Calcium Antagonists Toxicity: Symptoms, and Management

Introduction

Calcium channel antagonists (CCAs) toxicity are commonly prescribed for treating cardiovascular diseases and have been demonstrated to be effective in managing hypertension, cardiac arrhythmias, and angina. However, toxicity associated with an overdose may produce severe, life-threatening complications, including bradycardia, hypotension, metabolic acidosis, and shock. 10,513 cases of calcium channel antagonist (CCA) toxicity were reported in the United States in 2004, resulting in 62 deaths of the affected people.

The conventional approach to managing calcium channel antagonist (CCA) overdose consists of intravenous fluid resuscitation, administration of calcium, gut decontamination, glucagon, and atropine, and supportive care. In severe cases, the patient may suffer from bradycardia, and hypotension may require the placement of a temporary pacemaker and the administration of vasopressors and inotropes.

What Are Calcium Channel Blockers?

Calcium channel blockers (CCBs) belong to a class of medications used to treat problems related to blood pressure (hypertension). Calcium channel blockers block some of the calcium that enters and gets to the heart and arteries.

It is believed that calcium is a critical nutrient for the bones, but it also plays a vital role in the effective functioning of the heart. Calcium moves into the cells of the heart every time it beats, allowing a strong and even squeeze of the muscles to happen. If an individual has a problem with high blood pressure, the force of blood flowing through the arteries is higher than usual. Administrating the calcium channel blockers (CCBs) helps in reducing the flow of calcium into the heart and arteries, which helps to:

• Lower blood pressure.

• Open narrow blood vessels.

• Reduce heart rate.

Calcium channel blockers (CCBs) are also sometimes called calcium antagonists. They are considered as effective as ACE inhibitors in regulating blood pressure.

Calcium channel blockers (CCBs) are available in many forms. It can be indicated orally, ranging from short-acting dissolving tablets to extended-release capsules. The dosage will depend on the affected person's overall health and medical history.

What Is the Mechanism of Calcium Channel Blockers?

Calcium is an essential mineral primarily associated with healthy bones and teeth and also plays a vital role in blood clotting, helping muscles to contract, and regulating normal heart rhythms and nerve functions. It is an electrolyte, which means it has a positive charge when it is dissolved in water. The body uses ions (atoms with an electrical charge) in electrolytes to transport things into and out of the cells. The body constantly regulates and balances all the ions, which means when calcium ions enter a cell, sodium ions exit, and vice versa.

Those ions enter and exit the cells using channels, which act just like doorways to the inside of the cells. Those channels also have a type of selective membrane feature, which only allows ions that have the right type of charge (either positive or negative) and the right size to enter and leave. Calcium channel blockers have the advantage of the fact that certain types of calcium channels tend to exist only in certain parts of the body. This allows the targeting of medications depending on which channels they affect.

What Is Calcium Channel Blocker Toxicity?

Calcium channel blockers are classified into two main categories based on their physiological effects - Dihydropyridines (for example, Amlodipine, Nifedipine, Felodipine, Nicardipine) and Non-Dihydropyridines (for example, Verapamil and Diltiazem).

Dihydropyridines have an affinity for peripheral vascular smooth muscle cells, while non-dihydropyridines have an affinity for cardiomyocytes. Calcium channel blockers show pharmacological effects by stopping the alpha-1 subunit of L-type voltage-gated calcium channels resulting in the prevention of calcium influx intracellularly needed for myocardial, vascular, and gastrointestinal smooth muscle contraction.

Meanwhile, in turn, it assists in the vascular smooth muscles relaxation resulting in vasodilation and hypotension, myocardial depression caused by excessive negative inotropy, bradycardia resulting from negative chronotropic, and atrioventricular node blockade due to negative dromotropy.

In addition, calcium channel blockers also block the L‐type calcium channels in pancreas Islet cells, causing a reduction in insulin secretion, hyperglycemia, and reduced cardiac glucose utilization. The drop in blood pressure due to calcium channel blockers toxicity is a result of a fusion of negative myocardial inotropy and chronotropy, as well as peripheral vasodilation.

At therapeutic doses, calcium channel blockers have a selectivity towards certain tissues. However, at toxic or higher doses, calcium channel blockers lose their ability to select which results in potentially life-threatening conditions like bradycardia (slow heart rate), hypotension (low blood pressure), hyperglycemia (increase in blood sugar level), and renal insufficiency.

What Are the Symptoms of Calcium Antagonist Toxicity?

The following are the symptoms seen in patients with calcium antagonist toxicity -

• Agitation (hyperactivity).

