The Role of Calcium Channel Blockers in the Treatment of Arterial Hypertension and Stable Angina

Introduction

According to cardiovascular morbidity and mortality rates, Lithuania belongs to a high-risk region. Cardiovascular diseases account for 56.1% of all deaths in the country each year. In Lithuania, as in many other high-risk countries, despite the availability of modern diagnostic and treatment methods, atherosclerosis and the cardiovascular diseases it causes have reached the scale of a difficult-to-control epidemic. Mortality from ischemic heart disease (IHD) and stroke in Lithuania is among the highest in Europe, and cardiovascular morbidity and mortality rates are almost 2–3 times higher than the European Union average (1).

Calcium channel blockers (CCBs) are a large group of drugs used to treat cardiovascular diseases. This group is distinguished by its broad range of indications and the possibility of using these drugs in different clinical situations. CCBs are used to control arterial blood pressure (BP), treat stable angina, and manage arrhythmias. They are one of the most extensively studied groups of drugs (2).

According to their chemical structure, CCBs can be classified as dihydropyridines (nifedipine and its derivatives), phenylalkylamines (verapamil), and benzodiazepines (diltiazem). The evolution of CCBs began with first-generation agents such as short-acting verapamil, diltiazem, and nifedipine. Because of its rapid onset of action, nifedipine may cause a sudden decrease in BP, reflex tachycardia, and an increased risk of ischemic events. To reduce these adverse effects, second-generation CCBs with a slower onset of action due to slow-release formulations were developed (Table 1) (2).

Table 1. Classification of Calcium Channel Blockers

Group / Specificity	First Generation	Second Generation IIa	Second Generation IIb	Third Generation
Dihydropyridines Arteries >> Myocardium	Nifedipine	Nifedipine GITS Felodipine ER Nicardipine ER	Benidipine Felodipine Nicardipine Isradipine Manidipine Nilvadipine Nimodipine Nisoldipine Nitrendipine	Amlodipine Lacidipine Lercanidipine
Benzodiazepines Arteries ≥ Myocardium	Diltiazem	Diltiazem SR
Phenylalkylamines Arteries << Myocardium	Verapamil	Verapamil SR

Second-generation CCBs have a clear and well-established role in the treatment of cardiac rhythm disorders. Verapamil is a first-line drug for terminating supraventricular tachycardias and is also used for their prevention. It is also suitable for reducing heart rate in patients with atrial fibrillation and is used in patients with symptomatic supraventricular extrasystoles. Verapamil is particularly suitable for treating angina when arterial hypertension is also present (2).

Mechanism of Action of CCBs

Four main effects of CCBs are distinguished: peripheral vasodilation, a negative chronotropic effect (reduction in heart rate), a negative inotropic effect (reduced contraction), and a negative dromotropic effect (reduced conduction) (Table 2) (2).

Table 2. Effects of Calcium Channel Blockers

Effect	Diltiazem	Verapamil
Heart rate	↓	↓
Sinoatrial conduction	↓↓	↓
Atrioventricular conduction	↓	↓
Myocardial contraction	↓	↓↓
Coronary artery dilation	↑	↑
Peripheral arterial vasodilation	↑	↑

Ca²⁺ ions are important for the cardiovascular system because vascular smooth muscle tone, myocardial contractility, and atrioventricular conduction depend on them. The pharmacological and therapeutic effects of CCBs are explained by Ca²⁺ transport across cell membranes through L- and T-type channels. By blocking T-type calcium channels, CCBs suppress sinoatrial node automaticity and atrioventricular node conduction and reduce vascular smooth muscle tone. T-type calcium channels are more abundant in smooth muscle than in the myocardium and therefore have almost no effect on myocardial contractility.

L-type channels regulate the entry of Ca²⁺ into smooth muscle cells and directly affect the contractile apparatus. By blocking these channels, CCBs relax vascular smooth muscle. Phenylalkylamines (verapamil) exert a stronger effect on the myocardium and the cardiac conduction system, reducing heart rate, slowing conduction through the atrioventricular node, and decreasing myocardial contractility.

