CCBs effectively lower BP. Elderly and black patients generally

have greater BP reduction with a CCB than with other agents

(β-blockers, ACEIs, ARBs). The addition of a diuretic to a CCB

provides additive antihypertensive effects, but is not usually as

effective as the combination of an ARB with a CCB. 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.

For a table that summarizes the

pharmacologic effects of the two primary

subtypes of CCBs, see Online Table 14-3 at

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

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, peripheral edema).

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

321Essential Hypertension Chapter 14

TABLE 14-14

Calcium-Channel Blockers in Hypertensiona

Drug Usual Dosage Range (mg/d) Dosing Frequency

Nondihydropyridinesb

Diltiazem, sustained-release 120–480 Daily

Diltiazem, extended-releasec 120–540 Daily

Verapamil, sustained-release 180–480 Daily to BID

Verapamil, controlled-onset extended-releasec 180–480 QHS

Verapamil, chronotherapeutic oral drug absorption systemc 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 tabletd 30–90 Daily

Nisoldipine, extended-release tablet 17–34 Daily

a Immediate-release (IR) diltiazem, nifedipine, and verapamil should be avoided in hypertension.

b Many 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.

d Only sustained-release nifedipine is approved for hypertension. Immediate-release nifedipine should be avoided for the management of hypertension.

BID, twice daily; QHS, every night.

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. Diltiazem may have a lower incidence of constipation

than verapamil.

FORMULATIONS

Several CCBs are available for the treatment of hypertension.

They are listed in Table 14-14. Immediate-release formulations

should be avoided (see Chapter 21, Hypertensive Crises).149

SUSTAINED-RELEASE FORMULATIONS

CASE 14-7

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 controlledonset, extended-release verapamil and sustained-release

verapamil? Are they interchangeable?

All CCBs have short half-lives, except amlodipine. Immediaterelease 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, 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.

COMPELLING INDICATIONS

DIABETES

CASE 14-7, QUESTION 2: Why is diabetes a compelling indication for a CCB in C.F.?

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

with diabetes,3,91 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.70,71

The primary role of a CCB in the management of hypertension in diabetes is ideally as a component of sequential add-on

therapy, after an ACEI or ARB. In a subgroup of 6,946 patients

with diabetes from the ACCOMPLISH trial, patients on the combination of an ACEI with CCB had fewer CV events than patients

on the combination of an ACEI with thiazide diuretic.90 Therefore, these data support using a CCB ahead of a thiazide diuretic

as the second drug added to an ACEI (or ARB as an alternative)

for hypertension in diabetes. Because the BP goal in diabetes is

less than 130/80 mm Hg, most patients with diabetes need three

or more antihypertensive agents to achieve this goal. A CCB is

frequently needed in this population.

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

322 Section 2 Cardiac and Vascular Disorders

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.

CHRONIC CORONARY ARTERY DISEASE

CASE 14-8

QUESTION 1: A.P. is a 71-year-old man with a BP of 168/90

mm Hg (170/90 mm Hg when repeated) and a heart rate of

88 beats/minute. He has a history of chronic stable angina

that is treated with sublingual nitroglycerin as needed for

ischemic symptoms. He also has severe chronic obstructive

pulmonary disease that is worsened with β-blocker therapy. He currently has no ischemic symptoms. All laboratory

results are normal, except his serum creatinine is 1.3 mg/dL.

Is a CCB appropriate for A.P.? If yes, which type is preferred?

Chronic CAD (i.e., chronic stable angina) is a compelling

indication for use of a CCB, but CCBs are an alternative to a

β-blocker, or sequential add-on therapy to a β-blocker for

patients who require additional anti-ischemic effects.56,101 Alternatives to β-blockers are needed when contraindications or intolerances to β-blockers are present. Sustained-release CCB formulations or long-acting products (i.e., amlodipine) are always

preferred. When used as an alternative to a β-blocker, a nondihydropyridine CCB is preferred because they decrease myocardial oxygen demand, improve myocardial blood flow, and have

negative inotropic and chronotropic effects. All these may

benefit patients with CAD. Dihydropyridine CCBs are similar,

but do not lower heart rate, and have less negative inotropic

effects. They can be used in patients with chronic CAD and possibly acute CAD, but verapamil and diltiazem are preferred when

a CCB is used instead of a β-blocker.

Therapy with a CCB is preferred in A.P. because β-blockers

worsened his severe chronic obstructive pulmonary disease. Verapamil will lower his elevated heart rate and BP as well as reduce

episodes of ischemic symptoms (i.e., chest pain). Constipation,

which is more prevalent in the elderly, is a common side effect

with verapamil. This can be mitigated with dietary changes, bulkforming laxatives, or the regular use of a stool softener. Similar

to other antihypertensive agents, a low dose (120–180 mg daily)

should be used initially and slowly titrated at 2- to 4-week intervals.

