29,31,39,40 Placebo-controlled studies evaluating morbidity and mortality in
hypertension are now not only unnecessary, but considered unethical because of the
well-established benefits of treatment. Even small reductions in BP have been
associated with significant CV benefits. Based on prospective observational studies,
a persistent 5 mm Hg reduction in DBP is associated with a 21% reduction in CHD
and a 34% reduction in stroke.
Most antihypertensive drugs reduce LVH through varying mechanisms. It is logical
that regression of LVH is desirable, but this remains unproved.
CASE 9-1, QUESTION 10: Will D.C.’s early signs of hypertension-associated complications improve or
reverse with appropriate BP control?
Reductions in BP can reverse many of the changes associated with D.C.’s
retinopathy. Studies have demonstrated that the risk of retinopathy in diabetes
increases significantly when BP is elevated and that BP lowering can slow this
progression. Although D.C. has an elevated fasting glucose, he does not have
diabetes. Regardless, lowering BP is desirable for anticipated beneficial effects on
It is reasonable to assume that lifestyle modifications can partially help D.C.
achieve his BP goal. D.C. has multiple major CV risk factors and has early evidence
of hypertension-associated complications. Lifestyle modifications are germane to the
appropriate treatment of hypertension, but prospective clinical trials have not proven
that this treatment approach prevents CV disease in patients with hypertension
similar to what is proven antihypertensive drug therapy. Hence, initiation of drug
therapy should not be delayed unnecessarily, especially for patients with CV risk
CASE 9-1, QUESTION 12: Which lifestyle modifications can D.C. implement to lower his BP?
Weight reduction through dietary modifications and physical activity and sodium
restriction are the most apparent lifestyle modifications for D.C. to lower his BP. A
thorough patient interview (diet history to quantify total calories, sodium, fat, and
cholesterol, and social history to determine alcohol consumption and confirm
cigarette use) should be obtained. Based on this interview, customized
The DASH diet should be strongly encouraged in D.C. based on proven benefits.
D.C.’s BMI of 30 kg/m2 or more classifies him as obese. As little as a 5% to 10%
loss in weight (5–11 kg) will provide global health benefits. Strategies that increase
his aerobic activity, in addition to diet, can augment weight loss.
OTHER CARDIOVASCULAR RISK-REDUCTION STRATEGIES
CASE 9-1, QUESTION 13: Aside from treating hypertension, which other CV risk reduction strategies
should be recommended in D.C.?
Smoking is an important modifiable major CV risk factor. Cigarette smoking has been
shown to independently increase CV and overall mortality, and cessation can
decrease the incidence of CV disease.
43 Although smoking does not chronically
lower BP, smoking cessation is strongly recommended to improve overall health.
Hypertensive smokers should be continually educated about the risks associated with
cigarette smoking and directed to behavior-modification programs that can assist
smoking cessation efforts (see Chapter 91, Tobacco Use and Dependence).
Low-dose aspirin therapy (81 mg daily) is recommended by the US Preventive
Services Task Force (USPSTF) for the primary prevention of MI in certain men 45
to79 years old and ischemic stroke in certain women 55 to 79 years old.
recommendation is contingent on age and quantitative risk of CHD in men (e.g.,
Framingham risk scoring) and ischemic stroke in women. D.C. is not yet a candidate
for low-dose aspirin based on his age.
Controlling Other Comorbid Diseases
In addition to treating hypertension and lowering BP to goal, controlling other
comorbidities, which are themselves associated with increased CV risk, should be
performed. When present, dyslipidemia, diabetes mellitus, obesity, and any other
forms of CV disease should be diligently treated and controlled. D.C. has
dyslipidemia and requires statin treatment (individuals without clinical
atherosclerotic cardiovascular disease [ASCVD] or diabetes, who are 40–75 years
of age with LDL-C 70–189 mg/dL, and have an estimated 10-year ASCVD risk of
7.5% or higher—D.C’s calculated risk is 9.6%), and his CV risk would be reduced
with better control of this condition (see Chapter 8, Dyslipidemias, Atherosclerosis,
Pharmacotherapy for Primary Prevention Patients
EVIDENCE-BASED RECOMMENDATIONS
CASE 9-1, QUESTION 14: Which treatment principles need to be considered when choosing an initial
antihypertensive agent for D.C.?
