Reasons for Inadequate BP Control

CASE 9-4, 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 9-10). 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. 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

When patient cannot achieve optimal BP control with initial antihypertensive, JNC-8

recommends that the dose of the first drug may be increased (if patient has not yet

achieved maximum dose of the agent), or low dose of a second agent may be added.

Second agents of choice would be ACEI, ARB, CCB, or thiazide diuretics,

whichever one the patient is not already taking.

2 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.

85 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.

Table 9-10

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 9-

2)

Pseudohypertension

Secondary drug-induced causes

(Table 9-2)

Obesity

Clinician’s failure to intensify or

augment therapy (i.e., clinical

inertia)

Excessive alcohol intake

p. 151

p. 152

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.

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 first-line 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.

74 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.

Although individual dose titration is not simple with fixed-dose 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.

91

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.

92 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 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. Many ARBs are gradually becoming generic, so those may be potential

option as well; therefore a combination of ARB plus thiazide diuretic may be an

option too eventually.

Step-Down Therapy

CASE 9-5

QUESTION 1: T.J. is a 58-year-old man with a 10-year history of hypertension. He has been treated with

lisinopril/HCTZ 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 is 128/74 and 130/72 mm Hg. He has no significant

past medical history 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. 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 well controlled 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 or hypertension-associated 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 stepdown 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 and 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.

93

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

hypertension-associated complications, he has multiple major CV risk factors for

development of CV disease.

Angiotensin-Converting Enzyme Inhibitor

CASE 9-6

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 around155/90 mm Hg. Since then, she has had weekly BP

measurements, and her values have averaged 145/85 mm Hg despite strict adherence to her lifestyle

modifications. Her BP today is 144/84 mm Hg (142/88 mm Hg when repeated), and her heart rate is 78

beats/minute. She is not a smoker, and her BMI is 29 kg/m

2

. 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?

p. 152

p. 153

Table 9-11

Angiotensin-Converting Enzyme Inhibitors in Hypertension

Drug

Usual Starting Dose

(mg/day)

a

Usual Dosage Range

(mg/day) Dosing 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

aStarting dose may be decreased 50% if patient is volume depleted, has acute heart failure exacerbation, or is very

elderly (≥75 year).

BID, 2 times daily; TID, 3 times daily.

Several ACEIs are available (Table 9-11). Most ACEIs are dosed once daily in

hypertension (Table 9-11). In general, most ACEIs, if used in equivalent doses, are

considered interchangeable.

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 140/90 mm Hg.

CASE 9-6, 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.

94 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 antiinflammatory drug therapy, and heart failure). Serum

potassium and serum creatinine, in addition to BP, should be monitored in A.R.

within 2 to 4 weeks after starting ACEI therapy or increasing the dose.

CASE 9-6, 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?

The very elderly patients with volume depletion or patients with heart failure

exacerbation may experience a significant first-dose 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. In these patients, ACEI therapy should be initiated at half the normal dose

(Table 9-11), 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 9-6, 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. In fact, JNC-8 guideline does not recommend the use

of ACEI or ARB as first-choice antihypertensive in black patients for primary

prevention, including those with diabetes (unless they have CKD).

2 Elderly and black

patients are more likely to have low renin hypertension, which may partially explain

some of the differences in response. Nevertheless, many of these patients still

respond to ACEIs as monotherapy just to a less extent. Combination therapy,

especially with a thiazide diuretic, usually mitigates this race- and age-related

difference in BP response.

When an antihypertensive agent is being selected as initial monotherapy in a black

patient, an ACEI should generally not be chosen unless the patient has CKD. A

thiazide diuretic or CCB is otherwise preferred. In this case, considering switching

to a different agent (thiazide and CCB) may be a good alternative to improve A.R.’s

BP control. Of note, black patients have a twofold to fourfold increased risk of

angioedema and cough with ACEIs compared with white patients.

95 This does not

preclude ACEI use in black patients unless there is a prior history of angioedema.

CASE 9-6, 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 hypertension-associated renal disease.

They are contraindicated, however, in several situations, including bilateral renal

artery stenosis, pregnancy, and volume depletion (Table 9-9). 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.

