Calcium channel blockers (CCB) have extensive therapeutic applications. Three CCB were listed in the forty most commonly used prescriptions and over-the-counter drugs in the Slone Survey of Recent Medication Use by the adult ambulatory population of the United States in 1998 to 1999. Over the period 2001 to 2010 approximately 20% of hypertensive adults in the United States reported taking a CCB, with amlodipine being the most prescribed drug.
This chapter will focus on this class of medications in relation to systemic arterial hypertension. The use of CCB in combination therapy for hypertension is dealt with in Chapter 27 . Uses of CCB in other conditions including angina pectoris and ischemic heart disease, cardiac arrhythmias, congestive heart failure, pulmonary hypertension, migraine, Reynaud disease, obstetrics, and neurological diseases will not be covered, except to the extent that the coexistence of these conditions may influence the selection of this class of agents in hypertension. Consideration will also be restricted to clinically-used drugs that act selectively on voltage-gated calcium channels (VGCC). Consequently this chapter will not cover nonselective agents (e.g., piperazines, benzothiazinones, pyrazines, and indole sulfones) that are sometimes included in some CCB classification systems.
Calcium and Cells
Under resting conditions the cell membrane is highly impermeable to Ca 2+ ions and there is a considerable electrochemical gradient for Ca 2+ entry as a result of the negative cell membrane potential and the steep concentration gradient of Ca 2+ across the cell membrane. Ingress and efflux of Ca 2+ into and out of the cell depends on a number of specialized channels, exchangers and transporters, and changes in the concentration of intracellular Ca 2+ resulting from changes in net permeability to Ca 2+ play a major role in cell physiology from fertilization to cell death.
Molecular Biology and Physiology of Voltage-Gated Calcium Channels
VGCC comprise a large family of transmembrane proteins that play an important role in Ca 2+ entry into many cell types. Brief histories of their discovery and the key personalities involved have been published. As their name implies the gating of VGCC is sensitive to the cell membrane potential and depolarization is associated with an increase in probability of the channel adopting a conformation that allows Ca 2+ permeation (an ‘open state’). VGCC are considered to exist in at least four distinct conformational states: resting, partially activated, open, and inactivated ; and CCB can modify transition between channel states (see later). Under physiological conditions an open VGCC will allow more than 10 6 Ca 2+ ions to pass per second, while maintaining extremely high selectivity for Ca 2+ ions. The high selectivity of VGCC is attributed to four glutamate residues in the channel pore that act as a selectivity filter.
Voltage-Gated Calcium Channel Subtypes
VGCC were originally subdivided into subtypes based on their electrophysiological characteristics. Six main categories have been described: L (Long-lasting), T (Transient), N (Neither T nor L, or Neuronal), P (Purkinje cells), Q (after P), and R (Remaining, or Resistant, or after Q), each with many subtypes. More recently classification has been refined on the basis of the molecular biology of the α1 subunits ( Table 25.1 ).
| Ca 2+ Current | α1 Subunit | Gene | Chromosome | Specific Blocker | Function | Inherited Diseases |
|---|---|---|---|---|---|---|
| L-type | Ca V 1.1 | CACNA1S | 1q31-32 | DHP | Excitation-contraction coupling in skeletal muscle, gene transcription | Hypokalemic periodic paralysis |
| Ca V 1.2 | CACNA1C | 12p13.3 | DHP | Excitation-contraction coupling in cardiac and smooth muscle, endocrine secretion, neuronal Ca 2+ transients in cell bodies and dendrites, enzyme regulation, gene transcription | Timothy syndrome; cardiac arrhythmia with developmental abnormalities and autism spectrum disorders | |
| Ca V 1.3 | CACNA1D | 3p14.3 | DHP | Cardiac pacemaking, endocrine secretion, Ca 2+ transients in cell bodies and dendrites, auditory transduction | ||
| Ca V 1.4 | CACNA1F | Xp11.23 | DHP | Visual transduction | Stationary night blindness | |
| P/Q-type | Ca V 2.1 | CACNA1A | 19p13.1 | ω-CTx-GVIA | Neurotransmitter release, dendritic Ca 2+ transients | |
| N-type | Ca V 2.2 | CACNA1B | 9q34 | ω-agatoxin | Neurotransmitter release, dendritic Ca 2+ transients | |
| R-type | Ca V 2.3 | CACNA1E | 1q25.31 | SNX-482 | Neurotransmitter release, dendritic Ca 2+ transients | Familial hemiplegic migraine cerebellar ataxia |
| T-type | Ca V 3.1 | CACNA1G | 17q22 | Pacemaking and repetitive firing | ||
| Ca V 3.2 | CACNA1H | 16p13.3 | Pacemaking and repetitive firing | Absence seizures | ||
| Ca V 3.3 | CACNA1I | 22q13 |
Typically, VGCC consist of three subunits (α1, β, α2δ) ( Fig. 25.1 ); in skeletal muscle an additional subunit is present (γ subunit). The α1 subunit forms the core of the channel and is responsible for Ca 2+ permeation. It consists of four homologous domains (domains I-IV), each composed of six membrane-spanning α-helices (S1-S6). S4 is thought to act as the voltage sensor. Other auxiliary subunits ( Table 25.2 ) influence channel anchorage, trafficking, gating, and inactivation behavior, and may also associate with other channels or proteins influencing their function.
