I I

Impact of Age, Race, and Obesity on

Hypertensive Mechanisms and Therapy
MATTHEW R. WEIR, M.D., Bdtimore, Maryland

Despite the demonstrated

tional antihypertensive
blood pressure, hypertension
efficacy of tradi-
therapy in reducing
continues to be a
H ypertension remains a major contributor to
cardiovascular disease morbidity and mortal-
ity in this country. However, recent advances in
major cause of cardiovascular disease morbid- our understanding of hypertension have brought
ity and mortality. Stepped-care therapy is a about significant changes in how clinicians evaluate
nonphysiologic ap@roaCh that, due to potential and treat hypertensive patients-changes aimed at
metabolic derangements and stimulation of reducing the toll exacted by the disease. Perhaps
undesirable reflex responses, .may not substan- the most innovative concept to be introduced has
tially reduce the cardiovascular and renal com- been of the heterogeneous nature of essential hy-
plications associated with hypertension or im- pertension. Several discrete hemodynamic mecha-
prove long-term survival in many hypertensive nisms, which vary between individuals largely ac-
patients. Because of fundamental hemody- cording to age, race, and weight, play causative
namic differences related to the age, race, and roles in hypertension. Recognition of this variety-
weight of hypertensive patients, drug .treat- along with the emergence of clinical evidence show-
ment often elicits varying responses. Certain ing that traditional antihypertensive therapy has
classes of drugs are not only more effective but not significantly prevented the serious sequelae of
also more appropriate from a physiologic hypertension [1,2]-has led to a re-analysis of ther-
standpoint in specific types of patients. Ther- apeutic approaches.
apy selection based in part on hemodynamic To control hypertension in a physiologic way, it is
mechanisms and demographic patterns is a essential to consider the varying hemodynamic
more rational approach to patient management mechanisms involved. Stepped care based on initial
and may contribute to a better overall outcome diuretic therapy in all patients regardless of the
than has been observed with conventional pathogenesis of the disorder or individual patient
treatment. profile is no longer recommended. A more individu-
alized approach that attempts to match patient/
disorder characteristics with the antihypertensive
activity of specific drugs is warranted. To help de-
velop such an approach, a review of the pathophysi-
ologic mechanisms of hypertension, corresponding
demographic features, and the clinical profiles of
the major antihypertensive drugs is provided.

From the Division of Nephrology and Clinical Research Unit, Department of
Medicine, University of Maryland Hospital, Baltimore, Maryland.
Requests for reprints should be addressed to Matthew R. Weir, M.D., Ne-
phrology Division, University of Maryland Hospital, 22 South Greene Street,
Baltimore, Maryland 21201.
HEMODYNAMICSOF HYPERTENSION
The basic hemodynamic determinants of blood
pressure (BP) are: BP = CO x TPR, with CO de-
noting cardiac output and TPR, total peripheral
resistance. The development of hypertension is
therefore related to a) increased CO, b) increased
TPR, or c) increased CO and TPR.
Several specific factors influence these mecha-
nisms, however, including vascular structural al-
terations, the renin-angiotensin-aldosterone sys-
tem, the sympathetic nervous system, and intracel-
lular accumulation of calcium, Because effective
antihypertensive therapy hinges on the identifica-
tion and regulation of these causative factors in in-
dividual patients, a basic understanding of the

