- ACRONYMS AND DEFINITIONS
- AHA/ACC - American Heart Assoc / American College of Cardiology
- ARB - Angiotensin II receptor blockers
- AUA - American Urological Association
- BP - Blood Pressure
- bpm - beats per minute
- CCBs - Calcium Channel Blockers
- CrCl - Creatinine clearance
- CVD - Cardiovascular Disease (stroke and heart attack)
- DBP - Diastolic Blood Pressure
- EF - Ejection fraction
- FDA - U.S. Food and Drug Administration
- HCTZ - Hydrochlorothiazide
- HFpEF - Heart failure with preserved ejection fraction
- HFrEF - Heart failure with reduced ejection fraction
- RCT - Randomized controlled trial
- SBP - Systolic Blood Pressure
- DRUGS IN CLASS
- Dihydropyridines
- Amlodipine (Norvasc®, Katerzia®, Norliqva®)
- Isradipine (Dynacirc®)
- Nifedipine (Adalat CC®, Procardia®, Afeditab CR®)
- Nisoldipine (Sular®)
- Nicardipine (Cardene®)
- Felodipine (Plendil®)
- Nondihydropyridines
- Diltiazem (Cardizem®, Cartia XT®, Dilacor XR®, Taztia XT®, Tiazac®)
- Verapamil (Calan®, Isoptin SR®, Verelan PM®)
- Combination products with ACE inhibitors
- Lotrel® (amlodipine + benazepril)
- Prestalia® (amlodipine + perindopril)
- Tarka® (verapamil + trandolapril)
- Combination products with ARBs
- Twynsta® (amlodipine + telmisartan)
- Azor® (amlodipine + olmesartan)
- Exforge® (amlodipine + valsartan)
- Combination products with statins
- Caduet® (amlodipine + atorvastatin)
- Combination product with celecoxib
- Consensi® (amlodipine + celecoxib)
- CCB + ARB + HCTZ
- Exforge HCT® (amlodipine + valsartan + HCTZ)
- Tribenzor® (amlodipine + HCTZ + olmesartan)
- MECHANISM OF ACTION
- Arterial effects (all CCBs)
- Arterial smooth muscle contracts and relaxes to control blood pressure. During contraction, calcium flows into cells through calcium channels. Calcium channel blockers block these channels and inhibit contraction, thus lowering blood pressure.
- Heart effects (diltiazem and verapamil)
- Electrical activity in the heart depends in part on calcium channels. Diltiazem and verapamil block these channels and slow conduction, specifically at the atrioventricular node (AV node) [13]
- HYPERTENSION
- Overview
- CCBs are widely used to treat hypertension
- Diltiazem and verapamil (nondihydropyridines) have been around for a long time, and studies evaluating their BP-lowering effects are sparse. A randomized controlled trial that compared the effects of 6 different BP meds including diltiazem is detailed below. We found no good information for verapamil.
- A Cochrane meta-analysis that looked at the BP-lowering effects of dihydropyridine CCBs is also presented below
- The Veterans Affairs Cooperative study enrolled 1292 men with hypertension
Main inclusion criteria
- Male veteran
- DBP 95 - 109 mmHg off medications
Baseline characteristics
- Average age 59 years
- Average BP 152/99 mmHg
- Black race - 48%
- Current smoker - 32%
Randomized treatment groups
- Group 1 (188 patients) - Hydrochlorothiazide 12.5 - 50 mg once daily
- Group 2 (176 patients) - Atenolol 25 - 100 mg once daily
- Group 3 (188 patients) - Captopril 25 - 100 mg/day given in 2 divided doses
- Group 4 (177 patients) - Clonidine 0.2 - 0.6 mg/day given in 2 divided doses
- Group 5 (182 patients) - Diltiazem SR 120 - 360 mg/day given in 2 divided doses
- Group 2 (186 patients) - Prazosin 4 - 20 mg/day given in 2 divided doses
- Group 2 (186 patients) - Placebo
- There was a washout period of 4 - 8 weeks before randomization
- Patients were titrated over a period of 4 - 8 weeks to a DBP < 90 mmHg or until they reached the maximum drug dose
Primary outcome: Attainment of blood pressure goal during titration (DBP < 90 mmHg) and DBP of < 95 mmHg at one year
Results
Average BP reduction at the end of the titration phase (SBP/DBP mmHg) | ||||||
---|---|---|---|---|---|---|
HCTZ | Atenolol | Captopril | Clonidine | Diltiazem | Prazosin | Placebo |
14 / 10 | 11 / 12 | 9 / 10 | 16 / 12 | 13 / 14 | 12 / 11 | 3 / 5 |
|
Findings: Among men, race and age have an important effect on the response to single-drug therapy for hypertension. In addition to cost and quality of life, these factors should be considered in the initial choice of drug.