ADDITIONAL POPULATIONS

ISOLATED SYSTOLIC HYPERTENSION

CASE 14-9

QUESTION 1: T.C. is a 76-year-old woman with hypertension

and dyslipidemia. She has been adherent with her regimen

of chlorthalidone 25 mg daily for several years. Her BP values are 164/76 mm Hg (168/78 mm Hg when repeated). She

has no other evidence of hypertension-associated complications, and no compelling indications. Her laboratory values

and ECG are all normal. Amlodipine 5 mg daily is added to

her regimen. What are the benefits of using a CCB to treat

T.C.’s hypertension?

T.C. has ISH. This should be managed according to the general patient care principles for hypertension. Thiazide diuretics

have traditionally been considered first-line therapy for this population based on historical data demonstrating CV event lowering in elderly patients with isolated systolic hypertension. The

SHEP trial proved that treating ISH in the elderly is beneficial and

established thiazide diuretic-based regimens as first-line agents.47

Long-acting dihydropyridine CCBs have been shown to reduce

CV events in patients with ISH also. The Systolic Hypertension in Europe study was similar to the SHEP trial, but used a

nitrendipine-based (a long-acting dihydropyridine CCB similar

to long-acting nifedipine) regimen instead of a thiazide diureticbased regimen.50 Amlodipine is an appropriate add-on therapy

for T.C. to control her BP and reduce her risk of CV events.

EDEMA FROM DIHYDROPYRIDINE

CALCIUM-CHANNEL BLOCKERS

CASE 14-9, QUESTION 2: One month later, T.C.’s BP is down

to 148/70 mm Hg (150/70 mm Hg when repeated). She is

tolerating her amlodipine, except she has swelling in both

ankles. T.C. has never had this problem before. A complete

cardiovascular examination shows no signs of left ventricular dysfunction or other hypertension-associated complications that would explain this new peripheral edema. Her

amlodipine therapy is identified as the cause of this edema.

How should her edema be managed? Should chlorthalidone be changed to a loop diuretic, should amlodipine be

stopped, or is there another option?

Peripheral edema with CCB therapy, especially a dihydropyridine CCB, is a dose-dependent 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 though 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.

T.C.’s BP is not at her goal of less than 140/90 mm Hg, and

additional drug therapy is needed. Her best option is to add an

ACEI or ARB to minimize her edema. She has otherwise tolerated

amlodipine, so no urgent need exists to discontinue this agent.

Moreover, lowering the dose of amlodipine to 2.5 mg is an option,

but BP lowering with this low dose is minimal, and she would

still require the addition of another agent anyway.

ADDITIONAL POPULATIONS

Diltiazem and verapamil can also be used to treat atrial fibrillation, atrial flutter, and supraventricular arrhythmias owing to

their ability to block the AV node and lower heart rate. Verapamil is effective in migraine prophylaxis. Patients with Raynaud’s 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

LEFT VENTRICULAR DYSFUNCTION

CASE 14-9, QUESTION 3: Why are nondihydropyridine

CCBs contraindicated in left ventricular dysfunction (systolic

heart failure)?

323Essential Hypertension Chapter 14

CCBs, especially nondihydropyridines, have negative

inotropic effects that result in a decrease in cardiac contractility.

This is most pronounced with verapamil, but is also present

with diltiazem and with some dihydropyridines (Online Table

14-3). In left ventricular dysfunction, the primary physiologic

problem is decreased cardiac contractility. Thus, using a CCB in

this population can exacerbate left ventricular dysfunction, or

potentially unmask left ventricular dysfunction that has not yet

been diagnosed.

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.

β-Blockers

CASE 14-10

QUESTION 1: E.K. is a 78-year-old black man with a history of hypertension. He was hospitalized for an acute MI 2

months ago and has been treated with metoprolol succinate

50 mg daily and lisinopril 20 mg daily since then. Today his

BP readings are 148/92 and 146/90 mm Hg, and his heart

rate is 80 beats/minute. He denies medication-related side

effects. Because E.K. is black and elderly, will β-blocker therapy be effective?

β-Blockers reduce morbidity and mortality in patients with

certain compelling indications.3,15 These include left ventricular

dysfunction, CAD, and diabetes. β-Blocker therapy should not

be the primary antihypertensive agent for primary prevention

patients, but is an effective alternative add-on agent for primary

prevention patients to lower BP. Elderly and black patients may

have less BP reduction than young or white patients. E.K. is

elderly and might have more BP reduction with another agent

(i.e., thiazide diuretic or CCB), but these points are moot in

E.K. Age and race should never deter use of a β-blocker when a

compelling indication is present. Because of E.K.’s previous MI,

a β-blocker as first-line is compellingly indicated.