May 17, 1991 The American Journal of Medicine Volume 90 (suppl 5A) 5A-3s
smP0B1im or4 CALCIUM ANTAGONISTS/WEIR
mechanisms involved is helpful when selecting an
appropriate therapeutic approach.
Vascular Alterations
Peripheral resistance is typically elevated by
abnormalities in vascular structure-specifically,
narrowing of the vasculature [3]. This narrowing is
partly related to enhanced smooth muscle constric-
tion, which in turn stems from a) increased sympa-
thetic activity [4-61; b) increased levels of hormonal
pressor agents [7-101; and/or c) structural altera:
tions within the vasculature [11,12], i.e., increased
arterial wall thickness and increased quantity of
smooth muscle [ 13,141. Although investigations are
currently under way to define the relative roles of
these factors, the further control of hypertension in
patients requires antihypertensive therapy that
regulates this vasoconstrictive element.
Renin-Angiotensih-Aldosterone (RAA) System
The potent vasoconstrictive hormone angiotensin
II is the product of a series of physiologic conver-
sions in the kidney and lungs -[15]:
renin -+ renin substrate -+
angiotensin I -+ angiotensin II
Angiotensin II increases peripheral resistance not
only by causing arterial vasoconstriction, but also
by elevating blood volume, through stimulation of
aldosterone, and by direct effects on the kidney,
leading to retention of both salt and water [15]. The
renal effects of angiotensin II are representative of
its localized effects at other tissue sites as well. It is
now known that angiotensin II affects local vascu-
lar control, e.g., in the kidney, liver, or brain [16]-
independent of its systemic effects on blood pres-
sure. Consequently, antihypertensive therapy
should either interrupt the effects of the RAA sys-
tem or at least avoid stimulation of the system in
order to reduce peripheral vascular resistance and
maintain organ perfusion physiologically. Angio-
tensin-converting enzyme (ACE) inhibitors and cal-
cium antagonists may decrease the activity of the
RAA system at the vascular level through different
effects. ACE inhibitors block the formation of angi-
otensin II from angiotensin I, while calcium antago-
nists decrease the sensitivity of the vasculature to
angiotensin II, probably through decreasing cyto-
solic calcium concentration.
Sympathetic Nervous System (SNS)
Both components of the BP equation-TPR and
CO-are negatively affected by SNS stimulation
via
l direct nervous excitation of blood vessels and
the heart 1151;
5A4S May 17, 1991 The American Journal of Medicine
l indirect excitation of blood vessels and the
heart due to the release of norepinephrine and epi-
nephrine into the circulating blood [15].
Certain antihypertensive drugs effectively dis-
rupt the direct SNS effects ((wor p blockers, or cen-
trally acting agents [17-211) or the indirect SNS
effects related to norepinephrine activity (calcium
antagonists [22]). Other agents such as diuretics,
however, can cause reflex increases in sympathetic
outflow through volume contraction, increasing the
vascular effect of norepinephrine despite apparent
decreases in BP.
Intracellular Calcium Influx
Calcium is perhaps one of the most important
ions controlling arteriolar tone [15]. Increased in-
tracellular calcium activates the contractile process
of smooth muscle and increases vascular reactivity
to vasoconstrictor substances [i5]. Conversely,
decreasing smooth muscle-free intracellular cal-
cium levels may be associated with relaxation of
smooth muscle in the arteriolar wall [15]. The exact
relation between the intracellular dynamics of cal-
cium and essential hypertension has not been well
defined, although several theories exist. Agents
such as calcium antagonists have been developed to
inhibit intracellular calcium influx [23], and thus
mediate a reduction in peripheral vascular resist-
ance via smooth muscle relaxation.
DEMOGRAPHICDETERMINANTSOF
HYPERTENSION
The underiying hemodynamic mechanisms of
hypertension vary among young/old, black/white,
and obese patients. Although the distinctions in the
hemodynamic profiles of these patient groups are
not clear-cut, recognition of proven pathophysiolo-
gic patterns may improve our ability to select an
appropriate antihypertensive agent that physiolog-
ically reduces BP, i.e., protects end-organ function
and patients quality of life.
Young Patients
Hypertensive patients under the age of 35 repre-
sent only a small portion of the estimated 58 million
people in the United States with diagnosed hyper-
tension [24] (defined as systolic pressure of 140 mm
Hg or greater and/or diastolic pressure of 90 mm
Hg or greater). Fewer than 3% of children in the
United States have arterial hypertension, accord-
ing to The Report of the Second Task Force on
Blood Pressure Control in Children-1987 [251.
The Joint National Committee estimated that over
5% of young persons aged 6 to 17 were hyperten-
sive, whereas 2% to 23% (depending on sex and
Volume 90 (suppl 5A)
 SYMPOSIUM ON CALCIUM ANTAGONISTS/ WEIR

