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Calcium channel blockers


DRUGS INCLUDED


There are three types of calcium antagonists in common use. These three types are from three distinct chemical classes.

• The phenyl alkylamines, e.g. verapamil
• The benzothiazepines, e.g. diltiazem
• The dihydropyridine derivatives,
Amlodipine (Norvasc)
Aranidipine (Sapresta)
Azelnidipine (Calblock)
Barnidipine (HypoCa)
Benidipine (Coniel)
Cilnidipine (Atelec, Cinalong, Siscard)
Clevidipine (Cleviprex)
Isradipine (DynaCirc, Prescal)
Efonidipine (Landel)
Felodipine (Plendil)
Lacidipine (Motens, Lacipil)
Lercanidipine (Zanidip)
Manidipine (Calslot, Madipine)
Nicardipine (Cardene, Carden SR)
Nifedipine (Procardia, Adalat)
Nilvadipine (Nivadil)
Nimodipine (Nimotop)
Nisoldipine (Baymycard, Sular, Syscor)
Nitrendipine (Cardif, Nitrepin, Baylotensin)
Pranidipine (Acalas)


OVERVIEW


Verapamil and dilitazem have a higher relative toxicity than dhydropyridines

Morbidity and mortality is generally due to cardiovascular collapse resulting from a combination of extreme peripheral vasodilatation, myocardial depression and impaired myocardial conduction. Non-cardiogenic pulmonary oedema is a less common complication but heralds a poorer prognosis.

Sustained release preparations are available and produce both delayed and prolonged toxicity.

Individuals vary considerably in their response to CCBs dependent on underlying diseases and other medication. 2-3 times the normal dose may cause profound toxicity in susceptible individuals.

An early presentation of a potentially toxic ingestion of a calcium channel blocking agent is one scenario where early and aggressive gastrointestinal decontamination should be pursued.

MECHANISM OF TOXICITY


All act by preventing the opening of voltage-gated calcium channels (the L type). The major actions are vasodilatation (inhibiting contraction of vascular smooth muscle) and block of cardiac conduction, particularly the SA and AV nodes where there are no sodium gated channels and conduction is totally dependent on calcium flux.

Binding of the various calcium antagonists to these channels may be both use and voltage dependent.

At therapeutic doses nifedipine and other CCBs of the dihydropyridine class are predominately peripheral vasodilators with little direct cardiac effect. Both verapamil and, to a lesser extent, diltiazem have direct cardiac effects in addition to peripheral vasodilatation. The direct cardiac effects include decreased sinus node activity, AV conduction and myocardial contractility.


KINETICS IN OVERDOSE


Absorption


All calcium antagonists are rapidly absorbed from the small intestine. Peak concentrations is within 1-2 hours for standard formulations in therapeutic use Peak concentrations can be delayed in overdose to up to 6 hours for standard preparations and 22 hours for controlled release. Further delays in absorption can occur with the formation of pharmacobezoars of sustained-release preparations. This also alters the clinical presentation (i.e. causes delayed presentation and toxicity).

All of these drugs have a significant first pass effect with bioavailability being as low as 10 - 40% for verapamil and diltiazem. Increased bioavailability has been demonstrated for some CCBs in overdose suggesting that the first pass effect is saturable.

Verapamil has two enantiomers with different kinetics and activity. The S isomer is more active but has a shorter half-life and lower bioavailability than the R isomer. The higher proportion of S isomer that is available is the major reason why IV verapamil has more cardiac effects for a given serum concentration than oral verapamil.

Distribution


All CCBs have large volumes of distribution and moderate CNS penetration. The free fraction of verapamil may increase in overdose.

Metabolism - Elimination


All CCBs are metabolised in the liver to less active or inactive metabolites.

The half-life of nifedipine, verapamil and diltiazem in therapeutic use is short (3-8 hours). Most other dihydropyridine drugs have considerably longer half-lives. The apparent half-life of many CCB appears to be longer following overdose but is generally thought to reflect a rate limited absorption.

Controlled release medication


Due to their short half-lives, the older CCBs (verapamil, diltiazem, and nifedipine) are frequently sold in controlled release preparations. The kinetics of drugs in these preparations are quite different and alter in overdose. Peak levels of verapamil were seen at 22 hours following ingestion of 2.3 grams of a sustained release preparation with the onset of toxic effects of being delayed until 16 hours after ingestion. Further delays in absorption can occur with the formation of pharmacobezoars of sustained-release preparations. This also alters the clinical presentation (i.e. causes delayed presentation and toxicity). An early presentation of a potentially toxic ingestion of a calcium channel blocking agent is one of the relatively uncommon scenarios where early and aggressive gastrointestinal decontamination should be pursued.