| Subunit | Forms | Gene | Chromosome | Function |
|---|---|---|---|---|
| α 2 δ | Ca V α 2 δ-1 | CACNA2D1 | 7q21-q22 | Membrane trafficking of α 1 subunit, increase in current amplitude, activation/inactivation kinetics, voltage dependence of activation |
| Ca V α 2 δ-2 | CACNA2D2 | 3p21.3 | Increase in current amplitude | |
| Ca V α 2 δ-3 | CACNA2D3 | 3p21.1 | Increase in current density, voltage dependence of activation, steady state inactivation | |
| Ca V α 2 δ-4 | CACNA2D4 | 12p13.33 | Increase in current amplitude | |
| β | Ca V β1 | CACNB1 | 17q21-q22 | Membrane trafficking of α 1 subunit, targeting of α 1 1.1 to triads, increase in current amplitude, activation/inactivation kinetics |
| Ca V β2 | CACNB2 | 10p12 | Membrane trafficking of α 1 subunit, increase in current amplitude activation/inactivation kinetics, targeting of α 1 1.4 in retina | |
| Ca V β3 | CACNB3 | 12q13 | Membrane trafficking of α 1 subunit, increase in current amplitude, activation/inactivation kinetics | |
| Ca V β4 | CACNB4 | 2q22-q23 | Membrane trafficking of α 1 subunit, increase in current amplitude, activation/inactivation kinetics | |
| γ a | Ca V γ1 | CACNG1 | 17q24 | Inhibitory effect, activation/inactivation kinetics |
| Ca V γ6 | CACNG6 | 19q13.4 | Reduction of current amplitude |
a Total of 8 γ subunits have been identified but only γ1 and γ6 are considered to be subunits of voltage-gated calcium channels.
Voltage-Gated Calcium Channels in Cardiac and Smooth Muscle
L-type calcium channels (Ca V 1.2) are the predominant subtype present in cardiac and smooth muscle, but other subtypes (P/Q-type VGCC [Ca V 2.1] ; T-type VGCC [Ca V 3.1 and Ca V 3.2] ) coexist and contribute to cardiovascular function, albeit with seemingly minimal roles in overall blood pressure control. Conditional knockout of Ca V 1.2 in smooth muscle in the mouse markedly reduced blood pressure and abolished myogenic tone consistent with a major functional role for this channel subtype. Conversely knockout of Ca V 3.1 or Ca V 3.2 (T-type VGCC) had no effect on blood pressure, although atrioventricular conduction was delayed and resting heart rate was decreased by knockout of Ca V 3.1. Despite the lack of effect on blood pressure, evidence from knockout mice suggests Cav3.1 participates in neointima formation following vascular injury, whereas Cav3.2 participates in pressure-induced and angiotensin II-induced cardiac hypertrophy. Ca V 2.1 (P/Q-type VGCC) and Ca V 3.1 (T-type VGCC) are present in the arterial vasculature and may play a role in the regulation of renal vascular resistance. L-type and P/Q-type VGCCs are present and play a functional role in preglomerular arteries, whereas T-type VGCCs are present in both afferent and efferent arterioles.
