Combination Calcium Channel Blocker Therapy in the Treatment of Hypertension

Abstract

Effective control of blood pressure is usually achieved only with the use of two or more antihypertensive medications. The treatment options for hypertension are numerous, and the number of possible combinations large. The selection of a specific combination drug regimen has often been linked to the perceived need for diuretic therapy as first‐ or second‐step therapy; thus, the popularity of such drug combinations as an angiotensin‐converting enzyme (ACE) inhibitor/diuretic, an angiotensin‐receptor blocker/diuretic, or a β blocker/diuretic. Rational alternatives exist, including an ACE inhibitor/calcium channel blocker (CCB) or a dihydropyridine CCB/β blocker combination. Traditionally, recommendations have advised against the use of combination therapy with two drugs from the same therapeutic class. However, because of the different binding and pharmacologic characteristics of CCBs, a rationale exists for combining different agents in this class in the management of hypertension and/or symptomatic coronary artery disease. In the treatment of either hypertension or angina, combination CCB therapy can prove uniquely successful.

Ten calcium channel blockers (CCBs) are currently marketed in the United States. These agents are employed in the treatment of hypertension, angina, and/or supraventricular arrhythmias. Nimodipine is approved for short‐term use in patients who have suffered a subarachnoid hemorrhage. Diltiazem, nicardipine, and verapamil are the only CCBs currently available in intravenous formulations. Long‐term treatment with CCBs is typically by the oral route. Long‐acting CCBs are now the preferred mode of therapy in the treatment of hypertension and/or angina when a CCB is opted for (Table I). ¹

Table I.

Dosing Information for Calcium Channel Blockers Currently Marketed in the United States

Drug	Approved Indications	Form, Strength, and Dose	Time to Peak Effect	Elimination Half‐Life	Comments
Amlodipine (Norvasc®)	Hypertension; chronic stable and vasospastic angina	Tablet: 2.5, 5.0, 10 mg once daily	6–12 h	30–50 h	No effect of grapefruit juice on pharmacokinetics; available as a fixed‐dose combination with benazepril
Bepridil (Vascor®)	Refractory angina	Tablet: 200, 300, 400 mg once daily	2–3 h	26–64 h	Can cause torsade de pointes‐type ventricular tachycardia
Diltiazem (Tiazac®) (Cardizem®)	Hypertension; chronic stable and vasospastic angina; atrial fibrillation or flutter; paroxysmal SVT	Immediate‐ and sustained‐release: 80–480 mg once daily	0.5–1.5 h immediate) 6–11 h (sustained)	2–5 h 2.5 h	Contraindicated in patients with sick‐sinus syndrome and 2nd‐ or 3rd‐degree atrioventricular block
Felodipine (Plendil®)	Hypertension	Sustained‐release: 2.5, 5.0, 10.0 mg once daily	2.5–5.0 h	11–16h	Grapefruit juice causes a two‐fold or more ↑ in felodipine bioavailability; metabolized by CYP3A4; available as a fixed‐dose combination with enalapril
Isradipine (Dynacirc®)	Hypertension	Tablet: 2.5, 5.0 mg twice daily	1.5 h	8–12 h	Sustained‐release form in development
Nicardipine (Cardene®)	Hypertension; angina	Immediate‐release tablet: 20–40 mg three times daily sustained‐release tablet: 60–120 mg once daily	0.5–2.0 h	8h 8h	Available in intravenous form for hypertension treatment
Nifedipine (Adalat®) (Procardia®) (Procardia‐XL)	Hypertension; angina ®	Immediate‐release capsule: 10, 20 mg (dose varies by indication); sustained‐release capsule: 30, 60, 90 mg once daily	0.5 h	2h	Immediate‐release capsule should not be used for control of essential hypertension or acute reduction of blood pressure
Nimodipine (Nimotop®)	Subarachnoid hemorrhage	Capsule: 60 mg every 4 h for 21 days	1h	1–2 h	Crosses the blood‐brain barrier readily; oral therapy should commence within 96 h of hemorrhage
Nisoldipine (Sular®)	Hypertension	Sustained‐release tablet: 10, 20, 30, 40 mg once daily	6–12 h	7–12 h	Grapefruit juice significantly ↑ nisoldipine bioavailability
Verapamil (Calan®) (Calan‐SR®) (Covera‐HS®)	Hypertension; angina; atrial fibrillation or flutter;	Immediate‐release tablet: dose varies by indication; sustained release	0.5–1.0 h	4.5–12 h	Nocturnally indicated forms of verapamil available
(Verelan PM®)	paroxysmal SVT	tablet: 120–480 mg/day	4–6 h	4.5–12 h
CYP3A4=cytochrome P3A4; SVT=supraventricular tachycardia; AV=atrioventricular Adapted with permission from N Engl J Med. 1999;341:1447–1457. 1