Selecting an antihypertensive drug is complex. There are numerous choices, and
all agents can effectively lower BP. Depending on the dose used, BP reductions are
45 BP reduction, however, is only a surrogate end point of therapy and does
not necessarily reflect overall effectiveness. Reducing hypertension-associated
complications is the ultimate goal of treatment.
CASE 9-1, QUESTION 15: Which antihypertensive agents are appropriate first-line treatments for D.C.?
The JNC-8 report from 2013 outlines evidence-based pharmacotherapy
recommendations accumulated from more than 50 years of clinical trials.
D.C. is black and does not have CKD, JNC-8 recommends thiazide-like diuretics or
CCBs as first-choice antihypertensive therapy. This recommendation is based on the
propensity of data showing reduced morbidity and mortality with these drug
Traditional landmark placebo-controlled hypertension studies (e.g., the SHEP,
Swedish Trial of Old Patients with Hypertension,
31 and Medical Research Council
established that treating hypertension produces significant reductions in CV events
(e.g., stroke and MI) and mortality. These traditional landmark trials used thiazide
diuretic-based therapy, and thus thiazide diuretics have been the quintessential
antihypertensive agent for most patients. Subsequently, several clinical trials
evaluating newer agents (ACEI, ARB, and CCB) have provided additional evidence
12,40,47–67 Most of these trials do not include a placebo group
(because it is unethical to use placebo in long-term studies); rather, they use an active
antihypertensive agent as the comparator (often a thiazide diuretic or β-blocker or
both). In those studies in which newer antihypertensive agents were compared with
thiazide diuretics, very similar effects were seen. One of these studies was the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
In the ALLHAT, 33,357 patients with hypertension were randomly
assigned in double-blind manner to thiazide diuretic (chlorthalidone), CCB
(amlodipine), or ACEI (lisinopril)-based therapy. After a mean follow-up to 4.9
years, the incidence of the primary end point of fatal CHD or nonfatal MI was similar
among all three treatment arms.
CASE 9-1, QUESTION 16: Should monotherapy or two-drug therapy be started in D.C. as his initial
A monotherapy approach is an option for D.C. Monotherapy with a CCB, or
thiazide diuretic as recommended by JNC-8, will likely reduce his BP to less than
140/90 mm Hg. If D.C. is not black, ACEI and ARB would also be optimal
As monotherapy, it is well documented that a thiazide diuretic or a CCB is highly
effective in lowering BP in black patients. This is likely because of the profile of
low renin coupled with high plasma volume pattern of hypertension that is commonly
seen in black patients with hypertension. Conversely, ACEI, ARB, or β-blocker
monotherapy is less effective in lowering BP in blacks compared with white patients.
However, when these agents are used in combination, especially with a thiazide
diuretic, these race-based differences seen in BP lowering with monotherapy are
abolished. This information may aid in selecting one drug option over another in a
primary prevention patient, but does not apply to black patients with other
comorbidities, in whom choice of therapy follows an evidence-based approach to
selection based on the comorbidities.
D.C. does not have any other comorbidities for specific antihypertensive drug
therapy. His first-line treatment option is CCB or thiazide diuretic. Monotherapy with
either a thiazide diuretic or a CCB would be very effective in BP lowering; either of
these two drugs is an acceptable treatment option for him.
800 international units daily, and calcium carbonate 600 mg twice daily. She has been diagnosed with
Older patients with hypertension (>65 years of age) have the lowest rates of BP
control, and this rate decreases in even older populations.
B.D., similar to black patients, respond best to thiazides and CCBs and less to
ACEIs, ARBs, and β-blockers when these are used as monotherapy. However, it is
unclear whether these small differences in BP lowering among classes are clinically
significant; thus they are all recommended as first choice per JNC-8 guidelines.