94

If greater increases occur,

ACEI therapy should be stopped, and further medical evaluation should occur.

Patients with elevated serum creatinine at baseline (up to

p. 153

p. 154

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 9-6, QUESTION 6: What are the risks of using ACEIs in women of childbearing age?

Because ACEIs are teratogenic in the second and third trimester,

96

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 9-6, 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.

97 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.

CASE 9-6, QUESTION 8: How is an ARB different from an ACEI?

For A.R., switching to an ARB would likely eliminate the cough.

98 Although her

first-choice antihypertensive should be CCB or thiazide diuretics, 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. ARBs are first line. There

are eight ARBs (Table 9-12), and many are available as two-drug fixed-dose

combination products (Online Table 9-1), as well as two different three-drug fixeddose combination products (Online Table 9-2).

PHARMACOLOGIC DIFFERENCES BETWEEN AN ANGIOTENSINCONVERTING ENZYME INHIBITOR AND AN ANGIOTENSIN RECEPTOR

BLOCKER

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.

Table 9-12

Angiotensin Receptor Blockers in Hypertension

Drug Starting Dose (mg/day)

a

Usual Dosage Range

(mg/day) Dosing Frequency

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

aStarting dose may be decreased 50% if patient is volume depleted, very elderly, or taking a diuretic.

BID, 2 times daily.

CASE 9-6, QUESTION 9: Under what circumstances would an ARB be a more appropriate initial

antihypertensive agent than an ACEI?

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. ONgoing Telmisartan Alone and in Combination

With Ramipril Global Endpoint Trial (ONTARGET) was a prospective, doubleblind, randomized controlled trial that directly compared ARB-based therapy, ACEIbased therapy, and the combination of an ACEI with ARB.

99 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.

CASE 9-6, 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

p. 154

p. 155

of ACEI angioedema, and only 1 of these patients experienced repeat angioedema

that required discontinuation of the ARB.

99

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.

100 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.

79

Calcium-Channel Blockers

CCBs effectively lower BP. Elderly and black patients generally have greater BP

reduction with a CCB than with other agents (β-blockers, ACEIs, and ARBs). The

addition of a diuretic to a CCB provides additive antihypertensive effects. CCBs do

not alter serum lipids, glucose, uric acid, or electrolytes.

All CCBs inhibit the movement of extracellular calcium, but there are two primary

subtypes: dihydropyridines and nondihydropyridines (i.e., diltiazem and verapamil).

Each has distinctly different pharmacologic effects.

DIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS

Dihydropyridines are potent vasodilators of peripheral and coronary arteries. They

do not block AV nodal conduction and do not treat arrhythmias. Moreover, the potent

vasodilation associated with most dihydropyridines can induce a reflex tachycardia.

With the exception of amlodipine and felodipine, dihydropyridines decrease cardiac

contractility and should be avoided in patients with left ventricular dysfunction. Side

effects of dihydropyridines are related to their potent vasodilatory effects (e.g.,

tachycardia, headache, and peripheral edema).

Peripheral edema with CCB therapy, especially a dihydropyridine CCB, is a dosedependent side effect. It is a direct result of the potent peripheral arterial

vasodilation. When there is not equal vasodilation in the venous vasculature, a risk

exists for leaking through the capillaries in the legs and, thus, an increased risk of

peripheral edema. The best way to manage this side effect is to reduce the dose of the

dihydropyridine or to add an agent that blocks the RAAS to decrease the effects of

angiotensin II, which will result in a more balanced pressure gradient across her

peripheral vasculature by providing vasodilation of both the arteries and veins.

Adding either an ACEI or ARB can be used to accomplish this with the added benefit

of further lowering BP. Clinicians should note that using diuretics for the primary

purpose of treating peripheral edema that is secondary to CCB use is not

recommended and is not effective.

