topics

The ACEIs protect the kidney from the unrelenting deterioration that occurs with CKD, hypertension, and diabetes. Therefore, these agents are recommended as first-line therapy in CKD.

The increased intraglomerular pressure and mesangial cell proliferation that occurs in CKD leads to proteinuria and a progressive decline in kidney function. Reductions in renal blood

flow cause the kidneys to increase renin release, thus activating

the RAAS. This action constricts the efferent renal arteriole to

preserve glomerular pressure, but may propagate renal impairment. ACEIs preferentially dilate the efferent arteriole, which

relieves intraglomerular pressure. Data suggest that ACEIs may

have unique renal preservation properties, making CKD a compelling indication for ACEI therapy. Some of the risk reduction

is also related to systemic BP lowering.

Patients with diabetes are at high risk for nephropathy, especially those with type 1 diabetes. Evidence indicates that ACEI

therapy reduces progression to severe CKD and kidney failure in

patients with type 1 diabetes and proteinuria.92 In type 2 diabetes,

ACEI therapy has been proven to decrease initial development of

microalbuminuria, and to reduce worsening of proteinuria, but

evidence showing progression to severe CKD or failure is not

available.38,94 Nonetheless, both type 1 and type 2 diabetes are

considered compelling indications for the use of ACEI therapy.

CHRONIC AND ACUTE CORONARY ARTERY DISEASE

ACEI therapy is a first-line treatment in patients with chronic

CAD (post-MI, chronic stable angina) and acute CAD (non–STsegment elevation MI, ST-segment elevation MI).101,103,104 This

should be in addition to β-blocker therapy. The benefit of ACEI

therapy in patients with CAD is a reduced risk of CV events that

is independent of both left ventricular function and BP. Patients

with CAD who have controlled BP still appear to have reductions

in CV events with the addition of ACEI therapy.145 Because ACEI

therapy will not provide anti-ischemic effects, the role of ACEI

therapy in CAD is as an add-on to a β-blocker to reduce CV risk,

not to treat underlying ischemic symptoms.

PRIOR STROKE

The perindopril protection against recurrent stroke study

(PROGRESS) was a double-blind, placebo-controlled evaluation

of an ACEI in combination with a thiazide diuretic for 4 years

in 6,105 patients with a history of stroke or transient ischemic

attack.63 The incidence of stroke and total major vascular events

were significantly reduced with the combination regimen, and

reductions were seen regardless of baseline BP or reduction in

BP. These data justify the compelling indication to use an ACEI

(in combination with a thiazide diuretic) to reduce recurrence of

stroke in patients who have had a stroke.

LEFT VENTRICULAR DYSFUNCTION

ACEIs reduce morbidity and mortality in patients with left ventricular dysfunction as a component of standard therapy (diuretic

with an ACEI followed by the addition of a β-blocker).108 In

general, the CV benefits of ACEI therapy in left ventricular dysfunction are considered a class effect, and ACEIs are used interchangeably at equivalent dosages in these patients (see Chapter

19, Heart Failure).15

319Essential Hypertension Chapter 14

CASE 14-6, QUESTION 5: A.R. has microalbuminuria, and

lisinopril may help preserve kidney function. However, is

there a risk that lisinopril can cause acute renal dysfunction?

The ACEIs are effective in patients with hypertensionassociated renal disease. They are contraindicated, however, in

several situations, including bilateral renal artery stenosis, pregnancy, and volume depletion (Table 14-10). In the case of bilateral renal artery stenosis or volume depletion, high angiotensin

concentrations maintain renal blood flow, and acute renal dysfunction can occur when an ACEI is started. Because it is often

not known whether a patient has bilateral renal artery stenosis,

problems with ACEI can be minimized by starting with recommended doses and careful monitoring of serum creatinine within

2 to 4 weeks of starting therapy. Modest elevations in serum

creatinine that are less than 30% (for baseline creatinine values

<3.0 mg/dL) do not warrant adjustment in therapy.143 If greater

increases occur, ACEI therapy should be stopped, and further

medical evaluation should occur. Patients with elevated serum

creatinine at baseline (up to 3.0 mg/dL) may particularly benefit

from the vasodilatory effects of ACEIs in the kidney, but require

careful drug initiation and close monitoring. A.R.’s serum creatinine was normal after 4 weeks of lisinopril therapy. She is not

experiencing any kidney-related adverse effects from lisinopril.

CASE 14-6, QUESTION 6: What are the risks of using ACEIs

in women of childbearing age?