race) of persons aged 18 to 34 had elevated BP TABLE I

(Table I) [26]. Prevalence of Hypertension* in the U.S. Adult Population,
As in all other patients, children and young 1976-1980, by Race, Sex, and Age
adults require repeated measurements to evaluate
the lability of their BP elevation, Proper equipment Age Group White Males (%) White Females (%)
and technique should be used, in a quiet, nonstress- 18-24 16.2 2.3
ful environment, to assure accurate readings. A 25-34 21.1 5.7
35-44 26.4 16.6
careful medical history, physical examination, and 45-54 42.6 36.3
laboratory workup are warranted in order to deter- 55-64 51.4 50.0
65-74 59.2 66.2
mine the underlying cause as well as any complica-
Black Males (%) Black Females (%)
tions of the hypertension. It is important, for exam- 18-24 10.9 9.6
ple, to detect cases of secondary hypertension so 25-34 23.2 15.3
35-44 44.2 37.0
that treatment of the actual physiologic fault can be 45-54 55.2 67.4
initiated. Secondary hypertension is most likely in 55-64
__ _. 66.3
__ 74.3_
_.
bb-I4 61.1 (12.9
very young patients with extreme elevations in BP 18-74 37.9 38.6
[24]. The majority of young hypertensive patients
*As defined by the Joint National Committee Ill; based on average of three BP measure-
have borderline or labile hypertension [27] that is ments as reported in NHANES II. Includes persons with BP of at least 140190 mm Hg on
a single occasion or those taking antihypertenwe medication. Adapted from Hypetten-
characterized by a) increased cardiac output-lo% Sian,64,,
to 20% above normal [27-291; b) normal peripheral
vascular resistance/plasma volume [30,31]; and c)
increased heart rate, renal blood flow, plasma renin TABLE II
activity, and norepinephrine levels [32,33]. Prevalence of Isolated Systolic
These pathophysiologic factors describe a profile Hypertension in Elderly Patients
of hyperdynamic circulation [34] or cardiogenic
hypertension [35]. Except in cases of severe hy- Agebs) Prevalence (%)
pertension, nonpharmacologic therapies, e.g.,
weight reduction, smoking cessation, and alcohol ii
18
and sodium restriction, should be introduced at the >90 25
outset [24]. If the patient is unresponsive to this Adapted from Controlled Clin Trials [37].
type of intervention, antihypertensive drug ther-
apy may be instituted. Agents that will correct the
cardiogenic abnormalities fueling the younger pa- greater and diastolic pressure less than 90 mm Hg
tients hypertension-i.e., that normalize elevated after four visits) continue to rise 1361. This age-
CO (e.g., /3 blockers, calcium antagonists), in- related increase in the prevalence of isolated sys-
creased plasma renin (e.g., ACE inhibitors), and tolic hypertension (Table II) has been documented
higher adrenergic activity (e.g., centrally acting in various other studies as well [37-401.
agents, a! blockers, and ACE inhibitors)-without Because BP tends to vary more in older patients
causing adverse effects that compromise compli- than in younger patients, confirmation of hyperten-
ance or impair normal growth and development are sion in older patients requires that the average BP
the most appropriate and effective means of reduc- on three consecutive visits be 160190 mm Hg or
ing arterial pressure in these patients. greater [26]. Recordings should be a) taken in both
sitting and standing positions during all visits, due
Middle-Aged and Older Patients to the high incidence of orthostatic hypotension in
The prevalence of hypertension clearly increases this population; and b) taken from both arms during
with age. Although hypertension affects roughly the initial visit, using the arm with higher pressure
one half of all middle-aged Americans (45 to 64 for subsequent recordings. Many experts also rec-
years old), approximately two-thirds of the esti- ommend use of Oslers maneuver in older patients
mated 29 million elderly (>65 years old) in this to help identify cases of pseudohypertension
country have BP higher than 140190 mm Hg (Table caused by increased arterial stiffness of the brachial
I) [25]. The incidence of hypertension rises to about arteries-thus avoiding unnecessary treatment.
75% for Americans aged 75 or older [26]. Despite the high incidence of hypertension in
While the prevalence of diastolic hypertension older patients, elevated BP is not a natural conse-
reaches a plateau at about age 60, systolic pressure quence of aging. Studies in animal models [41,42] as
and the prevalence of isolated systolic hypertension well as primitive societies [43] have demonstrated
(defined as systolic pressure of 160 mm Hg or that increasing age is not causally related to in-