Clinically, reduced afterload and a reflex increase in heart rate compensate for the negative inotropic effect caused by CCBs; however, patients with impaired left ventricular ejection fraction lack this compensatory mechanism. For this reason, CCBs affect survival in patients with heart failure. Verapamil does not act on vascular smooth muscle and therefore produces pronounced negative chronotropic, dromotropic, and inotropic effects. Consequently, adverse reactions associated with verapamil are nonvascular in origin (e.g., constipation) (2, 3).

The Role of Verapamil in the Treatment of Arterial Hypertension

Arterial hypertension (AH) is one of the major risk factors contributing to increased mortality and premature death from cardiovascular disease. More than half of cardiovascular diseases and 75% of stroke cases are associated with elevated blood pressure (BP), while primary hypertension accounts for 6% of all deaths worldwide (4). It is important that a drug used to lower BP is effective, has a long duration of action, does not cause adverse reactions, and is convenient to use.

Another important issue is the global epidemic of diabetes, obesity, and ischemic heart disease (IHD), conditions that are often accompanied by elevated BP (5–7). When treating such patients, it is important to consider not only AH but also comorbid conditions.

A study published in Heart analyzed the effects of verapamil in patients with AH and IHD, with particular attention paid to older patients. The study involved 7 centers and was conducted as a double-blind, randomized trial. A total of 1,999 patients with IHD or AH were included. Of these, 1,042 patients received 180–540 mg of verapamil once daily in the evening for up to 10 weeks. The most commonly reported adverse reactions among all patients were constipation (13%), dizziness (6%), and back pain (3%). In a study examining the pharmacodynamics and pharmacokinetics of verapamil, 7 young, 10 older, and 7 elderly individuals were evaluated. Greater reductions in BP were recorded in older (–13.5±5.9 mm Hg) and elderly patients (–15.9±9.6 mm Hg). The elimination half-life of verapamil was longer in the older patient group (7.4±3.3 hours; p<0.01) (8, 9).

The International Verapamil-Trandolapril Study (INVEST) compared the effectiveness of a combination of an angiotensin-converting enzyme inhibitor and verapamil with a combination of atenolol and hydrochlorothiazide in the treatment of AH. The study included 22,576 patients who, in addition to elevated BP, had advanced IHD. Participants were followed for approximately 3 years. Women accounted for 52% of the INVEST population, with a mean age of 66 years. One-third of all patients were older than 70 years, including more than 2,000 patients aged >85 years. Participants were obese and had other cardiovascular risk factors, including diabetes mellitus and a history of myocardial infarction. The INVEST results provided new data not only on BP reduction but also on the use of effective drug combinations to reduce mortality and complications. INVEST demonstrated for the first time that, in high-risk patients with IHD, calcium channel blockers (CCBs) are beneficial and safe for controlling elevated BP and improving the condition of patients with other diseases, including diabetes mellitus, a history of myocardial infarction, and previous coronary artery bypass grafting (10).

The VHAS (Verapamil in Hypertension and Atherosclerosis Study) examined the role of verapamil in the treatment of AH and atherosclerosis. According to its results, verapamil effectively reduced BP by approximately 16.3–16.6%. Another important property of this drug is heart rate (HR) control; in the verapamil group, HR decreased by up to 5.8% (11).

The VAMPHYRE study compared the effects of the long-acting dihydropyridine CCB amlodipine and the non-dihydropyridine CCB verapamil on the autonomic nervous system. The study included 145 patients with diastolic BP of 95–110 mm Hg. It was a randomized, placebo-controlled, double-blind study. Participants received extended-release verapamil (240 mg) and amlodipine (5 mg) for 8 weeks and placebo for 4 weeks. BP was reduced equally effectively in both drug groups, from a mean of 153/100 mm Hg to 139/91 mm Hg.