- STUDY
- A Cochrane meta-analysis evaluated the effects of dihydropyridine CCBs on blood pressure in patients with hypertension
- The analysis included 16 randomized placebo-controlled trials (N=2768) that used amlodipine, lercanidipine, manidipine, nifedipine, felodipine, or nicardipine
- Results from the analysis are presented in the table below
Average hourly BP reduction (CCB minus Placebo) | |
---|---|
SBP | 9.5 - 13.2 mmHg |
DBP | 5.9 - 8.5 mmHg |
- Professional recommendations
- See hypertension guidelines for a review of recommended therapies and treatment goals from various professional organizations
- CARDIOVASCULAR DISEASE
- Overview
- Two studies that evaluated the effects of CCBs on cardiovascular outcomes are presented below. In the ALLHAT trial, the effect of amlodipine was compared to lisinopril and chlorthalidone in patients with hypertension. A Cochrane meta-analysis that compared cardiovascular outcomes with CCBs to other classes of blood pressure medications in patients with hypertension is also presented.
- The ALLHAT study enrolled 33,357 patients with hypertension and either a history of CVD or risk factors for CVD
Main inclusion criteria
- Age > 55 years
- SBP ≥ 140 and/or DBP ≥ 90 or treated hypertension
- One of the following: previous MI or stroke, left ventricular hypertrophy (LVH), type 2 diabetes, smoker, low HDL (< 35 mg/dl)
Main exclusion criteria
- History of hospitalized or treated symptomatic heart failure
- EF < 35%
Baseline characteristics
- Average age 67 years
- Race: White - 47% | Black - 32% | Hispanic - 16%
- Women - 47%
- Average BP - 146/84
- Receiving treatment for hypertension - 90%
- Qualifying risk factor: CVD - 52% | Diabetes - 36% | Smoker - 22% | LVH - 21% | Low HDL - 12%
Randomized treatment groups
- Group 1 (15,255 patients) - Chlorthalidone 12.5 - 25 mg a day
- Group 2 (9048 patients) - Amlodipine 2.5 - 10 mg/day
- Group 3 (9054 patients) - Lisinopril 10 - 40 mg/day
- Treatment was titrated to a BP goal of < 140/90
- If BP goal was not met taking the maximum tolerated dosage of the initial medication, open-label Step 2 agent (atenolol, 25-100 mg/d, reserpine, 0.05-0.2 mg/d, or clonidine, 0.1-0.3 mg twice per day), or an open-label Step 3 agent (hydralazine, 25-100 mg twice per day) could be added
- There was another arm of the study that used doxazosin. That arm was stopped early due to an increased risk of major CVD events. See ALLHAT doxazosin for more.
Primary outcome: Composite of fatal coronary heart disease or nonfatal myocardial infarction
Results
Duration: Average of 4.9 years | ||||
Outcome | Chlorthalidone | Amlodipine | Lisinopril | Comparisons |
---|---|---|---|---|
Primary outcome (6-year rate) | 11.5% | 11.3% | 11.4% | 1 vs 2 p=0.65 | 1 vs 3 p=0.81 |
Overall mortality (6-year rate) | 17.3% | 16.8% | 17.2% | 1 vs 2 p=0.20 | 1 vs 3 p=0.90 |
Stroke (6-year rate) | 5.6% | 5.4% | 6.3% | 1 vs 2 p=0.28 | 1 vs 3 p=0.02 |
Heart failure (6-year rate) | 7.7% | 10% | 8.7% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
Achieved BP goal (< 140/90) at 1 year | 57.8% | 55.2% | 50.6% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
Potassium < 3.5 mEq/L at 2 years | 12.7% | 2.6% | 1.5% | 1 vs 2 p<0.001 | 1 vs 3 p<0.001 |
New-onset diabetes at 4 years | 11.6% | 9.8% | 8.1% | 1 vs 2 p=0.04 | 1 vs 3 p<0.001 |
Findings: Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.