Isolated Systolic Hypertension
B.D. has isolated systolic hypertension (ISH), which is defined as an elevated SBP
2 This pattern of hypertension is most common in older patients
and incurs a significant risk for CV disease. It was once thought that patients with
ISH required high SBP to ensure normal perfusion of the heart and brain and that
treating ISH would further lower DBP and worsen organ perfusion. Evidence clearly
demonstrates, however, that treating ISH with antihypertensive drug therapy reduces
31,39,54 B.D.’s hypertension should be managed with drug therapy
in addition to lifestyle modifications.
The care of patients with ISH, including the very elderly, should follow the same
general hypertension care principles that apply to all patients, with two exceptions.
The first is that the BP goal is different. JNC-8 guideline recommends that BP goal of
patients 60 years or older be <150/90 mm Hg.
2 Unless they also have CKD and are
aged < 70 years, their BP goal would be similar to younger patient population, <
140/90 mm Hg. The second exception is that lower doses should be used when first
starting therapy because of higher risk of developing orthostatic hypotension.
Orthostatic hypotension occurs when standing upright results in an SBP decrease of
more than 20 mm Hg (or a DBP decrease of more than 10 mm Hg) after 3 minutes of
standing and is often accompanied by dizziness or fainting. This is a risk of rapid BP
lowering. Orthostatic hypotension is more frequent in elderly patients (especially
those with ISH), diabetes, autonomic dysfunction, volume depletion, and in patients
taking certain drugs (i.e., diuretics, nitrates, α-blockers, psychotropic agents, and
phosphodiesterase inhibitors). Antihypertensive dose increases should be gradual to
minimize the risk of hypotension. Moreover, initial therapy with two drugs should
probably be avoided in the elderly (age 80 years or older) owing to the increased
risk of orthostatic hypotension.
The very elderly (i.e., patients 80 years or older) have traditionally been
underrepresented in landmark placebo-controlled clinical trials. However, the
HYVET was a placebo-controlled, randomized trial evaluating the effect of
antihypertensive pharmacotherapy (ACEI with or without a thiazide-like diuretic) in
patients with hypertension aged 80 years and older.
prematurely, after 1.8 median years, owing to a significant reduction in overall
mortality in the treatment arm. The HYVET provides compelling evidence that
treatment of hypertension in the very elderly provides significant benefits. B.D.
should be started on a low-dose thiazide diuretic or CCB for the treatment of her
hypertension. For elderly patients with existing incontinence, diuretic therapy will be
problematic. Under this circumstance, a CCB would be a more reasonable first-line
option. Considering her advanced age, starting with monotherapy is appropriate to
reduce her risk of orthostatic hypotension.
QUESTION 1: You are developing a collaborative drug therapy management (CDTM) protocol for treatment
agent for a specific primary prevention patient?
It cannot be emphasized enough that selecting pharmacotherapy should follow an
evidence-based philosophy. In patients with other comorbidities, certain
antihypertensive drug classes are recommended in place of other options. In patients
without other comorbidities, factors such as concomitant diseases, medication costs,
serum electrolytes, and prior medication intolerances should be considered (Table 9-
7). These are helpful when selecting initial therapy for a primary prevention patient
who has more than one acceptable drug class as a first-line option or when selecting
add-on therapy to further lower BP. These are discussed later in this chapter.
Additional Considerations in Antihypertensive Drug Choice
CCB: dihydropyridine Raynaud phenomenon,
CCB: nondihydropyridine Raynaud phenomenon,
Peripheral edema, lownormal heart rate
Thiazide diuretic Osteoporosis or at
High-normal refers to patients in the high end of the normal range, but not above the range.
Low-normal refers to patients in the low end of the normal range, but not below the range.
aThese considerations should never replace drug recommendations for a compelling indication.
bMay use but requires diligent monitoring.
The costs of treating hypertension and related complications are substantial to
68 With expanding availability of generic agents, costs
attributed to drug acquisition are small in comparison with expenses for laboratory
evaluations, office visits, and medical care for hypertension-associated
complications. Whenever possible, affordable regimens that do not compromise
efficacy should be designed. Generic antihypertensive products are equally effective
and less expensive than brand-name products, and all first- and second-line
antihypertensive classes have generic alternatives. The frequency of administration
can influence treatment. Once-daily administration assists adherence; all major drug
Pharmacotherapy for Patients with Other
CASE 9-3, QUESTION 2: In your CDTM protocol, when should an ACEI or ARB be identified as first-line
therapy ahead of other antihypertensive agents?
