role of calcium channel blockers in treatment of...

50 PHARMACY TODAY�s�APRIL 2008 www.pharmacytoday.org

review

Go to www.pharmacist.com and take your test online for instant credit.

Objectives: To describe for pharmacists the basics of hypertension with a specific

emphasis on the role of calcium channel blockers in the management of this

condition.

Data sources: Published literature on hypertension identified via a search of

PubMed and pertinent government Web sites.

Data synthesis: Hypertension affects more than 70 million Americans, and many

patients are unaware of their condition. The pathophysiology, risk factors, and

nonpharmacologic and pharmacologic management of hypertension are described

in this article. Pharmacists can play a major role in educating patients on hyper-

tension, counseling patients on the importance of lifestyle modifications and drug

therapy, and encouraging adherence.

Conclusion: Hypertension is a major risk factor for cardiovascular morbidity and

mortality. By understanding hypertension and its appropriate management, pharma-

cists can effectively manage patients, reducing adverse events and improving long-

term outcomes.

Keywords: Hypertension, calcium channel blockers.

Pharmacy Today. 2008(Apr);14(4):50–65.

Role of calcium channel blockers in treatment of hypertension

Marieke Schoen and Maria G. Tanzi

review

^ÓäänÊLÞÊÌ�iÊ��iÀ�V>�Ê*�>À�>V�ÃÌÃÊ�ÃÃV�>Ì��ÊÊÊÊUÊÊÊÊÊ��ÊÀ�}�ÌÃÊÀiÃiÀÛi`°ÊÊÊÊÊUÊÊÊÊ*À��Ìi`Ê��Ê1°-°�°

Marieke Schoen, PharmD, BCPS, is Clinical

Associate Professor, Departments of Phar-

macy Practice and Medicine, and Maria G. Tanzi, PharmD, is Clinical Assistant Professor,

Department of Pharmacy Practice, College of

Pharmacy, University of Illinois at Chicago.

Continuing education credits: See learning

objectives below and assessment questions at

the end of this article, which is ACPE universal

program number 202-000-08-110-H01-P in

APhA’s educational programs. The CE exami-

nation form is located at the end of this article.

To take the CE test for this article online, go to

www.pharmacist.com/education and follow

the links to the APhA CE center.

Disclosure: The authors declare no conflicts of

interest or financial interests in any products

or services mentioned in this article, including

grants, employment, gifts, stock holdings, or

honoraria.

Reviewed by: Jeegisha Patel, PharmD, Clinical

Assistant Professor, Coordinator of Com-

munity Experiential Programs, and Clinical

Pharmacist Specialist, Fred Meyer Patient Care

Center, College of Pharmacy, Oregon State

University/Oregon Health & Science Univ-

eristy, Portland. Maryann Z. Skrabal, PharmD,

CDE, Assistant Director, Office of Experiential

Education, Assistant Professor, Department

of Pharmacy Practice, School of Pharmacy

and Health Professions, Creighton University,

Omaha, Neb.

This program was developed by the American

Pharmacists Association and supported by an

educational grant from Sciele Pharma, Inc.

Learning objectives NÊ �iÃVÀ�LiÊÌ�iÊi«�ì��}Þ]ÊiÌ��}Þ]Ê>�`Ê«>Ì�«�ÞÃ��}ÞÊvÊ�Þ«iÀÌi�Ã��°

NÊ >�iÊ>ÌÊ�i>ÃÌÊÌ�ÀiiÊÀ�Ã�Êv>VÌÀÃ]ÊìÃVÀ�LiÊ`�>}�ÃÌ�VÊVÀ�ÌiÀ�>]Ê>�`Ê��ÃÌÊV�>ÃÃ�wV>Ì��ÃÊvÀÊ�Þ«iÀÌi�Ã��°Ê

NÊ �À�Õ�>ÌiÊÌÀi>Ì�i�ÌÊ«�>�Ã]Ê��V�Õ`��}Ê`ÀÕ}Ê>�`Ê��`ÀÕ}ÊÌ�iÀ>«Þ]ÊvÀÊÛ>À�ÕÃÊÌÞ«iÃÊvÊ«>Ì�i�ÌÃÊ>vviVÌi`ÊLÞÊ�Þ«iÀÌi�Ã��°

NÊ �iÃVÀ�LiÊÌ�iÊÀ�iÊvÊV>�V�Õ�ÊV�>��i�ÊL�V�iÀÃÊ��ÊÌ�iÊÌÀi>Ì�i�ÌÊvÊ�Þ«iÀÌi�Ã��Ê��Ê«>Ì�i�ÌÃÊ>ÌÊ��}�ÊVÀ�>ÀÞÊÀ�Ã�]Ê«>Ì�i�ÌÃÊ

Ü�Ì�Ê`�>LiÌiÃ]Êi�ìÀ�ÞÊ«>Ì�i�ÌÃ]Ê>�`ÊL�>V�Ê«>Ì�i�ÌÃ°

NÊ >�iÊ>ÌÊ�i>ÃÌÊÌ�ÀiiÊ`ÀÕ}ÊÌ�iÀ>«ÞÊ«ÀL�i�ÃÊV��ÞÊi�VÕ�ÌiÀi`Ê��Ê>�Ì��Þ«iÀÌi�Ã�ÛiÊÌ�iÀ>«ÞÊ>�`Ê��`�V>ÌiÊÜ>ÞÃÊÌÊ

«ÀiÛi�Ì]ÊÀiÃ�Ûi]ÊÀÊ�>�>}iÊÌ�iÃiÊ«ÀL�i�Ã°

NÊ �iÃVÀ�LiÊ«À}ÀiÃÃÊ��Ê�i`�V>�ÊÀiÃi>ÀV�Ê��Ê��«ÀÛ��}Ê>�Ì��Þ«iÀÌi�Ã�ÛiÊ«�>À�>VÌ�iÀ>«Þ°

Abstract

www.pharmacist.com APRIL 2008 s�PHARMACY TODAY 51

review


Hypertension, defined as a persistent elevation in arterial

blood pressure, is a major risk factor for cardiovascular

morbidity and mortality.1 Millions of Americans have hyperten-

sion; however, many are unaware of their condition or may not

be receiving appropriate treatment. Therefore, pharmacists can

play an important role in educating patients on hypertension,

counseling patients on the importance of lifestyle modifications

and pharmacotherapy, and encouraging adherence.

This continuing education program will review the basics of

hypertension, including epidemiology, etiology, pathophysiology,

diagnosis, classification, and treatment recommendations based

on current practice guidelines— the Seventh Report of the Joint

National Committee on the Detection, Evaluation, and Treatment

of High Blood Pressure (JNC 7).2 Additionally, this program will

review the role of calcium channel blockers (CCBs) in the man-

agement of hypertension in various patient populations. Finally,

novel antihypertensive therapies will be explored.

Epidemiology

The 2008 update on heart disease and stroke statistics pub-

lished by the American Heart Association (AHA) and Ameri-

can Stroke Association states that approximately 73 million

Americans have hypertension.3 This correlates to nearly one in

three U.S. adults having elevated blood pressure. Additionally,

an estimated 37.4% of the U.S. population has prehypertension

(see “Classification of blood pressure” section). In general, the

prevalence of hypertension is similar among men and women 45

to 54 years of age; however, after the mid-50s, the prevalence of

hypertension is much higher in women. Overall, the prevalence

of hypertension in the elderly is high because blood pressure

values increase with age. Hypertension is also more prevalent in

non-Hispanic blacks (33.5%), followed by non-Hispanic whites

(28.9%) and Mexican Americans (20.7%).1 Blacks with hyper-

tension also have greater morbidity and mortality compared

with whites.3 Blacks have a 1.3-times greater rate of nonfa-

tal stroke, a 1.8-times greater rate of fatal stroke, a 1.5-times

greater rate of heart disease death, and a 4.2-times greater rate

of end-stage renal disease compared with whites.

The morbidity and mortality associated with hypertension is

substantial.3 Approximately 69% of patients with an initial myo-

cardial infarcation, 77% with an initial stroke, and 74% with heart

failure have a blood pressure greater than 140/90 mm Hg. Data

from the Framingham Heart Study indicated that hypertension

is associated with shorter overall life expectancy and shorter life

expectancy free of cardiovascular disease. Hypertension-asso-

ciated mortality has risen over the past decade (1994–2004),

with the age-adjusted death rate from hypertension increasing

by 26.6% and the actual number of deaths by 56.1%.

Etiology

Hypertension can be defined as either primary or secondary.1

Primary hypertension, also known as essential hypertension,

is diagnosed in the absence of an identifiable secondary cause.

