorbide dinitrate has been reportedo reduce cardiovascular mortality more than conventionalherapy in African Americans with severe heart failure67 andistorically more than the same therapy in Caucasian Amer-

cans,68 although the factors contributing to this ethnic dif-erence have not been defined clearly. Both drugs reduceeripheral resistance and have far less effect on venous ca-acitance. Decreasing arterial pressure by this mechanismauses reflex activation of the sympathetic nervous systemnd the renin-angiotensin system, resulting in tachycardiand renal retention of sodium.69 Consequently, these drugsre given most frequently with diuretics and �-blockers,ombined �–�-blockers such as labetalol or carvediolol, or
ympatholytic agents such as clonidine or reserpine.70,71

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ydralazineydralazine is a potent vasodilator that can be administeredarenterally or orally. The precise intracellular mechanism(s)y which the drug causes smooth muscle cell relaxation is notell established but likely culminates in an inhibition of cal-

ium release from the sarcoplasmic reticulum.72 The drug isnstable chemically and extensively converted to a variety ofetabolites; the relative concentrations of different metabo-

ites are dependent on the subject’s acetylator phenotype.cetylator phenotype (fast versus slow), however, does not

nfluence substantially the hypotensive response to thisrug.73 A volume of distribution larger than total body waterith sequestration of the drug or its active metabolites in

issues probably accounts for the observation that the hypo-ensive effect of the drug is longer than would be predicted byts elimination half-life of 13 to 125 minutes after oral admin-stration.69 To maintain 24-hour efficacy during chronic ther-py the drug must be administered every 6 to 8 hours. Inddition to the pharmacologic adverse effects often associ-ted with vasodilators (flushing, headache, palpitations, ar-hythmias, angina pectoris, myocardial infarction, and pe-ipheral edema), the drug produces a lupus-like syndrome inome patients usually after 6 to 24 months of therapy. Thenteraction of the hydrazine moiety of hydralazine with DNAo interfere with normal DNA methylation has been impli-ated in this condition,74 which almost always occurs in slowcetylators and is not predicted by a positive antinuclearntibody (ANA).69 The incidence of this drug-induced lupuss dose dependent and has been reported to occur in 5.4% ofatients receiving 100 mg of hydralazine daily and in 10.4%f those receiving 200 mg daily, with a slightly higher inci-ence in women than in men.75 Fortunately, the clinicalanifestations of the syndrome (arthralgias, glomerulone-hritis) resolve when the drug is discontinued.

inoxidilinoxidil activates adenosine triphosphate–sensitive potas-

ium channels, primarily in arterial rather than in venousmooth muscle. Activation of these channels promotes vas-ular relaxation by inhibiting the entry of calcium into theell (see Sica66 and Campese76 for review). After almost com-lete absorption by the gastrointestinal tract, the drug is me-abolized mainly in the liver. Of the 3 principal metabolitesglucuronide, sulfate, and 4-hydroxy minoxidil), the sulfates more active than the parent drug whereas the glucuronidend 4-OH metabolites are much less active.77 Similar to hy-ralazine, minoxidil has a volume of distribution larger thanotal body water, is concentrated in tissues, and therefore itsiologic effect lasts longer than would be expected from itslimination half-life of 2.8 to 4.2 hours.76 Although the drug,hose hypotensive effect is related to dose and extent oflood pressure increase, can be administered once dailyusual maintenance dose is 10-40 mg/d), it most often isiven twice daily to blunt a significant increase in heart ratehat may accompany peak plasma concentrations of the drug.he tachycardia and fluid retention that accompanies mi-
oxidil therapy is even more striking than that observed with S
ydralazine therapy. Edema and weight gain can be rapidnd profound, often necessitating high doses of loop diuret-cs. Empirically, it has been observed that the addition of

etolazone to the loop diuretic may augment the natriureticesponse more than further increasing the loop diuretic dose.luid can be retained in tissues other than the lower extrem-

ties. For example, pericardial effusions can occur rarely andll patients with profound fluid retention on minoxidilhould be monitored for this possibility. Minoxidil may causeidespread hypertrichosis of the face, scalp, and body inoth women and men, sometimes so emotionally disturbingo the patient that they choose to discontinue the drug. De-pite the challenges posed by the use of minoxidil, it is argu-bly the single most effective antihypertensive agent availableor the treatment of resistant hypertension.

