Download Verapamil vs. Diltiazem

Verapamil vs. Diltiazem
Replacement to the List
Peer Feedback:
“Verapamil is more constipating and is a stronger negative inotrope so more caution required in
the context of concern for heart failure (e.g. with concomitant atrial fibrillation)”
"(diltiazem has a) better side effect profile compared to verapamil which can be removed"
Literature Review Question:
What are the side effect profiles of calcium channel blockers?
What is the efficacy of various calcium channel blockers?
Literature Search:
eCPS – Supraventricular Tachycardia, Hypertension, Stable Angina
Pubmed – “calcium channel blocker AND (hypertension OR angina) AND (verapamil OR
diltiazem OR nifedipine OR amlodipine) AND (efficacy OR safety)”; “diltiazem AND verapamil
AND (safety or tolerability OR side effect)”; “nifedipine AND amlodipine AND review/metaanalysis”
Atrial fibrillation (acute onset) BMJ (2014)
One systematic review concluded that the available evidence suggests that calcium channel
blockers, such as diltiazem and verapamil, reduce ventricular rate in acute- or recent-onset atrial
fibrillation. However, these drugs are probably no better than placebo for restoring sinus rhythm.
We found no studies of the effect of rate-limiting calcium channel blockers on exercise tolerance
in people with acute- or recent-onset atrial fibrillation, but studies in people with chronic atrial
fibrillation found improved exercise tolerance. [27]
We found one systematic review (search date 1998) [52] and two additional RCTs [59] [60]
comparing digoxin with placebo in people with chronic atrial fibrillation, which found that control of
the ventricular rate during exercise was poor unless a beta-blocker or rate-limiting calcium
channel blocker (verapamil or diltiazem) was used in combination. One systematic review on
atrial fibrillation concluded that intravenous beta-blockers or rate-limiting calcium channel
blockers should be used for people requiring urgent pharmacological rate control. Where these
drugs are ineffective or contraindicated, amiodarone should be used. [27] It is not clear whether
these results can be extrapolated to people with acute atrial fibrillation.
Beta-blockers or non-dihydropyridine calcium channel antagonists are recommended as first-line
treatment for rate control of atrial fibrillation. [2] There is no RCT to compare the effects of
metoprolol or other drugs within the same class versus placebo in recent-onset atrial fibrillation.
By extrapolating data from persistent and chronic atrial fibrillation, beta-blockers, as a class,
seem to be a safe and effective treatment for rate control. Beta-blockers may exacerbate heart
failure and hypotension in acute atrial fibrillation and can precipitate bronchospasm. [63] Coadministration of beta-blockers and rate-limiting calcium channel blockers (diltiazem and
verapamil) may increase the risk of asystole and sinus arrest. [64] [65] [66]
Verapamil versus diltiazem: We found one small, double-blind, crossover RCT (17 men, 5 with
acute atrial fibrillation, 10 with atrial flutter, and 2 with a combination of atrial fibrillation and atrial
flutter; ventricular rate at least 120 beats/minute, systolic blood pressure at least 100 mmHg),
which compared iv verapamil versus iv diltiazem and found no difference in rate control or
measures of systolic function. [69] In the RCT, three people who received verapamil developed
symptomatic hypotension and were withdrawn from the study before crossover. [69] Two people
recovered, but the episode in the third person was considered life-threatening. In people with
Wolff-Parkinson-White syndrome, verapamil may increase ventricular rate, and can cause
ventricular arrhythmias. [57] Rate-limiting calcium channel blockers may exacerbate heart failure
and hypotension.
Gregory YH Lip and Stavros Apostolakis, “Atrial fibrillation (acute onset).” BMJ. 2014
Calcium Channel Blockers (2011)
Nondihydropyridine calcium channel blockers are more negatively chronotropic and inotropic than
the dihydropyridine subclass, which is important for patients with cardiac dysrhythmias or who
need b-blockers.