Because ACEIs are teratogenic in the second and third

trimester,146 their use in pregnancy is contraindicated. Moreover,

their use in women of childbearing potential is discouraged. If

used in this population, patient education should be explicitly

clear regarding risks to the fetus, which include potentially fatal

hypotension, anuria, renal failure, and developmental deformities. A highly effective form of contraception should be strongly

recommended.

Angiotensin Receptor Blockers

CASE 14-6, QUESTION 7: A.R.’s lisinopril is increased to 20

mg daily, then to 40 mg daily during a period of 8 weeks. Her

current BP is 136/78 mm Hg (134/76 mm Hg when repeated)

at an office visit today. Her serum potassium and creatinine

are unchanged from previous values. However, she reports

a persistent dry cough for the past few months. She has no

additional signs suggesting upper respiratory infection or

left ventricular dysfunction. How should A.R.’s therapy be

modified?

A well-known side effect of ACEIs is a nonproductive, dry

cough, which can occur in up to 15% of patients, with some estimates of cough prevalence being higher.147 Patients may describe

this as a tickling sensation in the back of the throat that commonly

occurs late in the evening. This is distinctly different from the

cough associated with left ventricular dysfunction, which might

be associated with crackles and rales (on auscultation) indicating

possible pulmonary edema. ACEI-related cough resolves with

discontinuation. Many agents have been used to treat an ACEI

cough with poor results. The best treatment option for a patient

with an intolerable ACEI cough is to switch agents. For A.R.,

switching to an ARB would likely eliminate the cough and is an

acceptable first-line treatment option for her considering her diabetes and microalbuminuria.89,91 A.R. will also require the addition of a second agent, either a CCB or thiazide diuretic, because

she has not achieved her goal BP of less than 130/80 mm Hg.

TABLE 14-13

Angiotensin Receptor Blockers in Hypertension

Azilsartan medoxomil 80 80 Daily

Candesartan cilexetil 16 8–32 Daily to BID

Eprosartan mesylate 600 600–800 Daily to BID

Irbesartan 150 75–300 Daily

Losartan potassium 50 25–100 Daily to BID

Olmesartan medoxomil 20 20–40 Daily

Telmisartan 40 20–80 Daily

Valsartan 80–160 80–320 Daily

a Starting dose may be decreased 50% if patient is volume depleted, very elderly,

or taking a diuretic.

BID, twice daily.

ARBs are first-line options for primary prevention patients and

have data demonstrating reductions in CV events.32,59 There

are eight ARBs (Table 14-13), and many are available as twodrug fixed-dose combination products (Online Table 14-1), as

well as two different three-drug fixed-dose combination products (Online Table 14-2).

PHARMACOLOGIC DIFFERENCES BETWEEN AN

ANGIOTENSIN-CONVERTING ENZYME INHIBITOR

AND AN ANGIOTENSIN RECEPTOR BLOCKER

CASE 14-6, QUESTION 8: How is an ARB different from an

ACEI?

Unlike ACEIs, ARBs specifically bind to angiotensin II receptors in vascular smooth muscle, adrenal glands, and other tissues. Access of angiotensin II to its receptors is blocked, and

angiotensin I–mediated vasoconstriction and aldosterone release

is prevented, resulting in BP reduction. ARBs do not affect

bradykinin; therefore dry cough does not occur.

Considerable investigation has focused on describing the pharmacologic differences between the angiotensin II type 1 and

type 2 receptors. Stimulation of the type 1 receptor causes vasoconstriction, salt and water retention, and vascular remodeling.

Other deleterious effects from type 1 receptor stimulation include

myocyte and smooth muscle hypertrophy, fibroblast hyperplasia, cytotoxic effects in the myocardium, altered gene expression,

and possible increased concentrations of plasminogen activator

inhibitor. Stimulation of the type 2 receptor results in antiproliferative actions, cell differentiation, and tissue repair.

Theoretically, an ideal antihypertensive agent would block

only type 1 and not type 2 receptors as is the case with

ARBs. Therefore, it is possible that an ARB would be superior

to an ACEI in reducing hypertension-associated complications

because ACEIs ultimately decrease stimulation of both type 1

and type 2 receptors by decreasing production of angiotensin

II. This argument is purely speculative and is not supported by

clinical trial data. ONTARGET was a prospective, double-blind,

randomized controlled trial that directly compared ARB-based

therapy, ACEI-based therapy, and the combination of an ACEI

with ARB.121 After a median of 56 months, the incidence of CV

events was no different among all three treatment groups. Therefore, ARB therapy is as effective as, but no more superior than,

ACEI therapy in the overall management of hypertension.