CCBs are a heterogeneous group of compounds, with distinctive structures and pharmacologic properties. There are three distinct subclasses of CCBs, which explains the differences observed with these agents. These subclasses are the phenylalkylamines (e.g., verapamil), the benzothiazepines (e.g., diltiazem) and the dihydropyridines (e.g., nifedipine, amlodipine, felodipine). All currently available CCBs are vasodilators and thereby reduce blood pressure. The relative potency of CCBs as vasodilators varies, with dihydropyridine‐type compounds, such as nifedipine, regarded as the most potent subclass, and verapamil, diltiazem, and bepridil as somewhat less potent.

In vitro, several calcium antagonists (e.g., nifedipine, nisoldipine, and isradipine) bind with some selectivity to the L‐type calcium channel present in blood vessels, whereas verapamil binds equally well to cardiac and vascular L‐type calcium channels. ² , ³ The applicability of these in vitro findings to treatment response in humans remains ill‐defined. In vitro, all CCB subclasses both depress sinus node activity and slow atrioventricular conduction. Only verapamil and diltiazem delay atrioventricular conduction or cause sinus node depression at doses in common use clinically. ¹ Similarly, all CCB subclasses exhibit a concentration‐dependent negative inotropic effect in vitro, but only verapamil and diltiazem do so in vivo. The disparities between the in vitro and in vivo effects may relate, in part, to the sympathetic activation triggered by dihydropyridine‐induced vasodilation, which blunts any direct negative chronotropic and inotropic effects.

HYPERTENSION

In the United States, amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil are currently approved for the treatment of patients with hypertension (Table I). Each of these drugs lowers both systolic and diastolic blood pressure during long‐term oral administration at the recommended doses. Most are available in long‐acting formulations that permit once‐daily administration (Table I). Verapamil is also available as a delayed‐onset and sustained‐release formulation indicated for nocturnal dosing. ⁴ In the United States, CCBs are currently recommended as first‐line therapy for hypertension only if there is a compelling reason not to administer a thiazide diuretic or a β blocker. ⁵ Patients with severe hypertension, such as renal failure and hemodialysis patients, present an obvious exception to this maxim. These patients typically require multiple agents for adequate control of blood pressure because of either inadequate control with single‐drug therapy or unacceptable side effects from high doses of a single agent. ⁶ This pattern of requiring multidrug therapy is also very common in patients with a wide range of comorbid conditions, such as diabetes. ⁷ Consequently, effective drug combinations are needed to safely and efficiently bring blood pressure to goal in many hypertensives.

CCBs are considered a single class of drugs because of their mechanism of action, yet they comprise a heterogeneous group of drugs that includes verapamil, diltiazem, and the dihydropyridine group. The intraclass differences that exist among the CCBs reside in each drug's predominant site of action. Hence, using combinations of CCBs from different groups has been observed to result in additive clinical effects in both the treatment of angina pectoris ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ and hypertension. ¹⁴ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ Early laboratory investigations provide a theoretic basis for the additive nature of CCB response. These studies suggested a synergistic effect on receptor binding, ²² as well as increased drug concentrations, when diltiazem and a dihydropyridine CCB were concurrently used. ²³ , ²⁴ , ²⁵ , ²⁶

DUAL CALCIUM CHANNEL BLOCKER THERAPY

Pharmacokinetic Aspects.