See also controlled release drugs in overdose.

CLINICAL EFFECTS


Cardiac effects


Hypotension, due to a combination of vasodilatation (relative volume depletion), heart block and myocardial depression develops over the first few hours if a standard preparation has been ingested or may be delayed in onset for up to 24 hours if a controlled release preparation has been ingested. Both cardiac and non-cardiogenic pulmonary oedema are reported. Non-cardiogenic pulmonary oedema can occur relatively late at a time when other cardiac parameters are improving. Intractable hypotension and/or asystole is the usual mode of death.

Increasing heart block typically occurs in a sequence from sinus bradycardia to 1st degree heart block to junctional bradycardia (with absent P waves) to a slow idioventricular rhythm to asystole. This may occur with any CCB but higher degrees of block are much more common with verapamil and diltiazem.

Gastrointestinal effects


Nausea and vomiting are common. The effect of CCBs on the gut can lead to an ileus, which may significantly interfere with gastrointestinal decontamination of controlled release preparations.

Metabolic
Other effects are rarely life threatening but include hyperglycaemia due to blockade of calcium regulated pancreatic islet cells, lactic acidosis reflects the decrease in tissue perfusion secondary to the circulatory shock induced, bowel ischaemia and seizures can also occur. These are less common and occur only in poisonings with significant cardiac effects.

Late presentation


This is most likely to occur with sustained release preparations and the clinical effects will be similar. If the patient is asymptomatic, and more than 24 hours have elapsed, then no treatment is indicated. In all other circumstances treatment, should proceed as usual. Gastrointestinal decontamination should be included in this however this may be rendered impractical in the context of a critically ill patient undergoing prolonged resuscitation and the risks and benefits should be considered.

INVESTIGATIONS


ECG
Blood Glucose
Electrolytes & Blood gases
Blood levels are not helpful in normal management

ECG


A 12 lead ECG looking for conduction disturbances associated with significant calcium channel blocking agent ingestion, should be performed along with continuous monitoring.
Echo
In cases of shock an echocardiogram will help define the contribution of vasodilation and reduced cardiac output. This information can be used to guide pressor use.

Electrolytes and Blood Gases

A high blood glucose has some correlation with severity
A baseline ionised calcium is useful as a doubling of ionised calcium is suggested endpoint for intravenous calcium in symptomatic pateints
A raised lactate generally indicates poor perfusion. Acidosis should be corrected

DIFFERENTIAL DIAGNOSIS


There are a number of drugs that can lead to a patient presenting with profound hypotension and bradycardia (such as beta blockers, clonidine and digoxin). Correct diagnosis is important as these drugs have different specific treatments.

DIFFERENCES IN TOXICITY WITH IN THIS DRUG CLASS


In therapeutic use, verapamil is relatively cardioselective with more significant effects on cardiac conduction while the dihydropyridines are predominantly selective for smooth muscle and lead primarily to peripheral vasodilatation. Diltiazem's effects lie between these two groups.
In overdose all these drugs have both cardiac and vasodilating actions. However the cardiac effects of verapamil and diltiazem appear to be generally more profound and few deaths have been reported from dihydropyridine overdose alone.

DETERMINATION OF SEVERITY


Prognosis correlates best with the degree of heart block. Hypotension due to vasodilatation without heart block usual responds to fluid loading and is rarely life threatening. Other factors that increase the severity of the overdose are
• patients with underlying heart disease
• late presentation
• coingestion/regular treatment with beta blockers or digoxin (antidotes to these drugs may also be considered in this case)
• old age

TREATMENT


For a summary of management see management of serious calcium channel blocker overdose in adults.

Supportive


IV access should be secured as soon as possible and crystalloid IV fluids instituted with a view to filling the intravascular compartment.
Other than trivial poisonings, all cases will require
· ongoing ECG monitoring
· blood pressure/Oxygen saturation monitoring
· regular venous blood gas monitoring
· an indwelling urinary catheter to measure hourly urine output.
A point of care ultrasound evaluating inferior vena cava size and collapse/lack of, may be of value in assessing intravascular volume depletion if skill and resources are available.
An echocardiogram may help to define whether reduced myocardial contraction is a significant contributor to refractory hypotension.

GI Decontamination


**Oral activated charcoal** should be given to all patients ingesting any overdose of a CCB. This should be followed by repeated doses of activated charcoal, particularly in verapamil poisoning (though controlled clinical trial data supporting this approach are lacking).

**Whole bowel irrigation** should be considered in ingestions of slow release preparations


PHARMACOTERAPY


A number of different agents have been used to treat calcium channel blocking agents with the evidence ranging from animal studies, anecdotal, isolated case reports and small case series.

