Antidotes for Calcium-channel-blocker and β-blocker Toxicities
Toxicity due to calcium-channel blockers (CCBs) or β-blockers results in significant morbidity and mortality. The manifestations of toxicity are generally extensions of the drugs' pharmacologic and therapeutic effects and often include hypotension, bradycardia, conduction block, and myocardial depression.[28,29] Depending on the amount of the offending drug ingested and the patient's underlying cardiovascular health, the patient could remain asymptomatic or progress to cardiovascular collapse.
Subtleties in presenting symptoms can help differentiate CCB and β-blocker poisoning. Patients experiencing a CCB overdose tend to remain awake and alert, even in the event of profound hypotension and bradycardia, while patients with β-blocker poisoning are more likely to have an altered mental status and respiratory depression. The more severe the CCB overdose, the more likely the patient is to exhibit hyperglycemia, because CCBs also inhibit the release of insulin from pancreatic β-cells via a calcium-dependent pathway. Children experiencing a β-blocker overdose may develop hypoglycemia, an uncommon symptom in adults. Dihydropyridine CCBs such as nifedipine are more potent peripheral vasodilators than nondihydropyridine CCBs; they have limited effects on cardiac rhythm and are more likely to cause hypotension with reflex tachycardia. Propranolol, a β-blocker with high lipophilicity and sodium-channel-blocking effects, is more likely than other β-blockers to cause patients to have a seizure and to exhibit a widened QRS complex on electrocardiography.[28,29] Toxicity resulting from the ingestion of the combination of a β-blocker and a CCB can be particularly serious and life-threatening. Even at therapeutic doses, the ingestion of more CCB or β-blocker medication than is prescribed can be life-threatening in a patient with a tenuous cardiac history.
Because of the pathophysiologic similarities of CCB toxicity and β-blocker toxicity, their management is similar. The treatment of patients with bradycardia and hypotension begins with fluids and atropine, but patients who are more than mildly poisoned typically do not have an adequate response to these therapies. Other treatment modalities include calcium, glucagon, hyperinsulinemia–euglycemia therapy (HIET), vasopressors, cardiac pacing, i.v. 20% fatty acid emulsion, extracorporeal circulatory support, and intra-aortic balloon pump therapy.
Calcium plays an integral role in myocardial function and is necessary for automaticity, conduction, contraction, and vascular tone. In theory, the administration of exogenous calcium to patients with CCB toxicity should competitively increase calcium entry into the myocardium via nonblocked channels. Calcium has also been used to treat β-blocker toxicity.
Along with atropine, calcium is considered a first-line therapy for CCB or β-blocker toxicity. Patients with mild toxicity seem to have an adequate response to calcium therapy; those with severe toxicity usually require additional therapies.
Calcium is available as either calcium chloride or calcium gluconate. Because of differences in the molecular weights of the chloride and gluconate components, 30 mL of 10% calcium gluconate is equivalent to 10 mL of 10% calcium chloride. Extravasation of calcium must be avoided. In particular, calcium chloride is extremely damaging to tissue should extravasation occur. For this reason, it is recommended that calcium chloride be administered through a central line or only with good peripheral venous access. Care should also be taken not to extravasate calcium gluconate, but the consequences are less severe, so the administration of calcium gluconate through a peripheral vein is more appropriate.
A reasonable starting dose in adults is 30 mL of calcium gluconate or 10 mL of calcium chloride, with additional doses administered in 15–20 minutes. After three doses, careful monitoring of ionized calcium is necessary to avoid dangerous hypercalcemia. Calcium is administered to improve hemodynamics.
Hypercalcemia may lead to an ileus, myocardial depression, hyporeflexia, and an altered mental status. The administration of calcium to a patient with cardioactive-steroid (e.g., digoxin) toxicity may lead to asystole and should be avoided.
Implications for the Pharmacist To avoid hypercalcemia and its associated risks, close monitoring of the serum ionized calcium level is required, especially in patients receiving multiple doses of exogenous calcium. The use of calcium should be avoided in a patient with known or suspected digoxin toxicity.
It is glucagon's ability to increase cardiac cyclic adenosine monophosphate (cAMP) directly and independently of the β-adrenergic receptor that has established its role in the management of β-blocker overdoses. The increase in cardiac cAMP enhances inotropy and chronotropy and may improve conduction. Glucagon can also be used to manage CCB toxicity because not only is it difficult to distinguish an overdose of a β-blocker from an overdose of a CCB, as the two types of medications are frequently consumed together, but also because the glucagon-induced increase in cAMP occurs regardless of whether the calcium channel is blocked. In severely poisoned patients, glucagon will likely be ineffective and additional interventions are necessary.
