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Jul.05.2012

Calcium Channel Blockers

Summary

  • In general, calcium channel blockers (CCBs) are used most often for the management of hypertension and angina.
  • There are 2 classes of CCBs: the dihydropyridines (DHPs), which have greater selectivity for vascular smooth muscle cells than for cardiac myocytes, and the non-DHPs, which have greater selectivity for cardiac myocytes and are used for cardiac arrhythmias.
  • The DHPs cause peripheral edema, headaches, and postural hypotension most commonly, all of which are due to the peripheral vasodilatory effects of the drugs in this class of CCBs.
  • The non-DHPs are negative inotropes and chronotropes; they can cause bradycardia and depress AV node conduction, increasing the risk of heart failure exacerbation, bradycardia, and AV block.
  • Clevidipine is a DHP calcium channel blocker administered via continuous IV infusion and used for rapid blood pressure reductions.
  • All CCBs are substrates of CYP3A4, but both diltiazem and verapamil are also inhibitors of 3A4 and have an increased risk of drug interactions. Verapamil also inhibits CYP2C9, CYP2C19, and CYP1A2.

Pharmacology/Mechanism of Action

CCBs selectively inhibit the voltage-gated L-type calcium channels on cardiac myocytes, vascular smooth muscle cells, and cells within the sinoatrial (SA) and atrioventricular (AV) nodes, preventing influx of extracellular calcium. CCBs act by either deforming the channels, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the major cellular calcium store, the endoplasmic reticulum. Calcium influx via these channels serves for excitation-contraction coupling and electrical discharge in the heart and vasculature. A decrease in intracellular calcium will result in inhibition of the contractile process of the myocardial smooth muscle cells, resulting in dilation of the coronary and peripheral arterial vasculature. As a consequence, peripheral resistance is decreased leading to a decrease in systemic BP, improved oxygen delivery to the myocardial tissue, reduction of heart rate, and slowing of AV conduction.[50075]

 

There are 2 general subclasses of CCBs, grouped according to their chemical structure: the dihydropyridines (DHPs - amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine) and the non-dihydropyridines (non-DHPs), which bind to different sites on the calcium channels.[50076] The latter group consists of the benzothiazepine diltiazem and the phenylalkylamine verapamil. DHPs have greater selectivity for vascular smooth muscle cells than for cardiac myocytes. Non-DHPs have a direct effect on the myocardium, causing negative inotropy, ie, depression of SA and AV nodal conduction, and therefore are used for some cardiac dysrhythmias.[50075]

Therapeutic Use

  • CCBs are considered a first-line treatment option for patients with hypertension as monotherapy or as a part of combination antihypertensive therapy.[62854] CCBs have been shown to reduce cardiovascular disease events in patients with diabetes in several clinical trials.[50078]
    • Large-scale meta-analyses of available data demonstrate that major antihypertensive drug classes do not differ significantly for their overall ability to reduce BP in hypertension.[50079] Studies established that the risk of all-cause mortality did not differ between CCBs and other first-line antihypertensive agents.[50075][50081][50083][50086]
    • Data suggest that CCBs are less effective in reducing the risk of heart failure;[50075][50078][50081][50083][50086][50087] however, they are more effective in reducing the risk of stroke and myocardial infarction [50081][50085][50086] compared with all other antihypertensive drugs.
    • With regard to reducing combined cardiovascular events including stroke and CHD (but excluding HF), CCBs are more efficacious than beta-blockers,[50086] but similar in efficacy to diuretics.[50083]
  • Because of their pharmacology, verapamil and diltiazem may be used to treat various arrhythmias, including atrial fibrillation and atrial flutter (without accessory pathways) and paroxysmal supraventricular tachycardia. Verapamil has more negative chronotropic effects than diltiazem and may be preferred for the acute and chronic treatment of atrial arrhythmias.[50076] ACLS guidelines recommend the use of diltiazem or verapamil for stable, narrow-complex tachycardias if rhythm remains uncontrolled or unconverted by adenosine or vagal maneuvers or if SVT is recurrent.[45649]
  • CCBs increase renal blood flow and glomerular filtration rate, and verapamil and diltiazem reduce albuminuria by improving glomerular permselectivity and/or by lowering renal perfusion pressure; however, CCBs are generally not used as monotherapy in patients with renal disease.[50076]
  • DHPs are potent peripheral vasodilators and therefore are beneficial in conditions involving peripheral vasospasm, including migraine and cluster headaches, intermittent claudication, and even premature labor;[50076] nimodipine, however, is selective for cerebral arterioles (rather than peripheral), and therefore is indicated to treat subarachnoid hemorrhage.[50080]
  • Clevidipine is an injectable short-acting DHP; it is used in patients with hypertension, including perioperative hypertension, hypertensive emergencies and urgencies, or in other situations where oral therapy is not feasible or desired. It is administered via continuous IV infusion, and has a very quick onset and short duration of action allowing for rapid dose titration. Relatively few drugs are available for the control of blood pressure before, during, and after a surgical procedure, and most are longer-acting than clevidipine and associated with potentially dangerous toxicities.