Summary Management

Normal saline bolus (10–20 mL/kg)
Correct pH
10% calcium chloride, 5–10 mL, or 10% calcium gluconate, 10–20 mL, over 5 minutes
  • Repeat every 3–5 minutes, up to three to five doses
  • If response, institute calcium infusion (10% calcium chloride, 1–10 mL/hour)
  • Monitor serum calcium after 30 mL of calcium chloride or equivalent
Atropine, isoprenaline (isoproterenol) and/or pacing may be tried if associated symptomatic bradycardia.
Dopamine infusion if persistent hypotension.
Begin insulin euglycaemia therapy in any patient whose resuscitation requires more than just IV fluids as there is normally a delay in effect. The insulin dose may need to be titrated upwards
Starting dose
Insulin bolus, 1 unit/kg with glucose, 50% dextrose, 25 ml i.v.
followed by
Insulin infusion, 1 units/kg/hour with 50% dextrose infusion, 0.5 g/hour, adjusted according to hourly glucose checks.
Monitor potassium.
As a last resort, extracorporeal blood pressure support (e.g. cardiopulmonary bypass) may be considered.

Calcium loading
Insulin-dextrose euglycaemia
Atropine
• Inotropic and vasopressor agents
• Lipid emulsions
• Extracorporeal life support
Cardiac pacing

Calcium loading


Primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem), elemental calcium is useful but more likely as an adjunctive treatment rather than sole therapy,particularly in severe toxicity.

The initial dose for treatment of CCB toxicity in adults is
· 10% calcium chloride, 5–10 mL, or
· 10% calcium gluconate solution, 15–25 mL. (approximately 2.5 times the volume to provide the same amount of elemental calcium)
· The dose in children is 10% calcium chloride 0.2 mL/kg
· 10% calcium gluconate, 0.7 mL/kg.

Calcium chloride should be infused at a rate no faster than 1–2 mL/minute, with the patient on a monitor. The initial dose can be followed by further doses every 3–5 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).

A continuous infusion may be started infusing 10% calcium chloride, 1–10 mL/hour. An ionised serum calcium of 2 mmol/L was effective in severe nifedipine toxicity and has been suggested as a target concentration. Many blood gas machines provide an ionised calcium level which allows regular monitoring and titration of the infusion.

The treatment of isolated hypotension should not usually require calcium or any cardioactive medication but should initially be treated with volume expansion and pressor agents.

Insulin-dextrose euglycaemia


High dose Insulin-dextrose euglycaemic therapy (HIET) is the inotropic agent of choice for CCB induced cardiotoxicity. Efficacy has been shown in a small case series with a regime of :
· 1u/kg IV bolus loading dose
· infusion commenced at 1u/kg/hour
· Increased by single unit increments every 10 - 15 minutes titrated to desired response
· Maximum dose 10u/kg/hour

Diseased hearts utilise carbohydrates as opposed to the utilisation of free fatty acids in healthy hearts. Insulin promotes the uptake of glucose by several different mechanisms which is the proposed basis for it's inotropic effect.

Whist insulin is inotropic it also causes vasodilatation and as such is unlikely to be of benefit where toxicity is suspected to be caused by vasodilatation ie dihydropyridine poisoning.

It is also sometimes necessary to supplement HIET with small doses of a vasopressor to counteract the vasodilatation that can also accompany the cardiac toxicity of verapamil and diltiazem. Where possible this treatment should be guided by an echocardiogram to look at ventricular function and cardiac output monitoring in a critical care environment.

Atropine


Atropine may be used in bradycardia to transiently increase heart rate whilst more definitive therapy is instituted, however overall it has a minimal to minor role in management.

Inotropic and vasopressor agents


Whilst HIET is the inotropic agent of choice in CCB induced cardiac toxicity, other appropriate inotropic agents may be efficacious provided the treatment is targeted toward managing a cardiogenic shock state. Adrenaline and dobutamine may be used for this purpose with small doses of Noradrenaline to counteract any vasodilatation if required. Noradrenaline may be used to manage cases where toxicity is felt to be primarily due to vasodilatation. The use of concentrated infusions of these agents requires a central line, invasive blood pressure monitoring and ongoing management in a critical care unit.

Adrenaline 1 to 20 micrograms/minute IV infusion
Or
Noradrenaline 1 to 20 micrograms/minute IV infusion
Metaraminol 0.5-1mg

Lipid emulsions


Lipid emulsions have been used with apparent success in CCB toxicity however the evidence is limited to case reports with highly subjective interpretation. Lipid emulsions are not currently recommended in CCB poisoning and it is suggested that management should centre around the better established therapies.