- STUDY
- A Cochrane meta-analysis compared cardiovascular outcomes with CCBs to those of other blood pressure medications in patients with hypertension
- Dihydropyridines were used in 14 of the trials and nondihydropyridines were used in 4
- Other blood pressure medications included thiazide diuretics, beta blockers, ACE inhibitors, and ARBs
- Results
- For overall mortality, there was no significant difference between CCBs and the other medications
- Risk of a heart attack was significantly lower with CCBs when compared to ARBs (relative risk reduction 17%)
- Risk of stroke was significantly lower with CCB when compared to beta blockers (relative risk reduction 23%), ACE inhibitors (relative risk reduction 11%), and ARBs (relative risk reduction 15%)
- Risk of heart failure was significantly worse with CCB when compared to diuretics (relative risk increase 37%), ACE inhibitors (relative risk increase 16%), and ARBs (relative risk increase 20%) [6]
- AHA recommendations
- The 2015 AHA recommendations on the treatment of hypertension in patients with CAD state that blood pressure lowering is more important than the class of antihypertensive used. They do not recommend one class of drugs over another. [61]
- Summary
- CCBs appear to be better than other medications at preventing stroke. This is consistent with the fact that stroke risk is closely tied to blood pressure, and CCBs tend to have a more consistent effect on blood pressures across different patient populations than other meds (ex. beta blockers, ACE inhibitors, ARBs). [1]
- CCBs appear to be worse than other medications in preventing heart failure. This is consistent with the fact that other medications are beneficial in heart failure (ex. diuretics, beta blockers, ACE inhibitors), where CCBs have no proven benefit.
- In the ALLHAT trial, amlodipine was equivalent to chlorthalidone and lisinopril for the primary outcome of fatal coronary heart disease or nonfatal myocardial infarction. Because of its diuretic effect, chlorthalidone was superior to both amlodipine and lisinopril for preventing heart failure. Overall mortality did not differ between the 3 treatments.
- In patients with CVD, achieving good blood pressure control is more important than the class of antihypertensive that is used to achieve it
- ATRIAL FIBRILLATION
- Overview
- Atrial fibrillation is a common heart arrhythmia that causes a rapid heart rate
- Atrial fibrillation can be treated in two ways:
- Rate control - slowing the rapid heart rate produced by the arrhythmia
- Rhythm control - attempting to convert the arrhythmia back to a normal rhythm or preventing the abnormal rhythm from occurring
- Rhythm control
- A small number of trials of varying design have looked at CCBs in the conversion of atrial fibrillation to a normal rhythm and in preventing atrial fibrillation
- There is no evidence that diltiazem or verapamil can convert atrial fibrillation or prevent it from occurring [22]
- Rate control
- Diltiazem and verapamil slow the heart rate so they are often used for rate control in A fib
- A number of small, older trials of varying design have demonstrated that diltiazem and verapamil are effective in helping to control the heart rate in atrial fibrillation
- Results from one of those trials found the following in patients with chronic A fib:
- Diltiazem (270 mg/day) lowered the average heart rate over 24 hours from 88 bpm to 76 bpm
- Verapamil (240 mg/day) lowered the average heart rate over 24 hours from 88 bpm to 80 bpm
- At maximal exercise, the heart rate was lowered from 179 to 159 with diltiazem
- At maximal exercise, the heart rate was lowered from 179 to 158 with verapamil [47]
- AHA recommendations
- STABLE ANGINA
- Overview
- Stable angina is predictable and reproducible cardiac chest pain that occurs with exertion and is relieved with rest
- Most studies evaluating CCBs in the treatment of stable angina are small and older
- We found one meta-analysis that compared different treatments for stable angina
- STUDY
- A JAMA meta-analysis from 1999 evaluated trials that compared CCBs to nitrates or beta blockers in the treatment of stable angina
- Nifedipine, verapamil, or diltiazem were the CCBs predominantly used in the trials evaluated
- When CCBs were compared to beta blockers, the following results were seen:
- Compared to calcium channel blockers, beta blockers were associated with 0.31 fewer episodes of angina per week (borderline significant, p=0.05)
- There was no significant difference in a composite outcome of heart attack or cardiac death
- There was no significant difference in nitroglycerin use per week
- CCBs were associated with a greater number of adverse events than beta blockers
- When CCBs were compared to long-acting nitrates, the following results were seen:
- There was no significant difference between groups for any outcome [28]
- Findings: Beta-Blockers provide similar clinical outcomes and are associated with fewer adverse events than calcium antagonists in randomized trials of patients who have stable angina
- AHA recommendations
- The AHA 2012 CAD guidelines recommend beta blockers as the first-line agent for the treatment of chronic angina
- If beta blockers are contraindicated or not tolerated, then calcium channel blockers (dihydropyridines and nondihydropyridines) or long-acting nitrates should be used
- If initial beta blocker therapy does not control symptoms, then a calcium channel blocker or long-acting nitrate should be added to beta blocker therapy [59]
- Summary
- Beta blockers are the preferred first-line agent in chronic angina because they improve heart failure outcomes
- Calcium channel blockers and long-acting nitrates are also effective
- Nifedipine and diltiazem should be used with caution in patients with heart failure because they may worsen outcomes. Amlodipine has been shown to be safe in heart failure.