Glucagon causes dose-dependent and rate-related nausea and vomiting with a risk of aspiration; thus, antiemetics such as metoclopramide and serotonin antagonists are often used in patients receiving the drug. Other adverse effects of glucagon can include hyperglycemia, followed by hypoglycemia in rare cases; gastrointestinal (GI) smooth-muscle relaxation and diarrhea; hypokalemia; and, rarely, allergic reactions. Tachyphylaxis with continued administration of glucagon is a theoretical concern.
Glucagon has a rapid onset of action and a short duration of effect, rarely longer than 15 minutes. As with other therapies used in toxicology, definitive glucagon dosing recommendations are lacking; a dosage of 50 μg/kg, or 3–5 mg up to a cumulative dose of 10 mg, is reasonable. This dose can be repeated as necessary. If there is a favorable response to glucagon boluses, a continuous infusion may be used.
Implications for the Pharmacist The doses of glucagon necessary for the management of β-blocker or CCB toxicity are much higher than those typically used to induce hyperglycemic or antispasmodic effects. The endpoints for discontinuing glucagon infusions are not clear; however, it is reasonable that once a patient is hemodynamically stable for a minimum of 6 hours, a slow taper of a single agent at a time can be employed. Anecdotal evidence and clinical experience suggest that once therapy is discontinued, close observation is necessary for a minimum of 12 hours.
The management and outcomes of patients severely poisoned by CCBs or β-blockers have improved substantially since the advent of HIET.[31,32] High-dose insulin has long been reported to be an inotrope. It was only in the late 1990s that HIET was demonstrated to be effective in treating patients severely poisoned with CCBs or β-blockers. The mechanism of HIET's effectiveness has not been clearly delineated; the available data suggest it enhances carbohydrate use and energy production by myocardial cells, resulting in improved contractility.[34–37] Because of the alterations in myocardial cell metabolism, it is not surprising that the beneficial effects of HIET in patients with CCB or β-blocker toxicity are delayed, generally occurring after 15–60 minutes.[37–39] Therefore, HIET should be started early in the course of management. If a patient remains hypotensive and bradycardic after receiving fluids, atropine, calcium, and glucagon, HIET should be administered. As HIET is particularly effective in improving myocardial contractility, the early administration of HIET may avoid the need for vasopressors or allow the use of lower doses, thereby reducing the potential for ischemic consequences.
The major adverse effects associated with HIET are hypoglycemia and hypokalemia. The sicker the patient is from a CCB overdose, the more likely it is that hyperglycemia will develop before HIET is instituted; as the patient recovers, the need for supplemental glucose increases. Insulin causes an intracellular shift of serum potassium, and potassium supplementation should be considered when the serum potassium concentration is <3 meq/L.
HIET should begin with an i.v. loading dose of 1 unit/kg of regular insulin followed by an infusion of 0.5–1 unit/kg/hr. The infusion dosage can be increased every 20–30 minutes. Doses of 2.5–3 units/kg/hr have been used depending on the response. Experimental studies have used even higher doses. Serum glucose should be maintained at a concentration of >100 mg/dL during HIET. A maximum insulin dose has not been established. If the initial blood glucose concentration is <400 mg/dL, an i.v. loading dose of 0.5 g/kg dextrose should be administered with the insulin and followed by an infusion of 0.5 g/kg/hr of dextrose, with meticulous and frequent monitoring of serum glucose and potassium concentrations. This dose of dextrose can be administered in a concentrated form (e.g., a 20–25% concentration) through a central line to avoid problems with fluid overload and venous irritation. The recommended goal is to maintain a serum glucose concentration of 100–250 mg/dL. A patient with a falling glucose concentration should be treated by increasing the amount of supplemental glucose (not by decreasing the insulin infusion) until the patient is hemodynamically stable.
Implications for the Pharmacist The use of HIET has resulted in a decline in mortality among patients with severe CCB or β-blocker toxicity. There is a delay in the benefits of HIET, so it should be started early. A general rule of thumb is to initiate HIET when it is apparent that calcium and glucagon are ineffective or as soon as the decision is made to initiate a vasopressor.
Am J Health Syst Pharm. 2012;69(3):199-212. © 2012 American Society of Health-System Pharmacists, Inc.
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