Calcium Channel Blockers

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.

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

Headache and postural or orthostatic hypotension, along with dizziness, are relatively common adverse effects associated with DHP calcium channel blocker therapy.[66459]

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]

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]

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.

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]

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

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]

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]

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]

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]

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.

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.

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.

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]

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.

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]