Extensive experience in comparative randomized trials indicates that an initial calcium antagonist
can prevent all major types of cardiovascular disease, except heart failure (for which a diuretic is
superior). Initial dihydropyridine calcium channel blockers have not reduced the rate of
progression of renal disease as well as inhibitors of the renin-angiotensin system, although
members of the nondihydropyridine subclass can reduce albuminuria.
High doses of dihydropyridine calcium channel blockers often cause edema, headache, flushing
and tachycardia; high doses of verapamil can cause constipation.
Common adverse effects of CCBs include edema, flushing, headache, dizziness, constipation
(particularly with high-dose verapamil), nausea, rash, and drowsiness. CCBs have many
important drug interactions. Verapamil and diltiazem increase digoxin levels. Verapamil,
diltiazem, and nicardipine increase plasma levels and decrease the dosing requirement for
cyclosporine. Verapamil and diltiazem are metabolized by CYP3A4, therefore inducers (eg,
rifampin) and inhibitors (eg, erythromycin, cimetidine) are likely to result in decreased and
increased plasma levels of these two CCBs, respectively. Concomitantly administered grapefruit
juice elevates the oral bioavailability of felodipine, nifedipine, nicardipine, nisoldipine, and
verapamil. Because of their shared negative effects on heart rate and myocardial contractility, bblockers and verapamil are not used simultaneously.
Elliott, William J., and C. Venkata S. Ram. "Calcium channel blockers." The Journal of Clinical Hypertension 13.9 (2011):
687-689.
Calcium Antagonists (2004)
Unlike the other calcium channel blockers, verapamil can have clinically significant bronchodilator
effects, but it is also the most likely to produce untoward constipation.
Grossman, Ehud, and Franz H. Messerli. "Calcium antagonists." Progress in cardiovascular
diseases 47.1 (2004): 34-57.
In Vitro Comparison (1996)
Inotropic effect
Nifedipine, verapamil and diltiazem produced concentration-dependent negative inotropic effects
on isolated guinea-pig left atrial preparations (Fig. 2). The potency order was
nifedipine>verapamil>diltiazem, EC30values being 4.94 × 10 8M, 1.49 x 10 7M and 8.03 × 107M, respectively (Table 1). Efonidipine, even at 1 ~tM produced no inotropic effect: I0 ~tM
efonidipine decreased the contractile force by about 20% (Fig. 2; Table 1)
Tanaka, Hikaru, et al. "Myocardial and vascular effects of efonidipine in vitro as compared with
nifedipine, verapamil and diltiazem." General Pharmacology: The Vascular System 27.3 (1996):
451-454.
CCAs Side-effects (1988)
Verapamil Side Effects
Relatively minor side effects are those of vasodilation--headaches and dizziness, with occasional
palpitations and hypotension [2]. Ankle edema may also result (Table IV-2). The side effect
causing trouble, especially in elderly patients, is constipation. Straining at stool can in turn cause
cardiovascular problems such as syncope. The incidence of constipation occurs in 25% to 40% of
patients [2, 3]. With a higher mean dose (416 mg daily), constipation occurred in 10 of 16
patients, i.e., 63% [4]. The minor side effects of verapamil, apart from constipation, are somewhat
less than those of nifedipine when both are used in doses equipotent for chronic stable angina [5]
or hypertension [6].
Severe side effects with verapamil were initially stressed by reports of fatality when intravenous
verapamil was abruptly given to isolated patients with pre-existing atrioventricular AV inhibition by
disease or ~-adrenergic blockade [7]. In addition to individual case reports of fatalities, largely
resulting from asystole, there have been several "near-misses" [3]. The thrust of Fleckenstein's
[8] original experiments in defining myocardial depression as a basic property of calcium channel
antagonists led to the view that calcium channel antagonists must be negative inotropic agents.