This form of hypertension cannot be cured; however, it can be

controlled with proper treatment. A multitude of pathologi-

cal mechanisms have been identified that may contribute to

the development of primary hypertension; however, the exact

mechanism is unknown. Secondary hypertension is caused by a

comorbid disease or drug associated with elevating blood pres-

sure (Table 1).1,2 In general, treating the underlying condition or

discontinuing the drug should result in an improvement in blood

pressure levels. A majority of cases of secondary hypertension

occur in patients with renal dysfunction. More than 90% of

American adults have primary hypertension, whereas second-

ary hypertension accounts for fewer than 10% of cases.1

Pathophysiology

The pathophysiology of primary hypertension is extremely

complex.1,4 Blood pressure is the mathematical product of car-

diac output and total peripheral resistance (BP = CO × TPR);

therefore, elevated blood pressure can result from increased

cardiac output and/or increased total peripheral resistance. Mul-

tiple factors, such as genetic predisposition, excess dietary salt

intake, and alterations in adrenergic tone, have been proposed to

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Table 1. Secondary causes of hypertension1,2

Diseases

N Chronic kidney disease

N Coarctation of the aorta

N Cushing’s syndrome and other glucocorticoid excess states

N Obstructive sleep apnea

N Obstructive uropathy

N Pheochromocytoma

N Primary aldosteronism and other mineralocorticoid excess

states

N Renovascular hypertension

N Thyroid or parathyroid disease

Drugs

N Corticosteroids

N Erythropoetin

N Estrogens (oral contraceptive agents with high estrogenic

activity)

N Immunosuppressant agents (cyclosporine, tacrolimus)

N Nonsteroidal anti-inflammatory drugs and cyclooxygenase

2 inhibitors

N Sympathomimetics (decongestants, anorectics)

N Street drugs (cocaine, ecstasy)

Food substances

N Sodium chloride

N Ethanol

N Licorice


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interact and produce elevated blood pressure. Increased car-

diac output can result from increased fluid volume secondary

to excess sodium intake/renal sodium retention or secondary to

excess stimulation of the renin–angiotensin–aldosterone system

(RAAS). Increased peripheral resistance can occur as a result of

functional vascular constriction secondary to excess stimulation

of the RAAS, sympathetic nervous system overactivity, genetic

alterations of cell membranes, or endothelial-derived factors.

The natural course of primary hypertension evolves over

time, with blood pressure values fluctuating between elevated

and normal levels for an extended period of time.1 The early

stage of hypertension has been characterized by increased car-

diac output and normal to low peripheral vascular resistance.

The increased cardiac output observed in the early stages of

hypertension is believed to be related to sympathetic overac-

tivity.4 In time, alterations in the structural and physical prop-

erties of the vasculature occur (vascular remodeling). These

changes result in persistent elevations in peripheral vascular

resistance, leading to sustained elevations in blood pressure.

Additionally, if hypertension is left untreated for an extended

period of time, patients can develop damage to a variety of

organs, including the heart, brain, kidneys, vasculature, and

eyes (Table 2).1,2

Cardiovascular risk

Hypertension is one of the major risk factors for developing

cardiovascular disease (Table 3).1,2 Data have shown risk for

myocardial infarction, left ventricular dysfunction, stroke, and

renal disease increases as blood pressure rises. Specifically, in

adults 40 to 70 years of age, each incremental increase of 20

mm Hg in systolic blood pressure (SBP) or 10 mm Hg in diastolic

blood pressure (DBP) across the entire blood pressure range

from 115/75 to 185/115 mm Hg doubles the risk of cardiovas-

cular disease.

SBP is a stronger predictor of cardiovascular risk than DBP

in adults older than 50 years.1,2 Elevations in SBP are believed

to occur as a result of pathological changes in the arterial vas-

culature that occurs with aging. These changes decrease the

compliance of the arterial wall, resulting in an increased risk of

cardiovascular adverse events.

Screening and diagnosis

The U.S. Preventive Services Task Force (USPSTF) published

a statement in December 2007 reaffirming that all adults

age 18 years or older should be screened for hypertension.5

USPSTF stated that adults should be screened for hypertension

to identify individuals at increased risk of cardiovascular dis-

ease. USPSTF also stated that early treatment of elevated blood

pressure will ultimately decrease the incidence of cardiovascu-

lar morbidity and mortality.

JNC 7 has specific recommendations for follow-up blood

pressure screenings for adults.2 The guidelines recommend a

routine blood pressure recheck every 2 years for adults with

SBP less than 120 mm Hg and DBP less than 80 mm Hg and

every year for those with SBP of 120 to 139 mm Hg or DBP of

80 to 89 mm Hg.

Hypertension is known as the “silent killer” because patients

with primary hypertension are generally asymptomatic.1

Patients may not be aware that they have hypertension until

they present to their physician’s office for a routine exam. Mea-

surement of blood pressure is most commonly performed with

a sphygmomanometer. JNC 7 recommends that patients avoid

caffeine, exercise, and smoking for at least 30 minutes prior

to the measurement.2 Patients should be seated quietly for at

least 5 minutes in a chair, an appropriate-sized blood pressure

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Table 2. Organ damage resulting from untreated

hypertension1,2

Heart

N Left ventricular hypertrophy

N Angina or prior myocardial infarction

N Prior coronary revascularization

N Heart failure

Brain

N Stroke or transient ischemic attack

N Dementia

N Chronic kidney disease

N Peripheral arterial disease

N Retinopathy

Table 3. Major cardiovascular risk factors2

N Age (men >55, women >65)

N Family history of premature cardiovascular disease (men

<55, women <65)

N Hypertension

N Cigarette smoking

N Obesity (defined as BMI r30 kg/m2)

N Physical inactivity

N Dyslipidemia (elevated LDL or total cholesterol, low HDL)

N Diabetes

N Microalbuminuria or estimated GFR <60 mL/min

Abbreviations used: BMI, body mass index; GFR, glomerular

filtration rate; HDL, high-density lipoprotein; LDL, low-density

lipoprotein.


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cuff should be used (cuff bladder encircling at least 80% of the

arm), and at least two measurements should be taken. Patients

are diagnosed with hypertension when two or more elevated

seated blood pressure readings are obtained on at least two dif-

ferent office visits. Some patients may experience “white coat”

hypertension when they present to the clinician’s office. Ambu-

latory blood pressure monitoring may be more appropriate in

these patients to ensure accurate diagnosis. JNC 7 also rec-

ommends performing routine tests such as electrocardiogram,

blood urea nitrogen and serum creatinine, urinalysis, serum

potassium, and fasting blood glucose and lipid profile before

initiating therapy. All patients should be screened for identifi-

able causes of hypertension and assessed for the presence or

absence of target organ damage.

#LASSIlCATION�OF�BLOOD�PRESSURE

Adult patients are placed into one of four categories based on

their blood pressure readings: normal, prehypertension, stage 1,

or stage 2 (Table 4).2 Prehypertension was a new category

added to the JNC 7 guidelines to increase awareness for the

need for lifestyle modifications (see “Nonpharmacologic thera-

pies” section) in individuals with blood pressure approaching

abnormal levels. The guidelines state that patients with prehy-

pertension require “health-promoting lifestyle modifications to

prevent cardiovascular disease.”

Liszka and colleagues conducted a longitudinal, population-

based, cohort study on adult participants in the National Health

and Nutrition Examination Survey (1971–1975) to assess risk

of major cardiovascular events in those classified as having

prehypertension.6 After 18 years of follow-up, participants

with prehypertension (n = 2,708) were 1.32 times more likely

to have a major cardiovascular event than those with normal

blood pressure. The authors concluded that the diagnosis of pre-

hypertension should serve as a warning sign for both patients

and clinicians that metabolic changes ultimately leading to car-

diovascular disease may be well under way.

Patients with DBP of 90 mm Hg or lower and SBP of 140 mm

Hg or greater are classified as having isolated systolic hyperten-

sion.2 Patients with blood pressure values more than 180/120

mm Hg are classified as having either a hypertensive emergency

or hypertensive urgency. Patients with high elevations in blood

pressure and acute target organ damage (i.e., encephalopathy,

intracranial hemorrhage, unstable angina) are categorized as

having a hypertensive emergency. Hypertensive urgencies are

high elevations in blood pressure without the presence of tar-

get organ damage. The pharmacological management of hyper-

tensive emergencies and urgencies will not be covered in this

review. Refer to the JNC 7 guidelines for recommended treat-

ment options.

'OALS�OF�THERAPY

The ultimate goal of antihypertensive treatment strategies is

to reduce hypertension-associated morbidity and mortality.2

JNC 7 recommends that treatment strategies should strive to

reduce blood pressure levels to less than 140/90 mm Hg for

most patients. A lower blood pressure goal of less than 130/80

mm Hg is recommended for patients with diabetes or renal

disease. A combination of lifestyle modifications and pharma-

cotherapy are generally needed to reach recommended goals.