May 17, 1991 The Amertcan Journal of Medicine Volume 90 (suppl 5A) 5A-5S
SYMPOSIUM ON CALCIUM ANTAGONISTS /WEIR
creased rates of hypertension. The phenomenon
therefore has been hypothetically related to the
salt- and fat-rich diet and sedentary lifestyle of in-
dustrialized societies.
The cause of hypertension in older patients is
unknown, however. Several etiologic factors have
been proposed [44], including:
l vascular changes (i.e., loss of elasticity of the
aorta and other large vessels);
l alterations in the RAA system (i.e., decreased
plasma renin);
l impairment of baroreceptor sensitivity;
l alterations in the SNS (i.e., reduced respon-
siveness to adrenergic stimulation);
l changes in renal structure/function (i.e., re-
duced renal mass and blood flow, declining glomer-
ular function).
The hemodynamic profile of the older patient
contrasts significantly with that of the younger pa-
tient. Hypertension in the elderly is typically ac-
companied by:
l increased peripheral vascular resistance
l decreased CO and heart rate
l contracted intravascular volume
l increased salt sensitivity and decreased plasma
renin activity and baroreceptor sensitivity [45-511.
With increasing age and prolonged high after-
load, the left ventricle tends to hypertrophy
[52,53], which has been associated with increased
ventricular ectopy and increased risk of myocardial
infarction and sudden death [54-561. There is also a
related decline in renal perfusion, which may be
associated with higher intraglomerular pressures.
This alteration in renal hemodynamics occurs more
commonly in hypertensive patients, or patients
with renal disease, potentially leading to nephro-
sclerosis and a decline in renal function [57]. Sev-
eral recent clinical trials [58-611 have documented
that older hypertensive patients clearly benefit
from antihypertensive therapy via a reduction in
cardiovascular morbidity and mortality. The longer
essential hypertension is left untreated, the greater
the risk of damage to major organs such as the
brain, heart, and kidneys [45].
Elevated systolic pressure is also closely corre-
lated with increased prevalence of cardiovascular
disease. According to the results of the Framing-
ham cohort [62], patients with isolated systolic hy-
pertension exhibited a two-to-seven times greater
risk than controls. Although it is uncertain whether
the treatment of isolated systolic hypertension in
older patients reduces this risk, at least one recent
trial [63] has documented the benefit of antihyper-
tensive therapy in the elderly, establishing the goal
of lowering both systolic and diastolic BP to the
extent tolerated in this population.
5A-6S May 17, 1991 The American Journal of Medicine
-
Because hypertension in older patients is charac-
terized by low CO, high TPR, and target organ dis-
ease, antihypertensive agents that improve CO,
lower resistance, and improve organ perfusion
would be preferred from both a physiologic and
side-effect standpoint. Monotherapy with vasodila-
tor agents such as calcium antagonists, ACE inhibi-
tors, or (Y blockers is considered more likely to fit
this profile than the traditional therapies-
diuretics or beta blockers. Older patients exhibit
reduced hepatic and/or renal excretion of many an-
tihypertensive drugs and may be more sensitive to
volume depletion and sympathetic inhibition than
younger patients. Consequently, antihypertensive
drugs should be initiated in smaller than usual
doses, with small increases made gradually as
needed. Given the higher prevalence of orthostatic
hypotension in elderly patients, drugs known to
produce this effect, e.g., guanethidine, should be
used carefully or avoided.
Black Patients
Hypertension in the black population is more
prevalent (Table I) and severe, has an earlier onset
and worse prognosis, and exhibits a slightly distinct
hemodynamic pattern compared with nonblack pop-
ulations [26,64-U]. Due to the greater prevalence
and severity of hypertension in these patients,
blacks experience a disproportionately higher rate
of cardiovascular disease as well [72].
A definitive explanation of black/white differ-
ences in the prevalence and severity of hyperten-
sion has not been formulated. Although genetic fac-
tors and psychosocial stresses may affect these dif-
ferences, other factors such as socioeconomic prob-
lems-i.e., the relatively low distribution of health
care professionals in the black community and rela-
tively high cost of treatment compared with income
levels-are believed to be the major contributors to
the high rate of undetected, untreated, and uncon-
trolled hypertension among blacks [73,74].
The hemodynamic profile of the black hyperten-
sive-regardless of age-is characterized by [75]:
l increased TPR
l potentially decreased CO
l increased salt sensitivity and decreased renin
production
l euvolemia or expanded plasma volume.
With the exception of potentially expanded plasma
volume [76,77], hypertension in blacks is similar to
that in older whites. In addition to high TPR and a
tendency toward decreased CO, these populations
share a tendency for increased target organ dam-
age. A higher incidence of renal vascular resistance
and renal insufficiency has been detected in black