Unlike previous editions of JNC guidelines, JNC-8 guidelines did not specifically
discuss how hypertension treatment should be managed in patients with other
comorbidities (besides diabetes and CKD). However, there are other coexisting
diseases or hypertension-associated complications in patients which may warrant the
use of certain classes of antihypertensive because these agents show significant
benefits in reducing CV morbidity or mortality in patients with those specific
Kidney disease and CV disease are both long-term hypertension-associated
complications that are at high risk of occurring in patients with diabetes. JNC-8
recommends the same four classes of antihypertensive agents as first choice in
nonblack patients with diabetes for primary prevention of CV events (ACEI, ARB,
CCB, and thiazide diuretics) and thiazide diuretics and CCB in black patients.
compared head to head, ACEIs are superior to dihydropyridine CCBs at reducing CV
57,58 Subgroup analyses of larger clinical trials further support CV event
reduction with ACEIs and ARBs. Therefore, ACEI and ARB may be preferred initial
antihypertensive therapy for a patient with diabetes if there is no other
CASE 9-3, QUESTION 3: In your CDTM protocol, how should significant CKD be defined so that patients
with CKD can be identified and treated appropriately?
It is common that CKD presents initially with microalbuminuria (30–299 mg albumin
in a 24-hour urine collection) that can progress over the course of several years to
30 Progression is accelerated in the presence of both hypertension
and diabetes. JNC-8 recommends ACEI or ARB therapy to be used as first-line
therapy in CKD patients because both have been shown to reduce the progression of
61,62 and in those without diabetes.
Recently, ARB therapy has also been shown to decrease risk of developing
microalbuminuria in patients with diabetes.
Although many of the long-term benefits of ACEI or ARB therapy may be from BP
lowering, their evidence base is robust enough to support their first-line use in
72,73 After ACEI or ARB therapy has been implemented, data support a CCB as
the second drug because this has been shown to reduce progression of CKD better
than a thiazide diuretic as the second drug added based on the Avoiding
Cardiovascular Events through Combination Therapy in Patients Living with Systolic
Hypertension (ACCOMPLISH) trial.
CASE 9-3, QUESTION 4: In your CDTM protocol, although β-blocker is no longer considered as a first
choice for primary prevention, are there any cases when β-blocker therapy would be identified as an
appropriate first-line antihypertensive drug therapy?
CHRONIC AND ACUTE CORONARY ARTERY DISEASE
The American College of Cardiology (ACC)/AHA have guidelines for chronic CAD
that recommend treatment with a β-blocker, followed shortly thereafter by the
75 β-Blockers (those without intrinsic sympathomimetic activity
[ISA]) decrease the risk of a subsequent MI or sudden cardiac death by decreasing
the adrenergic burden on the heart, and progression of coronary atherosclerosis.
ACEI therapy promotes cardiac remodeling, improves cardiac function, and reduces
the risk of CV events. An ARB is an alternative in patients who do not tolerate an
ACEI, because fewer data exist that assess the long-term impact of an ARB on CV
events compared with an ACEI in chronic CAD.
76,77 A thiazide diuretic can be added
to the core regimen of a β-blocker with an ACEI (or ARB) if additional BP reduction
is needed. However, if an additional agent is needed to treat ischemic symptoms for
patients with chronic stable angina, a dihydropyridine CCB can be added to this core
regimen. If a β-blocker cannot be used because of intolerance or contraindication, a
nondihydropyridine CCB can be used as an alternative to a β-blocker. Acute CAD,
also called acute coronary syndrome, includes unstable angina, non–ST-segment
elevation MI, and ST-segment elevation MI. The ACC/AHA guidelines for these
conditions indicate a β-blocker as first-line pharmacotherapy.
Pharmacotherapy for left ventricular dysfunction should include a three-drug
combination of an ACEI, a β-blocker, and an aldosterone antagonist, plus loop
diuretics depending on the need for diuresis.
