SPECIFIC SUBSTANCES

Calcium channel blockers

Mechanism of toxicity
CCBs act by preventing the opening of voltage-gated calcium
channels (L-type). Their major actions are vasodilatation (by
inhibition of contraction of vascular smooth muscle) and inhibition of cardiac conduction, particularly in the sinoatrial and
atrioventricular (AV) nodes, where there are no sodium-gated
channels and conduction is totally dependent on calcium flux.
Binding of CCBs to these calcium channels may be both usedependent and voltage-dependent.5
At therapeutic doses, nifedipine and other dihydropyridine
CCBs are predominantly peripheral vasodilators with little direct
cardiac effect. Verapamil and, to a lesser extent, diltiazem have
direct cardiac effects (including reduced sinus node activity, AV
conduction and myocardial contractility) in addition to peripheral vasodilatation. In overdose, all CCBs have both cardiac and
vasodilating actions. However, the cardiac effects of verapamil
and diltiazem appear to be generally more significant, and few
deaths have been reported from dihydropyridine overdose
alone.1,5

Ian Whyte
Nick Buckley
Andrew Dawson

Abstract
Overdose of calcium channel blockers is potentially lethal. Heart block
with marked bradycardia and hypotension are the most important
features. Verapamil and diltiazem are much more dangerous than dihydropyridines. Routine management usually comprises IV fluids, activated
charcoal, whole bowel irrigation (for modified-release products) and prolonged ECG monitoring. Antidotes for cardiac effects include calcium,
atropine, bicarbonate, high-dose insulin-euglycaemia, glucagon and
vasopressors.

Keywords antidotes; calcium channel blockers; cardiotoxicity; poisoning

Pharmacokinetics in overdose
There is a significant first-pass effect; bioavailability is as low as
10e40% for verapamil and diltiazem. Increased bioavailability
has been shown for some CCBs in overdose, suggesting that the
first-pass effect is saturable. CCBs have large volumes of distribution and moderate CNS penetration. The free fraction of
verapamil may increase in overdose. All are metabolised in the
liver to less active or inactive metabolites.
The apparent half-life of many CCBs appears to be longer
following overdose but this is generally thought to reflect
ongoing absorption.6 There may be significant enterohepatic
circulation, particularly with verapamil.
Modified-release preparations e the older CCBs (verapamil,
diltiazem and nifedipine) have a short half-life and are, therefore,
often sold as modified-release preparations. The pharmacokinetics of these preparations are different from the conventional
ones, particularly in overdose. Peak concentrations of verapamil
were seen at 22 hours following ingestion of 2.3 g of a modifiedrelease preparation and onset of toxic effects was delayed for
16 hours.5 Further delays in absorption can occur with the
formation of pharmacobezoars of modified-release preparations.7 This delays presentation and changes the preferred
method of gastrointestinal decontamination.

There are three types of calcium channel blockers (CCBs) in

common use, of three distinct chemical classes:
 phenylalkylamines (e.g. verapamil)
 benzothiazepines (e.g. diltiazem)
 dihydropyridines (e.g. amlodipine, felodipine, lercanidipine, nicardipine, nifedipine, nimodipine, nisoldipine,
nitrendipine).
Self-poisoning with CCBs is a common cause of in-hospital
death from self-poisoning.1,2 Morbidity and mortality generally
result from cardiovascular collapse caused by a combination
of extreme peripheral vasodilatation, myocardial depression
and impaired myocardial conduction.2,3 Extracardiac toxicity
(e.g. hyperglycaemia, lactic acidosis, seizures, non-cardiogenic
pulmonary oedema) is less common and implies a poorer prognosis. Modified-release preparations are available and produce
both delayed and prolonged toxicity.4 Individuals vary considerably in their response to CCBs independent of underlying disease
and other medication. Doses of only two to three times the
therapeutic dose may cause profound toxicity in susceptible
individuals.

