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50 PHARMACY TODAY�s�APRIL 2008 www.pharmacytoday.org
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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«�`i���}Þ]ÊiÌ��}Þ]Ê>�`Ê«>Ì�«�ÞÃ��}ÞÊvÊ�Þ«iÀÌi�Ã��°
NÊ >�iÊ>ÌÊ�i>ÃÌÊÌ�ÀiiÊÀ�Ã�Êv>VÌÀÃ]Ê`iÃVÀ�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�`iÀ�ÞÊ«>Ì�i�ÌÃ]Ê>�`ÊL�>V�Ê«>Ì�i�Ìð
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�ð
NÊ �iÃVÀ�LiÊ«À}ÀiÃÃÊ��Ê�i`�V>�ÊÀiÃi>ÀV�Ê��Ê��«ÀÛ��}Ê>�Ì��Þ«iÀÌi�Ã�ÛiÊ«�>À�>VÌ�iÀ>«Þ°
Abstract
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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
review
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
52 PHARMACY TODAY�s�APRIL 2008 www.pharmacytoday.org
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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
review
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,
review
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
review
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
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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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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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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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recommendation statement. Ann Intern Med. 2007;147:783–6.
6. Liszka HA, Mainous AG, King DE, et al. Prehypertension and
cardiovascular morbidity. Ann Fam Med. 2005;3:294–9.
7. Appel LJ, Brands MW, Daniels SR, et al. Dietary approaches to
prevent and treat hypertension: a scientific statement from the
American Heart Association. Hypertension. 2006;47:296–308.
8. Neter JE, Stam BE, Kok FJ, et al. Influence of weight reduction on
blood pressure: a meta-analysis of randomized controlled trials.
Hypertension. 2003;42:878–84.
9. The Trials of Hypertension Prevention Collaborative Research
Group. Effects of weight loss and sodium reduction intervention
on blood pressure and hypertension incidence in overweight
people and high-normal blood pressure: the Trials of Hyperten-
sion Prevention, phase II. Arch Intern Med. 1997;157:657–67.
10. Wexler R, Aukerman G. Nonpharmacologic strategies for manag-
ing hypertension. Am Fam Physician. 2006;73:1953–6.
11. ALLHAT Officers and Coordinators for the ALLHAT Collabora-
tive Research Group. Major outcomes in high-risk hypertensive
patients randomized to angiotensin-converting enzyme inhibitor
or calcium channel blocker vs diuretic: the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).
JAMA. 2002;288:2981–97.
12. Kaplan NM. Systemic hypertension: therapy. In: Zipes DP, Libby
P, Bonow RO, et al. Braunwald’s heart disease: a textbook of
cardiovascular medicine. 7th ed. Philadelphia: Elsevier Saunders;
2005:989–1010.
13. Staessen JA, Fagard R, Thijs L, et al. Randomized double-blind
comparison of placebo and active treatment for older patients
with isolated systolic hypertension: the Systolic Hypertension in
Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–64
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
64 PHARMACY TODAY�s�APRIL 2008 www.pharmacytoday.org
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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
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