79 ACEIs, β-blocker, and aldosterone
antagonists, all have numerous landmark clinical trials showing reduced morbidity
and mortality rates, whereas diuretics provide primarily symptomatic relief of
According to evidence-based medicine principles, only metoprolol, carvedilol,
and bisoprolol are indicated for left ventricular dysfunction. Other β-blockers (e.g.,
atenolol) should not be used in patients with left ventricular dysfunction because they
do not have supporting data demonstrating they reduce CV event rates in these
patients. Patients should be clinically euvolemic and hemodynamically stable before
adding a β-blocker. As discussed in Chapter 14 (Heart Failure), it is important to
start with very low doses of a β-blocker, then slowly titrate upward over the course
of several weeks to the recommended dosing range for left ventricular dysfunction.
An ARB can be used as an alternative to an ACEI.
Potassium serum concentrations must be carefully monitored in the situation when
ACEI (or ARB) and aldosterone antagonist are used together. Alternatively, the
combination of hydralazine with isosorbide dinitrate can be added in black patients.
This combination has been demonstrated to improve CV outcome in this patient
Four aspects of treatment must always be considered: (a) BP response to attain goal,
(b) adherence with lifestyle modifications and pharmacotherapy, (c) progression to
hypertension-associated complications, and (d) drug-related toxicity.
Reduction in BP should be evaluated 1 to 4 weeks after starting or modifying
therapy for most patients. BP usually begins to decrease within 1 to 2 weeks of
starting an agent, but steady-state antihypertensive effects can take up to 4 weeks. If
patients are in hypertensive crisis, evaluation should occur sooner, within hours to
days (see Chapter 16, Hypertensive Crises).
Two BP values separated by at least 1 minute should be measured during each
clinical evaluation, with the average used to make a proper assessment. If
dehydration or orthostatic hypotension is suspected, BP should be measured in both
the seated and standing positions to detect orthostatic changes. For routine
monitoring, measuring BP in the seated position is sufficient. Self-BP monitoring
values should be considered if available. Normally, however, they are slightly lower
(5 mm Hg) than clinical values even in patients without white-coat hypertension. For
example, patients with a goal BP value of less than 140/90 mm Hg should have home
measurements that are less than 135/85 mm Hg.
All patients should be questioned in a nonthreatening manner regarding adherence
with lifestyle modifications and drug therapy. This is especially important for
complex regimens, when drug intolerance is likely, or when financial constraints
hinder acquisition of medications. Evaluating hypertension-associated complications
and drug side effects are essential. New hypertension-associated complications may
QUESTION 1: B.A. is a 58-year-old woman who is postmenopausal, does not smoke, and never drinks
provider wants to start HCTZ 25 mg/day. Is HCTZ an appropriate agent for B.A.?
B.A. is a primary prevention patient with uncontrolled hypertension. According to
the JNC-8, her BP goal is less than 140/90 mm Hg.
reasonable. Appropriate first-line treatment options include an ACEI, ARB, CCB, or
thiazide diuretic. All of these drug classes have generic options and should be easily
affordable for B.A. A thiazide diuretic may also benefit her osteoporosis (Table 9-7)
and is an appropriate choice. Several types of diuretics are used to manage
26 All lower BP, with differences being duration of action,
potency of diuresis, and electrolyte abnormalities.
Thiazides are diuretics of choice for most patients with hypertension. Similar to loop
diuretics, an initial diuresis is experienced. After approximately 4 to 6 weeks of
thiazide diuretic therapy, diuresis dissipates, however, and is supplanted by a
decrease in PVR, which is responsible for sustaining antihypertensive effects.
CASE 9-4, QUESTION 2: How should a thiazide diuretic be started in B.A.?
Thiazide and thiazide-like Chlorthalidone 12.5–25 Daily
Hydrochlorothiazide 12.5–25 Daily
Potassium-sparing Amiloride 5–10 Daily to BID
Triamterene 50–100 Daily to BID
Potassium-sparing combination Triamterene/HCTZ 37.5/25–75/50 Daily
Spironolactone/HCTZ 25/25–50/50 Daily
Amiloride/HCTZ 5–10/50–100 Daily
Aldosterone antagonist Eplerenone 50–100 Daily to BID
Spironolactone 12.5–50 Daily to BID
BID, 2 times daily; HCTZ, hydrochlorothiazide.