320 Section 2 Cardiac and Vascular Disorders

COMPELLING INDICATIONS

CASE 14-6, QUESTION 9: Under what circumstances would

an ARB be a more appropriate initial antihypertensive agent

than an ACEI?

DIABETES

Patients with diabetes should be treated with either an ACEI

or ARB. ARB-based treatment regimens, similar to ACEI-based

treatment regimens, have been shown in clinical trials to reduce

the progression of diabetic nephropathy among patients with

type 2 diabetes and microalbuminuria.89 ARB-based therapy is

the only antihypertensive regimen for which evidence shows

reduced kidney failure in patients with type 2 diabetes who have

diabetic nephropathy with albuminuria (not microalbuminuria)

and elevated serum creatinine.73 Therefore, for patients with

type 2 diabetes and advanced nephropathy, evidence supports

ARB therapy, although ACEI therapy has not been studied in

this population.

CHRONIC KIDNEY DISEASE

An ARB, similar to an ACEI, minimizes damage that occurs with

CKD. Both ACEIs and ARBs preferentially dilate the efferent

arteriole, which relieves intraglomerular pressure. Thus, CKD is

a compelling indication for ARB therapy. For nondiabetic kidney

disease, less evidence supports ARB use, and these agents should

be reserved as alternatives to an ACEI.

CHRONIC AND ACUTE CORONARY ARTERY DISEASE

Angiotensin receptor blocker therapy is a reasonable alternative

to ACEI therapy in patients with CAD although data are limited.

PRIOR STROKE

The role of ARB therapy in patients with a history of stroke is controversial. In the Morbidity and Mortality after Stroke Eprosartan

Compared with Nitrendipine for Secondary Prevention study,

ARB-based therapy reduced the incidence of recurrent stroke

more than dihydropyridine CCB-based therapy in a large number

of patients with cerebrovascular disease.80 However, in the Prevention Regimen for Effectively Avoiding Second Strokes study

20,332 patients who recently had an ischemic stroke were randomly assigned to ARB therapy or placebo.107 After a mean of

2.5 years, there was no difference in the incidence of the primary end point of recurrent stroke between the two groups.

Therefore, it is unclear how well ARB therapy would work as

an alternative to ACEI therapy in patients with a history of

stroke.

LEFT VENTRICULAR DYSFUNCTION

Pharmacologic blockade of the RAAS in left ventricular dysfunction is of paramount importance. An ARB is a reasonable alternative in patients with hypertension and left ventricular dysfunction who cannot tolerate an ACEI (e.g., those who experience

cough).109 As sequential add-on therapy for patients with left ventricular dysfunction who are already treated with the standard

regimen of a diuretic with an ACEI and β-blocker, ARB therapy

has been proved to reduce risk of CV events.122 However, the

benefits are limited primarily to decreasing risk of heart failure

hospitalizations. This is not similar to the reduction in mortality

seen when adding an aldosterone antagonist. Aldosterone antagonists would be preferred over ARBs when considering sequential add-on therapy. Additionally, if an ARB is used with an ACEI,

there is a significant increase in risk of side effects.121

CASE 14-6, QUESTION 10: If A.R. experienced angioedema

from lisinopril, would treatment with an ARB be appropriate?

A history of ACEI-induced angioedema does not preclude the

use of ARB therapy. The cross-reactivity between angioedema

with an ACEI and ARB is not exactly known. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and

Morbidity Alternative study prospectively included patients with

a history of ACEI intolerance who were randomly assigned, in

a double-blind manner, to placebo or candesartan. Of the 2,028

patients enrolled, 39 had a history of ACEI angioedema, and only

1 of these patients experienced repeat angioedema that required

discontinuation of the ARB.109 In the Telmisartan Randomised

Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease trial, 5,926 patients with a history of ACEI intolerance

were randomly assigned in this double-blind trial to an ARB or

placebo for a median duration of 56 months.148 A total of 75

patients had a history of ACEI angioedema, and none of those

patients who were randomly assigned to the ARB treatment

arm experienced repeat angioedema. Therefore, cross-reactivity

in angioedema between ACEIs and ARBs appears possible, but

unlikely and very small. ARBs are an alternative for patients who

experience ACEI angioedema but should be reserved for patients

with a compelling indication for an ACEI. Of note, the ACC/AHA

guidelines recommend an ARB in patients who have experienced

angioedema from an ACEI.108

Calcium-Channel Blockers

that contain an ACEI with a dihydropyridine CCB or a nondihydropyridine CCB. Cost should be considered because this is a

concern for B.A. Multiple ACEI with thiazide diuretic combinations are available generically, but there is only one generic ACEI

with CCB combination.