Clinical features

Ian Whyte MBBS FRACP FRCPE is Director of Clinical Toxicology and

Pharmacology at Calvary Mater Newcastle, Newcastle, Australia, and
Conjoint Professor in Clinical Pharmacology at the University of
Newcastle. Competing interests: none declared.

Cardiac e hypotension results from a combination of vasodilatation (with relative volume depletion), heart block and myocardial depression. It develops over the first few hours following
ingestion of a standard preparation, but may be delayed for up to
18e24 hours with modified-release preparations. Both cardiogenic and non-cardiogenic pulmonary oedema have been reported. Non-cardiogenic pulmonary oedema can occur relatively
late, when other cardiac parameters are improving.3 Increasing
heart block typically occurs in a sequence, from sinus bradycardia
through first-degree heart block, junctional bradycardia (with
absent P-waves) and slow idioventricular rhythm to asystole. This
may occur with any CCB, but higher degrees of block are more

Nick Buckley MD FRACP is Professor in Medicine, Clinical Pharmacology

and Toxicology at the University of New South Wales, Sydney, Australia.
Competing interests: none declared.
Andrew Dawson MBBS FRACP FRCPE is Director of Clinical Toxicology at the
Royal Prince Alfred Hospital and Conjoint Professor in Clinical
Toxicology at the University of New South Wales, Sydney, Australia.
Competing interests: none declared.

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common with verapamil and diltiazem.1 Intractable hypotension

and/or asystole is the usual mode of death.
Gastrointestinal e nausea and vomiting are common. The
effects of CCBs on the gut can lead to an ileus or even gut
ischaemia,8 which may significantly interfere with gastrointestinal decontamination of modified-release preparations.4
Other effects are seldom life threatening and include hyperglycaemia, lactic acidosis and seizures. These do not appear to
occur in the absence of significant cardiac effects.
Late presentation is most likely with modified-release preparations. The clinical features are similar to the above. If the
patient is asymptomatic and more than 24 hours have elapsed
since ingestion of the CCB, no treatment is indicated.1 In all other
situations, treatment (including consideration of gastrointestinal
decontamination) should be undertaken as usual.

an overdose of a CCB and be followed by repeated doses,

particularly in verapamil poisoning1,9 (although controlled clinical trial data supporting this approach are lacking). Whole-bowel
irrigation with polyethylene glycol should be considered in those
who have taken a modified-release preparation.4
Specific treatment: Critical reviews support calcium as first-line
treatment. Acidosis should be corrected. Atropine, high-dose
insulineeuglycaemia and inotropes are probably the best
adjunctive treatments.
Bicarbonate e acidosis should be corrected to a pH within the
normal range (L-type calcium channel function is impaired when
pH is outside this). Acidosis enhances the effect of verapamil and
reduces that of calcium.10 In a swine model of verapamil
poisoning, sodium bicarbonate significantly improved myocardial contractility and cardiac output.11
Calcium loading is the most logical and appears to be the
most effective treatment in CCB poisoning.1,3,4 It is primarily
indicated in patients with heart block (who have usually taken
verapamil or diltiazem). The initial dose for treatment of CCB
toxicity in adults is calcium chloride 10%, 5e10 mL, or calcium
gluconate 10% solution, 10e20 mL (equivalent doses in children
0.2 mL/kg and 0.7 mL/kg, respectively). Calcium chloride should
be infused at a rate no faster than 1e2 mL/minute, with
concurrent cardiac monitoring. The initial dose can be followed
by further doses every 3e5 minutes if there is no response in
blood pressure or pulse rate. Large doses may be required (up to
10 g as initial treatment and 30 g in total have been used
successfully without evidence of calcium toxicity).4
If there is an initial response to calcium, a continuous infusion
may be warranted; this may be given as calcium chloride 10%,
1e10 mL/hour. Serum calcium should be measured, but note that
hypercalcaemia is the aim of treatment. Doubling of serum
calcium was associated with significant haemodynamic
improvement in animals and in humans. A serum ionized calcium
concentration of 2 mmol/L was effective in severe nifedipine
toxicity and has been suggested as a target concentration.
Hypotension with no evidence of cardiac conduction problems does not usually require calcium or any cardioactive
medication. Calcium may be cardiotoxic in this situation
(particularly in patients who have ingested a dihydropyridine
such as nifedipine) and may induce ventricular arrhythmias.
Hypotension alone should initially be treated with volume
expansion, followed by pressor agents if required.
High-dose insulineeuglycaemia is a treatment that has proved
more effective in animal models than calcium, adrenaline
(epinephrine) or glucagon.12 Its efficacy has been demonstrated in
a case series of clinically serious poisonings.13 There are now
many case reports of successful use of the treatment in CCB
toxicity and a small case series demonstrating it can be used safely
in an intensive care setting.14 Although the optimal regimen is still
to be determined, 1 U/kg insulin bolus followed by a 1e10 U/kg/h
continuous infusion has resulted in good outcomes and minimal
adverse events. Patients with hypotension refractory to volume
loading, correction of acidosis and calcium salts should be treated
using high-dose insulineeuglycaemia.
Vasopressors e it has been suggested that dopamine should
be the initial pressor agent of choice for diltiazem overdose.15
This and other pressor agents may need to be given in high

