Pharmacology

CCBs are classified into five groups based on structure or functional activity. The first group, exemplified by the T-channel blocker mibefradil, is unique because these agents antagonize T-type calcium channels. The other four groups all antagonize L-type calcium channels and are divided based on structural differences. These groups include the phenylalkylamines (e.g., verapamil), benzothiazepine (diltiazem), dihydropyridines (e.g., nifedipine and the synthetic agent, clevidipine), and diarylaminopropylamine ether (bepridil). Their mechanism of action involves inhibition of calcium influx through voltage-dependent L-type calcium channels.^2,3,4 This inhibition results in decreased intracellular calcium concentration, relaxation of vascular smooth muscle, decreased systemic vascular resistance, and inhibition of intracardiac nodal excitation.^3,5 Some CCBs, particularly verapamil, have higher binding affinity for myocardial calcium channels, resulting in sinoatrial and atrioventricular nodal inhibiton.^3,6

The most commonly used CCBs (verapamil, diltiazem, and nifedipine) are well absorbed, highly protein bound at therapeutic concentrations, and undergo a variable amount of first-pass metabolism following oral administration.^7,8 There is variability in volumes of distribution (V_d). For example, the V_d for verapamil is 5.3 L/kg, whereas the V_d for nifedipine is 0.8 L/kg. These characteristics (high protein binding and large V_d) suggest limited utility of hemodialysis for toxicity. After absorption, CCBs are hepatically metabolized by saturable enzymes to metabolites with variable activity.^7,9–11 Therapeutic half-lives range from less than two hours to longer than 60 hours. After massive ingestion or in patients with congestive heart failure or hepatic dysfunction, decreased metabolism leads to increased concentrations of active compounds and prolonged half-lives.^12–15 Patients with decreased hepatic perfusion or function may experience decreased elimination of CCBs.^10,16

All CCBs are pregnancy category C drugs and have been associated with teratogenic and embryocidal effects in animal studies. After therapeutic use, CCBs can be recovered from breast milk and exposed offspring, but the effects of these drugs on neonates require further investigation.^17–20

Clinical Manifestations of Toxicity

The potentially life-threatening effects of CCB intoxication are related to alterations in the function of the cardiovascular system. The most common clinical manifestations are sinus bradycardia, hypotension, and shock. Clinical effects may vary in mild to moderate poisoning, depending on the specific medication. Toxic doses of phenylalkylamines or benzothiazepines commonly cause bradycardia and hypotension secondary to the negative inotropic and chronotropic effects of these drugs.^21,22 Toxic doses of dihydropyridines, however, may result in hypotension with reflex tachycardia because of the affinity of these agents for the peripheral vasculature.^21,22 In massive overdoses, specificity is lost, and all CCBs can cause bradycardia, depressed cardiac contractility, and cardiovascular collapse.²² Furthermore, cardiovascular compromise may be compounded by ingestion of other cardiovascular toxins, in addition to underlying patient comorbidities. Of note, sustained-release preparations can cause delayed-onset toxicity as late as 12 hours or longer after ingestion.^2,21

Pulmonary toxicity from CCB poisoning includes both cardiogenic and noncardiogenic pulmonary edema secondary to several purported mechanisms: negative chronotropy, excessive fluid resuscitation, increased capillary permeability secondary to drug effects, and increased sympathetic discharge in response to shock.²³

Neurologic manifestations include myoclonus, dizziness, syncope, focal deficits, and seizures. These neurologic findings are most likely related to central nervous system hypoperfusion.^22,24 Gastrointestinal symptoms due to toxic doses of CCBs are nonspecific and include nausea and vomiting.²² CCB toxicity with ensuing shock can cause diffuse organ dysfunction, such as acute kidney injury, secondary to poor tissue perfusion.

Metabolic derangements can include hypokalemia and hyperglycemia. Abnormally high circulating glucose levels are due to calcium channel antagonism in the pancreatic beta islet cells, which inhibits insulin release.²⁵ Metabolic acidosis can be caused by poor tissue perfusion and mitochondrial dehydrogenase inhibition.²⁶

Differential Diagnosis

The most common agents in the differential diagnosis of CCB poisoning are β-adrenergic antagonists, cardiac glycosides, imidazolines, class 1a and 1c antidysrhythmics, cyanide, organophosphates, and late tricyclic antidepressants.^22,27 Also included in the differential diagnosis of CCB poisoning are nontoxicologic entities such as acute coronary syndromes, hyperkalemia, myxedema coma, hypothermia, and sepsis.