ympatholytic Drugsympatholytic drugs such as clonidine, �-methyldopa, reser-ine, and the ganglionic blockers (guanethidine, guanfacine,nd guanabenz) are prescribed rarely or not at all as primaryherapy for hypertension. They may, however, be used asdjunctive therapy for hypertensive patients who are resis-ant to therapy with 3 or more drugs from other classes or arentolerant of drugs from other classes.

ombination Drugreatment of Hypertension

ingle-drug therapy to control blood pressure likely will beffective in only a minority of hypertensive patients. Based onhe experience gained in randomized controlled trials, theNC 7 report recommends that clinicians consider initiationf therapy with 2 drugs when the blood pressure is 20/10 mmg or more above the desired goal.1 This recommendationould apply to patients with uncomplicated stage II hyper-

ension whose blood pressure is 160/100 mm Hg or highernd to those individuals with diabetes or chronic kidneyisease whose blood pressure is 150/90 mm Hg because theecommended goal in these patient populations is 130/80m Hg.Decisions about which drugs to combine usually are pred-

cated on the individual patient’s medical profile. Consider-tion should be given to the patient’s age, race, coexistentardiovascular and noncardiovascular conditions, and to thextent of blood pressure increase. Socioeconomic issues, theotential for serious adverse effects, and the drugs being usedo treat comorbid conditions such as arthritis, gastrointesti-al abnormalities, and hematologic disorders are factors thatay influence decisions about the most appropriate antihy-ertensive drugs of a specific patient.The choice of 2 or more drugs that target different patho-

hysiologic processes in hypertension and its sequelae oftenill result in blood pressure control superior to that achievedith single-drug therapy, a benefit that may be achieved with

ower doses of each drug and fewer adverse effects. Table 1ummarizes the drugs currently marketed in the United
tates for the treatment of hypertension that combine agents

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rom 2 different drug classes. Figure 2 shows the drugs mostrequently prescribed in combination, either as single agentsith 2 separate prescriptions or as components of a single pill

ombination, those that have been shown to have the leastdditive blood pressure lowering efficacy in clinical trials,nd those studied less well or not at all. Because diureticsctivate the renin-angiotensin-aldosterone system, it is logi-al to combine them with classes of drugs that inhibit thisotent vasoconstrictor (angiotensin II) and sodium-retainingaldosterone) system. Combinations of ACEIs or ARBs withiuretics, for instance, provide equivalent blood pressure re-uction in African Americans and Caucasians whereas ACEIsr ARBs alone do not.2,10,78 Limited data suggest that cardio-ascular event reduction with a �-blocker–based therapeuticegimen may be superior to an ARB-based regimen in Africanmericans although this possibility has yet to be tested rig-rously in an appropriately designed clinical trial.79 An addi-ional benefit of ACEI or ARB plus diuretic combinations is a

Figure 2 This figure depicts possible combinations of drtensive patients requiring at least two drugs for controlarrows represent those combinations for which there ievents, or both compared to monotherapy. Fixed dosecombinations. Dashed arrows connect two drug classesefficacy or reduced adverse events or for which fixed
Reproduced with permission, Advantage Communications, LL
able 1 Fixed-Dose Combination Drugs Marketed for Hyper-ension and other Cardiovascular Disorders

Drug 1 Drug 2 Number

iuretic (thiazide) Diuretic (K� sparing) 4iuretic (thiazide) �-blocker 10iuretic (thiazide) Vasodilator 1iuretic (thiazide) ACEI 8iuretic (thiazide) ARB 7iuretic (thiazide) DCA or NDCA 0iuretic (thiazide) �1 antagonist 0iuretic (thiazide) �2 agonist 1DCA ACEI 1CA ACEI 2CEI ARB 0

ugs from two drug classes that could be used to treat hyper-of elevated blood pressure. Drug classes connected by solid

s clinical trial evidence of superior efficacy, reduced adverses of the two drugs in a single pill also are available for thesefor which there is either little or no clinical trial evidence ofdose combinations are not available in the United States.