NONDIHYDROPYRIDINE CALCIUM-CHANNEL BLOCKERS

The two nondihydropyridine CCBs, diltiazem and verapamil, are similar to each

other. Relative to dihydropyridines, they are only moderately potent vasodilators, but

they directly decrease AV nodal conduction and have greater decreases in cardiac

contractility. The blockade of AV nodal conduction can slow heart rate and is the

basis for their use in controlling supraventricular tachycardias associated with

certain arrhythmias (e.g., atrial fibrillation). Most patients only have a modest

decrease in heart rate. However, heart block (first, second, or third degree) is a

potential adverse effect, especially with large doses. Both diltiazem and verapamil

should be avoided in patients with an underlying second- or third-degree heart block.

Under these circumstances, a dihydropyridine can be used if a CCB is needed.

Verapamil and diltiazem should be avoided in patients with left ventricular

dysfunction because they can significantly reduce cardiac contractility. When patients

with left ventricular dysfunction require a CCB to treat another condition (i.e., angina

or hypertension), amlodipine or felodipine may be used. They are the only CCBs that

have been safely used in clinical trials of patients with left ventricular dysfunction.

Unlike many other antihypertensive agents, they do not, however, protect against left

ventricular dysfunction-related mortality. Diltiazem may have a lower incidence of

constipation than verapamil. Verapamil is also an effective agent in migraine

prophylaxis and can be used if patients also have migraine. Patients with Raynaud

phenomenon can obtain symptomatic relief from the peripheral vasodilation

associated with a dihydropyridine CCB. Lastly, CCBs are effective in treating

cyclosporine-induced hypertension, but should be used cautiously because verapamil

and diltiazem increase cyclosporine concentration.

OTHER CONSIDERATIONS

Formulations

Several CCBs are available for the treatment of hypertension. They are listed in

Table 9-13. Immediate-release formulations should be avoided (see Chapter 16,

Hypertensive Crises).

Sustained-Release Formulations

CASE 9-7

QUESTION 1: C.F. is a 60-year-old man with hypertension, asthma, and type 2 diabetes. His hypertension is

treated with HCTZ 25 mg daily and ramipril 20 mg daily for many years. Today his BP is 148/74 mm Hg

(144/72 mm Hg when repeated), and his heart rate is 90 beats/minute. C.F.’s physician would like to add a

CCB to his regimen to improve BP control. What are the differences between controlled-onset, extendedrelease verapamil and sustained-release verapamil? Are they interchangeable?

All CCBs have short half-lives, except amlodipine. Immediate-release forms

require multiple daily doses to provide 24-hour effects. Sustained-released

formulations are preferred when a CCB is used to treat hypertension. Various

sustained-release delivery devices are available. Serum drug concentrations differ

among sustained-release CCBs, but overall BP lowering is usually similar.

Nonetheless, most of these products that include the same drug are not rated by the

US Food and Drug Administration as equivalent and identical. Insurance formularies

often encourage therapeutic substitution between these agents. Therapeutic

interchange between modified-release drug delivery formulations that allow for

once- or twice-daily dosing (e.g., sustained-release, extended-release, and

chronotherapeutic products), however, are not equivalent using a milligram-permilligram conversion. Therapeutic substitution among these products may result in

variable BP-lowering effects if not adjusted appropriately. BP and heart rate

monitoring should occur within 2 weeks of interchanging sustained-release CCBs.

CASE 9-7, QUESTION 2: Is there any clinical evidence on the use of CCB in diabetic outcomes?

CALCIUM-CHANNEL BLOCKER AND DIABETES

CCBs have been shown to reduce risk of CV events in patients with diabetes,

98

although the evidence is not as convincing as that seen with an ACEI. The results of

the Fosinopril versus Amlodipine Cardiovascular Events Randomized Trial and

Appropriate Blood Pressure Control in Diabetes trial suggest that ACEIs have more

CV protection than CCBs.

