Dihydropyridine/Nondihydropyridine Calcium Channel Blocker Combination Therapy

An 80‐year‐old woman was transferred to the Kaiser Permanente Anaheim Hospital for continuing evaluation of refractory stage 2 isolated systolic hypertension. She had been on antihypertensive medication for 35 years with good control but suffered a pontine stroke in 2002 with residual left‐sided weakness and speech difficulty. Systolic pressures were most often <140 mm Hg before her transfer; more recent systolic blood pressures (BPs) were 180–200 mm Hg despite changes in her medication regimen.

This patient had a history of thiazide‐related hyponatremia. Felodipine 10 mg daily had been added to lisinopril 40 mg daily; sustained‐release verapamil (verapamil sr) 120 mg daily was substituted for felodipine. Because of a systolic pressure of 200 mm Hg and lightheadedness, paramedics were called. At the referring hospital, a clonidine patch 0.2 mg was applied with a BP the next morning of 162/87 mm Hg on arrival at Kaiser Permanente Anaheim Hospital. She had also received lisinopril 40 mg and verapamil sr 120 mg. Following hospital discharge, BPs were between 156–164/76–88 mm Hg preceding her evaluation in the hypertension clinic.

It was decided to change her management to a dihydropyridine/nondihydropyridine calcium channel blocker (CCB) combination. Follow‐up clinic BPs were 128–138/68–72 mm Hg on lisinopril 40 mg, felodipine 20 mg, and verapamil sr 120 mg daily.

CASE TWO

A 79‐year‐old woman was evaluated in the hypertension clinic for refractory stage 2 systolic hypertension. She had been receiving antihypertensive medication for 40–45 years with good blood pressure control on hydrochlorothiazide (HCTZ)/triamterene and diltiazem. For the past 4 years, systolic BPs had been in the 150 mm Hg range. Over the 6 months immediately following her referral, there was chart record of a dozen systolic pressures of 152–184 mm Hg despite the addition of increasing doses of clonidine. HCTZ and furosemide, which had been added, were discontinued because of hyponatremia. When first seen in the hypertension clinic, she was taking atenolol 50 mg bid, diltiazem 240 mg in the morning and diltiazem 120 mg in the evening, clonidine 0.1 mg in the morning and clonidine 0.2 mg at bedtime BPs of 212–216/82–84 mm Hg were recorded over the prior 2 months.

A dihydropyridine/nondihydropyridine CCB strategy was pursued with follow‐up BPs of 136–138/80–82 mm Hg on lisinopril 40 mg, nifedipine extended release 60 mg, and diltiazem extended release 240 mg daily.

CASE THREE

A 62‐year‐old black man was referred to the hypertension clinic for persistent stage 1 hypertension despite a regimen of verapamil sr 240 mg bid and lisinopril 20 mg daily. A combination of lisinopril 20 mg/HCTZ 25 mg was substituted for lisinopril alone with subsequent BPs of 146–152/84–92 mm Hg. When nifedipine extended release 30 mg was added to verapamil sr 240 mg qd and lisinopril 20 mg/HCTZ 25 mg, the patient felt well with followup BPs of 126–134/82–86 mm Hg.

DISCUSSION

It is generally substandard practice to combine antihypertensive agents from the same class, with some notable exceptions. Guidelines note that two β blockers, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, or peripheral α‐1 blockers should be used in the same patient. Diuretic‐diuretic usage is common when a thiazide or thiazide‐like diuretic is combined with a potassium sparing or loop diuretic. The three case presentations illustrate the practicality of using dihydropyridine and nondihydropyridine CCBs together.

Three subclasses of CCBs—the phenylalkylamines (verapamil‐like), benzothiazepines (diltiazem‐like),and the dihydropyridines (nifedipinelike)— bind to different portions of the α 1C subunit of the L‐type calcium channel. ¹ All CCBs lower BP by vasodilatation and all are metabolized to less active derivatives by oxidative pathways in the liver, predominantly by cytochrome P‐450 CYP3A. ¹ The verapamil‐like and diltiazem‐like subgroups are more generally categorized as nondihydropyridine CCBs and share the important cardiac specific properties of rate slowing via atrioventricular conduction inhibition. The dihydropyridines are more potent vasodilators, lacking a conduction‐slowing effect, and therefore may be safely combined with a β blocker.Table I illustrates the distinctive cardiovascular effects of nifedipine compared with diltiazem and verapamil. ²

Table I.

Cardiovascular Profile of Calcium Channel Blockers

System	Nifedipine	Diltiazem	Verapamil
Coronary vessels
Tone	—	–	–
Flow	+++	++	++
Peripheral vasodilatation	+++	+	++
Heart rate	++	−	−
Contractility	0,+	0,−	0,−
Atrioventricular node conduction	0	−	−
+ and − signs indicate the degree of effect on various systems; 0 indicates no effect. Reproduced with permission from Kaplan's Clinical Hypertension, 8th ed. Philadelphia, PA: Lippincott Williams and Wilkins; 2002:271–277. 2

The side effect profiles of dihydropyridine and nondihydropyridine CCBs further distinguish these subclasses. Verapamil and diltiazem may be associated with bradycardia and generally should not be used together with other rate slowing agents such as β blockers and clonidine. Verapamil may cause constipation; however, the nifedipine group (nifedipine, felodipine, amlodipine, isradipine, and nicardipine) causes more dizziness, headache, flushing, and peripheral edema.Table II andTable III, ³ , ⁴ indicate that while the frequency of side effects and drug discontinuation are similar, the adverse effect profiles are different.