 

Oral Dosing of CCBs for Hypertension

DrugInitial Dose (mg/day)Dose Range (mg/day)Equivalent dose*Comments

Amlodipine

 

55 to 105 mg once dailyDemonstrates the longest half-life of the group. Due to its gradual onset, reflex tachycardia does not occur

Felodipine

 

52.5 to 105 mg once dailyGreater selectivity for vascular smooth muscle relative to myocardial muscle than nifedipine
Isradipine

5 (IR)

5 to 10 (IR)

2.5 mg twice daily (IR)

Isradipine is longer acting than regular-release nifedipine but has a shorter duration of action than amlodipine
Nicardipine (IR and SR)6060 to 120

20 mg 3x/day (IR)

30 mg twice daily (ER)

More selective for cerebral and coronary blood vessels than other DHPs
Nifedipine30 to 60 (ER)30 to 90 (ER)30 mg once dailyImmediate-release formulations should not be used for hypertension

Nisoldipine

 

1717 to 3417 mg once daily 

Diltiazem

 

120 to 240 (ER)

60 to 120 (SR)

120 to 540 (ER)

60 to 360 (SR)

NAImmediate release formulations not approved for hypertension

Verapamil

 

240 (IR and ER 24 hr)

180 (SR, 12-hr ER, ER controlled onset tabs)

200 (Verelan PM)

120 to 480 (IR and ER 24 hr)

120 to 480 (SR, 12-hr, ER, ER controlled onset tabs)

100 to 400 (Verelan PM)

NA

 

Exerts the most pronounced negative chronotropic effects, however it is less potent as a peripheral vasodilator

Abbreviations: ER, extended release; IR, immediate release; NA, not applicable; SR, sustained release

*The approximate equivalent dose is based on data from clinical trials and meta-analyses comparing 2 or more CCBs for hypertension; this approximation may not represent the equivalence for other indications.

Comparative Efficacy

  • Head-to-head trials within the class are uncommon. DHP CCBs have been shown to be more protective against the risk of death from all causes compared with non-DHP CCBs.[50081] Evidence from active-controlled trials was either insufficient or did not differentiate one CCB from another for effectiveness or safety for the treatment of hypertension, angina, supraventricular arrhythmia, or systolic dysfunction.[50075]

 

Calcium Channel Blocker Comparative Efficacy Trials

Citation/Study NameDesign/RegimenResultsConclusion

Lenert LA, et al. Am J Manag Care. 1999;5:1535-1540 [50090]

 

Retrospective review of effectiveness of amlodipine and nifedipine in the initial treatment of hypertension

Patients who switched to another CCB:

Amlodipine: 10.3%

Nifedipine: 15.8%

 

Patients who switched to another antihypertensive class:

Amlodipine: 13.2%

Nifedipine: 7.3%

 

Patients who received adjunctive antihypertensive drugs:

Amlodipine: 42%

Nifedipine: 35%

 

Rates of adherence and AEs were similar

Effectiveness of amlodipine and nifedipine in the treatment of hypertension is similar

Manzo BA, et al. Pharmacotherapy.