• Delirium (confused thinking and possible hallucinations).

• Breathing difficulty.

• Confusion.

• Constipation.

• Lightheadedness.

• Dizziness.

• Drowsiness.

• Increased blood sugar.

• Irregular heartbeat.

• Nausea.

• Vomiting.

• Rapid heartbeat.

• Slow heartbeat.

• Slurred speech.

• Shock.

• Low blood pressure.

• Weakness.

What Are the Investigations Performed for Diagnosing Calcium Antagonist Toxicity?

The following are the investing done to detect the toxicity -

• Electrocardiogram - It is a bedside investigation done to detect bradycardia, accelerated AV node conduction, second and third-degree heart block, sinus arrest with nodal escape, and asystole in the affected patient with toxicity.

• Blood Sugar - If the patient is hyperglycemic, then it is considered a serious condition.

• Detection of Gas Concentration in Blood - In patients with toxicity, hyperkalemia (high level of plasma potassium), metabolic acidosis, and impaired oxygen delivery are reported.

• Creatinine Test - It is done to detect organ dysfunction due to shock.

• Chest X-rays - Pulmonary edema is observed.

• Echocardiography - The finding of impaired contractility is observed.

What Are the Treatment Modalities for Calcium Antagonist Toxicity?

The following are the treatment options for calcium antagonist toxicity -

• Resuscitation - It requires early intubation and ventilation when life-threatening toxicity is anticipated. Early invasive blood pressure monitoring if evolving hypotension and shock.

• Specific Treatment for the Cardiovascular System - Fluid resuscitation is done to regulate hemodynamics to grain the tissue perfusion and, ultimately, the tissue oxygen delivery. It is given up to 20 milliliters per kilograms (mL/kg) crystalloid. Calcium can be useful for temporizing measures to increase heart rate and blood pressure. Atropine is indicated for maintaining the cardiovascular system.

• Gastrointestinal (GI) Decontamination - Gastrointestinal decontamination as a choice of treatment is rarely done in the emergency department. Gastrointestinal decontamination should be done within the first one to two hours post-ingestion of the calcium channel blocker. The use of this method is not recommended for hemodynamically unstable patients. Gastrointestinal decontamination can be done through whole-bowel irrigation (WBI), orogastric lavage, or indicating the administration of activated charcoal (AC).

• High-Dose Insulin Euglycemia Therapy (HIET) - High-dose insulin euglycemia therapy (HIET) works by a number of mechanisms in the treatment of calcium channel blocker toxicity. High-dose insulin euglycemia therapy (HIET) creates positive inotropic effects by improving vascular dilation, raising the cardiac output and regulating blood pressure, and escalating the intracellular transport of glucose into myocardial cells. In addition, high-dose insulin euglycemia therapy (HIET) helps in reducing the infusion requirements of catecholamines and hemodynamic instability as it does not affect the heart rate.

• Lipid Emulsions Therapy (LET) - Lipid emulsions therapy (LET) is used to reduce the toxicity of several lipophilic drugs, including non-dihydropyridine and Verapamil. However, lipid emulsions therapy (LET) should be indicated in patients who do not respond to first-line treatments, patients with refractory shock, and poly-drug toxicity.

• Inotropes and Vasopressors - In patients with calcium channel blocker toxicity, problems like peripheral vasodilation (widening of blood vessels), cardiac depression (decreased heart output), and conduction abnormalities (problems with the electrical system that controls the heart rate) are expected. The use of vasopressors is recommended to maintain hemodynamic stability.

Epinephrine increases heart rate, contractility, and blood pressure through the beta-1 and alpha-1 adrenergic receptors stimulation. Norepinephrine increases blood pressure by acting effectively on the alpha-1 adrenergic receptors. Dobutamine, on the other hand, increases heart rate and contractility through beta-1 receptor stimulation. Epinephrine and Dobutamine are recommended in patients with cardiogenic shock, while norepinephrine is indicated in vasogenic shock. But alone Dopamine or vasopressors are recommended due to poor clinical outcomes for calcium channel blocker toxicity.

• Dialysis - Calcium channel blockers are differentiated by their high protein-binding abilities, which minimizes their potential to dialyze them in cases of severe calcium channel blocker toxicity.

Conclusion

Calcium channel blocker toxicity is a commonly observed medical emergency that requires fast and accurate patient evaluation and assessment. Rapid and comprehensive early diagnosis and management are recommended, with monitoring based on the patient's condition and the severity of signs and symptoms. The first-line therapies include the indication of calcium, high-dose insulin euglycemia therapy (HIET), dialysis, and vasopressors.