A pharmacokinetic interaction importantly contributes to the additive response of different CCB subclasses. Diltiazem and verapamil are known inhibitors of the cytochrome (CY) P₄₅₀ system. ²⁷ In particular, verapamil and diltiazem inhibit the CYP_3A‐mediated biotransformation of drugs. A sampling of drugs that undergo CYP‐3A‐mediated biotransformation include simvastatin, ²⁸ lovastatin, ²⁹ cyclosporine, ²⁷ and the aforementioned dihydropyridine CCBs. ²⁴ , ²⁵ , ²⁶ In principle, the interaction between verapamil or diltiazem and a dihydropyridine CCB can be exploited clinically to more effectively treat the hypertensive patient. Diltiazem seems to inhibit the clearance of nifedipine in a dose‐dependent manner. ²⁴ , ²⁵ , ²⁶ This interaction occurs quickly and is nearly maximal within 3 days of dosing. ²⁶ Less well appreciated is the fact that nifedipine influences the pharmacokinetics of diltiazem. Early observations showed that pretreatment with nifedipine increased diltiazem concentrations, presumably secondarily to both a decrease in its hepatic clearance and an increase in its bioavailability. ²³

Pharmacodynamic Aspects.

The pharmacodynamic interaction of CCBs results in greater vasodilation than if only a single CCB is given. For example, the step‐up in forearm blood flow that accompanies amlodipine treatment is increased by an additional 50% when verapamil is coadministered. ²⁰ The mechanism of this augmentation is poorly worked out. It is likely that it is related, at least in part, to drug‐mediated alterations in receptor affinity. Drug‐induced alterations in receptor binding of CCBs differ from compound to compound. For example, dihydropyridines inhibit the receptor binding of coadministered dihydropyridines; diltiazem enhances receptor binding, ²² whereas verapamil inhibits the receptor binding of nitrendipine. ³⁰ , ³¹ Despite the supposedly negative effect of verapamil on nitrendipine binding, its clinical effect is additive, if not synergistic, in reducing blood pressure, a finding that, not surprisingly, contradicts the in vitro binding data. ³²

An important consideration in CCB pharmacodynamic interaction is the close correlation between the pharmacodynamic effects of nifedipine and its plasma concentration. A higher plasma level of nifedipine, and presumably of other dihydropyridine CCBs, achieves a greater hemodynamic effect. ³¹ Although appealing, the clinical relevance of the dual CCB pharmacodynamic interaction, in the treatment of coronary artery disease and/or systemic hypertension, requires additional study.

Angina Pectoris.

The largest body of literature assessing the use of dual CCB therapy is in the area of ischemic heart disease. As in the treatment of hypertension, the use of combination CCB therapy offers clinical benefit to patients who exhibit a subtherapeutic response to single‐agent antianginal therapy, particularly when an alternative, such as a β blocker, is contraindicated (Table II). ¹⁶

Table II.