56,57

p. 155

p. 156

Table 9-13

Calcium-Channel Blockers in Hypertension

a

Drug Usual Dosage Range (mg/day) Dosing Frequency

Nondihydropyridines

b

Diltiazem, sustained release 120–480 Daily

Diltiazem, extended release

c 120–540 Daily

Verapamil, sustained release 180–480 Daily to BID

Verapamil, controlled-onset extended release

c 180–480 QHS

Verapamil, chronotherapeutic oral drug

absorption system

c

100–400 QHS

Dihydropyridines

Amlodipine 2.5–10 Daily

Felodipine, extended-release tablet 2.5–10 Daily

Isradipine, controlled-release tablet 5–20 Daily

Nicardipine, sustained-release capsule 60–120 BID

Nifedipine, sustained-release tablet

d 30–90 Daily

Nisoldipine, extended-release tablet 17–34 Daily

a

Immediate-release (IR) diltiazem, nifedipine, and verapamilshould be avoided in hypertension.

bMany different long-acting products exist. Because their individual release characteristics vary, they are not

exactly interchangeable using a milligram-per-milligram conversion.

cChronotherapeutic agents are dosed primarily at bedtime and have a delayed drug release for a period of hours,

followed by slow delivery of drug that starts just before morning, with no delivery during the early evening;

because they use different delivery systems, they are not interchangeable products.

dOnly sustained-release nifedipine is approved for hypertension. Immediate-release nifedipine should be avoided

for the management of hypertension.

BID, 2 times daily; QHS, every night.

Nondihydropyridine CCBs (particularly diltiazem) may slow the progression of

CKD, although evidence is not as extensive or definitive as it is with an ACEI or

ARB. The proposed mechanism is dilation of both the afferent and efferent arterioles,

which would decrease intraglomerular pressure. Dihydropyridines have unclear

effects on progression of kidney disease. The prevailing opinion is that the renal

protective effects of an ACEI and ARB are superior to that of a CCB.

Resistant Hypertension

CASE 9-8

QUESTION 1: R.R. is a 52-year-old man with hypertension for 10 years. He has not yet experienced any

hypertension-associated complications or target-organ damage. He does not have a history of diabetes and does

not smoke. He has been treated with HCTZ 25 mg daily, amlodipine 10 mg daily, valsartan 320 mg daily, and

carvedilol 12.5 mg twice daily for 1 year. He reports rarely missing a dose of his medications, measures his BP

at home every day, and follows recommended lifestyle modifications as diligently as possible. He has tried other

medications that resulted in intolerances (doxazosin, dizziness; clonidine, dry mouth). His BP has never been

less than 140/90 mm Hg, which is his goal. His BP today is 150/90 mm Hg (152/92 mm Hg when repeated), his

heart rate is 60 beats/minute, serum potassium is 4.2 mEq/L, and serum creatinine is 1.0 mg/dL. He is 183 cm

tall and weighs 85 kg. Does R.R. have resistant hypertension? What are his treatment options?

R.R. has resistant hypertension. JNC-8 guidelines recommends that, if goal BP is

not reached within a month of treatment of initial drug treatment, increase the dose of

the initial drug or add a second drug from one of the first-choice classes of

antihypertensives (thiazide diuretic, CCB, ACEI, or ARB). If goal BP cannot be

reached with maximal tolerable doses of two drugs, add and titrate a third drug from

the preferred provided. Do not use an ACEI and an ARB together in the same

patient.

2

If goal BP cannot be reached using only the drugs in the preferred list,

because of a contraindication or the need to use more than three drugs to reach goal

BP, antihypertensive drugs from other classes can be used. Referral to a hypertension

specialist may be indicated for patients in whom goal BP cannot be attained using the

above strategy or for the management of complicated patients for whom additional

clinical consultation is needed to rule out secondary causes of hypertension. R.R.’s

treatment options are limited. Amlodipine and valsartan are both at the maximal

doses. Carvedilol could be increased to 25 mg twice daily, but this should not be

done because his heart rate is 60 beats/minute and increasing this dose would place

him at risk for bradycardia. It is possible to increase HCTZ to 50 mg daily because

this higher dose provides larger BP reductions than 12.5 or 25 mg daily based on 24-

hour ABPM.

85 The limitation of this approach is an increased risk of electrolyte

abnormalities and metabolic side effects.

CASE 9-8, QUESTION 2: How safe is it to add lisinopril 5 mg daily or spironolactone 25 mg daily in R.R.?