Step-Down Therapy

CASE 14-5

QUESTION 1: T.J. is a 58-year-old man with a 10-year

history of hypertension. He has been treated with lisinopril/hydrochlorothiazide 20/25 mg daily and amlodipine 10

mg daily for more than 2 years, and his BP has been well

controlled during this time. His BP at an office visit today

317Essential Hypertension Chapter 14

is 128/74 and 130/72 mm Hg. He has no compelling indications and has no hypertension-associated complications,

but he is a smoker. T.J. also has dyslipidemia, which is well

controlled with simvastatin 40 mg daily. His Framingham

risk score is 15%, and he denies dizziness or difficulties with

his medications. Should T.J.’s antihypertensive therapy be

changed to reduce his medication doses or possibly discontinue some of his medications?

Some patients with hypertension can have their BP medications slowly withdrawn, resulting in normal BP values for weeks

or months after discontinuation of their medications. This is

called step-down therapy. However, it is not a feasible option for

most patients with hypertension. Primary prevention patients

with no additional major CV risk factors who have very wellcontrolled BP for at least 1 year might be eligible for a trial of

step-down therapy. This option should not be considered for

patients with other major CV risk factors, a Framingham risk

score of 10% or more, compelling indications, or hypertensionassociated complications. Step-down therapy consists of attempting to gradually decrease the dosage, the number of antihypertensive drugs, or both without compromising BP control. Abrupt

or large dosage reductions should be avoided because of the risk

of rapid return of uncontrolled BP and even rebound surges in BP

(as is seen with rapid withdrawal of a β-blocker or an α2-agonist).

Step-down therapy is most often plausible for patients who

have lost significant amounts of weight or have drastically

changed their lifestyle. Any attempt at step-down therapy must

be accompanied by scheduled follow-up evaluations because

BP values can rise over the course of months to years after

drug discontinuation, especially if lifestyle modifications are not

maintained. With adherence to lifestyle modifications (weight

loss, reduction in sodium and alcohol), nearly 70% of patients

remained free of antihypertensives for up to 1 year after being

withdrawn from thiazide-based therapy in the Hypertension

Control Program.142

Step-down therapy in T.J. is not an option. Although he does

not have compelling indications or hypertension-associated complications, he has multiple major CV risk factors and an elevated

Framingham risk score that is greater than or equal to 10%.

Angiotensin-Converting

Enzyme Inhibitor

CASE 14-6

QUESTION 1: A.R. is a 49-year-old black woman with type

2 diabetes. She started lisinopril 10 mg daily 2 weeks ago

when her BP values were consistently in the stage 1 hypertension range (150/90 mm Hg). Since then, she has had

weekly BP measurements, and her values have averaged

142/85 mm Hg despite strict adherence to her lifestyle modifications. Her BP today is 144/84 mm Hg (140/88 mm Hg

when repeated), and her heart rate is 78 beats/minute. She

is not a smoker, and her BMI is 29 kg/m2. All her laboratory test results, including kidney function, are within normal limits, except that her spot urine albumin-to-creatinine

ratio is 80 mg/g (2 weeks ago it was 90 mg/g). Is 2 weeks of

lisinopril therapy long enough to assess her antihypertensive response?

Several ACEIs are available (Table 14-12). Most ACEIs are

dosed once daily in hypertension (Table 14-12). In general, most

ACEIs, if used in equivalent doses, are considered interchangeable.

TABLE 14-12

Angiotensin-Converting Enzyme Inhibitors in Hypertension

Usual Starting Usual Dosage Dosing

Drug Dose (mg/d)a Range (mg/d) Frequency

Benazepril 10 20–40 Daily to BID

Captopril 25 50–100 BID to TID

Enalapril 5 10–40 Daily to BID

Fosinopril 10 20–40 Daily

Lisinopril 10 20–40 Daily

Moexipril 7.5 7.5–30 Daily to BID

Perindopril 4 4–16 Daily

Quinapril 10 20–80 Daily to BID

Ramipril 2.5 2.5–20 Daily to BID

Trandolapril 1 2–4 Daily

a Starting dose may be decreased 50% if patient is volume depleted, in acute

heart failure exacerbation, or very elderly (≥75 year).

BID, twice daily; TID, three times daily.

The time to reach steady-state BP conditions is similar to what

is seen with other antihypertensive agents. It may take several

weeks before the full antihypertensive effects of ACEIs are seen.

Therefore, evaluating BP response 2 to 4 weeks after starting

or changing the dose of an ACEI is appropriate. A.R. has been

taking lisinopril for 2 weeks, and her present BP should be used

to determine whether she has attained goal. Both her BP range

during the past few weeks and today’s average BP are above her

goal of less than 130/80 mm Hg (because she has diabetes).