Other studies have shown that these two drugs similarly reduce total vascular resistance. However, their effects on the autonomic nervous system differed between the groups (6, 12), despite similar BP-lowering effects. There is clear evidence that parasympathetic nervous system activity predominates in the verapamil group, whereas patients receiving amlodipine demonstrate more pronounced sympathetic nervous system activity and increased heart rate variability. An increased HR is an indicator of sympathetic nervous system predominance and, in patients with AH, is associated with a higher risk of death. Therefore, suppression of sympathetic nervous system activity by an antihypertensive drug may be beneficial or, at the very least, should not worsen these parameters (6, 12).

It was found that during 6 weeks of treatment, amlodipine increased HR and doubled norepinephrine concentrations. This is thought to be a response to amlodipine-induced vasodilation, which results in reflex activation of the sympathetic nervous system. In contrast, HR control with verapamil is well documented. Verapamil does not increase plasma norepinephrine concentrations and inhibits its presynaptic release; therefore, verapamil may be appropriate for patients with pronounced sympathetic activity. Verapamil may also directly reduce sympathetic activity or increase n. vagus activity through central effects in the brain because it crosses the blood-brain barrier (6, 12).

The European Society of Cardiology states that all antihypertensive drugs may be used as first-line treatment for AH (Class I, Level A recommendation). All antihypertensive drugs are recommended and may be used to treat AH in older patients; however, diuretics and CCBs should be first-line medications in cases of isolated systolic hypertension.

The Role of Verapamil in the Treatment of Stable Angina

Once stable angina (SA) has been diagnosed, pharmacological treatment is often necessary and vital. HR control is one of the factors associated with survival and better outcomes. The HR-lowering effect results in reduced sympathetic nervous system activity and longer survival (5, 13, 14). Some CCBs also reduce ischemia and HR by blocking Ca2+ entry into myocytes and smooth muscle cells, thereby causing vasodilation. Verapamil is beneficial in patients with SA because it reduces myocardial oxygen demand by suppressing inotropic and chronotropic activity and lowering systemic blood pressure (15).

When the effectiveness of nifedipine, diltiazem, and verapamil was compared in patients with SA, verapamil was found to improve exercise capacity: exercise duration increased by 8 minutes in the nifedipine group and by 10 minutes in the verapamil group (13, 15). In another larger study involving 551 patients, the effects of amlodipine (10 mg/day) and its combination with atenolol (50 mg/day) were compared with extended-release verapamil administered at 480 mg/day before bedtime (5, 15). Verapamil effectively reduced the frequency and duration of myocardial ischemic episodes during ambulatory monitoring. Another placebo-controlled study of verapamil in patients with SA found that administration of 360–480 mg of verapamil per day improved exercise duration and reduced the frequency of angina episodes and nitroglycerin use (5, 13–15).

The literature contains increasing evidence regarding the role of non-dihydropyridine CCBs in the treatment of acute ischemic syndromes. Meta-analyses have demonstrated the benefits of non-dihydropyridine CCBs in the treatment of coronary artery spasm and in reducing the no-reflow phenomenon (16).

According to the latest American cardiology guidelines for the treatment of angina, CCBs should be used to reduce angina symptoms when beta-blockers cause severe adverse reactions or are contraindicated. CCBs may also be administered together with beta-blockers when monotherapy is unsuccessful and ineffective in controlling anginal pain.

The European Society of Cardiology states that CCBs should be used as first-line drugs to reduce SA symptoms and achieve effective rate control (Class I, Level A recommendation). Vasospastic angina is also specifically identified as an indication for treatment, in which beta-blockers should be avoided (Class IIa, Level B recommendation). In patients with microvascular angina, CCBs should be administered when beta-blockers are not tolerated or when their effectiveness is insufficient (Class I, Level B recommendation).

Summary

Verapamil is particularly suitable for the treatment of SA when AH is also present. It is also a first-line drug for the treatment of isolated AH.

Source: Internistas, No. 2, 2016