Table II.

Side Effects of Antihypertensive Treatment with Calcium Channel Antagonists (CCAs)

	SE		Discontinuation		Edema		Headache		Flush		Exanthema
CCA	n	%	n	%	n	%	n	%	n	%	n	%
Verapamil	185	35.1	37	20	9	4.9	10	5.4	1	0.5	2	1.1
Diltiazem	163	22.7	23	14	10	6.1	9	5.5	5	3.1	3	1.8
Nifedipine	295	28.5	52	17.6	42	14.2	10	3.4	18	6.1	3	1.0
Felodipine	426	30.0	59	13.8	69	16.2	29	6.8	13	3.1	14	3.3
SE=standard error; Reprinted with permission from J Hypertens. 2001;14:114A. 3

Table III.

Percentage of Adverse Reactions With Calcium Channel Blockers

Adverse Effect	Nifedipine	Verapamil	Diltiazem
Overall incidence	17.0	8.0	4.0
Dizziness or light headedness	10	3.6	‐
Peripheral edema	10	1.7	2.4
Headache	10	1.8	2.0
Flushing or heat sensation	10	‐	‐
Transient hypotension	5	2.9	‐
Nausea	10	1.6	2.7
Constipation	‐	6.3	‐
Bradycardia	‐	1.1	2.0
Rash	‐	‐	1.8
Reprinted with permission from Hypertension. 1988;11(3 pt 2):II42–II44. 4

Clinical trials tend to imply different roles for dihydropyridine and nondihydropyridine CCBs for patients with diabetic nephropathy and patients following myocardial infarction. Consensus guidelines state that nondihydropyridine CCBs have been shown to reduce proteinuria and diabetic nephropathy progression independent of an angiotensin converting enzyme inhibitor. ⁵ However, the renoprotective benefits of dihydropyridine CCBs are less convincing, and diabetic patients with microalbuminuria or nephropathy should have renin‐angiotensin‐aldosterone system protection with an angiotensin‐converting inhibitor or an angiotensin receptor blocker before adding a dihydropyridine CCB.

The International Verapamil‐Trandolapril Study (INVEST) ⁶ concluded that a verapamil‐based strategy was as effective as the β blocker treatment algorithm in preventing the combined end point of fatal and nonfatal myocardial infarction and stroke in hypertensive patients with coronary artery disease. In contrast, none of the dihydropyridine CCBs have been shown to play a similar cardioprotective role compared with β blockers in patients with coronary artery disease. However, combinations of diltiazem and nifedipine have been used successfully to reduce exertional angina. ⁷ , ⁸

Combined dihydropyridine/nondihydropyridine CCB therapy has been used effectively in hypertensive patients with additive and sometimes synergistic BP‐reducing properties. ⁹ , ¹⁰ , ¹¹ Saseen and colleagues ⁹ found that the addition of either verapamil or diltiazem significantly raised nifedipine blood levels, and this pharmacokinetic interaction was thought to play a role in the observed BP reduction. Improved exercise tolerance in angina patients receiving combined CCB therapy was also attributed to the interactive effect of diltiazem, raising the blood level of nifedipine. ⁷ Diltiazem and nifedipine used together had a slightly higher edema rate compared with either drug used alone in the angina study. ⁸ However, when used together for hypertension, Nalbantgil et al. ¹¹ found in a small study that verapamil and nitrendipine had a lower rate of side effects than either drug used alone. This benefit was attributed to the dose reduction of the individual agents used conjointly because of synergistic activity, as well as the counterbalancing of the increased heart rate effect of nitrendipine with the slowing effect of verapamil. Consensus guidelines for treating hypertensive patients with diabetes mellitus contain an algorithm for combined CCB treatment once an angiotensin‐converting enzyme inhibitor and possibly a β blocker are on board and are ineffective. ⁵

The three case presentations illustrate a legitimate role for CCB combination therapy in patients' refractory to usual stepped care drug regimens. Preferential therapy for the two elderly women would have involved a diuretic, but both individuals were diuretic intolerant with hyponatremia. Elderly patients ¹² , ¹³ and blacks share a low renin hypertensive pathophysiology and clinical trials have demonstrated these populations to be especially responsive to calcium channel treatment. Guidelines for the management of African American hypertension state, “thiazide diuretics and calcium channel blockers may have greater blood pressure‐lowering effects than do other classes in African Americans than in whites.” ¹⁴ An effective option for individuals in these populations refractory to the usual stepped care treatment regimens can be combination therapy with dihydropyridine and nondihydropyridine CCBs.