Cardiac Pacing/Extra corporeal life support


Cardiac pacing may be used for refractory bradycardia. Additionally in cases refractory to maximal treatment may be considered for extra corporeal therapies but availability of such services is often the limiting factor.

Elimination enhancement


High biliary concentrations of verapamil have been found following overdose. However, multiple dose activated charcoal (although theoretically attractive) has not been demonstrated to enhance elimination.

LATE COMPLICATIONS, PROGNOSIS -FOLLOW UP


Late complications/deterioration have been reported with controlled release preparations of verapamil and diltiazem. These may occur as late as 24 hours in asymptomatic patients and life threatening cardiovascular collapse and death can occur as late as two to three days post ingestion (in patients who were symptomatic within 24 hours).


REFERENCES



Achike FI, Dai S. Cardiovascular responses to verapamil and nifedipine in hypoventilated and hyperventilated rats. Br.J.Pharmacol. 1990;102-6.

Achike FI, Dai S. Influence of pH changes on the actions of verapamil on cardiac excitation-contraction coupling. Eur.J.Pharmacol. 1991;77-83.

Buckley CD , Aronson JK. Prolonged half-life of verapamil in a case of overdose: implications for therapy. Br.J.Clin Pharmacol. 1995;680-3.

Buckley NA, Dawson AH, Whyte IM, McManus P & Ferguson N. Six years of self-poisoning in Newcastle: 1987-1992. Med J Aust 1995;162:190-193.

Buckley NA, Dawson AH, Howarth DM, Whyte IM. Slow release verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993;158:202-204.

Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993;22(7):1229-33.

Ferner RE, Monkman S, Riley J, Cholerton S, Idle JR, Bateman DN. Pharmacokinetics and toxic effects of nifedipine in massive overdose. Hum.Exp.Toxicol. 1990;309-11.

Hariman RJ, Mangiardi LM, McAllister RG, Jr., Surawicz B, Shabetai R, Kishida H. Reversal of the cardiovascular effects of verapamil by calcium and sodium: differences between electrophysiologic and haemodynamic responses. Circulation 1979;797-804.

Howarth DM, Dawson AH, Smith AJ, Buckley NA, Whyte IM. Calcium Channel blocking drugs in overdose: an Australian series. Hum Exp Toxicol 1994;13:161-6.

Jaeger A, Sauder P, Bianchetti G, Kopferschmitt J, Dahlet M, Tritsch L, Flesch F. [Acute diltiazem poisoning: kinetic and haemodynamics study]. J.Toxicol.Clin Exp. 1990;243-8.

Kivisto KT, Neuvonen Tarssanen L. PJ. Pharmacokinetics of verapamil in overdose. Hum.Exp.Toxicol. 1997;35-7

Lam YM, Tse HF, Lau CP. Continuous calcium chloride infusion for massive nifedipine overdose. Chest 2001;1280-2.

Pearigen P, Benowitz N. Poisoning due to calcium antagonists. Drug Safety 1991;6(6):408-30.

Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann.Emerg.Med. 1993;196-200.

Sporer KA, Manning JJ. Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann.Emerg.Med. 1993;603-5.

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;547-53.

Toffoli G, Robieux I, Fantin D, Gigante M, Frustaci S, Nicolosi GL, De Cicco M, Boiocchi M. Non-linear pharmacokinetics of high-dose intravenous verapamil. Br.J.Clin Pharmacol. 1997;255-60.

Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999;37(4):463-74

Kenny J.Treating overdose with calcium channel blockers.BMJ. 1994 Apr 16;308(6935):992-3.

Kollef MH.Labetalol overdose successfully treated with amrinone and alpha-adrenergic receptor agonists.Chest. 1994 Feb;105(2):626-7

Recent literature




1. Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila) [Internet]. 2011 Apr ;49(4):277–83. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21563902
2. 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) [Internet]. 2007 May ;45(4):396–401. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17486481
3. Holger JS, Stellpflug SJ, Cole JB, Harris CR, Engebretsen KM. High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock. Clin Toxicol (Phila) [Internet]. 2011 Aug ;49(7):653–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21819291
4. Isbister GK. Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation with high dose intravenous calcium. Emerg Med J [Internet]. 2002 Jul ;19(4):355–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1725910&tool=pmcentrez&rendertype=abstract
5. Levine M, Curry SC, Padilla-Jones A, Ruha A-M. Critical care management of verapamil and diltiazem overdose with a focus on vasopressors: a 25-year experience at a single center. Ann Emerg Med [Internet]. 2013 Sep ;62(3):252–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23642908
6. Olson KR. What is the best treatment for acute calcium channel blocker overdose? Ann Emerg Med [Internet]. Elsevier Inc.; 2013 Sep ;62(3):259–61. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2356706