For resistant hypertension, three global treatment philosophies should be

considered: (a) assuring appropriate diuretic therapy, (b) appropriate use of effective

drug combination, and (c) use of alternative antihypertensive agents as appropriate.

13

Adding an ACEI to an already maximum dose of valsartan would not be

recommended. The combination of an ACEI and ARB overall is not very beneficial.

This combination should not be used specifically for the purpose of BP lowering,

especially in primary prevention patients. When this combination was evaluated in

the ONTARGET, the ACEI with ARB combination treatment arm provided only

minimal additional reduction in BP compared with either agent alone and most

importantly did not additionally lower risk of CV events. Moreover, there was a

higher risk of

p. 156

p. 157

adverse events (e.g., kidney dysfunction and hypotension) with the combination

arm.

The combination of an ACEI with ARB has been used in patients with left

ventricular dysfunction based on promising data of a reduced risk of heart failure

hospitalizations.

101,102 However, the overall clinical benefits of an ACEI with an

ARB versus an ACEI without an ARB are very small; addition of an aldosterone

antagonist is the preferred next step in patients with left ventricular dysfunction who

are already treated with the standard regimen of a diuretic, ACEI, and a β-blocker.

79

One potential niche for the use of an ACEI with an ARB is in the setting of CKD with

significant proteinuria (300 mg albumin/day or 500 mg protein/day or per gram of

urinary creatinine), in which the combination of an ACEI with an ARB seems to

reduce progression of proteinuria better than either drug alone.

73

Many patients with resistant hypertension have a significant component of volume

expansion. Detecting this may not be easily observed using routine clinical

examinations. However, identifying occult volume expansion using serial

hemodynamic measurements from noninvasive bioimpedance testing, followed by

enhancing diuretic therapy, has been shown to reduce BP better than treatment

selected by an experienced hypertension specialist.

103 Options to assure appropriate

diuretic therapy include switching diuretic agents, switching diuretic classes,

increasing the dose, or adding a different class of diuretic. Instead of increasing

HCTZ to 50 mg daily, switching HCTZ to the more long-acting chlorthalidone is

another possible option to enhance BP lowering. This is an option in R.R. Another

option is switching HCTZ to a loop diuretic (e.g., furosemide or torsemide). This

should be considered for patients with stage 4 or 5 CKD (GFR <30 mL/minute/1.73

m2

) or for those who need diuresis because of edema. This is not a reasonable

treatment option for R.R. because he does not have CKD. Another option is to add an

aldosterone antagonist, which is considered an alternative antihypertensive agent.

Patients with resistant hypertension often require the use of an agent(s) (Table 9-14)

that is not widely used as either a first- or a second-line therapy. These therapies

should not be used as monotherapy or a cornerstone of a multidrug regimen because

there is less evidence to support their role in reducing CV events. It should be

acknowledged, however, that some of these agents (e.g., reserpine and hydralazine)

served as add-on agents to diuretics and β-blockers in early placebo-controlled,

stepped-care approach trials in hypertension. R.R. has already failed to fully respond

to, or tolerate, several drug classes that typically are associated with reductions in

hypertension-associated complications. To attain his BP goal of less than 140/90 mm

Hg, an alternative agent, other than clonidine, should be selected because he did not

tolerate it in the past.

Table 9-14

Alternative Antihypertensive Agents

Drugs/Mechanism of Action

Usual Dosage Range

(mg/day) Dosing Frequency

Aldosterone Antagonists (see Table 14-9)

α1

-Blockers

Doxazosin 1–8 Daily

Prazosin 2–20 BID to TID

Terazosin 1–20 Daily to BID

Direct Renin Inhibitor

Aliskiren 150–300 Daily

α2-Agonists (Central)

Clonidine

Clonidine

0.1–0.8

0.17–0.52

BID

Daily

Clonidine transdermal 0.1–0.3 Once weekly

Methyldopa 250–1,000 BID

Arterial Vasodilators

Hydralazine 25–100 BID to TID

Minoxidil 2.5–80 Daily to BID

Adrenergic Neuron Blockers

Reserpine 0.05–0.25 Daily

BID, 2 times daily; TID, 3 times daily.