Hydrochlorothiazide Versus Chlorthalidone
HCTZ and chlorthalidone have been used in several major outcome trials, although
only chlorthalidone-based regimens have proven to be of benefit in the low doses
commonly used in practice today.
29,31,39,48,54,81,82 Both agents are inexpensive and
dosed once daily, but HCTZ is most frequently used in the United States and is more
widely available in fixed-dose combination products. The usual starting dose of
HCTZ or chlorthalidone is 12.5 mg once daily. A maintenance dose of 25 mg once
daily can effectively lower BP and has a low incidence of side effects (e.g.,
hypokalemia and hyperuricemia) that can be managed with routine monitoring.
Significant controversy surrounds the comparative efficacy of HCTZ and
chlorthalidone. Most clinicians, including the AHA, assume a class effect for these
10 However, class effects can be legitimized only after assurance of
equipotent dosing; for antihypertensives, when they are not directly compared in a
CV event trial, it assumes that if two agents achieve similar BP lowering then both
achieve similar reduction in CV events. With regard to HCTZ and chlorthalidone,
this assumption is unproven. Chlorthalidone is more potent on a milligram per
milligram basis and has a longer half-life than HCTZ (50–60 hours vs. 9–10 hours).
Based on a comparative study using 24-hour ABPM, it appears that the equipotent
dose of chlorthalidone 25 mg daily is HCTZ 50 mg daily, but this dose of HCTZ is
unpopular because of increased side effects. Consequently, it is believed by some
that the antihypertensive efficacy of chlorthalidone is greater than HCTZ when
contemporary doses are used; the 12.5- to 25-mg doses of chlorthalidone do not
appear to significantly increase the risk of hypokalemia more so than HCTZ.
Complicating this issue is evidence demonstrating that office BP tends to
overestimate the response to HCTZ, and the 24-hour BP lowering with HCTZ is only
comparable to other common agents (ACEI, ARB, CCB, and even β-blocker) when
85 Recently, data from the Multiple Risk Factor Intervention Trial
indicate that chlorthalidone reduces CV events more than HCTZ.
chlorthalidone is the most optimal and evidence-based thiazide diuretic for B.A.,
HCTZ remains currently accepted in the clinical environment as a reasonable
thiazide diuretic for hypertension assuming her BP goal can be readily achieved with
Loop diuretics produce a more potent diuresis, but a smaller decrease in PVR, and
less vasodilation than thiazide diuretics. They are subject to a significant postdose
antinatriuretic period, which offsets their antihypertensive effect. Therefore, a
thiazide is more effective at lowering BP than loop diuretics in most patients. Loop
diuretics are usually considered only for patients with severe CKD (estimated GFR
), left ventricular dysfunction, or severe edema. In these
patients, potent diuresis is often needed. Furosemide has a short duration of effect
and should be given twice daily when used in hypertension, whereas torsemide has a
longer duration of action and can be given once daily.
Potassium-sparing diuretics (triamterene and amiloride) should be reserved for
patients who experience hypokalemia while on a thiazide diuretic. With low-dose
thiazide diuretics, less than 25% of patients develop hypokalemia, and most cases
are not severe. Triamterene and amiloride usually do not provide significant
additional BP lowering when added to a thiazide diuretic. Several fixed-dose
products are available that include HCTZ with triamterene or amiloride. Empirically
starting all patients with hypertension treated with a thiazide diuretic on triamterene
or amiloride to avoid hypokalemia is not rational or necessary unless baseline serum
potassium is in the low-normal range.
A thiazide diuretic is an optimal first-line option in primary prevention in patients
like B.A., and she has no contraindications (Table 9-9). Although B.A. has
dyslipidemia, thiazide diuretics are unlikely to have a clinically significant effect on
cholesterol when used in low doses.
87,88 An appropriate starting dose of HCTZ is
12.5 or 25 mg daily. B.A. has no additional risks for orthostatic hypotension, so
starting at the higher 25-mg daily dose is safe and will have a better chance of
lowering her BP to goal than the lower 12.5-mg dose because most antihypertensive
agents provide a 10-mm Hg reduction in SBP and 5-mm Hg reduction in DBP with a
Side Effects and Contraindications of Antihypertensive Agents
ARB Dizziness Orthostatic hypotension
second- or thirddegree heart block,
second- or thirddegree heart block,
Increased potassium Hyperkalemia,
lipoprotein cholesterol; IV, intravenous.