CASE 14-6, QUESTION 2: Why should A.R. have serum

potassium and serum creatinine monitored while on lisinopril therapy?

Serum potassium can increase with ACEI therapy as a

result of aldosterone reduction. Potassium increases with ACEI

monotherapy are small (typically 0.1 to 0.2 mEq/L) and usually

do not cause hyperkalemia. This risk is increased when ACEIs are

used in patients with significant CKD (GFR<60 mL/minute/1.73

m2), or when they are used in combination with other drugs that

can also raise potassium.

ACEI therapy can also cause a small increase in serum creatinine owing to decreased vasoconstriction of the efferent arteriole

in the kidney. This results in a minor decrease in GFR that may

be evidenced by a small increase in serum creatinine. A common mistake is to discontinue an ACEI in response to this rise

in serum creatinine. Increases in serum creatinine of up to 30%

from the baseline creatinine value are safe and anticipated. In

these patients, the ACEI should be continued because a strong

association exists between acute increases in serum creatinine of

up to 30% that stabilize within the first 2 months of ACEI therapy and long-term preservation of renal function.143 Patients

with an increase in serum creatinine of greater than 30% should

have their ACEI therapy temporarily discontinued, as this may

indicate other medical problems. Some of these problems can be

underlying renal disease (such as bilateral renal artery stenosis) or

other situations that may be compromising renal blood flow (e.g.,

volume depletion, concomitant nonsteroidal anti-inflammatory

drug therapy, heart failure). Serum potassium and serum creatinine, in addition to BP, should to be monitored in A.R. within 2

to 4 weeks after starting ACEI therapy or increasing the dose.

CASE 14-6, QUESTION 3: A.R.’s lisinopril dose is increased

to 20 mg daily. Will this doubling of her dose place her at

risk for significant hypotension?

318 Section 2 Cardiac and Vascular Disorders

The very elderly, patients with volume depletion, or patients

with heart failure exacerbation may experience a significant firstdose response to an ACEI. This can manifest as orthostatic

hypotension, dizziness, or syncope. The increased pretreatment

activity of the RAAS, coupled with blockade of this system,

explains this effect. These patients should initiate ACEI therapy

at half the normal dose (Table 14-12), followed by slow titration

to standard doses.

Concurrent diuretic therapy may predispose some patients to

first-dose hypotension. When ACEIs were first approved, dosing

guidelines recommended starting at half the standard dose of the

ACEI, decreasing the dose of the diuretic, or stopping the diuretic

before initiating the ACEI. This was owing to fear that BP would

sharply and acutely drop. These dosing recommendations are

not necessary unless the patient is hemodynamically unstable

(volume depleted, hyponatremic, or poorly compensated heart

failure) or very elderly. A.R. does not have any of these characteristics and can safely increase her dose of lisinopril.

CASE 14-6, QUESTION 4: Is an ACEI an effective therapy in

a black patient such as A.R.?

ACEI monotherapy is generally more effective at lowering

BP in white patients than in black or elderly patients. Elderly and

black patients are more likely to have low renin hypertension,

strategy to minimize risk of developing diabetes.89

The magnitude of fasting glucose increases with thiazide

diuretics is variable and dose dependent. Patients with diabetes

and high risk for diabetes because of elevated fasting glucose

exhibit the greatest glucose increases, and patients without diabetes exhibit the smallest increases. When increases in serum

glucose concentration occur in patients without diabetes, they

are typically on average 3.6 to 6.7 mg/dL after multiple years

of thiazide diuretic therapy.41,133 It appears that these changes

are not clinically relevant because CV events are reduced despite

these changes. Moreover, diabetes is not a contraindication to

diuretic use; it is a compelling indication (Fig. 14-3) because risk

of CV events is reduced in patients with diabetes who are treated

with a thiazide diuretic.89,91

B.A.’s fasting glucose concentration is still considered normal.

Her fasting glucose values should be documented and monitored at least once a year to detect any increases. Adding either

an ACEI or ARB is a reasonable option for B.A. She should be

315Essential Hypertension Chapter 14

encouraged to continue dietary modifications, and response to

therapy should be re-evaluated in 2 to 4 weeks.

HYPOKALEMIA

CASE 14-4, 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,

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 effective strategy to manage diuretic-induced hypokalemia is to add a potassium-sparing

diuretic. Hypomagnesemia often accompanies diuretic-induced

hypokalemia, and must be normalized before hypokalemia can

be effectively reversed.