Lifestyle modifications alone are considered appropriate for

patients with prehypertension; however, all patients with

established hypertension require both lifestyle modifications

and pharmacotherapy.

.ONPHARMACOLOGIC�THERAPIES

Lifestyle modifications are an essential component in preventing

and treating hypertension.2 These modifications include altera-

tions in diet, sodium restriction, reductions in alcohol consump-

tion, physical activity, and weight loss (if overweight).

$IETARY�MODIlCATIONS

In 2006, AHA published a scientific statement on dietary

approaches to prevent and treat hypertension.7 The statement

summarized a variety of diet-related lifestyle modifications that

have been shown to effectively lower blood pressure (Table 5). In

general, the AHA recommendations are consistent with JNC 7;

however, the recommended daily sodium intake is lower. JNC 7

recommends that patients reduce dietary sodium intake to no

more than 2.4 grams sodium per day or 6 grams sodium chloride

per day.2 AHA did recognize that a reduction in sodium intake

to 1.5 grams per day is not easily achieved currently because of

the high sodium content in the available food supply; a reason-

able recommendation, therefore, is an upper limit of 2.4 grams

per day.7 Reductions in dietary sodium intake to less than 2.4

grams per day are estimated to correlate with a 2- to 8-mm Hg

reduction in SBP.2 Patients should be educated on the multiple

potential sources of dietary sodium, such as processed meats

and canned soups, and should be shown how to read a nutrition

label to determine whether food choices are high in sodium.

The Dietary Approaches to Stop Hypertension (DASH) diet

is recommended because it has been shown to lower SBP by 8

to 14 mm Hg.2,7 DASH emphasizes consuming fruits, vegetables,

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Table 4. Classification of blood pressure for adults2

Classification Systolic blood

pressure

(mm Hg)

Diastolic blood

pressure

(mm Hg)

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 hypertension 140–159 or 90–99

Stage 2 hypertension r160 or r100


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and low-fat dairy products and reducing saturated fats. Patients

are encouraged to consume whole grains, poultry, fish, and nuts

and to reduce intake of red meats, sweets, and sugar-containing

beverages. The DASH diet is also rich in calcium, magnesium,

and potassium. High potassium levels are associated with reduc-

tions in blood pressure. AHA recommends increasing potassium

intake to 4.7 grams per day by consuming foods that are rich in

potassium, rather than using supplements.7 Examples of DASH

diet meal plans can be located at the National Heart, Lung, and

Blood Institute Web site (www.nhlbi.nih.gov).

Alcohol consumption should be limited because observa-

tional studies have documented a direct dose-dependent rela-

tionship between alcohol intake and blood pressure, particu-

larly as the intake of alcohol increases above two drinks per

day.7 Alcohol consumption should be limited to no more than two

drinks per day for men and no more than one for women.2,7 One

drink is defined as 12 ounces of regular beer, 5 ounces of wine

(12% alcohol), and 1.5 ounces of 80-proof distilled spirits.2,7

Moderation of alcohol consumption has been shown to lower

SBP by 2 to 4 mm Hg.2

Physical activity, weight reduction,

and more

JNC 7 recommends that all able patients engage in 30 minutes

of regular aerobic physical activity most days of the week.2

Patients can be encouraged to participate in activities such as

brisk walking, jogging, swimming, and bicycling. Aerobic exer-

cise has been associated with a 4 to 9 mm Hg reduction in SBP.

Patients should obtain medical clearance from their physician

before starting an exercise program, especially if target organ

damage is present.1

A meta-analysis of 25 trials (n = 4,874) showed that mean

SBP and DBP reductions from an average weight loss of 5.1 kg

were 4.4 and 3.6 mm Hg, respectively.8 Additionally, data have

shown that modest weight loss in overweight prehypertensive

individuals decreases the incidence of hypertension signifi-

cantly.9 Both JNC 7 and AHA recommend achieving and main-

taining normal body weight (body mass index [BMI] 18.5–24.9

kg/m2).2,7 Patients with BMI of 25 kg/m2 or greater should be

encouraged to lose weight by changing their diet and increasing

physical activity.

For further cardiovascular risk reduction, patients who

smoke should also be encouraged to quit.1 Smoking is a major

independent, modifiable cardiovascular risk factor that places

hypertensive patients at increased risk of experiencing cardio-

vascular morbidity and mortality. Additionally, nicotine released

while smoking is also believed to affect blood pressure through

the arousal of the sympathetic nervous system.10 Cigarette use

has been shown to cause a 4 mm Hg increase in SBP and a 3 mm

Hg increase in DBP compared with placebo.

Some data are available showing that vitamin C, omega-3

fatty acids, coenzyme Q10, magnesium, and calcium may reduce

blood pressure.7,10 Unfortunately, none of the data evaluating the

efficacy of these compounds for treating hypertension are from

well-designed randomized controlled trials. Therefore, these

agents should not be recommended for managing hypertension.

Pharmacologic therapies

Currently, 10 classes of antihypertensive therapies are avail-

able: diuretics, beta-blockers, angiotensin-converting enzyme

(ACE) inhibitors, angiotensin II receptor blockers (ARBs),

CCBs, alpha-1 blockers, alpha-2 agonists, peripheral adren-

ergic antagonists, direct arterial vasodilators, and a direct

renin inhibitor.1,2 Diuretics are further subdivided into thiaz-

ides, loops, potassium sparing, and aldosterone antagonists;

beta-blockers are subdivided into cardioselective, nonselective,

intrinsic sympathomimetic activity, and mixed alpha- and beta-

blockers; and CCBs are subdivided into dihydropyridines and

nondihydropyridines.1

JNC 7 recommends using thiazide-type diuretics as ini-

tial therapy for most patients without compelling indications

for other therapies.2 For stage 1 hypertension, monotherapy

with a thiazide-type diuretic is recommended. If patients can-

not tolerate thiazide-type diuretics or have a contraindication

to the class, they may be treated with an ACE inhibitor, ARB,

beta-blocker, CCB, or combination therapy. All of these agents

have been proven to reduce cardiovascular events. Patients with

more severe hypertension (stage 2) should be treated with a

two-drug combination regimen that contains a thiazide-type

diuretic and an ACE inhibitor, ARB, beta-blocker, or CCB. Most

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Table 5. Diet-related lifestyle modifications that

effectively lower blood pressure7

Dietary modification Recommendation

Reduced salt intake Lower salt (sodium intake) as much

as possible, ideally to 1.5 grams

sodium per day or 3.8 grams

sodium chloride per day.

DASH-type dietary

patterns

Consume a diet rich in fruits and

vegetables (8–10 servings/day),

rich in low-fat dairy products (2–3

servings/day), and reduced in

saturated fat and cholesterol.

Increased potassium

intake

Increase potassium intake to 4.7

grams per day.

Moderation of alcohol

intake

For those who drink alcohol, consume

no more than two alcoholic drinks

per day for men and no more than

one alcoholic drink for women.

Abbreviation used: DASH, Dietary Approaches to Stop Hypertension.


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patients will require two or more antihypertensive agents to

achieve blood pressure goals. JNC 7 also recommends that ini-

tiating two drugs should be considered when blood pressure

is greater than 20 mm Hg above SBP goal or 10 mm Hg above

DBP goal. After antihypertensive therapy is initiated, patients

should be evaluated at monthly intervals (or more frequently in

patients with stage 2 hypertension) until goal blood pressure is

achieved. Serum potassium and creatinine should be monitored

at least one to two times per year. Once blood pressure is at

goal and stable, follow-up visits usually can be at 3- to 6-month

intervals.

The recommendation for using thiazide-type diuretics as

initial therapy for most patients is based on results of the Anti-

hypertensive and Lipid-Lowering Treatment to Prevent Heart

Attack Trial (ALLHAT), which was a randomized, double-blind,

active-controlled, clinical trial conducted from February 1994

through March 2002.11 A total of 33,357 participants 55 years of

age or older with hypertension and at least one other cardiovas-

cular risk factor were randomly assigned to receive 12.5 to 25

mg chlorthalidone per day (n = 15,255), 2.5 to 10 mg amlodipine

per day (n = 9,048), or 10 to 40 mg lisinopril per day (n = 9,054).

The primary outcome was to compare the combined endpoint of

fatal coronary heart disease and nonfatal myocardial infarction,

and other outcomes (e.g., heart failure, stroke) were analyzed

as secondary endpoints. After a mean follow-up of 4.9 years, no

significant difference was seen with respect to the primary out-

come; however, chlorthalidone had statistically fewer secondary

endpoints compared with amlodipine and lisinopril. Compared

with chlorthalidone, amlodipine was associated with a higher

6-year rate of heart failure and lisinopril with higher 6-year

rates of combined cardiovascular disease, heart failure, and

stroke. The investigators concluded that thiazide-type diuret-

ics were superior in preventing one or more major form of car-

diovascular disease and less expensive than amlodipine and

lisinopril.