CASE 9-4, QUESTION 3: B.A. is prescribed HCTZ 25 mg daily. How should she be counseled regarding
Several counseling points are summarized in Table 9-6. Some patients disregard
lifestyle modifications when they start antihypertensive therapy, so B.A. must be
encouraged to continue lifestyle modification to maximize her response to drug
therapy. B.A. should be informed that diuretics lower both BP and risk of CV events
and that taking her dose at about the same time each morning to minimize nocturia and
provide consistent effects is recommended. B.A. should expect to experience
increased urination when starting HCTZ, but should be informed that this diminishes
with time. Inform B.A. that missed doses should be taken as soon as possible within
the same day, but doubling doses the next day is not recommended. The potential for
hypokalemia, which is easily identified and managed, and the need for routine
monitoring of serum potassium should be reviewed. She should be counseled on the
signs and symptoms of electrolyte abnormalities (e.g., leg cramps and muscle
weakness) and encouraged to report these to her health care provider if they occur.
Increasing dietary intake of potassium-rich foods to minimize electrolyte depletion is
an option to minimize potassium loss. This should be encouraged only with thiazide
and loop diuretics, but not with potassium-sparing agents.
Despite improvements with lifestyle modifications and reported adherence with
HCTZ, B.A.’s goal BP of less than 140/90 mm Hg has not been met (her BP average
is 141/83 mm Hg). No new signs of hypertension-associated complications are seen.
She should be encouraged to continue with her current efforts, but other interventions
CASE 9-4, QUESTION 4: After 4 weeks of HCTZ 25 mg daily, B.A. has no complaints and has not missed
when repeated). Her fasting laboratory values are as follows:
Adverse reactions with low-dose thiazide diuretics (e.g., HCTZ 12.5–25 mg daily)
are minimal compared with higher-dose therapy (HCTZ > 25 mg daily). Moreover,
side effects and tolerability with low-dose thiazide diuretic therapy are similar to
other first-line drug therapy options and not much higher than what is seen with
33,35,36 Regardless, signs and symptoms of electrolyte and metabolic changes,
such as hypokalemia, hyponatremia, hyperglycemia, or hyperuricemia, should be
evaluated in all patients treated with thiazide diuretics. B.A. has experienced small
changes in serum potassium and uric acid, which are typical thiazide-induced
abnormalities. B.A. should be questioned about muscle cramps or weakness, which
can be caused by decreased potassium.
CASE 9-4, QUESTION 5: Is B.A.’s potassium decrease concerning? If so, how should this be managed?
Most total body potassium is intracellular (˜98%). Thiazide diuretics can cause
potassium loss and can result in potassium serum concentrations in the low end of the
normal range. However, with low-dose therapy, overt hypokalemia is not common.
HCTZ in doses of 12.5, 25, and 50 mg daily can decrease serum potassium by an
average of 0.21, 0.34, and 0.5 mEq/L, respectively.
33,87,88 This is usually considered
mild, with serum potassium concentrations reaching a nadir within the first month of
therapy and remaining stable thereafter. Restriction of dietary sodium in patients
receiving diuretic therapy has been shown to reduce the loss of potassium and should
CASE 9-4, QUESTION 6: When is potassium correction needed to manage diuretic-induced hypokalemia?
B.A.’s potassium is within the normal range. Potassium replacement is not
indicated. Diuretic-associated hypokalemia should be treated when serum
concentrations are below normal regardless of whether symptoms (e.g., muscle
cramps) are present. Serum potassium should be measured at baseline and 2 to 4
weeks after initiating therapy or increasing the diuretic dose.
Potassium-rich foods (e.g., dried fruit, bananas, potatoes, and avocados) may help
prevent small decreases in potassium, but they cannot be used as sole therapy to
correct hypokalemia. For instance, one medium-size banana has only 11.5 mEq of
potassium. The usual replacement dose of prescribed potassium chloride is 20 to 40
mEq/day but can range from 10 to more than 100 mEq/day. Potassium chloride,
bicarbonate, gluconate, acetate, and citrate salts are available for potassium
replacement therapy. Rather than supplement potassium, which does not effectively
correct the underlying mechanisms responsible for hypokalemia, a more appropriate
and must be normalized before hypokalemia can be effectively reversed.