C, 2004.

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ower incidence of hypokalemia than with diuretics alone. Inact, the concomitant use of potassium-sparing diuretics suchs triameterene, spironolactone, amiloride, or oral potassiumupplementation in patients taking these combinations is dis-ouraged in most because of the risk for hyperkalemia.45,80

iuretics often are combined with direct-acting vasodilatorsuch as hydralazine and minoxidil because of the peripheraldema that may develop when unopposed reflex activation ofhe sympathetic nervous system by drugs in this class resultsn increased renal sodium reabsorption.66 Frequently a thirdrug, a �-blocker or a central sympatholytic agent such aslonidine, is added to blunt the reflex tachycardia conse-uent to sympathetic activation.66

Combinations of calcium antagonists and ACEIs have beentudied extensively in randomized clinical trials. A fixed-doseombination of amlodipine/benazepril, 10/20 mg, controlledlood pressure in a greater percentage of patients with stage IIypertension (61%) than did amlodipine alone at 10 mg43%); the incidence of peripheral edema in patients takinghe combination was half that of patients on amlodipineonotherapy.81 In another study, patients with systolic hy-ertension achieved better blood pressure reduction on am-

odipine/benazepril 5/20 mg than patients receiving eithermlodipine 10 mg or benazepril 40 mg.82 Low fixed-dosemlodipine/benazepril also has been shown to improve arte-ial distensibility and reduce left ventricular mass in hyper-ensive patients more than higher doses of either drug givens monotherapy.83 Even though DCAs such as amlodipineiven as monotherapy either have no effect or worsen urinaryrotein excretion in patients with proteinuria,84,85 they doot negate the reduction in proteinuria observed with ACEIshen administered as part of an ACEI-DCA combination,86

robably because both systemic blood pressure and intraglo-erular pressure are reduced by the complementary action

f the 2 drugs on the afferent and efferent arteriole, respec-ively.87 The NDCA drugs such as verapamil have either aeutral or less-negative effect on proteinuria than the DCAsnd actually may improve urinary protein excretion wheniven with an ACEI.88 The pre-capillary arteriolar and post-apillary venular dilating effects of DCAs and ACEIs, respec-ively, balance pressure across the capillary which results in aeduction of the peripheral edema associated with DCAonotherapy in some patients.89

The effects of combining ARBs with CCBs on renal func-ion, proteinuria, surrogate markers of cardiovascular diseaseuch as left ventricular mass or arterial distensibility, andCB-associated adverse effects have not been studied system-tically to date. Therefore, it is not surprising that fixed-doseombinations of drugs representing these 2 classes are notvailable. Also absent from the list of fixed-dose combina-ions are drugs containing both an ACEI and an ARB. Interestn conducting studies to obtain Food and Drug Administra-ion approval for such combinations likely will increase ifilot trials of such combinations show a more marked reduc-ion in the rate of deterioration in renal function in diabeticnd hypertensive patients than is achieved with either ACEIsr ARBs alone.
The addition of drugs to the patient’s therapeutic regimen 1
o achieve goal blood pressure other than those combinationsncluded in Figure 2 sometimes is necessary. In selected pa-ients, especially those with evidence of increased sympa-hetic nervous system activity, �1-receptor antagonists andympatholytic agents including clonidine and reserpine maye indicated. In the patient whose blood pressure still is

ncreased despite 3-drug therapy (defined as resistant hyper-ension by JNC 71), the addition of low-dose spironolactonehould be considered. An additional mean blood pressureeduction of 25/12 mm Hg was achieved in both African-merican and Caucasian resistant hypertensive patients tak-

ng calcium antagonists, ACEIs, and diuretics 6 months afterdding spironolactone to this regimen in doses titrated up to0 mg.90 The response to spironolactone was similar in thoseatients with and without evidence of hyperaldosteronism.

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