#OMPELLING�INDICATIONS

Patients with hypertension can also present with concurrent

comorbid conditions.2 Comorbidities such as heart failure, post–

myocardial infarction, high coronary disease risk, diabetes,

chronic kidney disease, and recurrent stroke require specific

antihypertensive therapy based on positive outcome data from

clinical trials (Table 6). Although five agents are listed for heart

failure, ACE inhibitors should be initiated as first-line therapy

based on numerous outcome trials showing a reduction in both

morbidity and mortality.1,2 Loop diuretics are often initiated as

part of first-line therapy to aid in symptomatic relief of heart

failure symptoms. Beta-blockers are generally added onto an

ACE inhibitor regimen after patients are stable. For patients

who have experienced a myocardial infarction, beta-blockers

are considered the first drugs of choice, combined with an ACE

inhibitor, because both have been shown to reduce additional

cardiovascular events. Beta-blockers are also considered first-

line agents in patients at high coronary disease risk.

Patients with diabetes and hypertension should be treated

with an ACE inhibitor or ARB because both agents are renal pro-

tective.1,2 Additionally, a multitude of data have shown that ACE

inhibitors reduce both cardiovascular risk and risk of progres-

sive renal dysfunction in patients with diabetes. Because they

have renal-protective effects, an ACE inhibitor or ARB should

also be given to patients with chronic kidney disease. Finally,

data have shown that combination therapy with an ACE inhibitor

and a thiazide-type diuretic reduced the incidence of recurrent

stroke in patients with a history of stroke or transient ischemic

attacks.

2EVIEW�OF�PRIMARY�ANTIHYPERTENSIVE�AGENTS

Thiazide-type diuretics, beta-blockers, ACE inhibitors, ARBs,

and CCBs are all considered primary antihypertensive agents

because they all have been proven to reduce cardiovascular

events and are recommended as first-line agents.1,2 A brief

review of thiazide-type diuretics, beta-blockers, ACE inhibitors,

and ARBs is summarized here, and an expanded review of CCBs

is presented in the next section.

4HIAZIDE TYPE�DIURETICS

As discussed above, thiazide-type diuretics are the preferred

agents for managing hypertension based on the results of ALL-

HAT.1,2,11 Diuretics exert their mechanism of action by initially

causing a diuresis that results in reduced plasma and stroke

volume.1 This leads to reduced cardiac output and blood pres-

sure. After chronic use, diuretics produce decreases in total

peripheral resistance. Thiazide-type diuretics are also believed

Table 6. High-risk conditions with compelling

indications2

Compelling indication Recommended drug therapy

Heart failure Diuretic, ACE inhibitor, beta-

blocker, ARB, aldosterone

antagonist

Post–myocardial

infarction

Beta-blocker, ACE inhibitor,

aldosterone antagonist

High coronary disease

risk

Beta-blocker, ACE inhibitor, CCB,

diuretic

Diabetes ACE inhibitor, ARB, diuretic,

beta-blocker, CCB

Chronic kidney disease ACE inhibitor, ARB

Recurrent stroke

prevention

Diuretic, ACE inhibitor

Abbreviations used: ACE, angiotensin-converting enzyme; ARB,

angiotensin II receptor blocker; CCB, calcium channel blocker.


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to cause direct relaxation of vascular smooth muscle. Thiaz-

ide-type diuretics are most effective in patients with adequate

renal function (glomerular filtration rate >30 mL/min) and are

extremely effective in lowering blood pressure when given in

combination with other antihypertensive agents (typically ACE

inhibitors or beta-blockers).

Current guidelines suggest limiting the dose of hydrochloro-

thiazide or chlorthalidone to 12.5 to 25 mg/day, because doses

greater than 25 mg may not offer any additional blood pres-

sure–lowering effects.1 In general, thiazide-type diuretics are

well tolerated at lower doses. Adverse events associated with

thiazide-type diuretics include hypokalemia, hypomagnesemia,

hypercalcemia, hyperuricemia, hyperglycemia, dyslipidemia,

and sexual dysfunction. Elevations in uric acid may precipitate

a gout attack, especially in patients with a previous history of

gout. Additionally, patients with diabetes should be counseled

to monitor their blood glucose levels closely after initiating a

thiazide-type diuretic.

Beta-blockers

Beta-blockers inhibit beta-1 receptors on the heart, leading to

negative chronotropic and inotropic effects and reductions in

cardiac output.1 They also reduce plasma renin levels by inhibit-

ing beta receptors located on surface membranes of juxtaglom-

erular cells. Beta-blockers are the drugs of choice following

myocardial infarction and for patients at high coronary disease

risk.2 Four types of beta-blockers are available: cardioselective,

nonselective, intrinsic sympathomimetic activity, and mixed

alpha- and beta-blockers.1 Cardioselective agents are more

specific for beta-1 receptors than beta-2 receptors; however,

most beta-blockers lose cardioselectivity at higher doses. Beta-

blockers with intrinsic sympathomimetic activity have beta-

agonist and -antagonist effects and are rarely used in clinical

practice. Adverse events associated with beta-blockers include

bradycardia, atrioventricular conduction abnormalities, sexual

dysfunction, dyslipidemia, and hyperglycemia. Beta-blockers

may also mask signs of hypoglycemia such as tachycardia.

Administration of beta-blockers to patients with a history of

asthma or chronic obstructive pulmonary disease may cause

acute exacerbations of bronchospasms because of blockade of

beta-2 receptors in the lung. Beta-blockers should not be used

in patients with heart block.

ACE inhibitors

ACE inhibitors block the conversion of angiotensin I to angio-

tensin II, a potent vasoconstrictor and stimulator of aldosterone

secretion.1 ACE inhibitors also cause vasodilation of the effer-

ent arteriole of the kidney, leading to a reduction in glomerular

pressure. ACE inhibitors should be used as first-line agents in

heart failure, following myocardial infarction, when high coro-

nary disease risk exists, in diabetes, in chronic kidney disease,

and for recurrent stroke prevention. Adverse events associated

with ACE inhibitors include cough, hyperkalemia, and angioe-

dema. Cough is attributed to an increase in bradykinin caused

by ACE inhibitors. Approximately 20% of patients will develop

a dry nonproductive cough that may necessitate switching to an

alternative antihypertensive agent. Patients with ACE inhibitor–

induced cough are generally switched to an ARB. Angioedema

is a serious adverse event that occurs in approximately 2% of

patients. It is more common in blacks and patients who smoke.

Angioedema is characterized by lip and laryngeal swelling and,

in some patients, difficulty breathing. ACE inhibitors should be

discontinued permanently in patients who experience angioe-

dema. ACE inhibitors should not be used in pregnant patients

or those with bilateral renal artery stenosis.

ARBs

ARBs directly block angiotensin II at the receptor.1 ARBs are

generally used as alternatives to ACE inhibitors. As with ACE

inhibitors, ARBs cause vasodilation of the efferent arteriole of

the kidney, leading to reduced glomerular pressure. ARBs do not

cause elevations in bradykinin; therefore, they are not associ-

ated with a dry cough. ARBs can also cause hyperkalemia and

angioedema; however, the incidence of angioedema with ARBs

is lower compared with ACE inhibitors. ARBs should also be

avoided in pregnant patients or those with bilateral renal artery

stenosis.

CCBs

CCBs are a heterogeneous group of drugs that can be classi-

fied into two groups: dihydropyridines and nondihydropyridines

(Table 7).1,2 CCBs can also be classified according to duration

of action, ranging from short-acting formulations to modified-

release once-daily formulations. They exert their mechanism

of action by inhibiting influx of calcium across membranes by

blocking L-type calcium channels. Dihydropyridines prefer-

entially bind to L-type calcium channels in vascular smooth

muscle, resulting in vasodilation, and nondihydropyridines exert

their mechanism of action primarily by preferentially binding to

L-type calcium channels in the myocardium at the sinoatrial and

atrioventricular nodes. Nondihydropyridines decrease heart

rate and slow atrioventricular nodal conduction, whereas dihy-

dropyridines cause a baroreceptor-mediated reflex tachycardia

because of their potent peripheral vasodilating effects.