OTHER METABOLIC ABNORMALITIES

CASE 14-4, QUESTION 7: How should the increase in B.A.’s

uric acid be managed?

Thiazide diuretics can increase serum uric acid concentrations

in a dose-dependent fashion. Uric acid increases also occur with

loop diuretics, but to a lesser extent. Increased proximal tubular renal reabsorption, decreased tubular secretion, or increased

postsecretory reabsorption of uric acid contribute to diureticinduced hyperuricemia. Thiazide-induced hyperuricemia is usually small (≤0.5 mg/dL) and is not clinically significant in patients

without a history of gout.133 For patients with a 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, 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 14-4, 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.132,133 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 14-4, 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, psychotropic drugs), and patients should be counseled

to avoid excessive free water intake.

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 potassiumsparing agent as noted above if hypokalemia is also present.

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.

Reasons for Inadequate BP Control

CASE 14-4, QUESTION 10: What are common reasons for

inadequate patient response to antihypertensive pharmacotherapy?

B.A. has been on her current dose of HCTZ for 4 weeks.

The full antihypertensive effect of HCTZ has been achieved, but

she still has uncontrolled hypertension. She has had a response,

but it remains inadequate. Potential reasons for an inadequate

response, or lack of attaining BP goal values, with an antihypertensive should be considered before modifying her drug therapy regimen (Table 14-11). A comprehensive medication history

and medical evaluation is needed to rule out identifiable causes,

in particular nonadherence to the prescribed regimen. Her BP

reduction with HCTZ is typical. Her kidney function is good,

and no evidence exists of edema, so volume overload is unlikely.

316 Section 2 Cardiac and Vascular Disorders

TABLE 14-11

Reasons for Not Attaining Goal Blood Pressure Despite Antihypertensive Pharmacotherapy

Drug Related Health Condition or Lifestyle Related Other

Nonadherence Volume overload Improper blood pressure measurement

Inadequate antihypertensive dose Excess sodium intake Resistant hypertension

Inappropriate antihypertensive combination therapy Volume retention from chronic kidney disease White-coat hypertension

Inadequate diuretic therapy Secondary disease causes (Table 14-3) Pseudohypertension

Secondary drug-induced causes (Table 14-3) Obesity

Clinician failure to intensify or augment therapy (i.e.,

clinical inertia)

Excessive alcohol intake

There are no apparent secondary causes of elevated BP. It is reasonable to conclude that B.A. needs additional therapy to achieve

her goal BP. It is very common that most patients require two or

more agents to attain BP goal values.

Modifying Therapy

B.A.’s present dose of HCTZ is appropriate and should not be

increased to the maximal recommended dose of 50 mg daily

(considered high-dose therapy) because it may increase risk of

electrolyte and metabolic side effects. B.A.’s potassium dropped

to 3.8 mEq/L with HCTZ, and further dosage increases may

produce hypokalemia (<3.5 mEq/L) requiring correction. Her

hyperuricemia may also be worsened. The slightly increased antihypertensive response expected from increasing to 50 mg/day is

therefore not justified.130 Discontinuing HCTZ and starting a

different agent is an option, but it is not prudent to abandon the

HCTZ; she tolerated the treatment and experienced a reasonable BP response, and the HCTZ will augment the efficacy of

nearly any other agent that may be added, and may benefit her

osteoporosis.

TWO-DRUG REGIMENS

The role of two-drug regimens in the treatment of hypertension

is very clear. Most patients require multiple agents for BP control,

especially in populations with BP goals of less than 130/80 mm

Hg. Consensus guidelines recommend two-drug regimens as

initial therapy for patients in stage 2 hypertension, and list initial

two-drug regimen as an option in stage 1 hypertension.3,15,82,91

Adding a second agent to B.A.’s regimen is needed to reduce

BP to her goal. She is a primary prevention patient, so three

potential add-on antihypertensive agents that are considered firstline include an ACEI, ARB, or CCB. Ideally, a combination of two

drugs with different mechanisms of action should be selected to

produce a complementary effect to lower BP.

Adding an ACEI or ARB to B.A.’s HCTZ will result in additive antihypertensive effects that are independent of reversing

fluid retention. Diuretics reduce BP initially by decreasing fluid

volume, but maintain their antihypertensive effects by lowering

PVR. BP lowering, however, can stimulate renin release from the

kidney and activate the RAAS. This compensatory mechanism

is an in vivo attempt to neutralize BP changes and regulate fluid

loss. An ACEI or an ARB blocks the RAAS, explaining why combinations of these agents with diuretics are additive. Data from

the ACCOMPLISH trial support combination therapy for hypertension. In this randomized, double-blind trial, 11,506 patients

with hypertension were randomly assigned to the combination

of an ACEI with thiazide diuretic or an ACEI with CCB.115 After a

mean follow-up of 3 years, the risk of CV events was significantly

lower with the ACEI with CCB combination. Switching B.A.’s

HCTZ to an ACEI with CCB may be more effective in lowering CV events than adding an ACEI to her current HCTZ. This

would be an acceptable modification. However, considering her

response to HCTZ, simply adding an ACEI is also reasonable.