All genes for VGCC subunits can undergo alternative splicing ; for example the Ca V 1.2 gene contains 55 exons, of which 19 exons can undergo alternative splicing, potentially yielding 2 19 combinations. Variable splicing gives rise to ion channels with discernibly different gating characteristics, differing affinities for CCB and, in some cases, pathological consequences. VGCC behavior is modulated by a wide range of intracellular signaling mechanisms, with cyclic guanosine monophosphate-dependent protein kinase, cyclic adenosine monophosphate-dependent protein kinase, and protein kinase C playing important roles in mediating the effect of inotropic and chronotropic stimuli on the heart and vasomotor influences on the vasculature.
Drugs Acting on L-Type Voltage-Gated Calcium Channels
Dihydropyridines
1,4 dihydropyridines (DHP) are the most commonly used type of CCB in hypertension. DHP act by binding to a site that is formed by amino acid residues in two adjacent S6 segments plus the intervening S5 segment ( Fig. 25.1 ).
They gain access to this site from the extracellular side of the membrane, possibly via a sidewalk pathway similar to that postulated for local anesthetics. DHP bind preferentially to the open/inactivated state of the VGCC and binding results in modification of channel gating. All DHP used clinically act by promoting transition of VGCC into a nonconducting inactivated state as envisaged by the “modulated receptor” hypothesis. Agonist forms of DHP also exist, although they have no clinical role. Agonist DHP bind to the same region of the VGCC as antagonist DHP (although they may not have identical molecular targets ) and increase the likelihood of the channel adopting a long open state that occurs only rarely under normal conditions. In some cases (e.g., [S]-BAY K 8644 and [R]-BAY K 8644), enantiomers of the same chemical entity act as agonist and antagonist, respectively, and agonists can be converted to antagonists or vice versa following site-specific mutation of the channel or by modified experimental conditions.
The mechanism by which DHP reduce Ca 2+ entry has been studied extensively. A recent model suggests that DHP stabilize an impermeable state which binds a single Ca 2+ ion. The preferential binding of DHP to channels in the open or inactivated state means that the affinity of DHP is influenced by the membrane potential (i.e., voltage dependence). DHP show higher affinity for VGCC under more depolarized conditions because in these conditions the probability of the open or inactivated state is favored. The voltage-dependence of DHP partially explains why these drugs act preferentially on VGCC in vascular smooth muscle compared with cardiac muscle because vascular smooth muscle cells generally maintain a more depolarized membrane potential than cardiac myocytes. However, other factors also contribute to the preferential action of DHP on the vasculature. These factors include the lower DHP sensitivity of Ca V 1.3 and Ca V 1.4 subtypes in the heart, and the higher expression of splice variants of Ca V 1.2 in vascular smooth muscle that show greater affinity for DHP.
DHP can be further subclassified into first-, second-, and third-generation agents. Initially this was based on the sequence of drug development, however just because a drug is developed later does not necessarily imply superiority. A more recent and persuasive classification is based on the pharmacokinetic and pharmacodynamic properties of DHP ( Table 25.3 ). Other classifications based on vascular: cardiac selectivity and duration of action have also been proposed.
| First Generation | Second Generation | Third Generation b | |
|---|---|---|---|
| Novel Formulation (IIa) | New Chemical Entity (IIb) | ||
| Nifedipine Nicardipine | Nifedipine SR/GITS Felodipine ER a Nicardipine SR | Benidipine Felodipine a Isradipine Nilvadipine Nimodipine Nisoldipine Nitrendipine | Amlodipine Azelnidipine Clevidipine Efonidipine Lacidipine Lercanidipine Manidipine |
a Felodipine may be classified as either a IIa or a IIb agent.
b In some classifications clevidipine, lercanidipine, and lacidipine are referred to as fourth-generation dihydropyridines.