CASE 9-4, QUESTION 7: How should the increase in B.A.’s uric acid be managed?
extent. Increased proximal tubular renal reabsorption, decreased tubular secretion, or
increased postsecretory reabsorption of uric acid contributes to diuretic-induced
hyperuricemia. Thiazide-induced hyperuricemia is usually small (≤0.5 mg/dL) and is
not clinically significant in patients without a history of gout.
history of gout, diuretics are not contraindicated, but an increase in serum uric acid
may require a decrease in dose or possibly discontinuation of the diuretic, especially
for those not on preventive antihyperuricemic therapy (e.g., allopurinol and
febuxostat). Acute gouty arthritis precipitated by diuretic therapy should be treated,
and the diuretic should be discontinued, at least temporarily. Future use of the
diuretic will depend on whether long-term antihyperuricemic therapy is to be added
and the risk versus benefit for continuing the diuretic. B.A.’s serum uric acid
concentration is elevated, but switching to a different agent or lowering the dose of
HCTZ is unnecessary because she is not symptomatic of gout.
It should be noted that changes in parameters such as uric acid can be informative
regarding dosing. When a given dose of a diuretic fails to lower BP, it is often
unclear as to whether the failure is a result of mechanisms other than volume driving
the hypertension or a result of the diuretic dose being insufficient to achieve the
desired physiologic effect. For example, the absence of an increase in uric acid
suggests that the administered dose was insufficient, and that a higher dose merits
consideration. In B.A.’s case, the increase in uric acid confirms that the given dose
was sufficient to have had a physiologic effect, so adding an antihypertensive agent
from a different drug class would be preferable to increasing the diuretic dose if
further BP lowering is necessary.
CASE 9-4, QUESTION 8: How much will HCTZ alter B.A.’s cholesterol values?
Small increases in LDL-C and triglycerides are potential side effects of diuretic
therapy. Dietary fat restrictions help minimize, but do not necessarily prevent, these
effects. Contrary to other biochemical disturbances, diuretic-induced changes in the
lipid profile are not dose related, and overall changes are small. Many clinical trials
lasting more than 1 year have shown that these alterations with diuretic therapy are
not sustained with prolonged use.
87,88 Even if these changes are persistent, they are
very small and are not clinically significant. The presence of dyslipidemia should
never be a reason to avoid diuretic therapy.
CASE 9-4, QUESTION 9: What other potential electrolyte abnormalities should be evaluated in B.A.
because of her thiazide diuretic therapy?
Hyponatremia is a serious, yet infrequent, adverse effect of diuretics. Changes in
sodium concentrations are usually small, and the majority of patients are usually
asymptomatic. Frail, elderly women appear more susceptible to experiencing severe
hyponatremia (<120 mEq/L) from diuretics, which rarely occurs, but definitely
requires discontinuation of therapy. Attention should be paid to the presence of other
medications that can contribute to hyponatremia (e.g., selective serotonin reuptake
inhibitors and psychotropic drugs), and patients should be counseled to avoid
Hypomagnesemia is an often overlooked metabolic complication of diuretic
therapy. Both thiazide and loop diuretics increase urinary excretion of magnesium in
a dose-dependent manner. Symptoms of significant hypomagnesemia include muscle
weakness, muscle tremor or twitching, mental status changes, and cardiac
arrhythmias. Presence of these symptoms would necessitate magnesium
supplementation or use of a potassium-sparing agent as noted above if hypokalemia
Thiazide diuretics decrease urinary calcium excretion and can be used to prevent
calcium-related kidney stones. The retention of calcium does not significantly
increase serum calcium concentrations and does not place patients at risk for
hypercalcemia. This effect, however, may be beneficial in women at risk for
osteoporosis (e.g., postmenopausal) such as B.A. or in patients with osteoporosis.
Conversely, loop diuretics increase renal clearance of calcium.
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