All CCBs manage hypertension effectively.1 Dihydropyri-

dines are particularly effective at managing hypertension in

older adults with isolated systolic hypertension. Nondihydro-

pyridines are effective at managing tachyarrhythmias because

of their effects on heart rate and cardiac conduction.1 Addition-

ally, CCBs have been shown to be extremely effective at man-

aging hypertension in blacks. JNC 7 recommends that CCBs

can be used as an initial treatment option in patients who

cannot tolerate thiazide-type diuretics or have a contraindica-

tion to the class.2 JNC 7 also lists CCBs as a treatment option


review


for the compelling indications of high coronary disease risk and

diabetes. Based on historical data, short-acting CCBs (particu-

larly liquid nifidepine capsules) should never be used to manage

hypertension because of reports of increased risks of myocar-

dial infarction and mortality.12

Adverse events associated with dihydropyridines are pri-

marily related to their vasodilating properties and include dizzi-

ness, flushing, headache, and peripheral edema.1 These adverse

events are reduced with the use of slow-release and longer-

acting formulations. Because nondihydropyridines decrease

cardiac conduction, these agents can cause bradycardia and

atrioventricular block. Constipation is a frequent adverse event

associated with verapamil, occurring in approximately 7% of

patients.

)SOLATED�SYSTOLIC�HYPERTENSION��

IN�ELDERLY�PATIENTS�

Dihydropyridine CCBs are extremely effective at control-

ling blood pressure in older patients with isolated systolic

hypertension. Three large-scale trials have been conducted

to evaluate the efficacy of CCBs in treating isolated systolic

hypertension.13–15 These trials used CCBs that are not currently

approved in the United States but are similar to dihydropyri-

dine agents available here. The first large-scale outcome study

evaluating the efficacy of using a CCB as first-line treatment

of patients with isolated systolic hypertension was the Sys-

tolic Hypertension in Europe (Syst-Eur) trial.13 A total of 4,695

patients aged 60 years or older with SBP ranging from 160 to

219 mm Hg and DBP less than 95 mm Hg were randomized to

treatment with nitrendipine (a CCB similar to nisoldipine, isra-

dipine, felodipine, and nicardipine), given in combination with

enalapril and/or hydrochlorothiazide as needed, or to match-

ing placebos. After a median follow-up of 2 years, sitting SBP

and DBP had decreased by 23 and 7 mm Hg in the active treat-

ment group (n = 2,398) and by 13 and 2 mm Hg in the placebo

group (n = 2,297), respectively. Additionally, the total rate of

stroke was lowered by 42% and all fatal and nonfatal cardiac

endpoints, including sudden death, declined by 26%.

Systolic Hypertension in China (Syst-China) was another

large-scale outcome trial evaluating the efficacy of a CCB in

patients aged 60 years or older with isolated systolic hyperten-

sion.14 Patients with average SBP of 170.5 mm Hg and DBP of

86.0 mm Hg at baseline were assigned to treatment with nitren-

dipine, given in combination with enalapril and/or hydrochlo-

rothiazide as needed, or to matching placebos. After a median

follow-up of 2 years, sitting SBP and DBP had fallen by 20.0 and

5.0 mm Hg in the active treatment group (n = 1,253) and by 10.9

and 1.9 mm Hg in the placebo group (n = 1,141), respectively.

Additionally, active treatment reduced total strokes by 38%,

all-cause mortality by 39%, and all fatal and nonfatal cardio-

vascular endpoints by 37%.

More recently, results of the Systolic Hypertension in the

Elderly: Lacidipine Long-term (SHELL) trial were published.15

SHELL was an open-label trial with 1,882 patients aged 60

years or older with isolated systolic hypertension (SBP r160

mm Hg and DBP b95 mm Hg). Patients were randomized to

chlorthalidone or lacidipine (a long-acting CCB similar to amlo-

dipine), with the option of adding fosinopril for additional blood

pressure control. After a median follow-up of 32 months, sitting

SBP and DBP had fallen by 38.4 and 7.9 mm Hg in the lacidipine

group and 36.8 and 8.1 mm Hg in the chlorthalidone group,

respectively. Approximately 84.8% and 72% of patients were

on lacidipine and chlorthalidone monotherapy, respectively, at

follow-up. No difference was noted between the two groups with

respect to the primary endpoint of a composite of cardiovascu-

lar and cerebrovascular events.

Clinical trial data show that dihydropyridine CCBs are effec-

tive in managing older patients with isolated systolic hyperten-

sion.13–15 The 2007 guidelines for managing arterial hyperten-

sion published by the European Society of Hypertension and

European Society of Cardiology recommend CCBs and thiazide-

type diuretics as the drugs of choice for controlling isolated

systolic hypertension in elderly patents.16

JNC 7 recommends that treatment of hypertension in older

patients should be based on the general algorithm and individual

compelling indications.2 The guidelines also state that combina-

tion therapy is generally required in older patients to achieve

blood pressure goals. The results of Syst-Eur, Syst-China, and

SHELL support the use of a dihydropyridine CCB as part of a

combination regimen to manage older patients with isolated

systolic hypertension.

"LACKS

Hypertension is more prevalent in blacks and is associated with

a greater degree of cardiovascular morbidity and mortality.17

In general, numerous studies have shown that blacks respond

better to diuretics and CCBs than to beta-blockers and ACE

Table 7. Select calcium channel blockers approved

in the United States1

Dihydropyridines Amlodipine

Felodipine

Isradipine

Nifedipine long-acting

Nicardipine

Nisoldipine

Nondihydropyridines Diltiazema

Verapamila

aMultiple brand names available.


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inhibitors. The exact mechanisms behind these differences in

response to therapy are not fully understood; however, blacks

are believed to be more salt-sensitive and to have lower plasma

levels of renin and aldosterone compared with whites. Salt sen-

sitivity is characterized by retention of more sodium because

of a reduced ability to excrete sodium load. The RAAS in black

hypertensive patients is also believed to be suppressed in

response to sodium retention by the kidney. Because diuretics

cause an increase in urinary sodium excretion and free water

clearance, their effectiveness in blacks supports the salt-sensi-

tivity theory. CCBs have been shown to be effective in low-renin

hypertensive patients.

A systematic review of antihypertensive therapy in black

patients was conducted to compare the efficacy of different

agents in reducing blood pressure, morbidity, and mortality.18

A search of various databases, including Medline, EMBASE,

LILACS, African Index Medicus, and the Cochrane Library was

conducted from their inception through November 2003 to iden-

tify trials that evaluated different classes of antihypertensive

drugs in blacks. A total of 30 trials involving 53 interventions,

8 classes of antihypertensive drugs, and 20,006 black patients

were included in the review (26 blood pressure trials, 4 outcome

trials). The blood pressure trials included patients with baseline

SBP up to 225 mm Hg and DBP up to 155 mm Hg, and median

duration of treatment was 8 weeks. The review noted that the

efficacy of beta-blockers in reducing SBP and the efficacy of

ACE inhibitors in achieving DBP goals (b90 mm Hg or a reduc-

tion of 10%) did not differ statistically compared with placebo.

Other reviewed agents such as CCBs, diuretics, centrally act-

ing agents, alpha-blockers, and ARBs were more effective than

placebo in reducing both SBP and DBP. Approximately 46% of

those receiving CCBs, 31% receiving diuretics, 23% receiv-

ing centrally acting agents, 19% receiving beta-blockers, 19%

receiving ARBs, and 13% receiving alpha-blockers achieved

the DBP goal. The review also noted that only CCBs remained

effective in all prespecified subgroups, including patients with a

baseline DBP of 110 mm Hg or greater. Main morbidity and mor-

tality outcomes did not differ significantly between treatment

groups when drugs were combined to reach blood pressure

goals. The reviewers concluded that for many black patients,

CCBs might seem appropriate for first-line treatment, followed

by diuretics in patients who cannot afford CCB therapy.

A consensus statement of the Hypertension in African Amer-

icans Working Group of the International Society on Hyperten-

sion in Blacks was published in 2003 to provide clinicians an

evidence-based tool for managing hypertension in blacks.19

The guidelines differ from JNC 7 in that they recommend using

combination therapy as first-line therapy for patients with a

SBP of 15 mm Hg or more or a DBP of 10 mm Hg above target

blood pressure. The guidelines stress the importance of lifestyle

modifications. Because black patients are salt sensitive, limit-

ing sodium intake is key. Additionally, the guidelines state that

combination antihypertensive therapy will most likely be

required to control hypertension in blacks. The following

combinations are recommended: beta-blocker/diuretic, ACE

inhibitor/diuretic, ACE inhibitor/CCB, or ARB/diuretic. The

guidelines acknowledge that monotherapy with a beta-blocker,

ACE inhibitor, or ARB may not reduce blood pressure to goal;

however, addition of a low-dose second agent such as diuretic

or CCB will typically lower blood pressure sufficiently. Compel-

ling indications discussed in JNC 7 for ACE inhibitors, ARBs,

and beta-blockers should be applied equally to blacks, as these

agents have been shown to improve renal and/or cardiovascular

outcomes.

JNC 7 recommends basing hypertension treatment for black

patients on the general algorithm and individual compelling indi-

cations.2 Although the responsiveness to monotherapy with ACE

inhibitors, ARBs, and beta-blockers is less than the responsive-

ness to diuretics and CCBs, JNC 7 also agrees that these differ-

ences are generally corrected by combination therapy.