Logically, the combination of therapy by calcium channel antagonists and ~-blockade was feared
[9]. It is now becoming apparent that calcium channel antagonists, when correctly used, seldom
induce a serious negative inotropic state [10]. Furthermore, careful patient selection has
diminished the possibility of severe side effects. In the case of verapamil, sick sinus syndrome,
pre-existing AV nodal disease, excess therapy with 13-adrenergic blockade or digitalis or
quinidine, and myocardial depression, are all still contraindications which especially apply in the
intravenous therapy of supraventricular tachycardias [3, 11, 12]. In the rarer type of WolffParkinson-White syndrome with anterograde (= antegrade) conduction through the bypass tract,
the risk of verapamil is that atrial fibrillation can be too rapidly conducted to the ventricles with
fear of ventricular fibrillation. Nonetheless, verapamil can be safely used in the vast majority of
patients with supraventricular tachycardias and narrow QRS complexes.
Diltiazem Side Effects
Subjective or relatively minor side effects. When diltiazem is given for angina, the incidence of
side effects seems to be remarkably low [2]. In the United States, the package insert claims that
side effects of oral therapy are similar to those of placebo, but lists nausea (3%), pedal edema
(2%), headache (2%), and heart block (0.4%), and in two trials diltiazem for stable angina was
"remarkably free of adverse effects" in doses of 240 mg daily [33] and all doses (up to 360 mg
daily) were "extremely well tolerated" [34]. The true incidence of side effects will clearly depend
on the severity of underlying myocardial or conduction system disease, the skill of the prescribing
physician, and the dose of diltiazem.
Potentially serious nodal and myocardial side effects of diltiazem. Because experience with the
intravenous form has been limited to carefully controlled studies, the type of serious negative
chronotropic or inotropic side effect previously found with verapamil has not yet been reported.
Furthermore, the general impression (supported by animal data; see Table I-6) is that diltiazem is
less negatively inotropic than verapamil. However, few or no careful comparative clinical studies
with these end points appear to exist. Even the oral drug can inhibit AV and/or sinus nodal tissue
with AV dissociation and severe sinus bradycardia, as shown by the three patients with angina or
coronary artery spasm reported by Ishikawa et al. [40]. Such side effects can especially be
expected when the patients selected for diltiazem therapy have pre-existing sinus or AV nodal
disease or when there is co-therapy with ~- blockade or during digitalis toxicity [12]. With due
care such side effects should therefore be rare. Firstdegree AV block can be expected in about
one-fifth of patients with angina treated with diltiazem up to 360 mg daily [34].
Opie, Lionel H. "Calcium channel antagonists part IV: Side effects and contraindications drug interactions and
combinations." Cardiovascular drugs and therapy 2.2 (1988): 177-189.
eCPS – Supraventricular Tachycardia (2014); Hypertension (2015); Stable angina (2014)
Hypotension is the most common manifestation of CCB overdose. Impaired myocardial
contractility and bradycardia are other important features. Verapamil and diltiazem have more
pronounced negative inotropic and chronotropic effects than the dihydropyridines (e.g.,
amlodipine, felodipine and nifedipine). Dihydropyridines are primarily vasodilators, and reflex
tachycardia may occur following overdose. Extreme hypotension can lead to lethargy, dizziness,
syncope, altered mental status, metabolic acidosis and renal failure. Profound calcium channel
blockade inhibits insulin release and can result in hyperglycemia. Seizures have been reported.
Heart Rate Control in Patients with Persistent or Permanent Atrial Fibrillation or Flutter
Most patients will need drugs to achieve rate control, with the exception of some patients with
intrinsic AV nodal disease (usually elderly individuals). Pharmacologic control of heart rate should
initially be attempted with a beta-blocker or a calcium channel blocker (diltiazem or verapamil)
(Table 7). Digoxin is usually inadequate alone for rate control. Because of its potential
toxicity, amiodarone should be used only as a last resort.