2003;23:1508-1512 [50092]

 

Determine patient satisfaction and tolerability of conversion from amlodipine to felodipine. Also compared blood pressure and heart rate effects

Parameters reduced when amlodipine was switched to felodipine:

Mean systolic BP: by 4.4 mm Hg (p=0.166)

Mean diastolic BP: by 2.6 mm Hg (p=0.187)

Heart rate: by 4.2 beats/minute (p=0.008)

 

Felodipine was as effective in reducing BP and well tolerated

 

White WB, et al. Am J Hypertens. 2003;16(9 Pt 1):739-745 [50091]

 

A prospective trial to determine efficacy of nisoldipine compared to amlodipine on BP and HR in Black patients

Mean changes from baseline in 24 h BP:

Nisoldipine ER: -23/-16 +/- 3/2 mm Hg

Amlodipine: -20/15 +/- 3/2 mm Hg

(Between-group comparisons, p=0.07 for systolic BP; p=0.50 for diastolic BP)

 

Similar reductions were observed for clinic, awake, and sleep BP

Nisoldipine ER was as efficacious as amlodipine in reducing 24 h BP in Black patients with hypertension

Menzin J, et al. J Int Med Res. 2004;32:233-239 [50094]

 

A retrospective, review evaluating treatment adherence in clinical practice among older hypertensive adults (>= 50 years) prescribed amlodipine or felodipine as initial therapy

Likelihood of discontinuation after 6 months:

Amlodipine: 33.1%

Felodipine: 41.7%

p<0.05, OR (95% CI): 0.79 (0.66-0.96)

 

Study discontinuation after 1 prescription:

Amlodipine: 20%

Felodipine: 30%

(p<0.05)

 

Persistence over 1 year:

Amlodipine: 53.1%

Felodipine: 49.7%

(p=NS)

The use of amlodipine may be associated with improved adherence, compared with felodipine, among older outpatients in the Medi-Cal program

Makani H, et al. J Hypertens. 2011;29:1270-1280 [50088]

 

Meta-analysis involving 106 studies (n=99,469) to determine the incidence and withdrawal rate due to peripheral edema between DHPs and non-DHPs

Peripheral edema:

DHPs: 12.3%; 95% CI, 12.2-12.5

Non-DHPs: 3.1%; 95% CI, 2.8-3.4

p<0.0001

 

Withdrawal due to edema:

DHPs: 2.4%; 95% CI, 2.2-2.5

Non-DHPs: 0.6%; 95% CI, 0.35-0.85; p<0.0001

Compared with non-DHP, more patients receiving a DHP CCB experienced peripheral edema and discontinued drug therapy due to edema.

Abbreviations: AE, adverse event; BP, blood pressure; CI, confidence interval; NS, not significant; OR, odds ratio; RR, relative risk.

Adverse Reactions/Toxicities

Peripheral edema

Peripheral edema can occur with all CCBs but is more commonly reported with the dihydropyridines (DHP). The incidence increases with duration of therapy and leads to discontinuation of treatment in greater than 5% of patients.[50088] Peripheral edema is a dose-related effect and is more common in women.[62854][66459] The peripheral edema can be confused with symptoms of heart failure; clinicians should be aware of this relatively common adverse effect.

Constipation

Compared to other CCBs, the rate of constipation appears to be highest with verapamil.[50865]

Headache / Postural hypotension

Headache and postural hypotension along with dizziness are relatively common adverse effects associated with DHP calcium channel blocker therapy.[66459] Both effects are thought to be secondary to vasodilation. Postural hypotension is of concern in elderly patients as this can increase the risk of falls.[60742]

Rash

Skin reactions can occur with verapamil or diltiazem. These reactions are generally mild and regress with discontinuation of therapy but, in some cases, can progress to erythema multiforme, exfoliative dermatitis, or Stevens-Johnson syndrome. Diltiazem has been associated with acute generalized exanthematous pustulosis (AGEP). [27736]

Bradycardia / AV block

Diltiazem and verapamil depress AV node conduction and can cause bradycardia and AV block, especially in patients with heart failure, conduction abnormalities or taking beta-blockers. Heart rate should be monitored in patients taking diltiazem and verapamil.[62854][66459][66466]

Drug Interactions

Cytochrome P450 metabolism

All CCBs (except clevidipine) are substrates of cytochrome P450 3A4 (CYP3A4); therefore, coadministration with inducers or inhibitors of CYP3A4 is likely to result in altered plasma concentrations of the CCB. Additionally, verapamil and diltiazem are inhibitors of CYP3A4 and P-glycoprotein (P-gp). Coadministration with drugs that are CYP3A4 and/or P-gp substrates may result in increased concentrations of the drug due to CYP3A4 inhibition by verapamil or diltiazem. Verapamil also is an inhibitor of CYP2C9, CYP2C19, and CYP1A2.