FIXED-DOSE COMBINATION PRODUCTS

Several fixed-dose combination products including two or three

drugs are available.

For tables showing fixed-dose combination

products that include two or three drugs, see

Online Tables 14-1 and 14-2 at

http://thepoint.lww.com/AT10e.

Although individual dose titration is not simple with fixeddose combination products, their use can reduce the number

of tablets or capsules taken by patients. This has been demonstrated to improve adherence compared with using two separate

single-drug products.141 Improved adherence may increase the

likelihood of achieving goal BP values.

Most fixed-dose combinations include a thiazide diuretic, and

many are available generically. Other fixed-dose combination

products combine a CCB with either an ACEI or ARB. These

combinations, similar to a thiazide with an ACE or ARB, are

highly effective in lowering BP. An economic advantage may even

exist to using a fixed-dose combination if it allows the patient

to receive two drugs for one medication copayment. The Simplified Treatment Intervention To Control Hypertension study

demonstrated that initiating therapy with a fixed-dose combination product according to a treatment algorithm was superior in

attaining goal BP values when compared with usual management

according to national guidelines.117 These data further support

using a fixed-dose combination product for initial therapy.

B.A. is a candidate for fixed-dose combination product. If the

combination of an ACEI with HCTZ is selected for her, many

options exist. All of the products with an ACEI also include HCTZ

at the dose she is currently on. If the combination of an ACEI

with a CCB is selected, fewer options exist, but there are products

Significant controversy surrounds the comparative efficacy of

HCTZ and chlorthalidone. Most clinicians, including the AHA,

assume a class effect for these two drugs.15 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 versus 9–10 hours).128 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.129

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 50 mg daily

is used.130 Recently, data from the Multiple Risk Factor Intervention Trial indicate that chlorthalidone reduces CV events more

than HCTZ.131 Although 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 its use.

LOOP DIURETICS

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 <30 mL/minute/1.73 m2), 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 can be given once daily.

POTASSIUM-SPARING DIURETICS

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 unless baseline

serum potassium is in the low-normal range.

CASE 14-4, QUESTION 2: How should a thiazide diuretic be

started in B.A.?

B.A. has stage 1 hypertension, and monotherapy with a thiazide diuretic is reasonable. A thiazide diuretic is a first-line option

in primary prevention patients like B.A., and she has no contraindications (Table 14-10). Although B.A. has dyslipidemia, thiazide diuretics are unlikely to have a clinically significant effect on

cholesterol when used in low doses.132,133 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