Table 7: Drug Therapy for Control of Heart Rate in Patients with Supraventricular Tachycardia
Class
Adverse
Effects
Drug
Interactions
5–10 mg iv. May give
extra 10 mg iv in 30 min
Usual starting dose:120
mg/day po; maximum:480
mg/day po. IR given in
divided doses TID–QID;
SR given daily or divided
doses BID
Bradycardia,
hypotension,
constipation,
flushing.
0.25 mg/kg iv. May give
another 0.35 mg/kg
ivafter 15 min if necessary
180–540 mg/day
po. IRgiven in divided
doses TID–QID; SR in
divided doses BID; CD
and Tiazac given daily
Bradycardia,
hypotension.
Drug
Dosage
Calcium Channel
Blockers,
nondihydropyridine
verapamil
Calcium Channel
Blockers,
nondihydropyridine
diltiazem
Isoptin SR,generics
Cardizem
CD, Tiazac,Tiazac
XC,generics
Comments
Costa
Beta-blockers,

digoxin,
amiodarone.
Use with
caution in
patients with
HF.
iv:$$$
Beta-blockers,

digoxin,
amiodarone.
Use with
caution in
patients with
HF.
iv$c:
Cardiovascular Disorders: Supraventricular Tachycardia; David Birnie, MD and Pablo Nery, MD;
Date of Revision: May 2014
po:$$
po:$
Long-acting Calcium Channel Blockers (Hypertension)
Long-acting dihydropyridine CCBs can be used as first-line agents but in practice they are
generally used in combination therapy. Short-acting formulations of these agents have caused an
increase in cardiovascular events in randomized controlled trials and should not be used. Elderly
patients with isolated systolic hypertension and black patients are particularly responsive to
CCBs.
The data regarding the use of nondihydropyridine calcium channel blockers17,18 and alphablockers in pregnancy is very limited, so these agents are typically deferred or exchanged for
other preferred agents.
Class
Adverse
Effects
Drug Interactions
Comments
Costa
Drug
Dosage
Calcium Channel
Blockers,
dihydropyridine
amlodipine
Norvasc,
generics
Initial: 2.5 mg/day
Maximum: 10
mg/day
Once daily po
Ankle
edema,
flushing,
headache
and
palpitations.
CYP3A4 substrate (many potential
interactions).
Strong inhibitors include azole antifungals,
protease inhibitors, macrolides and quinidine.
Grapefruit juice may increase serum
concentrations.
Calcium Channel
Blockers,
dihydropyridine
felodipine,
extendedrelease
Plendil,
generics
Initial: 2.5 mg/day
Usual: 10 mg/day
Maximum: 20
mg/day
Once daily po
Ankle
edema,
flushing,
headache
and
palpitations.
CYP3A4 substrate (many potential

interactions).
Strong inhibitors include azole antifungals,
protease inhibitors, macrolides and quinidine.
Grapefruit juice may increase serum
concentrations.
Grapefruit juice
causes marked
elevations in
felodipine serum
levels and adverse
events.
Felodipine does not
have Health
Canada approval
for angina
$$

$
Calcium Channel
Blockers,
dihydropyridine
nifedipine,
extendedrelease
Adalat
XL, generics
Initial: 30 mg/day
Usual: 60 mg/day
Maximum: 120
mg/day
Once daily po
Ankle
edema,
flushing,
headache
and
palpitations.
CYP3A4 substrate (many potential

interactions).
Strong inhibitors include azole antifungals,
protease inhibitors, macrolides and quinidine.
Grapefruit juice may increase serum
concentrations.
Do not use shortacting nifedipine
formulations for
treatment of
essential
hypertension.
$$
Calcium Channel
Blockers,
nondihydropyridine
diltiazem
Cardizem
CD, Tiazac, Ti
azac XC,
generics
Initial: 120 mg/day
Usual:240–360
mg/day
Maximum:360
mg/day
Give CD or XC
formulation once
daily po, SR
formulation divided
BID po
Headache,
dizziness,
bradycardia,
heart block,
new onset or
worsening of
heart failure.
CYP3A4 substrate (many potential

interactions).