- PRINZMETAL'S ANGINA
- Overview
- Prinzmetal's angina, also referred to as "variant angina," "vasospastic angina," and "coronary artery spasm," is a syndrome where the coronary arteries spasm and close spontaneously. Prinzmetal's angina causes ischemia, which produces symptoms similar to obstructive angina. The cause of the spasms is unknown.
- Recommended treatments for vasospastic angina include CCBs (nondihydropyridines and dihydropyridines) and nitrates [32]
- AHA recommendations
- The AHA/ACC recommends CCBs and nitrates as first-line treatment for vasospastic angina
- Moderate-to-high doses of CCBs are often required: Example: Verapamil 240-480 mg a day, diltiazem 180 - 360 mg a day, or nifedipine 60 - 120 mg a day
- In some cases, a combination of nitrates and two CCBs of different classes (ex. amlodipine + verapamil or diltiazem) may be required [51]
- KIDNEY STONES
- Overview
- Kidney stones occur when minerals crystallize and form masses in the renal collecting system
- Renal stones are typically asymptomatic. If a renal stone passes into the ureter, it usually becomes symptomatic.
- The size of the stone dictates whether it will be able to pass through the ureters into the bladder
- Nifedipine relaxes smooth muscle in the wall of the ureter. Theoretically, this relaxation may facilitate the passage of kidney stones. [45]
- Studies
- A number of small studies of varying design have looked at the effects of nifedipine on kidney stone passage. Meta-analyses of these studies came to the conclusion that nifedipine improves stone passage rates. [52]
- In 2015, a large randomized controlled trial was published in the Lancet that compared nifedipine to alpha blockers and placebo. That study is detailed here - Tamsulosin vs Nifedipine vs Placebo for Kidney Stone Passage
- Professional recommendations
- Use of medications to facilitate ureteral stone passage is called "medical expulsive therapy"
- Recommendations on medical expulsive therapy are available here - kidney stone treatment recommendations
- CCBs in HFrEF
- Overview
- Heart failure with reduced ejection fraction (HFrEF), also called "systolic heart failure," is heart failure caused by a reduced ability of the left side of the heart to pump blood effectively which leads to a reduced ejection fraction (compare to HFpEF where ejection fraction is preserved)
- Nondihydropyridines CCBs (diltiazem and verapamil) can decrease the force of heart contraction and worsen heart failure in some patients. For this reason, diltiazem and verapamil should generally be avoided in patients with systolic heart failure. Dihydropyridine CCBs do not generally have this effect. The PRAISE study detailed below was specifically designed to look at the safety of amolodipne in patients with HFrEF.
- The PRAISE study enrolled 1153 patients with severe heart failure
Main inclusion criteria
- NYHA class III or IV heart failure
- EF < 30%
Main exclusion criteria
- SBP < 85 or > 159
- DBP > 89
- Serum creatinine > 3 mg/dl
- Treatment with beta blockers
- Treatment with CCB
Baseline characteristics
- Average age 64 years
- NYHA class: III - 81% | IV - 19%
- Average BP - 117/72
- Average EF - 21%
Randomized treatment groups
- Group 1 (571 patients) Amlodipine once daily with a target dose of 10 mg (average dose achieved was 8.8 mg)
- Group 2 (582 patients) Placebo once daily
- Almost all patients in the study were taking digoxin, an ACE inhibitor, and diuretics
- Randomization was stratified by type of heart failure - ischemic or nonischemic dilated cardiomyopathy
Primary outcome: Composite of death from any cause or hospitalization for major cardiovascular event defined as
acute pulmonary edema, severe hypoperfusion, acute myocardial infarction, or sustained or hemodynamically destabilizing ventricular tachycardia or fibrillation
Results
Duration: Median of 13.8 months | |||
Outcome | Amlodipine | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 39% | 42% | p=0.31 |
Overall mortality | 33% | 38% | p=0.07 |
Peripheral edema | 27% | 18% | p<0.05 |
Pulmonary edema | 15% | 10% | p<0.05 |
Drug discontinuation | 14.4% | 16% | N/A |
|
Findings: Amlodipine did not increase cardiovascular morbidity or mortality in patients with severe heart failure. The possibility that amlodipine prolongs survival in patients with nonischemic dilated cardiomyopathy requires further study.
