Pediatric Calcium Channel Blocker Toxicity Medication

Initial management for a symptomatic calcium channel blocker overdose includes cardiovascular support with IV fluids and positive inotropy. (In addition, always use basic GI decontamination in overdose situations.) Calcium administration can partially overcome channel blockade and, in all but the most severe cases, should improve the clinical condition. By increasing intracellular cAMP concentrations, glucagon also reportedly improves blood pressure and heart blockade.

High-dose insulin has been recently established as an effective therapy for calcium channel blocker overdose. Lipid emulsion therapy may be beneficial and should be considered in the patient in extremis, refractory to all other treatment modalities. Newer agents, such as levosimendan, are also showing promise in the treatment of this occasionally fatal ingestion.

Class Summary

These agents theoretically increase calcium's concentration gradient, overcoming the channel blockade and driving calcium into the cells. Calcium is given to reverse hypotension and improve cardiac conduction defects.

Calcium chloride

Calcium chloride moderates nerve and muscle performance by regulating the action potential excitation threshold.

Calcium gluconate

Calcium gluconate moderates nerve and muscle performance and facilitates normal cardiac function.

Class Summary

These agents augment blood pressure by stimulating dopamine, alpha-adrenergic receptors, and beta-adrenergic receptors. This extracellular effect is transduced across the cell membrane and activates adenylyl cyclase in the cell to form cAMP. The activation induces calcium inflow from the endoplasmic reticulum and the extracellular space, which initiates muscle cell contraction. Sympathomimetics lead to vasoconstriction and increased cardiac inotropy, chronotropy, and dromotropy.

Norepinephrine (Levophed)

Norepinephrine stimulates beta1- and alpha-adrenergic receptors, which, in turn, increase cardiac muscle contractility, heart rate, and vasoconstriction. As a result, systemic blood pressure and coronary blood-flow increases. Mix 4 mg in 500 mL D5W to yield 8 mcg/mL.

Epinephrine (Adrenalin)

Epinephrine has alpha-agonist effects, which include causing increased peripheral vascular resistance, reversed peripheral vasodilatation, systemic hypotension, and vascular permeability. The drug's beta-agonist effects include bronchodilatation, chronotropic cardiac activity, and positive inotropic effects. Mix 1 mg in 250 mL D5W to yield 4 mcg/mL.

Dopamine

Dopamine activates dopamine receptors first, then beta1 receptors, and then alpha1 receptors. A low dose of 0.5-3 mcg/kg/min activates dopamine receptors and causes splanchnic vasodilation. An intermediate dose of 3-7.5 mcg/kg/min activates beta1 receptors, increasing cardiac inotropy and chronotropy. High doses of 7.5 mcg/kg/min or greater activate alpha1 receptors, causing vasoconstriction.

Doses of greater than 20 mcg/kg/min are unlikely to produce additional effects; therefore, the addition of a second agent (eg, norepinephrine) is probably indicated at that time. Mix 400 mg of dopamine in 250 mL D5W to yield 1600 mcg/mL.

Class Summary

Glucagon uses a different receptor than that used by sympathomimetics to stimulate intracellular cAMP production, increasing cardiac conduction and contractility. Glucagon has positive inotropic and chronotropic effects, which may be useful for treating bradycardia caused by calcium channel blockers.

Glucagon (GlucaGen)

Glucagon binds to a specific cell surface receptor found on cardiac myocytes and stimulates adenyl cyclase via G proteins. This results in the release of intracellular cAMP, thereby increasing phosphorylation of L-type calcium channels and calcium influx into cells.

One study showed that glucagon performed its action on cardiac function best in a normocalcemic environment. Mix glucagon with 0.9% sodium chloride (NaCl) to yield 1 mg/mL (1 U = 1 mg); do not use the diluent (propylene glycol) supplied with the single-dose ampule.

Class Summary

Atropine, an anticholinergic medication, works by blocking muscarinic acetylcholine receptors. Use of this drug theoretically lets the sympathetic characteristics of the autonomic nervous system prevail over the parasympathetic system. This action includes vasoconstriction and increased cardiac inotropy and chronotropy.

Atropine IV/IM (Isopto)

This agent blocks muscarinic acetylcholine receptors.

Class Summary

Case reports of patients treated with high-dose insulin are beginning to support the use of this drug in calcium channel blocker toxicity. Insulin increases cardiac output and may increase survival as long as plasma glucose levels are monitored and supplemented with exogenous dextrose. To date, no prospective human trials have been published supporting this practice.