Clinical Trials Evaluating Dual Calcium Channel Blocker Therapy in Angina

Reference	Disease and Number of Subjects	Study Design	Monotherapy (Mean Dosage)	Dosage of Dual Therapy	Results of Dual Therapy
Prida et al. 8	Coronary artery spasm n=9	R/P‐C; D‐B mono; O‐L dual, cross‐over	Diltiazem 90–360 mg/d; nifedipine 30–120 mg/d	Diltiazem 90–360 mg/d (206 mg/d); nifedipine 30–120 mg/d (61 mg/d)	Intolerable adverse effects in 33% (3/9); clinical improvement in 22% (2/9); no improvement in 44% (4/9)
Pucci et al. 9	Stable effort angina n=12	D‐B/P‐C; 4 × 4 400‐mg once daily Latin‐square	Diltiazem 60 mg × 1 and felodipine 10 mg × 1	Diltiazem 60 mg × 1 with felodipine 10 mg × 1	Prolongation of exercise time to ischemic threshold and to peak exercise; 1 patient with hypotension
Frishman et al. 10	Stable effort angina n=13	R/PL, D‐B mono; O‐L dual, cross‐over	Diltiazem 180–360 (352 mg/d) and nifedipine 30–120 mg/d (95 mg/d)	Diltiazem 180–360 (320 mg/d) and nifedipine 30–120 mg/d (52 mg/d)	Improved exercise tolerance and ↓ in angina attacks; ↑ nifedipine concentrations with dual therapy
Toyosaki et al. 11	Stable effort angina n=11	R/P‐C/D‐B, cross‐over	Diltiazem 120 mg/d and nifedipine 40 mg/d	Diltiazem 120 mg/d with nifedipine 40 mg/d	↑ exercise time; ↑ nifedipine concentrations with dual therapy
R=randomized; P‐C=placebo‐controlled; D‐B=double‐blind; O‐L=open‐label; PL=placebo Adapted with permission from Ann Pharmacother. 1996;30:802–810. 16

On the basis of favorable responses observed in these studies, it has been suggested that the vasodilator effects of diltiazem are additive to those of a dihydropyridine CCB. The high incidence of adverse effects observed in some of these studies is cause for concern. ⁸ This may occur because of increased nifedipine concentrations, or simply because the compounds have comparable adverse event profiles. ⁸ Dual CCB therapy may be particularly useful when treatment options for symptomatic coronary artery disease are limited by contraindications to other more traditional agents, such as β blockers.

Hypertension.

In 1991, Kaesemeyer et al. ¹⁹ assessed the combined use of nifedipine 120 mg/day, verapamil 480 mg/day, and spironolactone 200 mg/day to control blood pressure when captopril 550 mg/day and verapamil 480 mg/day had previously failed. A subsequent case series reported by Comerio et al. ¹⁵ noted that the combination of verapamil and lacidipine reduced blood pressure to a greater degree (−20 mm Hg systolic and −10 mm Hg diastolic) than either agent alone. This reduction was independent of any noteworthy change in heart rate. Moreover, the renin‐angiotensin‐aldosterone system was not unduly activated by this CCB combination (Table III).

Table III.

Clinical Trials to Evaluate Dual Calcium Channel Blocker Therapy in Hypertension

Reference	Disease and Number of Subjects	Study Design	Monotherapy (Mean Dosage)	Dosage of Dual Therapy	Results of Dual Therapy
Comerio et al. 15	Hypertension n=13	R/D‐B	Lacidipine 4 mg/d; verapamil 240 mg/d	Lacidipine 4 mg/d with verapamil 240 mg/d	Combined lacidipine and verapamil reduced BP from 160±11/101±7 to 140±11/92±5
Kiowski et al. 20	Hypertension n=8	O‐L, cross‐over	Amlodipine 44.5 µg/min/100 mL of forearm tissue	Amlodipine 44.5 µg/min/100 mL 2.5 h of forearm tissue with verapamil 40 µg/min/100 mL of forearm tissue	↑ forearm blood flow (2.9±1.7 to a maximum of 23.6±7.6 mL with amlodipine); further increase to 34.4±9.8 mL/min/100 mL with verapamil
Andreyev et al. 12	Hypertension and stable effort angina n=16	O‐L, cross‐over	Diltiazem 240 mg/d; nitrendipine 20 mg/d	Diltiazem 120 mg/d with nitrendipine 20 mg/d	Better BP control compared with diltiazem monotherapy but not nitrendipine monotherapy; better ischemic control with dual therapy
Nalbantgil et al. 21	Hypertension n=40	R/P‐C/D‐B, cross‐over	Verapamil 240 mg/d and nitrendipine 20 mg/d	Verapamil 120 mg/d with nitrendipine 10 mg/d	Improved BP control and fewer adverse effects with dual therapy
Kaesemeyer et al. 17	Mild hypertension n=23	Retrospective analysis		Verapamil 120–360 mg/d with nifedipine 30–90 mg/d	BP controlled in 100% (23/23) and leg edema in 30% (7/23)
Kaesemeyer et al. 17	Moderate to severe hypertension n=27	Retrospective analysis		Verapamil 120–480 mg/d with nifedipine 180 mg/d or verapamil 480 mg/d with nifedipine 30–180 mg/d	BP controlled in 89% (24/27) and leg edema in 26% (7/27)
Saseen et al. 18	Hypertension n=16	R/D‐B, three‐period crossover	Nifedipine‐SR 30 mg/d	Nifedipine‐SR 30 mg/d with either diltiazem‐SR 180 mg/d or verapamil‐SR 180 mg/d; cross‐over to diltiazem or verapamil	Both combinations ↓ systolic and diastolic BP more than nifedipine alone; verapamil and diltiazem ↑ nifedipine plasma concentrations by 49% and 21%, respectively; 50% of subjects with constipation in the nifedipine and verapamil group
R=randomized; D‐B=double‐blind; O‐L=open‐label; P‐C=placebo‐controlled; BP=blood pressure; SR=sustained release Adapted with permission from Ann Pharmacother. 1996;30:802–810. 16