- Professional guidelines:
- The AHA/ACC recommends that diltiazem and verapamil not be used in patients with heart failure
- They state that amlodipine has not been shown to adversely affect survival
- CCBs in HFpEF
- Overview
- Heart failure with preserved ejection fraction (HFpEF), also referred to as "diastolic heart failure," is a syndrome where the signs and symptoms of heart failure are present in patients with a normal ejection fraction
- HFpEF is thought to be caused by reduced ventricular compliance, meaning the left ventricle does not relax appropriately when it is filling with blood
- The ideal treatment of HFpEF has not been defined, and results from good clinical trials are lacking [16,17]
- A handful of very small trials have shown that verapamil may improve heart function in patients with diastolic heart failure [18,19,20]
- AHA 2017 recommendations
- Diuretics should be used for relief of symptoms due to volume overload in patients with HFpEF
- The use of beta-blocking agents, ACE inhibitors, and ARBs in patients with hypertension is reasonable to control blood pressure in patients with HFpEF [60]
- StraightHealthcare analysis
- The AHA 2017 HFpEF guidelines do not mention CCBs in the treatment of HFpEF
- The ideal treatment for HFpEF has not been defined
- For now, therapy should focus on blood pressure and symptom control
- SIDE EFFECTS
- Slow heart rate (bradycardia)
- Verapamil and diltiazem can slow the heart rate
- The effect can be additive with other medications that also slow the heart rate (beta blockers, digoxin)
- In trials, diltiazem and verapamil slow the average resting heart rate by about 4 beats per minute [35-40]
- Swelling of the legs and feet (peripheral edema)
- Dihydropyridines can cause swelling of the feet and legs in 5-12% of patients [7,8,9,10,11,12]
- Nondihydropyridines (verapamil and diltiazem) cause swelling to a lesser degree, 1-3% of patients [12,13]
- Constipation (verapamil)
- Verapamil can cause constipation in about 7-8% of patients [13]
- Gingival hyperplasia (overgrowth of the gums)
- Gingival hyperplasia is an overgrowth of gum tissue. All CCBs can cause gingival hyperplasia.
- The overall incidence of gingival hyperplasia from CCBs is not well-defined. Nifedipine may pose a greater risk than other CCBs. [42]
- Smoking and certain concurrent medications (ex. phenytoin, cyclosporine) may increase the risk of gingival hyperplasia. Smokers and patients who are taking these medications may want to avoid CCBs.
- STUDY
- A case-control study in the British Journal of Clinical Pharmacology looked at the risk of gingival hyperplasia with CCBs
- The study involved 4290 patients who underwent oral examination by specially trained dentists
- The following results were seen when CCB users were compared to nonusers:
- The odds of having gingival hyperplasia with a probing depth of > 4 mm at more than 10% of sites was 1.5 in the CCB group (probing depth > 3 mm is considered abnormal)
- CCBs were not associated with greater tooth loss or attachment loss (a measure of gum health) [43]
- Flushing (warm feeling of the face)
- Dihydropyridines can cause flushing to occur (2-6% of patients) [7,8,11]
- This appears to be worse with immediate-release nifedipine (up to 17% of patients) [8]
- This does not appear to be a significant problem with nondihydropyridines [12,13]
- First degree heart block
- Prolongation of the PR interval (PR > 200 msec) on an EKG is called first degree heart block
- First degree heart block is typically benign and of little clinical significance
- In trials, verapamil and diltiazem have been shown to prolong the PR interval and cause first degree heart block in a small percentage of patients (0 - 4% of patients) [12,13]
- CONTRAINDICATIONS
- Amlodipine (Norvasc®)
- Known hypersensitivity
- Isradipine (Dynacirc®)
- Known hypersensitivity
- Diltiazem (Cardizem®, etc.)