Phenylalkylamines
Verapamil, a member of the phenylalkylamine (PAA) subclass of CCB (other members of this subclass include gallopamil and tiapamil) was the first CCB to be discovered and is the only member of this subclass to be widely used in hypertension. Verapamil binds to amino acids in the S6 segments in domains III and IV of the α1 subunit of the VGCC. The PAA binding site overlaps with the site to which DHP bind ( Fig. 25.2 ) and binding of verapamil may result in allosteric modulation of DHP binding.
Unlike DHP, verapamil gains access to its binding site via an intracellular route and shows preferential binding to channels in the open state. Verapamil therefore displays frequency-dependence or use-dependence, that is, its binding is favored by frequent repetitive opening of VGCC. This accounts for the efficacy of verapamil in the treatment of supraventricular arrhythmias, and the more pronounced cardiac effects of verapamil compared with DHP. Unlike DHP, verapamil slows the heart rate after chronic use in hypertension, an effect that is more marked during exercise. Nevertheless verapamil has minimal effects on cardiac output due to a compensatory increase in stroke volume, and blood pressure lowering is attributable to a reduction in systemic vascular resistance.
Benzothiazipines
Diltiazem, is the only example of the benzothiazepine subclass of CCB used clinically. Diltiazem inhibition of VGCC is effected by binding to amino acid residues located in segments IIIS6, IVS6. Some, but not all, of these amino acids are also involved in binding of DHP and PAAs ( Fig. 25.2 ). Verapamil and diltiazem do not compete with one another for binding, although they can both modulate DHP binding. Diltiazem, similar to verapamil, inhibits VGCC in a frequency and use-dependent manner, although the use-dependence of diltiazem is less prominent than for verapamil and its cardiodepressant effects are less marked. Despite its cardiodepressant activity, diltiazem lowers blood pressure by a reduction in systemic vascular resistance.
Pharmacokinetics and Drug Interactions
The pharmacokinetics of the first-generation DHP and the non-DHP, verapamil and diltiazem are relatively similar. They are almost completely absorbed after oral administration and primarily eliminated by hepatic metabolism, but their bioavailability ranges between 10% and 60% because of differences in first-pass metabolism. The duration of action of first-generation DHP and immediate-release formulations of verapamil and diltiazem is quite short, making them less than ideal in the treatment of hypertension. Immediate-release formulations of first- and shorter-acting second-generation DHP (e.g., nifedipine, nicardipine, nimodipine, nitrendipine) had rapid onsets of action which were associated with tachycardia mediated by baroreflex activation. This phenomenon may explain cases of angina pectoris following nifedipine. In a case-control study in 1995 Psaty et al. reported that the use of short-acting CCB, especially in high doses, was associated with an increased risk of myocardial infarction. A subsequent meta-analysis based on 16 secondary-prevention randomized clinical trials (RCTs) found a significant adverse effect on total mortality, largely attributable to RCTs that used 80 mg or more of nifedipine per day. Although controversial, these findings and others led to calls to avoid short-acting DHP. A consensus view is that these short-acting formulations have no place even in hypertension management, even in the emergency setting and that long-acting drugs in once daily formulations are preferable.
Subsequently modified-release formulations of nifedipine were developed to achieve a slower onset and more prolonged duration of action; a once daily use of such formulations reduces tachycardia and attains 24-hour levels of blood pressure control and peak-to-trough ratios that are similar to newer generation CCB. Newer generation CCB have slow onset and longer duration of action allied to greater preferential effects on the vasculature (vascular/cardiac ratios >100) and are not associated with much if any reflex tachycardia. The pharmacokinetic properties of selected CCB are summarized in Table 25.4 .
| Drug | Half-Life, Hours | T max , Hours | Reference |
|---|---|---|---|
| Amlodipine | 35-50 | 6-12 | |
| Clevidipine a , b | 0.25 (i.e., ∼15 mins) | 0.03-0.06 (i.e., 2-4 mins) | |
| Felodipine | 20-25 | 2-8 | |
| Isradipine | 8-12 | 1.5 | |
| Lacidipine | 6-19 | 1-2 c | |
| Lercanidipine | 2-5 | 1.5-3 | |
| Nicardipine | 1-4 | 1-2 | |
| Nifedipine GITS | 2 | 6 | |
| Nisoldipine | 6-19 | 1-2 | |
| Diltiazem | 2.5 | 6-11 | |
| Verapamil | 4.5-12 | 4-6 |
a Indicated for the reduction of blood pressure by the Federal Drugs Agency when oral therapy is not feasible or not desirable.
b Approved for use to lower blood pressure in adults preparing for surgery, undergoing surgery, or immediately after surgery by Medicines & Healthcare products Regulatory Agency.
c Despite a relatively short plasma half-life, lacidipine has a long duration of action, probably because of its high lipophilicity.