Kaesemeyer et al. ¹⁷ subsequently observed similar additive responses with verapamil and nifedipine in a retrospective review of combination verapamil and nifedipine therapy in 27 patients with moderate to severe hypertension, uncontrolled on two or more separate classes of drugs. Twenty‐four of these 27 patients (88%) had their blood pressure reduced to <160/90 mm Hg. Edema occurred in seven subjects (25.9%). A verapamil‐to‐nifedipine ratio of 4:1 seemed to be an optimum combination in this group of moderate to severe hypertensives. Unfortunately, this dosing ratio of verapamil‐to‐nifedipine is not easily applied in current clinical practice, on the basis of these studies. Kaesemeyer et al. ¹⁷ used both short‐ and long‐acting forms of verapamil and nifedipine and gave a maximum dose of 480 and 120 mg of verapamil and nifedipine, respectively. These doses are far in excess of what is currently viewed as acceptable for each of these drugs. Moreover, dual CCB therapy has not been carefully studied with short‐acting CCBs.

Clinical Implications of Combined CCB Therapy.

Dual CCB administration has been suggested as an effective means of therapy for over a decade; unfortunately, too many questions remain for this to be viewed as a standard form of therapy. For example, is low‐dose dual CCB therapy as effective and safe as maximum CCB monotherapy? There are no direct comparisons in the literature that directly answer this question. Indirectly, the studies of Andreyev et al. ¹² and Nalbantgil et al. ²¹ indicate that two CCBs given together in low doses achieve better blood pressure control than moderate‐dosage CCB monotherapy. Also, is dual CCB therapy most effective with low dosage of two agents, or is the combination of a high and low dose of two agents preferable? Kaesemeyer et al. ¹⁷ observed that two CCBs given together in moderate dosages could effectively control blood pressure in patients with mild hypertension. Alternatively, in patients with moderate to severe hypertension, high‐dose combination CCB therapy is required to gain blood pressure control. ¹⁰ For dual CCB therapy to become a viable treatment option, various combinations of CCBs must be formally tested and compared with traditional combinations of antihypertensive agents. Moreover, because different combinations of CCBs have not been directly compared with one another, it is unknown whether verapamil or diltiazem is the most effective agent added to a dihydropyridine CCB.

Who are potential candidates for dual CCB therapy? Patients with inadequate blood pressure control while taking multiple antihypertensive agents can be considered for dual CCB therapy. In addition, partial responders to maximal tolerated doses of a single CCB who have relative contraindications to other medication classes are suitable candidates. Unfortunately, until more definitive treatment information becomes available, dual CCB therapy should be considered only as a secondary treatment option.