Calcium Channel Blocker Toxicity

Published on 26/03/2015 by admin

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Last modified 26/03/2015

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173 Calcium Channel Blocker Toxicity

Calcium channel blockers (CCBs), also referred to as calcium entry blocking agents or calcium antagonists, are commonly used in the treatment of angina, hypertension, and headache disorders. Their use is complicated by adverse side effects, iatrogenic errors, and intentional overdoses. Significant morbidity and mortality can occur after accidental or intentional poisoning. In 2008, the American Association of Poison Control Centers recorded 10,398 human exposures to CCBs and 60 deaths. As a group, cardiovascular drugs including CCBs were responsible for more than 91,000 human exposures and 238 deaths.1

image 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 (Vd). For example, the Vd for verapamil is 5.3 L/kg, whereas the Vd for nifedipine is 0.8 L/kg. These characteristics (high protein binding and large Vd) suggest limited utility of hemodialysis for toxicity. After absorption, CCBs are hepatically metabolized by saturable enzymes to metabolites with variable activity.7,911 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.1215 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.1720

image 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

image 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.

image 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

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