Digoxin

Verapamil and diltiazem increase peak and steady-state serum digoxin concentrations. Verapamil and diltiazem reduce renal and nonrenal clearance of digoxin. Monitor digoxin serum concentrations periodically during therapy. In addition, verapamil and diltiazem have additive effects to slow AV conduction.[50096][50097]

Beta-blockers

Additive hypotensive effects occur when CCBs are coadministered with beta-blockers, which is often a wanted therapeutic effect. However, beta-blockers and verapamil and diltiazem are negative inotropes and chronotropes and coadministration can cause significant AV nodal blockade manifesting in heart block, bradycardia, cardiac conduction abnormalities and/or prolonged PR interval. Furthermore, diltiazem has been shown to increase propranolol concentrations by 50%, [28277] and verapamil has been shown to decrease the clearance of metoprolol and propranolol.[28273

Immunosuppressants

Coadministration of verapamil, diltiazem, amlodipine, or nicardipine with cyclosporine can lead to increased cyclosporine concentrations and toxicity. Also, cyclosporine may increase nifedipine concentrations. Use cautiously in patients stabilized on cyclosporine; changes in dose may be required. Coadministration of amlodipine, felodipine, nicardipine, diltiazem, or verapamil and tacrolimus may increase tacrolimus plasma concentrations; dosage adjustments may be necessary.[29198]

Simvastatin

Because of the increased risk of myopathy, including rhabdomyolysis, there are daily dose limits for some calcium channel blockers when taken with simvastatin, and vice versa. In patients taking verapamil, do not exceed a simvastatin dose of 10 mg/day. In patients taking diltiazem, do not exceed a diltiazem dose of 240 mg/day and/or a simvastatin dose of 10 mg/day. The maximum daily dose of simvastatin is 20 mg/day in patients taking amlodipine. For patients maintained on simvastatin 80 mg/day, consider switching to an alternative statin with less potential for an interaction. Amlodipine, diltiazem, and verapamil increase simvastatin exposure by approximately 1.5-fold, 5-fold, and 2-fold, respectively. Coadministration of nicardipine and simvastatin may also increase simvastatin exposure.[25454].[31978][60469]

Safety Issues

Sublingual nifedipine

Although immediate-release nifedipine (including sublingual or 'bite and swallow' administration) was frequently used for the treatment of hypertensive urgencies prior to 1995,[24121] serious adverse effects have been reported with its use, primarily due to the unpredictable rate and degree of blood pressure lowering. Profound hypotension, myocardial infarction, and death have been reported when immediate-release nifedipine was used to lower blood pressure acutely. Therefore, according to recommendations of the Joint National Committee on Prevention, Detection Evaluation, and Treatment of High Blood Pressure (JNC-VII), the use of nifedipine liquid-filled capsules is not acceptable in the setting of hypertensive urgency, hypertensive crisis, or hypertensive emergency.[50078][24732]

Heart failure

Nifedipine, verapamil, and diltiazem should be avoided in patients with heart failure. Nifedipine can precipitate or exacerbate heart failure due to its negative inotropic effects, particularly in patients receiving concomitant beta-blocker therapy. The development or worsening of pulmonary edema is a marker for discontinuation of nifedipine. Both diltiazem and verapamil can precipitate or exacerbate heart failure; do not use in patients with heart failure with reduced ejection fraction. Additionally, the DHP class of calcium channel blockers are often associated with peripheral edema; when using a DHP in patients with heart failure, the etiology of the peripheral edema should be identified (drug adverse effect vs. disease state).[62854][66459]

Renal impairment

Although dosage adjustments are not generally needed, the manufacturer does recommend cautious use of verapamil in patients with renal impairment. Approximately 70% of a dose is excreted renally.

Hepatic impairment

All CCBs are metabolized hepatically. Cautious use in patients with hepatic disease is warranted. Dosage reductions may be required; the dose should be adjusted as clinical response dictates.