CCB have many important interactions with other drugs. Some arise from pharmacodynamic interactions; for example, beta-blockers and verapamil should not be used simultaneously because of their additive negative inotropic and chronotropic effects on the heart. The combination of dantrolene and verapamil has also been reported to result in hyperkalemia and myocardial depression, probably because hyperkalemia enhances the cardiodepressant effects of verapamil. Other interactions may be attributed to pharmacokinetic effects; for example, verapamil and diltiazem increase digoxin levels probably by decreasing renal and extrarenal clearance. Verapamil and diltiazem also increase levels of cyclosporine, carbamazepine, phenytoin, prazosin, and theophylline. Verapamil and diltiazem are metabolized by CYP3A4, therefore inducers (e.g., rifampin) and inhibitors (e.g., erythromycin, itraconazole, cimetidine) are likely to result respectively in decreased and increased plasma levels of these two CCB. Grapefruit juice, which contains flavonoids that inhibit gut CYP3A4 increases the oral bioavailability of several CCB, with the most marked effect on felodipine. In addition, verapamil inhibits P-glycoprotein–mediated drug transport, which may alter the intestinal absorption of several drugs and affect their distribution into peripheral tissues and the central nervous system.
Caution should be exercised in using CCB in patients with liver disease because their metabolism may be reduced leading to higher plasma concentrations and potential toxicity. In general lower starting and maintenance doses of CCB should be used in hepatic impairment. Dose modification for most CCB is not usually required in renal insufficiency, although verapamil may be an exception.
Actions on Non-L-Type (N-Type, P/Q-Type, and T-Type) Voltage-Gated Calcium Channels
The three major classes of CCB were originally identified on the basis of their blocking effects on L-type VGCC. Other (non-L-type) VGCC were considered to be relatively insensitive to DHP. More recently, however, several CCB have been found to inhibit N-type and P/Q-type and/or T-type VGCC at concentrations that overlap with or are close to those that inhibit L-type VGCC ( Table 25.5 ). Blockade of N-type VGCC could result in more pronounced sympatho-inhibitory effects, or inhibitory effects on aldosterone release. Inhibitory actions on P/Q-type VGCC could augment vasodilator effects, particularly in the renal circulation. Inhibition of T-type VGCC could lessen reflex tachycardia, reduce aldosterone secretion, and contribute to renal protective effects. Differences between first- and second/third-generation DHP have been attributed in part to such differences in pharmacodynamics with second/third-generation agents tending to possess a more mixed inhibitory profile on VGCC, although as discussed above differences in pharmacokinetics are also likely to be clinically important.
| Channel Subtype | Drug | References |
|---|---|---|
| N | Amlodipine, barnidipine, benidipine, cilnidipine, nicardipine | |
| P/Q | Amlodipine, barnidipine, benidipine, nicardipine (equivocal or inconsistent evidence for cilnidipine and nimodipine) | |
| T-type | Barnidipine, benidipine, isradipine, efonidipine, manidipine, nicardipine, niguldipine, nisoldipine (equivocal or inconsistent evidence for amlodipine, felodipine, nimodipine, and nitrendipine) |
Recently other CCB have been developed with the aim of having preferential or equipotent effects on non-L-type VGCC. These include mebefradil (Ro 40-5967), a benzimidazolyl-substituted tetraline derivative, which showed selectivity for T-type over L-type VGCC, but also affected other channels and was withdrawn as a result of risks from drug-drug interactions. Efonidipine, a third-generation DHP, shows a slight selectivity for T-type VGCC, but is probably best regarded as a mixed blocker of L-type and T-type VGCC.