populations [69], as well as an increased risk for left
Volume 90 (suppl 5A)

ventricular hypertrophy [78]. With the recognition
of the high incidence and greater severity of hyper-
tension in black patients and the considerable po-
tential for reducing hypertension-related morbidity
and mortality in this population, efforts to control
the disease in blacks have steadily been escalated.
Given the pathophysiologic differences between the
patient subgroups, it is not surprising that drugs
that are effective for the young, salt-insensitive,
high-renin, nonblack patient will not always be ef-
fective for the salt-sensitive, low-renin, black pa-
tient. For example, black hypertensives are typi-
cally less responsive to p blockers than their white
counterparts [24].
Because of the earlier onset of hypertension and
the higher incidence of cardiovascular disease in
blacks, special care should be taken to select anti-
hypertensive agents that reduce BP in a physiolo-
gic way that is directed to the hemodynamics of
their disorder. In all hypertensives, but particu-
larly in black patients characterized by markedly
elevated vascular resistance and increased risk for
cardiovascular disease, the ideal antihypertensive
agent needs to lower BP and TPR while maintain-
ing organ perfusion and function. The drug should
reduce afterload (to improve decreased CO and
expand myocardial reserves), cause a regression of
left ventricular hypertrophy, and reduce intrarenal
pressures. Antihypertensive therapy with calcium
antagonists as monotherapy, or low-dose diuretics
alone or with ACE inhibitors or 01blockers, perhaps
comes closest to filling these requirements.
ObesePatients
The relationship between obesity and hyperten-
sion has been established in a variety of racial and
social groups. The prevalence of hypertension in
obese patients is not clear, however. In the most
obese group of the Framingham population, 46%
reportedly were hypertensive. Evidence suggests
that the incidence may vary with sex, race, and age
of obese patients. Although the pathogenesis of
obesity-related hypertension has not been deter-
mined, dietary salt and hemodynamic and neuroen-
docrine factors are all suspected mechanisms [79].
The increase in body mass of the obese patient
requires both an increase in intravascular volume
and an increase in CO to meet metabolic require-
ments. Because of the heightened CO, TPR tends
to be lower for any given BP level compared with
nonobese hypertensives [80]. The hemodynamic
profile of the obese hypertensive patient therefore
is described by a unique combination of factors [80-
821:
l high CO
l expanded plasma volume
May 17, 1991
SYMPOSIUM ON CALCIUM ANTAGONISTS i WEIR
l increased salt sensitivity and decreased renin
activity
l normal to decreased peripheral vascular resist-
ance
l elevated SNS activity.
Although reduced TPR in obese patients may
protect against target organ damage, the increased
preload stemming from excessive body weight and
the increased afterload resulting from hypertension
create a heavy burden on the left ventricle. The
consequence is an increased incidence of left ven-
tricular dysfunction and premature congestive
heart failure in obese patients [45].
From a physiologic standpoint, antihypertensive
therapy in the obese patient may target either the
cardiogenic, volume-dependent, or adrenergic as-
pects of their hemodynamic profile. Any of the
major classes of antihypertensive agents may be
effective, although those that are known to reduce
left ventricular hypertrophy may be preferred.
INDIVIDUALIZEDTHERAPEUTICAPPROACH
Physicians have become increasingly aware of
the pathophysiologic differences of hypertension
among the various demographic populations. This
improved understanding of the hemodynamics of
hypertension has led to a corresponding revision in
therapeutic strategy. Specifically, attempts are
now made to select antihypertensive treatment
that is directed not only toward lowering arterial
pressure but also, most significantly, toward cor-
recting the underlying pathogenic mechanism as
well. In the long term, such a physiologic approach
should beneficially affect cardiovascular morbidity
and mortality, and in the short term, it should re-
duce adverse effects and improve patients quality
of life and compliance with their treatment regi-
men.
Recent clinical and experimental evidence has
demonstrated that the traditional stepped-care
approach may in fact be iout of step with the het-
erogeneous nature of hypertension. Investigators
have shown that stepped-care therapy may not re-
duce the death rate from cardiovascular disease to
as significant an extent as would be predicted by its
BP-lowering effects [l]. The most likely explana-
tion lies in the unphysiologic antihypertensive
action and potential long-term metabolic complica-
tions associated with first- and second-step agents,
i.e., diuretics and p blockers.
The major classes of antihypertensive drugs-as
recommended by the recent report of the Joint Na-
tional Committee [24]-have different effects on
the basic pathophysiologic components of hyperten-
sion and have elicited varying responses from the
The American Journal of Medicine Volume 90 (suppl 5A) 5A-7s
SYMPOSIUM ON CALCIUM ANTAGONISTS /WEIR