High coronary risk

Primary prevention of cardiovascular events with amlodipine

was shown to be equivalent compared with chlorthalidone and

lisinopril in ALLHAT.11 Additionally, primary protection with

verapamil-based therapy was shown to be similar to diuretic-

or beta-blocker–based therapy in CONVINCE (Controlled Onset

Verapamil Investigation of Cardiovascular End Points) and

INVEST (International Verapamil-Trandolapril Study).20,21

A scientific statement by AHA was released in 2007 on the

role of hypertension treatment in preventing and managing isch-

emic heart disease.22 AHA recommends that sufficient evidence

exists from comparative trials to support using an ACE inhibi-

tor, ARB, CCB, or thiazide-type diuretic as first-line agents for

primary prevention of cardiovascular disease in hypertensive

patients. Beta-blockers are recommended as first-line therapy

for managing stable angina and acute coronary syndromes.

AHA also recommends using nondihydropyridine CCBs

(verapamil, diltiazem) in patients with hypertension and stable

angina or in those with hypertension and acute coronary syn-

dromes if beta-blockers are contraindicated or produce intoler-

able adverse events.22 However, AHA recommends not using

nondihydropyridine CCBs in patients with left ventricular dys-

function. Additionally, if hypertension is not controlled after a

beta-blocker is added in patients with stable angina or acute

coronary syndromes, then a long-acting dihydropyridine CCB

may be added.

Diabetes

JNC 7 indicates that CCBs are a good treatment option to control

hypertension in patients with diabetes, particularly as part of a

combination regimen.2 Data from numerous trials have shown

that CCBs are as effective as other antihypertensive therapies

at reducing cardiovascular adverse events in patients with


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diabetes.23,24 An analysis of patients with diabetes (n = 13,101),

impaired fasting glucose (n = 1,399), and normal glucose levels

(n = 17,012) enrolled in ALLHAT was conducted to assess if

chlorthalidone, amlodipine, or lisinopril was more beneficial in

reducing the incidence of primary and secondary outcomes.23

The analysis showed that no difference existed in the combined

primary endpoint of fatal coronary heart disease and nonfatal

myocardial infarction in patients with diabetes or normal glu-

cose levels, who were assigned to amlodipine or lisinopril versus

chlorthalidone, or in patients with impaired fasting glucose, who

were assigned to lisinopril versus chlorthalidone. The authors

did note, however, that a significantly higher relative risk for

the primary outcome was seen in patients with impaired fast-

ing glucose assigned to amlodipine versus chlorthalidone, that

stroke was more common in patients with normal glucose lev-

els assigned to lisinopril versus chlorthalidone, and that heart

failure was more common in patients with diabetes and those

with normal glucose levels assigned to amlodipine or lisinopril

versus chlorthalidone.

An analysis by the Blood Pressure Lowering Treatment

Trialists’ Collaboration assessed the effects of different blood

pressure–lowering regimens on major cardiovascular events

in individuals with and without diabetes.24 A total of 27 ran-

domized trials involving 33,395 individuals with diabetes and

125,314 without diabetes were included in the analysis. The

reviewers noted that total cardiovascular events were reduced

to a comparable extent in individuals with and without diabetes

who were being treated with ACE inhibitors, CCBs, ARBs, and

diuretics/beta-blockers. The reviewers concluded that the data

suggest that clinicians may reasonably choose from a wide range

Table 8. Medication therapy management tips for hypertension12

N Educate the patient about hypertension and its

treatment.

N Articulate the goal of therapy to patients.

N Involve patients in the decision-making process.

N Educate patients on proper lifestyle modifications.

N Demonstrate the appropriate use of home blood pressure

monitors.

N Provide verbal and written instructions.

N Encourage family support.

N Maintain contact with patients.

N Schedule follow-up visits to assess blood pressure

control and adherence to prescribed regimens.

N Review home blood pressure readings and provide

feedback to patients and other providers.

N Contact patients who do not return for follow-up or to

refill prescriptions.

N Keep care inexpensive and simple.

N Use thiazide-type diuretics unless contraindicated or a

compelling indication is present.

N Use generic drugs if available.

N Use once-daily doses of long-acting drugs if possible.

N If appropriate, use combination tablets to reduce pill

burden and cost.

N Tailor medication regimens to daily routines.

N Anticipate adverse events.

N Educate patients on potential adverse events.

N Adjust therapy as needed to reduce adverse events.

Table 9. Select adverse events with antihyperten-sive therapy and management strategies1,12

Electrolyte abnormalities

N Hypokalemia (diuretics): Use the smallest dose of diuretic

needed and tell patients to increase dietary potassium

intake.

N Hyperkalemia (ACE inhibitors, ARBs): Counsel patients

to avoid potassium-containing salt substitutes (e.g., Mrs.

Dash).

Sexual dysfunction (diuretics, beta-blockers)

N Counsel patients to report any symptoms of sexual

dysfunction.

N Alterative therapy should be given, as sexual dysfunction

may lead to nonadherence.

Swelling of the lips (ACE inhibitors)

N Educate patients to contact their prescriber immediately, as

ACE inhibitor needs to be discontinued and changed to an

alternative agent. (Cross sensitivity has been reported with

ARBs.)

Chronic dry cough (ACE inhibitors)

N If cough is intolerable and affecting adherence to therapy,

patients should discuss this adverse event with their pre-

scriber.

N ARBs are generally given to patients with ACE inhibitor–

associated cough.

Metabolic abnormalities (diuretics, beta-blockers)

N Glucose abnormalities: Counsel patients to monitor their

blood glucose levels closely and to report any persistent

elevations to their prescriber immediately.

Dizziness/orthostatic hypotension

N Counsel patients to change positions slowly (from lying

down to sitting to standing) to decrease the likelihood of sud-

den decreases in blood pressure.

N If dizziness persists, blood pressure readings should be

reviewed, as a dosage reduction may be required.

Abbreviations used: ACE, angiotensin-converting enzyme; ARB,

angiotensin II receptor blocker.


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review

of antihypertensive agents to reduce blood pressure in patients

with diabetes. The reviewers also noted that the specific renal-

protective effects of various agents were not evaluated and that

these effects need to be kept in mind when selecting antihyper-

tensive therapy for patients with diabetes. Based on the data

presented above, CCBs appear to be a reasonable treatment

option for hypertension in patients with diabetes, especially as

part of a combination regimen.

Medication therapy management

Medication therapy management (MTM) services for hyper-

tensive patients should focus on a few key areas: educating

patients about hypertension and key lifestyle modifications,

discussing the importance of self-monitoring of blood pres-

sure and adherence to recommended antihypertensive thera-

pies, and providing information on potential adverse events

associated with antihypertensive therapies and how to man-

age these events (Tables 8 and 9). Recent 6-year results from

the Asheville Project showed that patients with hypertension

and/or dyslipidemia who received long-term MTM services

not only significantly increased use of their cardiovascular

medications but decreased cardiovascular events and related

medical costs.25

The importance of adherence can be emphasized by explain-

ing the complications associated with uncontrolled hyperten-

sion. Because it is a “silent disease,” many patients may not

think that they have hypertension or require therapy to control

their blood pressure. Teaching patients how to self-monitor

blood pressure and to keep a daily log will help them have a bet-

ter understanding of blood pressure control. Patients often seek

advice from the pharmacist to help them select a home blood

pressure monitoring kit. Pharmacists can help patients choose

the correct cuff size, as cuffs that are too small or large will lead

to inaccurate readings, and teach them how to take their blood

pressure accurately. Patients should be counseled to be seated

and relaxed for a few minutes before the reading and should be

shown the correct arm positioning (at heart level) during the

reading to ensure accuracy. Follow-up visits to assess blood

pressure control and adherence to prescribed regimens should

be scheduled. Home blood pressure monitoring logs should be

reviewed and feedback given to the patient and other members

of the health care team. Adherence to prescribed regimens may

also be increased by using once-daily doses of long-acting drugs

(if possible), using combination tablets to reduce pill burden and

cost, and tailoring medication regimens to the patient’s daily

routine.

Patients on antihypertensive therapy should be educated

on potential adverse events associated with therapy and how

to deal with these events if they occur (Table 9). Additionally,

patients should be educated on OTC products to avoid because

of the potential for these products to increase blood pressure

(Table 1).

What’s new with antihypertensive therapy?

Over the last year, FDA has approved two new antihyperten-

sive therapies, expanded indications for currently available

products, and approved a novel antihypertensive dosage form.

Aliskiren (Tekturna—Novartis), the first direct renin inhibitor,

was approved in March 2007 for the treatment of hypertension.