- Sick sinus syndrome (without pacemaker)
- Second- or third-degree AV block (without pacemaker)
- Hypotension (SBP < 90 mmHg)
- Known hypersensitivity
- Acute heart attack with pulmonary edema
- Felodipine (Plendil®)
- Known hypersensitivity
- Nicardipine (Cardene®)
- Known hypersensitivity
- Advanced aortic stenosis
- Nifedipine (Procardia®, etc.)
- Known hypersensitivity
- Nisoldipine (Sular®)
- Known hypersensitivity
- Verapamil (Calan®)
- Sick sinus syndrome (without pacemaker)
- Second- or third-degree AV block (without pacemaker)
- Hypotension (SBP < 90 mmHg)
- Known hypersensitivity
- Severe left ventricular dysfunction
- Atrial fibrillation or flutter with accessory pathway (eg. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes)
- PRECAUTIONS
- Kidney disease
- Amlodipine (Norvasc)
- No dose adjustment necessary in kidney disease
- Diltiazem (Cardizem, Cardizem CD, Cartia XT)
- Diltiazem is excreted by the kidneys. Start low and titrate slowly.
- A single study in 9 patients with severe kidney disease showed no difference in diltiazem pharmacokinetics compared to those with normal function.
- Diltiazem (Cardizem LA)
- No dose adjustment is necessary
- Diltiazem (Dilacor XR)
- Patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function
- Diltiazem (Taztia XT, Tiazac)
- Use caution. Patients with severely impaired renal function (creatinine clearance < 50 mL/min) who received immediate-release diltiazem had modestly increased diltiazem concentrations compared to patients with normal renal function
- Felodipine (Plendil)
- No dose adjustment necessary
- Isradipine (Dynacirc)
- Mild renal impairment (creatinine clearance 30 - 80 mL/min) increases the AUC of isradipine by 45%. Progressive deterioration reverses this trend, and patients with severe renal failure (creatinine clearance < 10 mL/min) who have been on hemodialysis show a 20% - 50% lower AUC than healthy volunteers. Starting dose of 2.5 mg twice a day is recommended in mild renal impairment.
- Nicardipine (Cardene)
- Exposure is increased. Start with 20 mg three times a day and titrate slowly.
- Nifedipine (Procardia IR, Adalat CC, Afeditab CR, Procardia XL)
- Has not been studied. Use caution.
- Nisoldipine (Sular)
- Dose adjustments in mild to moderate renal impairment are not necessary
- Verapamil (Calan, Calan SR, Verelan. Verelan PM)
- About 70% of verapamil dose is excreted by the kidneys. Use caution in patients with impaired renal function and monitor for abnormal prolongation of the PR interval.
- Liver disease
- Amlodipine (Norvasc)
- Amlodipine is extensively metabolized by the liver and the plasma elimination half-life is 56 hours in patients with impaired hepatic function. Use a starting dose of 2.5 mg once daily and titrate slowly.
- Diltiazem (Cardizem, Cardizem CD, Cartia XT)
- Diltiazem should be used with caution in patients with significant liver disease
- In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
- Diltiazem (Cardizem LA)
- Child Pugh A and B: no dose adjustment is likely to be needed
- Child Pugh C: manufacturer makes no recommendation. In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
- Diltiazem (Dilacor XR)
- Diltiazem should be used with caution in patients with significant liver disease
- In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
- Diltiazem (Taztia XT, Tiazac)
- Use caution. In a study of patients with cirrhosis, diltiazem's half-life was increased, and there was a 69% increase in AUC compared to patients with normal liver function.
- Felodipine (Plendil)
- Clearance is reduced by about 60%. Starting dose should be 2.5 mg and blood pressure should be monitored closely while titrating.
- Isradipine (Dynacirc)
- In patients with hepatic impairment, AUC is increased by 52%. Recommended starting dose is 2.5 mg twice a day.
- Nicardipine (Cardene)
- Exposure is increased. Use caution. In severe liver disease, start with 20 mg twice a day and titrate slowly while maintaining twice daily dosing.
- Nifedipine (Procardia IR, Adalat CC, Afeditab CR, Procardia XL)
- Exposure is increased. Use caution.
- Nisoldipine (Sular)
- Exposure is increased. Use a starting dose of 8.5 mg and titrate slowly.