Diagnostic Testing

The diagnosis of CCB poisoning is based predominately on history and physical examination. Both routine and comprehensive drug screening assays routinely miss CCBs.²⁸ Although there are no specific laboratory tests available to diagnose CCB poisoning, some laboratory studies should be obtained to aid clinical management.

A 12-lead electrocardiogram should be obtained to define the cardiac rhythm and intervals. Arterial or venous blood gas measurements offer rapid assessment of tissue perfusion, acid-base status, and critical electrolytes. Chest radiography can demonstrate cardiac size and pulmonary edema. Serum electrolytes and markers of renal function should be measured. Serum calcium levels are neither affected by CCBs nor routinely helpful, but serial levels may be necessary for patients treated with parenteral calcium. Echocardiography may help management decisions based on fluid status, global function, and chamber sizes.

Serum levels of cardioactive medications with established therapeutic concentrations (e.g., digoxin) should be obtained for patients with a suggestive history or physical examination.

Treatment

Gastric decontamination plays a limited role in the vast majority of acute poisonings, including CCB poisoning. A single dose of activated charcoal, without a cathartic, may be administered within one hour after ingestion if the patient is willing to drink. Insertion of a nasogastric tube solely for the purpose of charcoal administration is not recommended.²⁹ Whole-bowel irrigation also has been used following the ingestion of sustained-release CCBs but is not routinely indicated.^30,31

Treatment of the patient poisoned by CCBs focuses on early recognition of shock and aggressive cardiovascular support. Endotracheal intubation and mechanical ventilation are indicated to ensure adequate oxygenation and ventilation if any of the following are present: obtunded mental status, poor airway protective mechanisms, hypoxemia, or arterial hypotension. A low threshold should be used to initiate invasive monitoring techniques (arterial, central venous, or pulmonary arterial catheters) for both administration of treatments and assessment of clinical responses. All symptomatic patients should have a bladder catheter placed to accurately monitor urinary output.

Treatment of patients with CCB toxicity should generally be guided by the degree of end-organ dysfunction (e.g., mental status, cardiac output, urine output) and not solely by blood pressure. For example, a bradycardic patient with normal mental status, normal blood pressure, and no demonstrable acidosis or renal dysfunction may not require further treatment unless clinical deterioration ensues.

Treatment of symptomatic bradycardia includes atropine, external or internal pacing, parenteral calcium, glucagon, vasopressors, and even extracorporeal hemodynamic support. No treatment has been studied in randomized controlled human studies, and their use is based on animal data and/or human case reports. Severely poisoned patients typically require several concomitant therapies to achieve cardiovascular stabilization.

Intravenous (IV) fluids should be administered to hypotensive patients to improve blood pressure and tissue perfusion. In adults, 2 L of lactated Ringer’s or normal saline solution should be given. Care should be maintained not to administer excessive volumes of crystalloid solutions to patients poisoned by CCBs because of the risk of pulmonary edema.²³

Atropine has limited utility in reversing bradycardia, but it may be administered on an emergency basis while other therapies are being prepared.^22,32

External or internal pacemaker therapy may be attempted to ameliorate symptomatic bradycardia. If capture is achieved, the heart rate should be set at 60 bpm. The target systolic blood pressure should be 90 to 100 mm Hg in order to ensure adequate tissue perfusion. However, pacemaker therapy is often ineffective in sustaining hemodynamic improvement.^22,32

Administration of parenteral calcium salts may occasionally augment heart rate and blood pressure in the face of CCB poisoning.³² Calcium chloride contains approximately three times the amount of calcium as the gluconate salt and is the preferred agent.³³ Slow boluses of one to three g of calcium chloride may be given, and a continuous infusion of two to six g/h may be initiated if a response is noted.^34,35 Serum ionized calcium levels should be monitored during parenteral calcium infusions and maintained at approximately 2 to 3 mmol/L.^22,33 If digoxin toxicity is suspected, use of parenteral calcium salts should be avoided; use of digoxin antibodies should be considered.²²