ALTERNATIVE ANTIHYPERTENSIVE AGENTS

Aldosterone Antagonists

Spironolactone and eplerenone are aldosterone antagonists that are especially useful

as an add-on therapy in patients with resistant hypertension and would be a

reasonable addition to R.R.’s regimen.

8,104 Many patients with resistant hypertension

have increased activation of the RAAS, which can result in increased aldosterone.

Moreover, up to 20% of patients with resistant hypertension have primary

aldosteronism.

8 These characteristics of patients with resistant hypertension make the

addition of an aldosterone antagonist very effective in lowering BP in resistant

hypertension.

R.R.’s potassium is in the normal range, but could increase after adding

spironolactone. Therefore, it should be monitored 2 to 4 weeks after therapy is

started to assure R.R. does not experience hyperkalemia. Eplerenone is more specific

than spironolactone in aldosterone blockade, although some data suggest that

spironolactone is more effective in primary aldosteronism.

105 Compared with

spironolactone, gynecomastia is less frequent with eplerenone. The incidence of

hyperkalemia may be greater with eplerenone, however. When used for hypertension,

eplerenone is contraindicated in populations at high risk for hyperkalemia including

patients with an estimated creatinine clearance of less than 50 mL/minute or elevated

serum creatinine (>1.8 mg/dL in women and >2.0 mg/dL in men).

CASE 9-8, QUESTION 3: How beneficial would more intensive lifestyle modifications be in R.R.?

In addition to nonadherence with drug therapy, lifestyle factors (obesity, sodium

ingestion, and heavy alcohol intake) are a significant contributor to resistant

hypertension.

8 Lifestyle modifications should continually be reinforced in patients,

especially those with resistant hypertension. As previously discussed, these

modifications should include dietary changes and physical activity. R.R should be

instructed to restrict his daily sodium to less than 1.5 g because this has been shown

to decrease SBP by more than 20 mm Hg in resistant hypertension.

23

α-Blockers

CASE 9-9

QUESTION 1: J.L. is a 64-year-old man with hypertension. His BP is 158/84 mm Hg (156/86 mm Hg when

repeated). His current antihypertensive regimen is HCTZ 25 mg daily, irbesartan 300 mg daily, and nifedipine

extended-release 60 mg daily. J.L. is not completely adherent with lifestyle modifications, but insists he is doing

the best he can. He has been experiencing frequent nocturia, difficulty in starting urination, and a decrease in

his urinary flow for the past several months and is diagnosed with benign prostatic hyperplasia (BPH). J.L.’s

physician is considering changing one of his antihypertensive agents to an α-blocker. How do α-blockers

compare with other agents in reducing CV events?

p. 157

p. 158

α-Blockers are not first-line agents in the management of hypertension. The

ALLHAT trial originally included an α-blocker (doxazosin) treatment arm.

48

Interim

results after a mean follow-up of 3.3 years revealed that doxazosin had a statistically

higher risk of combined CV disease and heart failure when compared with

chlorthalidone.

106 Therefore, the ALLHAT data show that chlorthalidone was more

effective in lowering some hypertension-associated complications than was

doxazosin. This study did not include a placebo group; therefore, to conclude that

doxazosin is harmful is inaccurate. For J.L., discontinuing HCTZ, irbesartan, or

nifedipine to start an α-blocker is not prudent. It may be appropriate, however, to add

an α-blocker to his regimen; an α-blocker will also have a benefit on his BPH (Table

9-7).

CASE 9-9, QUESTION 2: How can an α-blocker improve J.L.’s BPH?

The smooth muscle surrounding the prostate is innervated by α1

-receptors. By

blocking these receptors, an α-blocker can improve the symptoms of BPH by

reducing urethral tone and alleviating bladder outlet obstruction. Terazosin and

doxazosin are both approved for the treatment of BPH. Prazosin should not be used

because of the need for frequent dosing. Improvements in BPH symptoms with αblockers are dose related. A high dose is often needed, and this increases the risk of

side effects, such as orthostatic hypotension. In J.L., an α-blocker will lower his BP

and improve his urinary symptoms.