Lipid disorders and pancreatitis

Disorders of lipid metabolism can be aggravated by the emulsion vehicle in which clevidipine is delivered. Clevidipine is an emulsion that provides 0.2 gram of lipid (approximately 2 kcal) per ml. If fat is inadequately cleared from the body, clevidipine dosage adjustment may be needed. As such, clevidipine is contraindicated in patients with defective lipid metabolism such as pathologic hyperlipidemia, acute pancreatitis accompanied by hyperlipidemia, and lipoid nephrosis. Lipid restrictions to compensate for the amount of lipid infused as part of the clevidipine formulation may be necessary for patients with disorders of lipid metabolism.

Gastroesophageal reflux disease

It is thought that CCBs decrease lower esophageal sphincter pressure, and, as a result, symptoms of reflux may be exacerbated in patients with gastroesophageal reflux disease (GERD). Elderly patients may be especially susceptible.[50095]

Severe obstructive coronary heart disease

Rarely, patients with severe obstructive coronary heart disease may experience precipitation or exacerbation of angina or an acute myocardial infarction following initiation of or dose increase in CCB therapy.

AV block

Diltiazem and verapamil are contraindicated in patients with second or third degree atrioventricular (AV) block, sick sinus syndrome, or cardiogenic shock. Diltiazem and verapamil have the potential to precipitate or exacerbate heart failure, induce severe bradycardia, impair atrioventricular conduction, cause cardiac conduction abnormalities, cause asystole, or lead to severe hypotension in these patient populations.[62854][66459][66466]

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[24732]Grossman E, Messerli FH, Grodzicki T, et al. Should a moratorium be placed on sublingual nifedipine capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996;276:1328-31.

[25454]Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998;64:177-82.

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[29198]Sandimmune (cyclosporine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015 Mar.

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[45649]Neumar RW, Otto CW, Link MS, et al. Part 8: Adult Advanced Cardiovascular Life Support: 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation 2010;122:S729-S767.

[50075]McDonagh MS, Eden KB, Peterson K. Drug Class Review on Calcium Channel Blockers. Portland, Oregon: OHSU; March, 2005. Oregon Health & Science University.

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[50078]Jones DW, Hall JE. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and evidence from new hypertension trials. Hypertension. 2004;43(1):1-3.

[50079]Mancia G, Laurent S, Agabiti-Rosei E, et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. Blood Press. 2009;18(6):308-347.

[50080]Tomassoni D, Lanari A, Silvestrelli G, Traini E, Amenta F. Nimodipine and its use in cerebrovascular disease: evidence from recent preclinical and controlled clinical studies. Clin Exp Hypertens. 2008;30(8):744-766.

[50081]Costanzo P, Perrone-Filardi P, Petretta M, et al. Calcium channel blockers and cardiovascular outcomes: a meta-analysis of 175,634 patients. J Hypertens. 2009;27(6):1136-1151.

[50083]Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-2997.

[50085]Webb AJ, Fischer U, Mehta Z, Rothwell PM. Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet. 2010;375(9718):906-915.

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[50087]Sciarretta S, Palano F, Tocci G, Baldini R, Volpe M. Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk. Arch Intern Med. 2011;171(5):384-394.

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[50090]Lenert LA, Linde-Zwirble W, Newbold R, III, Korenblat BM, Doherty J, Smith ME. Using administrative data to compare the relative effectiveness of amlodipine vs nifedipine CC. Am J Manag Care. 1999;5(12):1535-1540

[50091]White WB, Saunders E, Noveck RJ, Ferdinand K. Comparative efficacy and safety of nisoldipine extended-release (ER) and amlodipine (CESNA-III study) in African American patients with hypertension. Am J Hypertens. 2003;16(9 Pt 1):739-745.

[50092]Manzo BA, Matalka MS, Ravnan SL. Evaluation of a therapeutic conversion from amlodipine to felodipine. Pharmacotherapy. 2003;23(11):1508-1512.

[50094]Menzin J, Lang K, Elliott WJ, et al. Adherence to calcium channel blocker therapy in older adults: a comparison of amlodipine and felodipine. J Int Med Res. 2004;32(3):233-239.

[50095]Hamada A, Ishii J, Doi K, et al. Increased risk of exacerbating gastrointestinal disease among elderly patients following treatment with calcium channel blockers. J Clin Pharm Ther. 2008;33(6):619-624.

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