Although more commonly associated with β-adrenergic antagonist poisoning, IV glucagon may offer another treatment modality. Intravenous glucagon activates adenyl cyclase, leading to increased intracellular levels of the second messenger, cyclic adenosine monophosphate (cAMP). In cardiac myocytes, increased levels of cAMP lead to improvements in cardiac contractility and rate.^21,36 Intravenous boluses of glucagon (2-10 mg) may be administered; if hemodynamics improve, glucagon should be infused at the effective IV mg dose per hour. Side effects of glucagon administration include nausea, vomiting, and hyperglycemia.^22,37

Although several vasoactive medications have been advocated for the treatment of CCB toxicity, there is no one agent that is clearly optimal. Norepinephrine, dopamine, epinephrine, isoproterenol, amrinone, and aminophylline all have demonstrated efficacy. In general, patients with severe CCB poisoning should receive a pressor titrated to achieve a perfusing blood pressure. In the face of significant hypotension, the choice of vasopressor should be based on the preexisting heart rate. For example, if the patient is hypotensive with reflex tachycardia, an α-adrenergic agonist should be employed. Norepinephrine or epinephrine are reasonable first-line agents, based on the patient’s presenting heart rate, blood pressure, and pharmacologic properties.

Four novel therapies for CCB toxicity are insulin/dextrose infusion, hypertonic saline, 4-aminopyridine, and lipid emulsion. The use of an insulin/dextrose infusion (high insulin–euglycemia treatment [HIE] therapy) may correct the state of hypoinsulinemia and impaired cellular glucose uptake found in CCB poisoning.²⁵ The underlying mechanism of HIE may involve altered myocardial metabolism. Under normal physiologic conditions, the heart preferentially utilizes fatty acids for energy production. However, when drug-induced cardiac dysfunction is present, carbohydrates are used for myocardial energy requirements.^38,39 Despite a lack of concensus, a reasonable starting regimen can be found in Table 173-1. Potassium and glucose concentrations should be monitored closely; blood glucose levels and hemodynamic response will dictate changes in insulin or glucose administration.^3,40,41 Although animal data and human case reports describing the use of HIE are increasing, it is not recommended as a first-line agent.^26,41–45

TABLE 173-1 Pharmaceutical Interventions After Calcium Channel Blocker Toxicity

Hypertonic saline has been studied only in animals as a potential treatment for verapamil poisoning. The proposed mechanism involves increasing the pH around the calcium channel and reversing potential verapamil-induced sodium channel blockade.⁴⁶ The drug 4-aminopyridine blocks the outward rectifying potassium channel, allowing more calcium to enter the myocardial cell.²² This drug has demonstrated success in animal models and in a single verapamil-poisoned patient receiving hemodialysis.⁴⁷

Lipid emulsion (Intralipid) infusion has been used for the treatment of several lipophilic drug-induced toxicities, including verapamil.^48–51 The mechanism of action involves the IV administration of lipids (fat emulsion) that reduce the V_d of lipophilic drugs (e.g., verapamil). By serving as a “sink” for lipophilic drugs, these lipid microspheres bind to intravascular drug and keep it from reaching target tissues. This mechanism suggests that the optimal effect would occur if the lipids are administered very soon after the exposure when a large percentage of the drug is still in the intravascular space.

The use of any experimental therapies, particularly as a first-line approach, cannot be recommended. Before routine use is warranted, further investigation is needed. In terms of CCB toxicity, lipid emulsion therapy should be reserved for verapamil exposures only.

Treatment endpoints are maintenance of oxygenation, heart rate, and blood pressure to sustain adequate tissue perfusion. Continuous monitoring of hemodynamic parameters, mentation, urine output, and acid-base status are paramount and will help guide effective therapy. Patients who remain in a state of cardiovascular collapse despite aggressive resuscitation may be candidates for extracorporeal blood pressure support using cardiopulmonary bypass or intraaortic balloon pump.^21,52

Table 173-1 presents a summary of pharmaceutical interventions after CCB toxicity.