CASE 9-9, QUESTION 3: J.L. prefers to try doxazosin rather than undergo surgery to relieve his symptoms

of BPH. How should this agent be started?

For J.L., it would be best to add a low dose of doxazosin to his present regimen.

Based on his BP response and tolerance, the dose can be titrated up. One of his other

antihypertensive agents can be decreased if he becomes hypotensive. The initial dose

of doxazosin should not exceed 1 mg daily and it should be given at bedtime. This

can minimize orthostatic hypotension, which is the most frequent side effect of α-

blockers. This complication is most pronounced with the first dose, but can persist in

some patients. Moreover, if an α-blocker is selected as add-on therapy in patients

like J.L. with resistant hypertension, nighttime administration of an α-blocker has

been shown to be effective in further lowering BP.

107

CASE 9-9, QUESTION 4: How should J.L. be counseled regarding side effects of doxazosin?

α-Blockers are well tolerated if dosed appropriately. J.L. could experience side

effects, such as drowsiness, headache, weakness, palpitations from reflex

tachycardia, and nausea, but these do not occur in all patients. Patients starting an αblocker should be instructed to take the initial dose at bedtime and to anticipate the

first-dose effect of orthostatic hypotension. Specifically, patients should be

counseled to rise more slowly from a seated or supine position.

Miscellaneous Agents

ALISKIREN

CASE 9-10

QUESTION 1: R.P. is a 68-year-old man with hypertension and a history of ischemic stroke (1 year ago).

Two months ago, his BP value was 164/94 mm Hg (162/98 mm Hg when repeated), with a heart rate of 62

beats/minute while on sustained-release diltiazem 240 mg daily. He was started on benazepril/HCTZ 10/12.5

mg daily 2 months ago. His BP today is 142/82 mm Hg (144/82 mm Hg when repeated). All his laboratory

values are normal except his serum creatinine, which is 1.9 mg/dL. J.L. has implemented lifestyle modification

to the best of his ability. His physician is wondering if aliskiren be added to his drug regiment considering he is

also on ACEI.

DIRECT RENIN INHIBITORS

Aliskiren is a direct renin inhibitor. It inhibits the first step of the RAAS, which

results in reduced PRA and BP lowering.

CASE 9-10, QUESTION 2: How is aliskiren different from an ACEI or ARB?

This is different from the decreased production of angiotensin II with ACEIs and the blocked angiotensin II

receptor effects with ARBs; however, BP-lowering effects are similar to those with ACEIs and ARBs.

Aliskiren has a 24-hour half-life and, similar to most ACEIs and ARBs, is dosed once daily.

Some similarities and some differences exist among the side effects associated

with aliskiren when compared with ACEIs and ARBs. Aliskiren should not be used

in pregnancy because of the known teratogenic effects from blocking the RAAS

system. Increases in serum creatinine and serum potassium have been associated with

aliskiren. These are similar to ACEI and ARB therapy and are mediated by the

inhibition of angiotensin II vasoconstrictive effects on the efferent arterioles of the

kidney and blocking of aldosterone. Monitoring of serum creatinine and serum

potassium should be done in patients treated with aliskiren, particularly in those

treated with the combination of aliskiren and an ACEI, ARB, potassium-sparing

diuretic, or aldosterone antagonist. Angioedema has also been reported in patients

treated with aliskiren.

CASE 9-10, QUESTION 3: What is the role of aliskiren in treating R.P.’s hypertension?

The exact role of aliskiren in treatment of hypertension is unclear. It is approved

as monotherapy or in combination therapy. The BP reductions with aliskiren as

monotherapy are similar to those seen with an ACEI, ARB, or CCB (specifically

amlodipine). Aliskiren provides additive BP lowering when used in combination

with HCTZ, ACEI, ARB, and CCB. Its efficacy in combination with maximal doses

of ACEI is unknown, however. Aliskiren is an alternative antihypertensive agent at

this time because of unknown long-term effects on CV events.

MIXED αβ-BLOCKERS AND NEBIVOLOL

Labetalol and carvedilol (Table 9-15) are nonselective β-blockers that also have α1

-