Ancillary Actions
Some CCB may possess ancillary actions unrelated to their ability to block VGCC. Several DHP, including amlodipine, benidipine, nisolidipine, nitrendipine, and nifedipine (the latter inconsistently) have been reported to increase endothelial nitric oxide release in vitro and/or in vivo. This property seems unrelated to a drug’s ability to block VGCC as it is displayed by VGCC agonists, such as BAY 8644 and the inactive enantiomer, (R)-amlodipine. It may be related to the presence of nitric oxide (NO) donor furoxans in DHP, antioxidant properties, or disruption of cell membrane caveolae. The antioxidant properties of some DHP have also been proposed to contribute to antiatherosclerotic actions of CCB, but as with other ancillary actions whether or not these effects should influence selection of CCB in clinical practice remains to be established.
Calcium Channel Blockers in the Management of Hypertension
Blood Pressure Lowering and Hemodynamic Actions
Although they were originally envisaged as antianginal and antiarrhythmic agents, CCB have been used as hypotensive agents since the late 1970s. All CCB lower blood pressure when given acutely and following chronic administration, and the maximum blood pressure lowering effects of the various subclasses of CCB are similar. All CCB lower blood pressure as a consequence of arterial vasodilation, although there are some differences between CCB subclasses with respect to regional blood flow. CCB do possess modest venodilator actions, but have minimal effects on total venous capacitance. This may explain why orthostatic hypotension is not especially common with CCB therapy compared with other vasodilators. There is evidence that CCB are more effective compared with angiotensin-converting enzyme (ACE) inhibitors or beta-blockers in people of African heritage, or individuals with low plasma renin levels.
Effective blood pressure reduction over 24 hours is a desirable feature of any antihypertensive agent, and newer generation CCB and prolonged release formulations provide sustained blood pressure control. A recent systematic review of 16 RCTs of DHP (2768 participants; drugs studied: amlodipine, lercanidipine, manidipine, nifedipine, and felodipine [once daily] and nicardipine [administered twice daily]) reported that all these CCB lowered blood pressure by a relatively similar amount each hour over the course of 24 hours.
Longer term variability in blood pressure (i.e., over periods of months or years) has also been proposed as a risk factor for cardiovascular disease, particularly stroke. CCB have been reported to be the most effective antihypertensive class in reducing this long-term variability. The extent to which this contributes to their beneficial effects on cardiovascular (CV) outcomes in hypertension is uncertain.
Differences in antihypertensive efficacy on aortic (central) and brachial (peripheral) blood pressure may also influence CV outcomes in hypertension. A recent meta-analysis indicated that CCB lowered central and peripheral blood pressures to similar extents, unlike diuretics and beta-blockers which were less effective in lowering central blood pressure.
CCB decrease renal vascular resistance and consequently renal blood flow is maintained despite reductions in blood pressure. Typically, CCB also increase glomerular filtration rate and, unlike most other arterial vasodilators (e.g., hydralazine and minoxidil), cause a modest natriuresis, which is partly as a result of inhibition of tubular reabsorption of sodium.
Effects on Target Organ Damage in Hypertension
Left Ventricular Hypertrophy
Left ventricular hypertrophy (LVH) and abnormal left ventricular geometry is associated with an increased incidence of CV events independent of blood pressure, and individuals who show regression of LVH during antihypertensive therapy have better CV outcomes than those who do not.
A number of RCTs have examined the ability of CCB to induce regression of LVH in comparison with other antihypertensive agents. In the Effects of Amlodipine and Lisinopril on LV Mass and Diastolic Function (ELVERA) study, amlodipine was as effective as lisinopril in reducing LV mass index in 166 newly diagnosed hypertensive individuals over 2 years of treatment. The Prospective Randomized Enalapril Study Evaluating Regression of Ventricular Enlargement (PRESERVE) study showed similar regression of LVH by nifedipine gastrointestinal therapeutic system (GITS) or enalapril in 235 patients over 1 year of treatment. A substudy of the European Lacidipine Study on Atherosclerosis (ELSA) reported no significant difference in LV mass index reduction in 174 patients treated with lacidipine or atenolol after 4 years of treatment. A substudy of the ASCOT trial also found no difference in LV mass regression following treatment of 536 participants with either amlodipine-based or atenolol-based therapy for an average of 3.5 years. A meta-analysis of 80 RCTs, 146 active treatment arms (3767 patients), and 17 placebo arms (346 patients) found significant differences between antihypertensive agents in their ability to cause regression of left ventricular mass index, with CCB and ACE inhibitors being more effective than beta-blockers.