- Verapamil (Calan, Calan SR, Verelan, Verelan PM)
- Exposure is increased. For patients with severe liver disease, the dose of verapamil should be about 30% of the dose given to patients with normal liver function.
- Heart failure
- Heart attack / unstable angina
- The AHA/ACC states that verapamil or diltiazem should be given in patients with continuing or frequent ischemia if beta blockers are contraindicated and no clinically significant heart failure or heart block is present
- Immediate-release dihydropyridines (ex. nifedipine) should only be used in patients if they are receiving adequate doses of beta blockers [51]
- Summary
- Beta blockers and nitrates are the first-line drug treatments for heart attack and unstable angina
- The AHA/ACC states that diltiazem and verapamil may be used in patients with contraindications to beta blockers
- Unfortunately, verapamil, diltiazem, and beta blockers share many of the same contraindications (ex. symptomatic heart failure, heart block), so CCB use in these patients will be limited
- Immediate-release dihydropyridines are not widely used anymore, and they should only be used in patients who are on adequate doses of beta blockers
- Second and third degree heart block
- Verapamil and diltiazem slow conduction through the AV node and should not be taken by patients with second or third degree heart block [12,13]
- Sick sinus syndrome
- Verapamil and diltiazem slow conduction through the AV node and should not be taken by patients with sick sinus syndrome [12,13]
- A fib or flutter with an accessory bypass tract (ex. Wolff-Parkinson-White syndrome)
- Intravenous verapamil has been shown to induce ventricular arrhythmias in patients with accessory bypass tracts
- The risk with oral verapamil has not been established, but may exist
- Verapamil should not be used in these patients [13]
- Hypertrophic cardiomyopathy
- Verapamil has been shown to be detrimental in patients with hypertrophic cardiomyopathy [13]
- Neuromuscular conditions
- Verapamil has been reported to decrease neuromuscular transmission in patients with conditions where neuromuscular transmission is attenuated (ex. Duchenne's muscular dystrophy, myasthenia gravis, vecuronium administration)
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- All CCB
- Clarithromycin (Biaxin®) - Hypotension and acute kidney injury have been reported in patients taking CCBs with the antibiotic clarithromycin. Most reports have occurred in patients ≥ 65 years [55]
- Nitroglycerin - marked symptomatic orthostatic hypotension has been reported when calcium channel blockers and organic nitrates were used in combination [54]
- Amlodipine
- Cyclosporine - amlodipine may increase cyclosporine levels. Monitor cyclosporine levels closely.
- CYP3A4 inhibitors - amlodipine is a sensitive CYP3A4 substrate. Moderate and strong CYP3A4 inhibitors may increase exposure to amlodipine and lead to hypotension and/or edema. Monitor patients closely when combining.
- Simvastatin (Zocor®) - Simvastatin dose should not exceed 20 mg/day while taking amlodipine
- Tacrolimus - tacrolimus blood levels may increase when taken with amlodipine. Monitor tacrolimus blood levels and adjust dose accordingly.
- Diltiazem
- CYP3A inhibitors/inducers/substrates - may affect the metabolism of diltiazem and vice versa
- Digoxin - diltiazem may increase digoxin levels. Monitor digoxin levels when starting or changing diltiazem therapy.
- Ivabradine (Corlanor®) - diltiazem may increase blood levels of ivabradine and cause severe bradycardia. Diltiazem should not be given with ivabradine.
- Lovastatin (Mevacor®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
- Medications that slow the heart rate - verapamil and diltiazem slow the heart rate. When they are taken with other medications that slow the heart rate, the effect may be potentiated.
- Common medications that slow the heart rate
- Amiodarone (Cordarone®)
- Beta blockers
- Clonidine (Catapres®)
- Digoxin (Lanoxin®)
- Fingolimod (Gilenya®)
- Ivabradine (Corlanor®)
- Siponimod (Mayzent®)
- Simvastatin (Zocor®) - Simvastatin dose should not exceed 10 mg/day. Diltiazem dose should not exceed 240 mg/day.
- Topiramate (Topamax®) - topiramate may decrease diltiazem levels, and diltiazem may increase topiramate levels
- Felodipine
- CYP3A inhibitors/inducers/substrates - may affect the metabolism of felodipine and vice versa
- Oxcarbazepine (Trileptal®) - oxcarbazepine may decrease Felodipine levels by 28%
- Isradipine
- Cimetidine - cimetidine may increase exposure to isradipine. Monitor for adverse events and adjust dose if necessary.