Insulin and dextrose

Calcium channel blockers inhibit the production of islet cells and the secretion of insulin and block free fatty acid uptake by the heart muscle. High-dose insulin may augment myocyte uptake of glucose during times of stress induced by calcium channel blocker overdose. Insulin's action provides additional metabolic support to improve cardiac contractility.

Class Summary

Activated charcoal adsorbs ingested medication remaining in the GI system and creates a concentration gradient to "pull back" medication circulating in the blood stream. Cathartics increase GI transit time. Lipid emulsion therapy sequesters highly lipid-soluble drugs from target sites.

Activated charcoal (Actidose-Aqua, Char-Caps, EZ-Char)

Activated charcoal is used in emergency treatment for poisoning caused by drugs and chemicals. A network of pores adsorbs 100-1000mg of drug per gram. Activated charcoal does not dissolve in water. Administer it as soon as possible after poison ingestion. Repeated doses may help to lower systemic levels of ingested compounds, especially sustained-release preparations. Activated charcoal is usually administered with sorbitol in alternating doses.

Lipid Emulsion (Intralipid)

Lipid emulsion therapy is used in the emergency treatment of severe toxicity from highly lipid-soluble drugs. It is the antidote of choice for bupivacaine cardiotoxicity and is currently being investigated across other poisonings. Its primary mode of action is as a "lipid sink," sequestering lipid-soluble drugs from their target sites. Some research suggests that it provides a direct inotropic effect by activating myocyte calcium channels. No adverse effects from this modality have been reported. Although still under active investigation, lipid emulsion therapy should be considered in calcium channel blocker poisonings in patients in extremis who are refractory to all other therapies.

Class Summary

Osmotic laxatives cause cathartic actions in the GI tract, increasing bowel transit time.

Polyethylene glycol (Colyte, MoviPrep, CoLyte, GoLYTELY)

Polyethylene glycol is a bowel irrigation solution with electrolyte and osmotic effects that has cathartic actions in the GI tract. It increases bowel transit time and interrupts enterohepatic circulation, yet it causes minimal net water and electrolyte shifts.

Class Summary

These drugs inhibit the voltage-sensitive potassium channels.

Fampridine (4-Aminopyridine [4-AP])

Fampridine is a potassium channel blocking agent that is under investigation in the United States for various neurologic and neuromuscular disorders. It increases acetylcholine release at the neuromuscular junction and CNS. However, fampridine has not been proven in human studies to increase survival after calcium channel blocker ingestion. It probably should not be used in calcium channel blocker toxicity until it has been more thoroughly researched.

3,4-Diaminopyridine (3,4-DAP)

This potassium channel blocking agent is under investigation in the United States for variety of neurologic and neuromuscular disorders. It increases acetylcholine release at the neuromuscular junction and CNS. The medication is used as an orphan drug for Lambert-Eaton myasthenic syndrome but has not been proven in human studies to increase survival after calcium channel blocker ingestion. It is 6 times more potent than 4-aminopyridine but probably should not be used in calcium channel blocker toxicity until it has been more thoroughly researched.

Class Summary

Augmenting the intravascular volume may help to move the patient to a more favorable Starling curve, in addition to filling dilated peripheral vascular structures.

Lactated Ringer solution

It is used to expand intravascular volume. It is isotonic and has volume-restorative properties.

Fluid resuscitation should be started with the pharmacologic treatments above.

Isotonic sodium chloride solution

It is used to expand intravascular volume. It is isotonic and has volume-restorative properties. Fluid resuscitation should be started with the pharmacologic treatments above.

Class Summary

Studies to treat heart failure with the calcium sensitizing agent levosimendan are currently underway in the United States.

Levosimendan

Levosimendan is investigational in the United States. It elicits inotropic, vasodilating, and calcium-sensitizing effects. The drug is an intracellular agent that sensitizes myocytes to calcium by binding to cardiac troponin C, without increasing intracellular calcium. It is thought to stabilize the kinetics of actin-myosin cross-bridges without increasing myocardial adenosine triphosphate (ATP) consumption. Levosimendan also opens K+ channels, which leads to vasodilation and thereby decreases afterload to aid cardiac output in depressed myocardial states. Levosimendan is available as a 2.5mg/mL solution for IV infusion (dilute with D5W prior to infusion).