Arterial Stiffness
Increased arterial stiffness (higher pulse wave velocity [PWV] or reduced arterial compliance) plays a key role in the age-dependent increase in pulse pressure and isolated systolic hypertension (ISH), and predicts cardiovascular events independently of blood pressure. Central pulse pressure and augmentation index, although related to arterial compliance and wave reflection, should not be interpreted as direct measures of arterial stiffness. Interpreting the effect of antihypertensive agents on arterial stiffness is complicated by its inherent pressure-dependence ; hence blood pressure reduction should inherently reduce arterial stiffness. Consequently the reductions in PWV observed following administration of CCB may simply be a consequence of blood pressure lowering. There is, however, some evidence that antihypertensive agents can reduce arterial stiffness beyond that expected simply on the basis of the reduction in mean arterial pressure. A study comparing valsartan plus hydrochlorothiazide with amlodipine in 131 patients with type 2 diabetes, pulse pressure 60 mm Hg or higher and raised albumin excretion rate found a greater reduction in PWV for valsartan/hydrochlorothiazide than amlodipine (difference = −0.9 m/s [95% confidence interval {CI} −1.4 to −0.3]; p = 0.002) despite similar reductions in brachial and central pulse pressure. However, a recent meta-analysis found no evidence of difference in the ability of individual antihypertensive agents to reduce PWV, although the number of eligible studies was small and confidence limits were wide. Whether or not CCB can reduce PWV through mechanisms unrelated to blood pressure reduction therefore remains uncertain.
Renal Function and Progression of Kidney Disease
Blood pressure lowering is associated with diminished urinary protein excretion and reduced progression of nephropathy in patients with chronic kidney disease (see also Chapter 33 ). In the Systolic Hypertension in Europe (Syst-Eur) trial patients randomized to nitrendipine had a 64% lower incidence of mild renal dysfunction and a 33% lower incidence of new proteinuria than those randomized to placebo.
Several RCTs have compared CCB with other antihypertensive regimens and reported renal functional outcomes. In INSIGHT there was a lower incidence of impaired renal function in patients treated with nifedipine than a diuretic (1.8% versus 4.6%, p < 0.0001), ALLHAT reported higher estimated glomerular filtration rate (eGFR) with amlodipine than chlortalidone (75.1 versus. 70.0 mL/min/1.73m 2 ; p = 0.001) or lisinopril (75.1 versus 70.7 mL/min/1.73 m 2 ), and no significant difference in the incidence of end-stage renal disease (ESRD) when analysis was restricted to patients with reduced renal function at baseline. VALUE also reported no difference in renal outcomes with amlodipine or valsartan. However, in an RCT that recruited African-American hypertensive patients with nondiabetic nephropathy, amlodipine was associated with a greater decline in eGFR than ramipril, especially in those with significant proteinuria. A recent meta-analysis of 26 trials (152,290 participants), including 30,295 individuals with reduced estimated glomerular filtration rate, found little evidence of a difference between drug classes for the prevention of cardiovascular events in chronic kidney disease.
A meta-analysis indicates that non-DHP may have more favorable effects on proteinuria and the progression of kidney disease than DHP despite similar hypotensive effects. New generation DHP that additionally block non-L-type VGCC may improve renal function more than classical DHP, although evidence related to specific drugs is limited. A meta-analysis of 24 studies (1696 participants) that compared T-type CCB (efonidipine, azelnidipine, benidipine, manidipine, nilvadipine) to L-type CCB (amlodipine or nifedipine) or to renin-angiotensin system (RAS) antagonists found that proteinuria (mean difference = −0.73 [95% CI −0.88, −0.57]; p < 10 −5 ), protein-to-creatinine ratio (mean difference = −0.22 [95% CI −0.41, −0.03]; p = 0.02), and urinary albumin-to-creatinine ratio (mean difference = −55.38 [95% CI −86.67, −24.09]; p = 0.0005) were reduced when T-type CCB were compared with L-type CCB despite similar blood pressure reductions. The effects of T-type CCB did not significantly differ from RAS antagonists in terms of blood pressure or renal measures. A multi-center, open-labeled, and randomized trial comparing cilnidipine, an L/N-type blocker, with amlodipine in 339 participants found a significant reduction in urinary protein-to-creatinine ratio with no difference in blood pressure after 12 months of treatment.