Investigations
Blood concentrations of CCBs are unhelpful in the management
of poisoning. The most useful investigation is repeated ECGs,
with continuous monitoring if available; this is a measure of
severity and is the best guide to the need for specific treatment.
Arterial blood gases should be determined and venous blood
taken for serum electrolytes and calcium, blood glucose and
assessment of renal function. Renal impairment may be associated with accumulation of active metabolites of verapamil and
diltiazem.
Assessment of severity
Prognosis in CCB poisoning correlates best with the degree of
heart block (and thus is generally much worse after verapamil
and diltiazem poisoning). Hypotension from vasodilatation
without heart block usually responds to fluid loading and is
seldom life threatening.
Other factors that increase the severity of overdose are:
 underlying heart disease
 late presentation and/or ineffective gastrointestinal
decontamination
 co-ingestion or regular treatment with beta-blockers or
digoxin (antidotes to these drugs may also be considered in
these situations)
 elderly patient.

Management
Supportive care: intravenous access with fluid resuscitation using
sodium chloride 0.9% should be instituted as soon as possible.
Most patients with hypotension with no evidence of a conduction
defect respond to volume expansion and should be given a bolus of
sodium chloride 0.9% (10e20 mL/kg). Patients whose blood
pressure does not respond to such a fluid challenge should
undergo central venous pressure monitoring. ECG monitoring in
an ICU is indicated in all but the most trivial poisonings.1,9
Gastrointestinal decontamination: Gastric lavage should be
considered in patients who present within 1 hour of ingestion of
modified-release verapamil or diltiazem. Atropine should be given
before lavage, and in any patient who is vomiting, because of the
risk of vagal stimulation causing increased heart block. Oral
activated charcoal should be given to patients who have ingested