TABLE 14-10 Side Effects and Contraindications of Antihypertensive Agents Side Effects Innocuous but Sometimes Annoying Potentially Harmful Usually Requires Cessation of Therapy, at Least Temporarily Contraindications Thiazide diuretics Increased urination (at onset of therapy), muscle cramps, hyperuricemia (without gout) Hypokalemia,a hyponatremia, hyperglycemia, hypovolemia, pancreatitis, photosensitivity, hypercholesterolemia, hypertriglyceridemia, hyperuricemia with gout, orthostatic hypotension (more frequent in elderly) Hypercalcemia, azotemia, skin rash (cross-reacts with only certain sulfonamide allergies), purpura, bone marrow depression, lithium toxicity in patients on lithium therapy, hyponatremia Anuria, kidney failure Loop diuretics Increased urination, muscle cramps, hyperuricemia (less than with thiazides) Hypokalemia,a hyperglycemia, hypovolemia, pancreatitis, hypercholesterolemia, hypertriglyceridemia, hearing loss with large IV doses, orthostatic hypotension (more pronounced in elderly) Hyponatremia, hypocalcemia, azotemia, skin rash (cross-reacts with only certain sulfonamide allergies), photosensitivity, lithium toxicity in patients on lithium therapy Anuria ACEI Dizziness, dry cough Orthostatic hypotension (more pronounced in elderly treated with a diuretic), increased serum creatinine, increased potassium Angioedema, severe hyperkalemia, increase in serum creatinine >35% Bilateral renal artery stenosis, volume depletion, hyponatremia, pregnancy, history of angioedema ARB Dizziness Orthostatic hypotension (more pronounced in elderly treated with a diuretic), increased serum creatinine, increased potassium Severe hyperkalemia, increase in serum creatinine >35% Bilateral renal artery stenosis, volume depletion, hyponatremia, pregnancy CCB: dihydropyridines Dizziness, headache, flushing Peripheral edema, tachycardia Significant peripheral edema Left ventricular dysfunction (not with amlodipine or felodipine) CCB: nondihydropyridines Dizziness, headache, constipation Bradycardia Heart block, left ventricular dysfunction, interactions with certain drugs Left ventricular dysfunction, second- or third-degree heart block, sick sinus syndrome β-Blocker Bradycardia, weakness, exercise intolerance Masking the symptoms of hypoglycemia in diabetes, hyperglycemia, aggravation of peripheral arterial disease, erectile dysfunction, increased triglycerides, decreased HDL-C Left ventricular dysfunction (not with carvedilol, metoprolol, bisoprolol), bronchospasm in patients with asthma or COPD (more pronounced with nonselective agents) Severe asthma, second- or third-degree heart block, acute left ventricular dysfunction exacerbation, coronary artery disease for agents with intrinsic sympathomimetic activity Aldosterone antagonist Menstrual irregularities (spironolactone only) or gynecomastia (spironolactone only) Increased potassium Hyperkalemia, hyponatremia Kidney failure. kidney impairment (for eplerenone: CrCl <50 mL/min, or type 2 diabetes with proteinuria, and creatinine >1.8 in women, >2.0 in men), hyperkalemia, hyponatremia aRoutine addition of potassium supplementation or empiric concurrent potassium-sparing diuretics should be discouraged unless hypokalemia is demonstrated, the patient is taking digoxin, or potassium is in the low-normal range. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker; COPD, chronic obstructive pulmonary disease; CrCl, creatinine clearance; HDL-C, high-density lipoprotein cholesterol; IV, intravenous.

313

314 Section 2 Cardiac and Vascular Disorders

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 standard starting dose.81

PATIENT EDUCATION

CASE 14-4, QUESTION 3: B.A. is prescribed HCTZ 25 mg

daily. How should she be counseled regarding this therapy?

Several counseling points are summarized in Table 14-7. 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, 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.

CASE 14-4, QUESTION 4: After 4 weeks of HCTZ 25 mg

daily, B.A. has no complaints and has not missed a dose.

She is exercising and is following the DASH diet. Her BP

values are 142/86 mm Hg (140/84 mm Hg when repeated).

Her fasting laboratory values are as follows:

Serum potassium, 3.8 mEq/L

Uric acid, 7.3 mg/dL

Glucose, 99 mg/dL

All other values are unchanged. Last month, potassium

was 4.0 mEq/L, uric acid was 6.8 mg/dL, and fasting glucose was 95 mg/dL. What is your assessment regarding the

efficacy and toxicity of B.A.’s antihypertensive therapy?

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 are warranted.

POTASSIUM LOSS

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 firstline drug therapy options and not much higher than what is

seen with placebo.41,43,44,57 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 14-4, 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.41,132,133 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 be encouraged in

B.A.134

SUBCLINICAL POTASSIUM DECREASES

The clinical significance of small potassium decreases when

serum potassium concentrations are still in the normal range

is controversial. B.A.’s potassium has dropped slightly, and her

current serum concentration is in the low end of the normal

range. Low serum potassium values have been cited as an independent predictor of development of diabetes.135 Some data suggest that patients treated with a thiazide diuretic who experience

the greatest decreases in potassium also experience the greatest

increases in glucose values,136 although this is not consistently

demonstrated in other analyses.137

Large outcome trials have demonstrated that thiazide

diuretic-based treatment results in a higher incidence of developing type 2 diabetes compared with other antihypertensive

therapies.34,138,139 Because of the possible association between

potassium decreases and development of diabetes, some clinicians believe that it is optimal to maintain serum potassium in

the middle to high end of the normal range (e.g., between 4.0

and 5.0 mEq/L) in patients treated with thiazide diuretics.140 This

may minimize the risk, albeit small, of increasing fasting glucose

concentrations, and possibly development of type 2 diabetes.

Although this is not necessarily a universally accepted recommendation to mitigate risk of developing type 2 diabetes in patients

treated with thiazide diuretics, keeping serum potassium concentrations in the 4.0 to 5.0 mEq/L range can be accomplished by

combining the thiazide diuretic with a potassium-sparing diuretic

(including an aldosterone antagonist), or an ACEI, ARB. These

strategies are particularly attractive when additional BP lowering is needed. Moreover, lifestyle modifications remain the best