I BLACK
PATIENTS
OBESE
PATIENTS
YOUNG
ADULTS
OLDER
PATIENTS I

l &CO l 7 CO/ ? preload l tco l Ice

l tTPR l t plasma volume l Normal TPR l ?TPR

Pathophysiologic
Findings l 1 plasma volume, l J renin activity, l 1 RAA system/ l 1 plasma volume
renin activity, salt sensitivity adrenergic activity
salt sensitivity l 1 renin, adrenergic
l Normal/ .!. plasma activity,,salt
l lTPR
l ? LVH/ J renal volume sensitivity
blood flow l 7 SNS activity
l 7 LVH/ 4 renal
blood flow

Calcium Low-dose diuretic Beta blockers Calcium

antagonists antagonists
l 1 afterload & preload l Potent negative ino-
Appropriate . J afterload chronotropic elf ects J afterload
l natriuretic efl ects l
Antihypertensive Rx/ physiologic
l l physiologic
Pharmacologic vascdilatron vasodilation
Beta blockers ACE inhibitors
Effects l LVH regression
l .J renin activity l LVH regression/
l f renal blood flow l ICO
t renal blood flow
l 1 SNS activity
Low-dose diuretic Vasodilators
with ACE inhibitor, b,zCE;;hibitor, alpha
alpha blocker or
antiadrenergic l Mild negative ino- antiadrinergic) with
chronotropic effects low-dose diuretic (if
l 3. afterload necessary)
l LTPR l 1 TPR w/out reflex . 1 TPR w/out reflex
7 CO 8 t SNS activity ? CO & ? SNS activity l 1 afterload
l natriuretic effects
l maintain organ l &TPR
perfusion l maintain organ
perfusion

Figure 1. Physiologic components of hypertension by demographic subgroup and recommended antihypertensive therapy

patient populations presented (Figure 1). Although nant antihypertensive effect remains the reduction
these effects are not the sole consideration involved of peripheral vascular resistance. Subsequently
in selecting appropriate antihypertensive therapy- developed calcium antagonists-the dihydropyri-
factors such as concomitant medical conditions and dines, including nifedipine and nicardipine-are
patient personality and lifestyle must also be recog- potent vasodilators that cause substantial reduc-
nized-they represent an essential basis for more tions in TPR.
rational therapeutic decisions. This physiologic relaxation of resistance vessels
does not cause reflex stimulation of the SNS and
CALCIUMANTAGONISTS RAA systems, as is seen with nonspecific vasodila-
By blocking the transport of calcium across cell tors and diuretics [84]. Studies suggest that calcium
membranes, all calcium antagonists reduce the con- antagonists may protect the vasculature from the
traction and the tone of cardiac and vascular smooth muscle mitogenic effects of angiotensin II
smooth muscle and thereby decrease peripheral and norepinephrine [%I.
vascular resistance and BP [83]. To some extent, Data from Messerli et al show that calcium antag-
they are a pharmacologically heterogeneous group onists lower arterial pressure by lowering TPR
of compounds, however. The first generation of while maintaining or even increasing renal blood
agents, i.e., verapamil and diltiazem, have inhibi- flow [86,87]. Recent clinical studies conducted by
tory effects on the vasculature and heart, lowering Bakris [88,89] have demonstrated that the calcium
both TPR and CO. The negative inotropic effects of antagonists verapamil and diltiazem reduce urinary
these agents are mild, however, and their predomi- protein excretion in diabetic men, which may be