Cognitive Function and Dementia
The association between blood pressure and cognitive function and dementia is complex and seems to be modified by age. There is reasonably convincing evidence that elevated blood pressure in mid-life (40 to 64 years) is associated with subsequent impaired cognitive function or dementia. However, evidence that antihypertensive treatment (usually initiated in later life) can prevent this is unconvincing, and relatively few RCTs have looked at cognitive function or dementia as an outcome. In Syst-Eur, which included participants 60 years of age or older with systolic hypertension and without dementia at baseline, nitrendipine treatment (with enalapril and/or hydrochlorothiazide added if necessary) was associated with a 50% reduction in incident dementia (vascular and Alzheimer) over a median 2-year follow-up compared with placebo. At present this study remains the only RCT examining the effect of CCB on dementia. A meta-analysis of all data including observational studies was unable to provide clear evidence either way regarding the effects of CCB on cognitive function and dementia. Further clinical trials are required to definitively establish whether or not CCB have benefits for cognitive function and prevention of dementia.
Major Clinical Outcomes
There have been numerous RCTs examining the effect of CCB on major cardiovascular outcomes (e.g., myocardial infarction, stroke, angina, coronary revascularization, congestive heart failure, and peripheral arterial disease) in hypertension. Relevant RCTs are shown in Table 25.6 . In the majority of these trials treatment was initiated with a CCB or comparator and other agents were added as necessary to achieve target blood pressure ( Table 25.7 ); in some, CCB or comparator was added to existing antihypertensive therapy. These studies have convincingly established that CCB are effective in reducing cardiovascular events compared with placebo, and that they have broadly similar effects on outcomes to other major classes of antihypertensive agents (diuretics, beta-blockers, angiotensin- converting enzyme inhibitors, and angiotensin receptor blockers). Studies have been conducted in the elderly, patients with stable coronary heart disease, and some non-European/Caucasian ethnic groups and so have reasonably wide applicability. These conclusions are supported by recent meta-analyses of data from RCTs. The Blood Pressure Lowering Treatment Trialists’ Collaboration undertook a prospectively designed meta-analysis of placebo-controlled RCTs of calcium antagonists (two trials, 5520 patients mostly with hypertension) and showed strong evidence of cardiovascular benefit of CCB: a 28% (95% CI 13, 41) reduction in major cardiovascular events, with similar magnitude reductions in coronary heart disease, stroke, heart failure, and cardiovascular death. A subsequent meta-analysis that included 27 RCTs (175,634 individuals) confirmed that CCB reduced major cardiovascular events by 24% and provided evidence that the risk of major cardiovascular events (pooled fatal and nonfatal myocardial infarction, stroke, cardiovascular death, heart failure) was similar between CCB and non-CCB drugs (beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers). Compared with other antihypertensive medications, CCB were associated with a modestly lower risk of stroke (odds ratio [OR] 0.86 [95% CI 0.82, 0.90]), similar risks of coronary heart disease and a modestly increased risk of heart failure (OR 1.17 [95% CI 1.11, 1.24]). A more recent meta-analysis based on 18 RCTs (141,807 participants) compared individual classes of antihypertensive agent ( Fig. 25.3 ). This analysis found that all-cause mortality was not different between first-line CCB and any other first-line antihypertensive classes. Compared with beta-blockers, CCB reduced total cardiovascular events, cardiovascular mortality, and stroke but were associated with increased total cardiovascular events and congestive heart failure events compared with diuretics. CCB also reduced stroke compared with ACE inhibitors and reduced stroke and myocardial infarction compared with ARBs, but increased congestive heart failure events compared with ACE inhibitors or ARBs. The other evaluated outcomes did not differ significantly.