Aliskiren was shown to reduce blood pressure in more than

2,000 patients with mild to moderate hypertension with minimal

adverse events. More recently, Novartis announced that Tekturna

HCT (aliskiren and hydrochlorothiazide) received FDA approval.

Tekturna HCT is indicated for patients whose blood pressure is

not controlled on the individual components of the drug.

In December 2007, nebivolol (Bystolic—Forest), a beta-

1–selective adrenergic blocker, was also approved by FDA for

the treatment of hypertension. Nebivolol is distinct from other

beta-1 blockers in that it has additional vasodilating activity

mediated by the L-arginine–nitric oxide pathway. Pharmaco-

logic trials with nebivolol have shown that stimulation of this

pathway leads to decreased oxidative stress and may help pre-

serve endothelial function. Nebivolol also has a higher degree

of beta-1 selectivity compared with currently marketed beta-1

blockers; it is 3 to 10 times more cardioselective than both biso-

prolol and metoprolol.

Irbesartan/hydrochlorothiazide (Avalide—Bristol-Myers

Squibb) received approval by FDA for use as initial therapy

in patients who are likely to need multiple drugs to achieve

blood pressure goals. The drug was originally approved for use

in patients not adequately controlled with monotherapy. The

approval of this combination therapy as a first-line treatment

option to control blood pressure shows that combination ther-

apy is being used more regularly as initial therapy.

Although not the focus of this review, valsartan (Diovan—

Novartis) recently received FDA approval for pediatric hyper-

tension treatment in children aged 6 to 16 years. The approval

of valsartan for pediatric patients shows that manufacturers

recognize the importance of safely controlling hypertension

across all age groups. The revised labeling for valsartan also

includes a recipe for preparing an oral suspension (4 mg/mL)

for children who cannot swallow tablets or children for whom

the calculated dosage does not correspond to the available

strengths of valsartan.

In January 2008, Sciele announced FDA approval of a new

dosage formulation for nisoldipine (Sular). Using a “slow quick”

extended-release Geomatrix delivery system, the new Sular

tablets are composed of a combination of layers, each with dif-

ferent rates of swelling, gelling, and erosion. The outer coat

contains 80% of the total dose distributed in a hydrophobic gel–

forming polymer matrix, while the core has immediate-release

characteristics for the 20% of active ingredient that remains.

When the tablet comes into contact with water in the gastroin-

testinal (GI) tract, swelling and erosion of the coat allows the

drug to dissolve and be absorbed.


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review

The Geomatrix delivery system results in controlled release

of nisoldipine in two phases. Nisoldipine is initially released at

a constant rate into the proximal GI tract, followed by a quick

burst in the distal GI tract. This novel Geomatrix delivery sys-

tem provides sustained pharmacodynamic effects, resulting in

24-hour blood pressure reduction. Once-daily dosing of Sular

may encourage adherence to therapy. The new Sular tablets have

15% less nisoldipine per dose and are now available in strengths

of 8.5, 17, 25.5, and 34 mg. These new strengths correspond to

the older 10-, 20-, 30-, and 40-mg doses of Sular, respectively.

Clinical trials with Sular have shown that it reduces blood pres-

sure to a degree similar to that of ACE inhibitors, beta-blockers,

and other CCBs such as amlodipine and felodipine. The most

common adverse event with Sular is edema; however, it occurs

at a rate similar to that of other dihydropyridine CCBs.

Conclusion

Hypertension affects millions of Americans and is associated

with substantial morbidity and mortality. Current practice

guidelines advocate using lifestyle modifications along with

antihypertensive agents to control blood pressure. Data have

shown that CCBs are effective at managing hypertension. CCBs

are particularly effective for controlling hypertension in older

adults with isolated systolic hypertension and in blacks. Addi-

tionally, CCBs appear to be as effective in preventing cardiovas-

cular events as other primary therapies.

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14. Liu L, Wang JG, Gong L, et al. Comparison of active treatment and

placebo in older Chinese patients with isolated systolic hyperten-

sion: Systolic Hypertension in China (Syst-China) Collaborative

Group. J Hypertens. 1998;16:1823–9.

15. Malacco E, Mancia G, Rappelli A, et al. Treatment of isolated

systolic hypertension: the SHELL study results. Blood Press.

2003;12:160–7.

16. Mancia G, DeBacker G, Dominiczak A, et al. 2007 guidelines for

the management of arterial hypertension: the Task Force for the

Management of Arterial Hypertension of the European Society of

Hypertension (ESH) and of the European Society of Cardiology

(ESC). Eur Heart J. 2007;28:14625–36.

17. Lindhorst J, Alexander N, Blignaut J, et al. Differences in hyper-

tension between blacks and whites: an overview. Cardiovasc J

Afr. 2007;18:241–7.

18. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review:

antihypertensive drug therapy in black patients. Ann Intern Med.

2004;141:614–27.

19. Douglas JG, Bakris GL, Epstein M, et al. Management of high

blood pressure in African Americans: consensus statement of

the Hypertension in African Americans Working Group of the

International Society on Hypertension in Blacks. Arch Intern Med.

2003;163:525–41.

20. Black HR, Elliott WJ, Granditis G, et al. Principal results of the

Controlled Onset Verapamil Investigation of Cardiovascular End

Points (CONVINCE) trial. JAMA. 2003;289:2073–82.

21. Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al. A calcium

antagonist vs a non-calcium antagonist hypertension treatment

strategy for patients with coronary artery disease: the Interna-

tional Verapamil-Trandolapril Study (INVEST): a randomized

controlled trial. JAMA. 2003;290:2805–16.

22. Rosendorff C, Black HR, Cannon CP, et al. Treatment of hyperten-

sion in the prevention and management of ischemic heart dis-

ease: a scientific statement from the American Heart Association

Council for High Blood Pressure Research and the Councils on

Clinical Cardiology and Epidemiology and Prevention. Circulation.

2007;115:2761–88.

23. Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in

antihypertensive treatment of type 2 diabetes, impaired fasting

glucose concentration, and normoglycemia: Antihypertensive

and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALL-

HAT). Arch Intern Med. 2005;165:1401–9.

24. Turnbull F, Neal B, Algert C, et al. Effects of different blood

pressure-lowering regimens on major cardiovascular events in in-

dividuals with and without diabetes mellitus: results of prospec-

tively designed overviews of randomized trials. Arch Intern Med.

2005;165:1410–9.

25. Bunting BA, Smith BH, Sutherland SE. The Asheville Project:

clinical and economic outcomes of a community-based long-term

medication therapy management program for hypertension and

dyslipidemia. J Am Pharm Assoc. 2008;48:23–31.


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CE Credit:

To obtain 2.0 contact hours of continuing education credit (0.2 CEUs) for “Role of calcium channel blockers in treatment of

hypertension,” complete the assessment exercise, fill out the CE examination form at the end of this article, and return to

APhA. You can also go to www.pharmacist.com and take your test online for instant credit. CE processing for this program

is free for APhA members and nonmembers. A Statement of Credit will be awarded for a passing grade of 70% or better.

Pharmacists who complete this exercise successfully before April 1, 2011, can receive credit.

The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a

provider of continuing pharmacy education. The ACPE Universal Program Number assigned to the program by the

accredited provider is 202-000-08-110-H01-P.

“Role of calcium channel blockers in treatment of hypertension” is a home-study continuing education program for pharma-

cists developed by the American Pharmacists Association.

Assessment Questions

Instructions: You may take the assessment test for this program on paper or online. For each question, circle the letter on the

answer sheet corresponding to the answer you select as being the correct one. There is only one correct answer to each ques-

tion. Please review all your answers to be sure that you have circled the proper letters. To take the CE test for this article

online, go to www.pharmacist.com and click Education. To take the CE test for this article online, go to www.pharmacist.com/

education.cfm, and click Education. Once you are on the Education welcome page, look in the Online CE Quick List for the title.

Follow the online instructions to take and submit the assessment test. This CE will be available online at www.pharmacist.com

after April 30, 2008. You can also find it on www.pharmacytoday.org.

Assessment Questions

Questions 1 to 5 refer to the following case: P.T. is a

45-year-old white man with no major prior medical condi-

tion who was last seen in clinic 1 month ago. At that time,

his blood pressure was 144/94 mm Hg (average of two

readings). He was counseled on lifestyle modifications

and returns to clinic today for follow-up. His blood pres-

sure today is 152/90 mm Hg (average of two readings),

and his heart rate is 80 bpm.