- Rifampicin - rifampicin may decrease exposure to isradipine. Concomitant use is not recommended.
- Nicardipine
- Cyclosporine - nicardipine inhibits cyclosporine metabolism and increases its exposure. Monitor cyclosporine levels closely when given concomitantly.
- Tacrolimus - nicardipine inhibits tacrolimus metabolism and increases its exposure. Monitor tacrolimus levels closely when given concomitantly.
- Nifedipine
- CYP3A inhibitors/inducers/substrates - may affect the metabolism of nifedipine and vice versa
- Nisoldipine
- CYP3A inhibitors/inducers/substrates - may affect the metabolism of nisoldipine and vice versa
- Verapamil
- CYP3A inhibitors/inducers/substrates - may affect the metabolism of verapamil and vice versa
- Digoxin - verapamil may increase digoxin levels. Monitor digoxin levels when starting or changing verapamil therapy.
- Disopyramide (Norpace®) - Manufacturer recommends disopyramide not be administered 48 hours before or 24 hours after verapamil is administered
- Ethanol (beverage alcohol) - verapamil may inhibit the metabolism and ethanol and increase blood alcohol levels
- Inhalation anesthetics - inhaled anesthetics may depress cardiac activity and potentiate the effects of verapamil. Use caution when combining.
- Ivabradine (Corlanor®) - verapamil may increase blood levels of ivabradine and cause severe bradycardia. Verapamil should not be given with ivabradine.
- Lovastatin (Mevacor®) - lovastatin starting dose should be 10 mg/day. Lovastatin dose should not exceed 20 mg/day when combining.
- Medications that slow the heart rate - verapamil and diltiazem slow the heart rate. When they are taken with other medications that slow the heart rate, the effect may be potentiated.
- Common medications that slow the heart rate
- Amiodarone (Cordarone®)
- Beta blockers
- Clonidine (Catapres®)
- Digoxin (Lanoxin®)
- Fingolimod (Gilenya®)
- Ivabradine (Corlanor®)
- Siponimod (Mayzent®)
- mTOR inhibitors (e.g. temsirolimus, sirolimus, everolimus) - verapamil increases blood levels of mTOR inhibitors and mTOR inhibitors increase blood levels of verapamil. In one study, co-administration of verapamil and sirolimus increased sirolimus Cmax and AUC by 130% and 120%, respectively. Plasma S (-) verapamil Cmax and AUC were both increased 50%. In another study, co-administration of verapamil with everolimus increased the Cmax and AUC of everolimus by 130% and 250%, respectively. Consider reducing doses of both medications when combining.
- Neuromuscular blocking agents - verapamil may potentiate the effects of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of one or both drugs when combining.
- Oxcarbazepine (Trileptal®) - verapamil may decrease oxcarbazepine levels by 20%
- P-glycoprotein substrates/inducers/inhibitors - may affect the metabolism of verapamil and vice versa
- Simvastatin (Zocor®) - simvastatin dose should not exceed 10 mg/day while taking verapamil
- Theophylline - verapamil may inhibit the clearance of theophylline and increase its levels
- Metabolism and clearance
- Amlodipine (Norvasc®, Katerzia®)
- CYP3A4 - Sensitive substrate and weak inhibitor
- Diltiazem (Cardizem®, Cartia®, Dilacor®, etc.)
- CYP2D6 - Weak inhibitor
- CYP3A4 - Substrate and inhibitor
- P-glycoprotein - Substrate and inhibitor
- Felodipine (Plendil®)
- CYP3A4 - Substrate
- P-glycoprotein - Substrate
- Isradipine (Dynacirc®)
- CYP3A4 - Substrate and inhibitor
- Nicardipine (Cardene®)
- CYP2D6 - Substrate and inhibitor
- CYP2C8 - Substrate and inhibitor
- CYP2C19 - Inhibitor
- CYP3A4 - Substrate and weak inhibitor
- P-glycoprotein - Inhibitor
- Nifedipine (Adalat®, Procardia®, Afeditab®)
- CYP3A4 - Substrate and inhibitor
- Nisoldipine (Sular®)
- CYP3A4 - Substrate
- Verapamil (Calan®, Verelan®, Isoptin®)
- DOSING
- LONG-TERM SAFETY
- CCBs have been in use since the 1980s
- They have been widely prescribed
- When prescribed appropriately, they have been shown to be safe in long-term use
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