Strong inhibitors include azole antifungals,
protease inhibitors, macrolides and quinidine.
Grapefruit juice may increase serum
concentrations.
Nondihydropyridines inhibit the metabolism
of carbamazepine, cyclosporine, lovastatin,
simvastatin.
Rifampin induces metabolism of
nondihydropyridines.
Additive negative inotropic effects with
amiodarone, beta-blockers and digoxin.
Caution in patients
with heart failure,
or 2nd or 3rddegree
heart block without
a functioning
pacemaker.
$$
Calcium Channel
Blockers,
nondihydropyridine
verapamil
Isoptin
SR, generics
Initial: 80 mg TID
po
Maximum:160 mg
TID po
SR (once daily or
divided BID po):
Initial: 180 mg/day;
Usual: 180–480
mg/day; Maximum:
480 mg/day
Headache,
dizziness,
bradycardia,
heart block,
new onset or
worsening of
heart failure.
Constipation.
CYP3A4 substrate (many potential

interactions).
Strong inhibitors include azole antifungals,
protease inhibitors, macrolides and quinidine.
Grapefruit juice may increase serum
concentrations.
Nondihydropyridines inhibit the metabolism
of carbamazepine, cyclosporine, lovastatin,
simvastatin.
Rifampin induces metabolism of
nondihydropyridines.
Additive negative inotropic effects with
amiodarone, beta-blockers and digoxin.
Verapamil increases digoxin levels by 50–
75% within 1 wk (monitor levels).
Caution in patients
with heart failure,
or 2nd or 3rddegree
heart block without
a functioning
pacemaker.
$-$$
Legend: $<$20
$-$$ <$20–40
$$ 20–40
$$$ 40–60
$$$$ 60–80
Cardiovascular Disorders: Hypertension ; Norm R.C. R. C. Campbell, MD, FRCPC, Paul Gibson,
MD, FRCPC, and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of Revision: March 2015
Calcium Channel Blockers (Angina)
Practically speaking, there are 2 classes of calcium channel blockers. The nondihydropyridines verapamil and diltiazem act more centrally and thus behave similarly to betablockers: they decrease myocardial oxygen demand by lowering heart rate, contractility and blood
pressure. The dihydropyridines exert their effects primarily by arterial
dilation. Amlodipine, felodipine, and nifedipine have been effective in stable angina, though
felodipine does not have Health Canada approval for this indication. They reduce blood pressure
and, consequently, myocardial oxygen demand. Furthermore, by dilating coronary arteries,
dihydropyridines may also increase myocardial oxygen supply
When using a calcium channel blocker to treat angina in a patient who is already on a betablocker, a peripherally acting dihydropyridine is preferred; close monitoring of heart rate and AV
nodal function is required if verapamil or diltiazem is combined with a beta-blocker.
Note: Chart of medications from eCPS was the same in hypertension and asthma, except
felodipine is not indicated for angina.
Cardiovascular Disorders: Stable Angina; Michael Froeschl, MD, MSc, FRCPC, FACC; Date of
revision: November 2014
Medication
verapamil
amlodipine
Uses
Contraindications (CI), drug
interactions (DI) or cautions
atrial fibrillation,
super ventricular
arrhythmia,
angina – stable,
hypertension,
cardiomyopathy
CI: WPW syndrome
angina - stable,
hypertension variant
DI: grapefruit juice Decrease dose in
hepatic insufficiency
DI: amiodarone, alcohol,
carbamazepine, cyclosporine, digoxin,
dofetilide, erythromycin, grapefruit
juice, lithium, pimozide, ranolazine,
rifampin, simvastatin,
terazosin
Adverse Effects
(common and
severe)
HF, AV block,
constipation
hypotension,
dizziness,
palpitations,
lightheadedness,
edema ankles/feet,
flushing
Initial dose;
typical dose
40mg; 40-80mg
every 8 hours
5mg; 5-10mg one
time a day
Monitoring
LFTs, BP