1. How would you classify P.T.’s blood pressure today?

a. Normal

b. Prehypertensive

c. Stage 1

d. Stage 2

e. Stage 3

2. What is P.T.’s goal blood pressure?

a. <120/80 mm Hg

b. <130/80 mm Hg

c. <140/90 mm Hg

d. <160/100 mm Hg

e. <130/85 mm Hg

3. Which of the following is the most appropriate initial

therapy to manage P.T.’s hypertension?

a. Lisinopril

b. Atenolol

c. Amlodipine

d. Hydrochlorothiazide

e. Losartan

4. Based on JNC 7 recommendations, how many grams

per day should P.T. limit his sodium intake to?

a. 2.4

b. 1.5

c. 3.8

d. 8.0

e. 10.0


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One month later, P.T. returns to clinic for follow-up. His

blood pressure is 144/84 mm Hg, and his heart rate is 78

bpm. He complains of chest pain and shortness of breath

on exertion. He undergoes an exercise treadmill test, and

based on the results, he is diagnosed with chronic stable

angina.

5. Which of the following is most appropriate to manage

P.T.’s blood pressure at this time?

a. Add spironolactone

b. Add hydralazine

c. Add atenolol

d. Add candesartan

e. Add furosemide

6. K.T. is a 54-year-old Hispanic woman with a history

of type 2 diabetes treated with once-daily glyburide

5 mg who presents to clinic with a blood pressure of

138/90 mg Hg. Her blood pressure was 140/90 mm

Hg at her last visit 1 month ago. Labs today: serum

creatinine 2.0 mg/dL and potassium 4.0 mEq/L; uri-

nary analysis positive for microalbuminuria. All other

labs are within normal limits, and physical exam does

not yield any major findings. Which of the following is

most appropriate for managing her blood pressure?

a. Hydrochlorothiazide

b. Lisinopril

c. Atenolol

d. Methyldopa

e. Furosemide

Questions 7 and 8 refer to the following case: T.P. is a

54-year-old man who was recently diagnosed with hyper-

tension and heart failure with left ventricular systolic

dysfunction. Today in clinic, his blood pressure is 154/86

mm Hg, and his heart rate is 72 bpm. All labs are within

normal limits.

7. Which of the following drugs is most appropriate for

managing T.P.’s blood pressure?

a. Hydrochlorothiazide

b. Enalapril

c. Amlodipine

d. Diltiazem

e. Methyldopa

8. Which of the following antihypertensive drugs should

be avoided in T.P.?

a. Furosemide

b. Spironolactone

c. Metoprolol

d. Verapamil

e. Losartan

9. According to the American Heart Association and

American Stroke Association, approximately how

many Americans have hypertension?

a. 73 million

b. 50 million

c. 25 million

d. 33 million

e. 10 million

10. Which antihypertensive drug should be avoided in a

patient with bradycardia?

a. Atenolol

b. Candesartan

c. Lisinopril

d. Amlodipine

e. Furosemide

11. Which antihypertensive drug should be avoided in a

patient with a history of angioedema?

a. Verapamil

b. Enalapril

c. Furosemide

d. Clonidine

e. Hydrochlorothiazide

12. Which of the following OTC products is associated

with secondary hypertension?

a. Cetirizine

b. Guaifenesin

c. Loratadine

d. Acetaminophen

e. Ibuprofen

13. According to the U.S. Preventive Services Task Force,

at what age should adults be screened for hyperten-

sion?

a. 21 years old

b. 18 years old

c. 30 years old

d. 40 years old

e. 50 years old


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14. Which of the following best describes the pathophysi-

ology of primary hypertension?

a. Results from increases in cardiac output and/or total

peripheral resistance

b. Results from decreases in both cardiac output and

total peripheral resistance

c. Results from decreased activity of the renin–angio-

tensin–aldosterone system

d. Results from an underlying condition such as renal

disease

e. Results from an offending agent

15. Which of the following antihypertensive classes have

been shown to be effective in managing isolated sys-

tolic hypertension in the elderly?

a. Calcium channel blockers (CCBs)

b. Beta-blockers

c. Angiotensin-converting enzyme (ACE) inhibitors

d. Angiotensin II receptor blockers (ARBs)

e. Alpha-1 blockers

16. Which of the following antihypertensive combinations

is recommended by the Consensus Statement of the

Hypertension in African Americans Working Group of

the International Society on Hypertension in Blacks?

a. Beta-blocker/ACE inhibitor

b. Beta-blocker/ARB

c. ACE inhibitor/ARB

d. ACE inhibitor/CCB

e. CCB/diuretic

17. If a patient with chronic kidney disease experiences

a chronic dry cough with an ACE inhibitor, which anti-

hypertensive therapy should be given?

a. Amlodipine

b. Atenolol

c. Verapamil

d. Hydrochlorothiazide

e. Losartan

18. Which of the following antihypertensive combinations

is recommended for recurrent stroke prevention?

a. Beta-blocker/ACE inhibitor

b. Beta-blocker/ARB

c. ACE inhibitor/CCB

d. ACE inhibitor/diuretic

e. CCB/diuretic

19. Which of the following CCBs has been reformulated

using a Geomatrix delivery system?

a. Amlodipine

b. Nisoldipine

c. Nifedipine

d. Verapamil

e. Diltiazem

20. Which of the following is/are a major cardiovascular

risk factor?

a. Hypertension

b. Cigarette smoking

c. Obesity

d. Diabetes

e. All of the above alternatives are correct.


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1. a b c d e 6. a b c d e 11. a b c d e 16. a b c d e2. a b c d e 7. a b c d e 12. a b c d e 17. a b c d e3. a b c d e 8. a b c d e 13. a b c d e 18. a b c d e4. a b c d e 9. a b c d e 14. a b c d e 19. a b c d e5. a b c d e 10. a b c d e 15. a b c d e 20. a b c d e

CE EXAMINATION FORM

CE ASSESSMENT QUESTIONS—ANSWERS Please circle your answers (one answer per question).

To receive 2.0 contact hours of continuing education credit (0.2 CEU), please provide the following information:

1. Type or print your name and address in the spaces provided.

2. Mail this completed form for scoring to: American Pharmacists Association—CE Exam

P.O. Box 791082 Baltimore, MD 21279-1082

3. For this program, CE processing is free for APhA members and nonmembers.

A Statement of Credit will be awarded for a passing grade of 70% or better. If you fail the exam, you may retake it once. If you do not pass the second time, you may no longer participate in this continuing pharmacy education program. Please allow 6 weeks for processing. Pharmacists who complete this exercise success-fully before April 1, 2011, may receive credit.

The American Pharmacists Association is accredited by the Accredi- tation Council for Pharmacy Education as a provider of continuing pharmacy education. The ACPE Universal Program Number assigned to the program by the accredited provider is 202-000-08-110-H01-P.

PARTICIPANT INFORMATION

NAME

ADDRESS

CITY STATE ZIP

E-MAIL

WORK PHONE

HOME PHONE

How long did it take you to read the program and complete this test?

_____Hours ____ Minutes

My signature certifies that I have independently taken this CE examination:

EXCELLENT POOR

PLEASE RATE THE FOLLOWING ITEMS.1. Overall quality of the program 5 4 3 2 1

2. Relevance to pharmacy practice 5 4 3 2 1

3. Value of the content 5 4 3 2 1

PLEASE ANSWER EACH QUESTION, MARKING WHETHER YOU AGREE OR DISAGREE.4. The program met the stated learning objectives: Agree Disagree

After reading this CE article, the pharmacist should be able to:N Describe the epidemiology, etiology, and pathophysiology of hypertension. O O

N Name at least three risk factors, describe diagnostic criteria, and list classifications for hypertension. O O

N Formulate treatment plans, including drug and nondrug therapy, for various types of patients affected by hypertension. O O

N Describe the role of calcium channel blockers in the treatment of hypertension in patients at high coronary risk, patients with diabetes, elderly patients, and black patients. O O

N Name at least three drug therapy problems commonly encountered in antihypertensive therapy and indicate ways to prevent, resolve, or manage these problems. O O

N Describe progress in medical research in improving antihypertensive pharmacotherapy.5. The program increased my knowledge in the subject area. O O

6. The program did not promote a particular product or company. O O

IMPACT OF THE ACTIVITYThe information presented (check all that apply):

7. O Reinforced my current practice/treatment habits O Will improve my practice/patient outcomes

O Provided new ideas or information I expect to use O Adds to my knowledge

8. Will the information presented cause you to make any changes in your practice? O Yes O No

9. How committed are you to making these changes? (Very committed) 5 4 3 2 1 (Not at all committed)

10. Do you feel future activities on this subject matter are necessary and/or important to your practice? O Yes O No

PROGRAM EVALUATION

2OLE�OF�CALCIUM�CHANNEL�BLOCKERS�IN�TREATMENT�OF�HYPERTENSION

FOLLOW-UPAs part of our ongoing quality-improvement effort, we would like to be able to contact you in the event we conduct a follow-up survey to assess

the impact of our educational interventions on professional practice. Are you willing to participate in such a survey? O Yes O No

role of calcium channel blockers in treatment of...

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