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2 Howarth DM, Dawson AH, Smith AJ, Buckley N, Whyte IM. Calcium
channel blocking drug overdose: an Australian series. Hum Exp
Toxicol 1994; 13: 161e6.
3 Salhanick SD, Shannon MW. Management of calcium channel
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4 Buckley N, Dawson AH, Howarth D, Whyte IM. Slow-release verapamil
poisoning. Use of polyethylene glycol whole-bowel lavage and highdose calcium. Med J Aust 1993; 158: 202e4.
5 DeWitt CR, Waksman JC. Pharmacology, pathophysiology and
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6 Luomanmaki K, Tiula E, Kivisto KT, Neuvonen PJ. Pharmacokinetics of
diltiazem in massive overdose. Ther Drug Monit 1997; 19: 240e2.
7 Sporer KA, Manning JJ. Massive ingestion of modified-release
verapamil with a concretion and bowel infarction. Ann Emerg Med
1993; 22: 603e5.
8 Perbet S, Constantin JM, Guerin R, et al. Non-occlusive colonic
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9 Pearigen PD, Benowitz NL. Poisoning due to calcium antagonists.
Experience with verapamil, diltiazem and nifedipine. Drug Saf 1991;
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on cardiac excitation-contraction coupling. Eur J Pharmacol 1991;
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11 Tanen DA, Ruha AM, Curry SC, Graeme KA, Reagan CG. Hypertonic
sodium bicarbonate is effective in the acute management of verapamil toxicity in a swine model. Ann Emerg Med 2000; 36: 547e53.
12 Lheureux PE, Zahir S, Gris M, Derrey AS, Penaloza A. Bench-to-bedside
review: hyperinsulinaemia/euglycaemia therapy in the management
of overdose of calcium-channel blockers. Crit Care 2006; 10: 212.
13 Yuan TH, Kerns WP, Tomaszewski CA, Ford MD, Kline JA. Insulinglucose as adjunctive therapy for severe calcium channel antagonist
poisoning. J Toxicol Clin Toxicol 1999; 37: 463e74.
14 Greene SL, Gawarammana I, Wood DM, Jones AL, Dargan PI. Relative
safety of hyperinsulinaemia/euglycaemia therapy in the management
of calcium channel blocker overdose: a prospective observational
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calcium channel blocker overdoses: toxicity and treatment. Ann
Emerg Med 1993; 22: 196e200.
16 Holger JS, Engebretsen KM, Fritzlar SJ, Patten LC, Harris CR,
Flottemesch TJ. Insulin versus vasopressin and epinephrine to treat
beta-blocker toxicity. Clin Toxicol (Phila) 2007; 45: 396e401.
17 Bailey B. Glucagon in beta-blocker and calcium channel blocker
overdoses: a systematic review. J Toxicol Clin Toxicol 2003; 41:
595e602.

doses but will usually increase blood pressure in hypotensive

patients to some extent. However, particularly in verapamil and
diltiazem toxicity, there is severe myocardial impairment and the
addition of pressor agents that predominantly increase afterload
(such as vasopressin and adrenaline) have been shown in an
elegant pig model of b-blocker toxicity (where there is also severe
myocardial impairment) to produce an initial improvement in
haemodynamic parameters but a markedly shortened survival
time compared to high-dose insulin-euglycaemia.16 Moreover,
these agents are often ineffective in reversing bradycardia in
patients with a high degree of conduction block15 because they
act predominantly by increasing the frequency of impulses
originating from the blocked sinoatrial node. Vasopressors
should be used only as a bridging treatment while high-dose
insulin-euglycaemia is established and patients should be
weaned as soon as possible.
Glucagon has been used as an antidote for b-blocker
poisoning. The rationale for its use in CCB poisoning is that it
activates myosin kinase independent of calcium flux.5 Case
reports and animal studies suggest that it is less effective in this
setting than in b-blocker poisoning. Typically, a 5e10 mg intravenous bolus followed by the same amount as an hourly infusion
may reverse bradycardia and possibly hypotension in some CCB
overdoses; however, the case report data are limited and the
animal data show no survival benefit.17
Cardiac pacing can be undertaken to increase heart rate,
provided ventricular rather than atrial pacing is performed. In
severe poisoning, the heart may fail to capture and pharmacological therapy will be required.

Late complications
Late complications or deterioration have been reported following
ingestion of modified-release verapamil or diltiazem. They may
occur as late as 24 hours in asymptomatic patients. Lifethreatening cardiovascular collapse and death can occur 2e3
days after ingestion (in patients who were symptomatic within 24
hours). Long-term sequelae have not been reported and no followup is required after resolution of the clinical signs and ECG findings unless the patient has been profoundly hypotensive.
A

REFERENCES
1 Olson KR, Erdman AR, Woolf AD, et al. Calcium channel blocker
ingestion: an evidence-based consensus guideline for out-of hospital
management. Clin Toxicol (Phila) 2005; 43: 797e822.

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