5A-as May 17, 1991 The American Journal of Medicine Volume 90 (suppl 5A)

Figure 2. Comparative response to treatment
with a p blocker (50-100 mg atenolol qd), ACE
inhibitor (25-50 mg captopril bid), and calcium
antagonist (240-360 mg verapamll SR qd) in
black hypertensives with baseline mean supine
systolic/diastolic blood pressure of 152.01100.5
mm Hg, Mean changes in supine diastolic and
systolic blood pressure from baseline.
particularly significant in patients who have, or are
at risk of developing, kidney impairment. Messerli
et al [90] also found that these agents reduce left
ventricular mass and the prevalence and severity of
ventricular dysrhythmias-thereby potentially
diminishing the risk of sudden death associated
with left ventricular hypertrophy. Due to their
physiologic and multifaceted mechanisms of action,
calcium antagonists have demonstrated efficacy in
many subsets of patients with hypertension. Al-
though few age-specific studies have been con-
ducted in young hypertensive patients, certain cal-
cium antagonists such as verapamil have been
shown to lower BP in this population [91,92]. In a
recent open multicenter trial [92], verapamil re-
duced BP in over 80% of young patients (~45 years)
with mild to moderate hypertension. Because hy-
pertension in young patients is typically character-
ized by elevated CO, use of the non-dihydropyri-
dine calcium antagonists may be more appropriate,
given their specific cardioinhibitory effects.
A generally excellent response of elderly hyper-
tensive patients to calcium antagonists has been
uniformly observed [93-961. As the antihyperten-
sive effect of the calcium antagonists does not de-
pend on the activity of the RAA system and is fo-
cused on normalizing TPR, they are very useful in
the elderly, who tend to have lower renin levels and
high peripheral resistance. Calcium antagonists are
also preferred in elderly populations-charac-
terized by target organ disease-because of their
potential beneficial effects on the left ventricle and
the renal vasculature. Calcium antagonists appear
equally well suited from a physiologic standpoint to
the black hypertensive with low renin production,
salt sensitivity, high peripheral and renal vascular
resistance, and low CO. Trials have shown, in fact,
May 17, 1991
SYMPOSIUM ON CALCIUM ANTAGONISTS/WEIR
Mean Changes in Blood Pressure
Atenolol Captopril Verapamil SF?
(N = 109) (N = 98) (N = 100)
q Supine diastolic
0 Supine systolic
that these agents are clearly effective in blacks [97-
1011.
In the largest study of its kind, a recent multicen-
ter trial [loll in over 300 hypertensive black pa-
tients compared the efficacy, safety, and quality of
life associated with therapy with a /3 blocker, an
ACE inhibitor, and a calcium antagonist-atenolol,
captopril, and verapamil sustained release (SR),
respectively. Patients were randomized to one of
the three agents and to either a low dose/low dose
or a low doseihigh dose sequence of administration.
No significant differences existed in patient demo-
graphics between treatment groups.
Consistent with the differences in antihyperten-
sive mechanism of action and pathophysiology, pa-
tients taking the calcium antagonist verapamil SR
showed a significantly greater reduction in supine
diastolic and systolic blood pressure than patients
treated with the /3 blocker or ACE inhibitor (Fig-
ure 2) in all treatment periods during the study. A
significantly greater proportion of patients re-
sponded to therapy with the calcium antagonist at
both low and high doses (Table III). The incidence
of side effects observed was minimal and compara-
ble for all three drugs. This studys results suggest
that use of the calcium antagonist verapamil SR as
monotherapy is more effective than, and as safe as,
the p blocker atenolol, or the ACE inhibitor capto-
pril, and should be considered an attractive option
for first-line therapy in treating black patients with
mild to moderate hypertension [loll.
The effects of these antihypertensive medica-
tions on quality-of-life measures in this black hyper-
tensive population were analyzed in a separately
published report [102]. The researchers determined
that all three medications-+ blocker, ACE inhibi-
tor, and calcium antagonist-either improved or
The American Journal of Medicine Volume 90 (suppl 5A) 5A-9S
 SYMPOSIUM ON CALCIUM ANTAGONISTS I WEIR
TABLE III
Comparative Response to Antihypertensive
Black Hypertensives
Successful response*
(% patients)
Treatment Phase Atenolol Captopril
Initial
(low doset) 55.1 43.8
Maintenance/titration
(low doset and
high dose+) 59.6 57.1
Maintenance/titration
(high doset only) 58.9 61.7
I
*supine diastolic blood pressure <90 mm Hg and/or reduction of >lO mm Hg
tatenolol, 50 mg every AM;captopril, 25 mg every 12 hrs; verapamil, 240 mg every AM
tatenolol, 100 mg every AM; captopril, 50 mg every 12 hrs; verapamil, 240 mg every
.4~+120 mg every PM.Adapted from Arch Intern Med [98].
caused no change in treated patients total quality-
of-life scale scores over the 8-week study period.
No significant differences were observed in patient
response to the p blocker, ACE inhibitor, or cal-
cium antagonist in terms of quality of life. The rate
of withdrawal from treatment due to adverse ef-
fects was low and similar in all three treatment
groups, regardless of titration level and patient
age.
Unlike the older generation of antihypertensive
drugs, which produced frequent and potentially
severe adverse reactions in many patients, these
agents were shown to lower blood pressure without
compromising quality of life in the black hyperten-
sive patients studied. While further study is re-
quired to document the consequences of such a
therapeutic improvement, we can assume that the
low rate of withdrawal and preserved quality of life
reported in this trial will have a beneficial impact on
patient compliance. As in the elderly, a final impor-
tant advantage of the calcium antagonists in black
hypertensives is their potential renal and cardio-
protective effects. Because they are at increased
risk of end-organ damage, black hypertensives may
gain particular benefit from the protection provided
by this class of agents.
Although several reports have suggested that
calcium antagonists are more efficacious in low-
renin hypertensive populations [103,104], this find-
ing remains controversial. Numerous published
studies comparing the responsiveness of younger
vs. older and black vs. white patients to calcium
antagonists have failed to document a significant
difference [97,105-1111. Because of their low
plasma renin activity, obese patients may also be
responsive to calcium antagonists. However, there
are few studies of antihypertensive efficacy in this
population, Although diuretics may be an impor-
tant treatment choice, given their dual effect of
diminishing ventricular afterload and extracellular
volume [45], calcium antagonists may be more ap-
5A-10s May 17, 1991 The American Journal of Medicine
propriate for obese patients with left ventricular
hypertrophy. Side effects with calcium antagonists
Treatment in
exist, but are generally mild and infrequently limit
their usefulness in these patient subgroups. These
effects differ among individual calcium antagonists:
headache, dizziness, flushing, and peripheral
Verapamil SR edema are most common with the dihydropyridine
agents, and gastrointestinal complaints are most
65.2 notable with verapamil and diltiazem. The mild car-
diodepressant effects of verapamil and diltiazem
73.0 may prohibit their use in patients with advanced
83.3 left ventricular or atrioventricular nodal dysfunc-
tion, but these effects are commonly offset by their
ability to reduce afterload and improve diastolic
compliance and overall left ventricular function.
ACE INHIBITORS
The BP-lowering effect of ACE inhibitors is prin-
cipally due to the prevention of angiotensin II for-
mation and related vasoconstriction and thus the
reduction of TPR. These agents appear to block the
formation of this peptide not only in the peripheral
circulation but also at the tissue level [112].
Like calcium antagonists, ACE inhibitors may
improve perfusion to the kidneys and cause regres-
sion of left ventricular hypertrophy [113,114]. They
are particularly beneficial in reducing many of the
major cardiovascular complications of hyperten-
sion, including congestive heart failure [115]. They
have also been demonstrated to reduce urinary pro-
tein excretion, which may be helpful in reducing
glomerulosclerosis [ 1161.
Although ACE inhibitors normalize blood pres-
sure in a substantial proportion of all hypertensive
patients [117-1191, studies have suggested that
these agents may exhibit less efficacy as monother-
apy in low-renin, salt-sensitive hypertensives, e.g.,
the older patient and blacks [103,119-1211. ACE
inhibitors may be most effective in the older pa-
tients and black patients if combined with thiazide
diuretics. Combination ACE/diuretic therapy may
dilute some of the formers advantages, however,-in
reducing cardiovascular consequences of hyperten-
sion in these high-risk patients. ACE inhibitors
appear to have limited adverse effects and promote
a good quality of life compared with traditional
therapies [122]. Caution must be used when treat-
ing patients with reduced effective arterial blood
volume to the kidney, e.g., renal artery stenosis,
because treatment with ACE inhibitors may lead to
functional insufficiency if excessive diuresis takes
place.
DIURETICS
By causing a prompt diuresis and natriuresis that
results in contraction of the extracellular fluid vol-
ume, diuretics effectively lower BP in many hyper-
Valume 90 (suppl 5A)

