Cardiovasc Prev Pharmacother.  2023 Oct;5(4):113-125. 10.36011/cpp.2023.5.e16.

Calcium channel blockers for hypertension: old, but still useful

• Lee EM

• KMID: 2547302
• DOI: http://doi.org/10.36011/cpp.2023.5.e16

Abstract

Calcium channel blockers (CCBs) constitute a heterogeneous class of drugs that can be divided into dihydropyridines (DHPs) and non-DHPs. DHP-CCBs are subcategorized into four generations based on the duration of activity and pharmacokinetics, while non-DHP-CCBs are subcategorized into phenylethylamine and benzodiazepine derivatives. DHP-CCBs are vascular-selective and function as potent vasodilators, whereas non-DHP-CCBs are cardiac-selective and are useful for treating tachyarrhythmia, but reduce cardiac contractility and heart rate. Traditional DHP-CCBs (nifedipine) mainly block L-type calcium channels, whereas novel CCBs block N-type (amlodipine) and/or T-type channels (efonidipine) in addition to L-type channels, leading to organ-protective effects. DHP-CCBs have a potent blood pressure–lowering effect and suppress atherosclerosis and coronary vasospasm. Diltiazem, a non-DHP-CCB, is highly effective for vasospasm control. CCBs reduce left ventricular hypertrophy and arterial stiffness. Amlodipine, a DHP-CCB, reduces blood pressure variability. L/N- and L/T-type CCBs combined with renin-angiotensin system blockers reduce proteinuria and improve kidney function compared with L-type CCBs. According to large-scale trials, DHP-CCBs reduce cardiovascular events in patients with isolated systolic hypertension, as well as in elderly and high-risk patients. Accordingly, CCBs are indicated for hypertension in elderly patients, isolated systolic hypertension, angina pectoris, and coronary vasospasm. Non-DHP-CCBs are contraindicated in high-grade heart block, bradycardia (<60 beats per minute [bpm]), and heart failure with reduced ejection fraction (HFrEF). DHP-CCBs should be used with caution in patients with tachyarrhythmia, HFrEF, and severe leg edema, and non-DHP-CCBs should be used carefully in those with constipation. Each CCB has distinct pharmacokinetics and side effects, underscoring the need for meticulous consideration in clinical practice.

Keyword

Hypertension; Anti-hypertensive drugs; Calcium channel blockers; Dihydropyridine

Figure

• 

  Fig. 1. Classification and pharmacological actions of calcium channel blockers (CCBs). DHP, dihydropyridine; PAA, benzodiazepine; Non-DHP, non-dihydropyridine; SR, sustained release; ↑↑↑, strongest; ↑↑, very strong; ↑, strong positive action; →, neutral action; ↓, negative action.Based on data from Sueta et al. [3], and Wang et al. [4], Elliott et al. [5], Wang et al. [6].

• 

  Fig. 2. Three main pharmacological mechanisms of calcium channel blockers (CCBs): treatment of hypertension through peripheral vasodilation; treatment of angina pectoris through coronary artery vasodilation and decreased ventricular contraction and heart rate; and arrhythmia treatment through decreased impulse conduction system excitation. Downward arrow indicate negative action, upward arrow indicate positive action (the degree is presented by the number of arrows). DHP, dihydropyridine; BTZ, benzothiazepine; PAA, phenylalkylamine; SMC, smooth muscle cell; SA node, sinoatrial node; AV node, atrioventricular node.Based on data from Sueta et al. [3].

• 

  Fig. 3. Voltage-gated calcium channels and three representative types. (A) Voltage-gated calcium channels. Voltage-gated extracellular calcium (Ca2+) channels consist of four subunits, α1 and α2, δ, β, and γ, and they are pharmacologically classified into different subtypes; the characteristics of which are determined by the pore-forming α1 subunit. Calcium channel blockers (CCBs) disrupt the inward movement of Ca2+ through the calcium channel. (B) Three representative types of calcium channel. Calcium channels are pharmacologically classified into different subtypes: high voltage–activated (L- and N-type) and low voltage–activated (T-type). L-type channels act as potent vasodilators, N-type channels have decreased norepinephrine (NE) release in the sympathetic nerve ending, and T-type channels have improvement of renal microcirculation. It is speculated that the combined blocking of N- or T-channels in addition to traditional L-type blocking in CCBs leads to different pharmacologic impacts and adverse effects of dihydropyridine CCBs.

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