tensive patients. Although the initial antihyperten-
sive effect of these agents stems from the loss of
plasma volume and related reduction in CO, their
long-term effects are associated with a combined
effect of mild reduction of plasma volume and de-
creased peripheral vascular resistance.
Diuretics are effective in approximately 50% to
60% of hypertensives and may enhance the BP-
lowering effects of other major classes of antihyper-
tensive drugs. Although diuretics are particularly
effective in the elderly [63]-most likely because of
their low-renin activity and salt sensitivity-from a tients with cardiogenic hypertension, i.e., younger
physiologic standpoint they may not be the most
appropriate antihypertensive choice in this patient
subgroup. If diuretics cause excessive volume con-
traction in this already volume-depleted popula-
tion, they can potentially increase peripheral vascu-
lar resistance through activation of the RAA axis or
the SNS and further reduce perfusion to target or-
gans. For example, despite their reduction of sys-
temic BP, diuretics have been shown experimen-
tally to cause vasoconstriction of the efferent arte-
riole and thus maintain high glomerular capillary
pressures, which may contribute to renal dysfunc-
tion and nephrosclerosis [113].
Black patients have been shown to be very re-
sponsive to diuretic therapy [26]. Physiologically,
the use of diuretics makes more sense in the black
hypertensive who tends to be volume-expanded
with increased vascular resistance. However, the
hazards of excessive volume contraction-
potentially increased peripheral vascular resistance
and reduced organ perfusion-threaten this popu-
lation as well.
Knowledge of the adverse metabolic effects of
diuretics-e.g., hypokalemia, hyperuricemia, car-
bohydrate intolerance, and hyperlipidemia-has
also led to more cautious use of these agents, par-
ticularly in the groups most responsive to their an-
tihypertensive effects. Diuretic-induced hypokale-
mia may exacerbate arrhythmias, especially in pa-
tients with underlying left ventricular hypertro-
phy, and diuretic use has not been associated with
the regression of left ventricular hypertrophy [go].
An increase in cardiac mortality with long-term
diuretic treatment has been suspected in certain
patient populations despite BP control, as a result
of cardiac arrhythmias from diuretic-induced hypo-
kalemia [1,2].
To avoid these damaging metabolic and counter-
regulatory effects, when diuretic therapy is se-
lected-either as monotherapy or adjunctive
therapy-low doses (6.25 mgld or 12.5 mgld) are
recommended.
BETA BLOCKERS
Beta-adrenergic receptor blocking agents are
May 17, 1991
SYMPOSIUM ON CALCIUM ANTAGONISTS/WEIR
believed to reduce BP by blocking a) sympathetic
effects on the heart (decreasing heart rate and CO);
and b) adrenergic nerve-mediated release of renin
from the juxtaglomerular cells (decreasing periph-
eral vascular resistance). In addition to their BP-
lowering effects, p blockers can cause regression of
left ventricular hypertrophy, offer cardioprotection
after myocardial infarction, and reduce angina [122-
1261.
Because they reduce BP primarily by reducing
CO, p blockers have proven most effective in pa-
or obese patients. A substantial amount of informa-
tion has indicated that young patients respond very
well to p-blocker therapy, whereas elderly and
black hypertensives display a less favorable re-
sponse [2,102,103,127]. This lack of responsiveness
in blacks and the elderly may be attributed to the
tendency of these patients to have low renin activ-
ity (hence the antirenin mechanism of p blockers is
ineffective) and low CO (further reductions in CO
will not improve BP).
Regardless of their waning efficacy in elderly and
black hypertensive patients, p blockers may not be
a physiologic means of controlling BP in these popu-
lations. Agents such as propranolol have been
shown to increase TPR via reflex mechanisms and
produce vascular spasm despite lowering BP [128].
Drug-induced reduction of CO in these patients
may also be counterproductive, leading to symp-
toms related to excessively low CO. Beta blockers
have several adverse effects, including broncho-
spasm, bradycardia, impotence, nightmares, and
hallucinations. They also raise concern regarding
metabolic abnormalities and may exacerbate left
ventricular dysfunction, peripheral vascular dis-
ease, or bronchospastic pulmonary disease.
CONCLUSIONS
A more rational physiologic approach to the
treatment of essential hypertension is required to
improve patients long-term health as well as their
more immediate quality of life. Such an approach
can be based on identification of the specific under-
lying hemodynamics and pathophysiologic conse-
quences of the disease (which may be predicted in
part by factors such as patient age, race, and
weight), and selection of antihypertensive agents
that are most likely to correct those hemodynamic
flaws and prevent their effects. Although the ef-
fects of these therapeutic changes on morbidity and
mortality remain to be seen, the use of antihyper-
tensive agents that are specifically directed toward
the patients abnormal pathophysiology should at
the very least allow a more appropriate BP correc-
tion, with minimal adverse effects and optimal com-
pliance and quality of life.
The American Journal of Medicine Volume 90 (suppl 5A) 5A-11s
SYMPOSIUM ON CALCIUM ANTAGQNISTS /WEIR
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