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CALCIUM CHANNEL BLOCKERS Perspective Verapamil and nifedipine, the earliest calcium channel antagonists, were introduced in Europe in the 1970s and in the United States in the early 1980s. Calcium antagonists have found many clinical applications: angina pectoris, hypertension, supraventricular dysrhythmias, hypertrophic cardiomyopathy, and migraine prophylaxis. Over the last several years, more than 2000 cases of poisoning have been reported annually to American poison centers. Most fatalities occur with verapamil, but severe toxicity and death have been reported for most drugs of this class. Pathophysiology Calcium channel antagonists block the slow calcium channels in the myocardium and vascular smooth muscle, leading to coronary and peripheral vasodilation. They also reduce cardiac contractility, depress SA nodal activity, and slow AV conduction. In cases of overdose, verapamil has the deadliest profile, combining severe myocardial depression and peripheral vasodilation. Both verapamil and diltiazem act on the heart and blood vessels, whereas nifedipine causes primarily vasodilation. As with β-blockers, selectivity is lost in cases of overdose, and toxicity is fourfold, with negative effects on inotropy, chronotropy, dromotropy, and vasotropy. All calcium channel blockers are rapidly absorbed, although first-pass hepatic metabolism significantly reduces bioavailability ( Table 150-4 ). Onset of action and toxicity ranges from less than 30 minutes to 60 minutes, which has important implications for therapy. Peak effect of nifedipine can occur as early as 20 minutes after ingestion, but peak effect of sustained-release verapamil can be delayed for many hours. High protein binding and Vd greater than 1 to 2 L/kg make hemodialysis or hemoperfusion ineffective. Fortunately (except with sustained-release preparations), their half-lives are relatively short, limiting toxicity to 24 to 36 hours. Table 150-4 -- Selected Characteristics of Some Calcium Channel Blockers Vd (L/kg) Half-life Verapamil 4 Protein (hr) Binding (%) 3–12 90 Comments Most fatalities; impairs contractility and cardiac conduction more than most other calcium antagonists Diltiazem 1.7–5.3 3–7.9 70–80 Suppression of atrioventricular node similar to verapamil; myocardial depression otherwise less Nifedipine 1.4–2.2 1–5 92–98 Vasodilation greatest effect Vd (L/kg) Half-life Nicardipine 0.64 Nimodipine 0.94–2.3 Protein Comments (hr) Binding (%) 8–9 95 Vasodilation 1–2 95 No reports of oral overdosage (2005 PDR) Amlodipine 21 30–50 98 Vasodilation Bepridil 8 33–42 99 Class I as well as class IV antidysrhythmic; prolongs QT: torsade de pointes Felodipine 10 10 99 Vasodilation Isradipine 3 1.9–16 95 Vasodilation Nisoldipine 4–5 7–12 99 Vasodilation Vd, volume of distribution. Clinical Features Severe calcium antagonism eventually affects multiple organ systems, but cardiovascular toxicity is primarily responsible for morbidity and mortality. Hypotension and bradycardia occur early, and other rhythm disturbances include AV block of all degrees, sinus arrest, AV dissociation, junctional rhythm, and asystole. Nifedipine overdose more commonly causes reflex sinus tachycardia from peripheral vasodilation. Calcium channel blockade has little effect on ventricular conduction, so QRS widening is not seen early on. Ventricular dysrhythmias are also uncommon except with bepridil, which has class I antidysrhythmic properties. This drug prolongs the QT interval in a dose-related fashion, and intervals greater than 520 msec are associated with increased risk of ventricular tachycardia, especially torsades de pointes ( Box 150-10 ). BOX 150-10 Manifestations and Complications of Calcium Channel Blocker Poisoning Cardiovascular: hypotension, sinus bradycardia, sinus arrest, AV block, AV dissociation, junctional rhythm, asystole; ventricular dysrhythmias uncommon except with bepridil Pulmonary: respiratory depression, apnea; pulmonary edema; adult respiratory distress syndrome Gastrointestinal: nausea, vomiting, bowel infarction (rare) Neurologic: lethargy, confusion, slurred speech, coma; seizures (uncommon); cerebral infarction (rare) Metabolic: metabolic (lactic) acidosis; hyperglycemia (mild); hyperkalemia (mild) Dermatologic: flushing, diaphoresis, pallor, peripheral cyanosis AV, atrioventricular. Diagnostic Strategies Serum levels of calcium antagonists are not readily available, nor will urine toxicology screens reliably detect this class of drugs. Blood samples should be obtained for measurement of glucose and electrolytes (including calcium and magnesium). Hyperglycemia secondary to insulin inhibition occurs occasionally, but the elevation is usually mild (150 to 300 mg/L), is usually short lived (less than 24 hours), and generally requires no treatment.[39] A metabolic (lactic) acidosis is often observed with hypotension and hypoperfusion. An electrocardiogram should be promptly obtained, with special attention to atrial and ventricular rates and PR, QRS, and QT intervals. A prolonged QRS or QT interval suggests bepridil or a co-ingested cardiac toxin such as a tricyclic antidepressant. Differential Considerations Differential diagnosis is similar to that of β-blocker cases. Until characteristic rhythm disturbances supervene, many other toxic, metabolic, traumatic, and cardiovascular disorders are considered. Like the β-blockers, calcium antagonists cause early toxicity, and symptoms can be expected within 6 hours of ingestion of normal-release preparations.[40] Toxicity can be delayed 12 to 24 hours with sustained-release preparations. As with β-blockade, CNS-depressive effects are common and include lethargy, confusion, and coma. Unlike β-blockers, calcium antagonists seldom induce seizures. Pulmonary effects include noncardiogenic pulmonary edema. Apnea can also occur. As with digitalis and β-blocker overdose, nausea and vomiting are common. Management Initial management includes rapid establishment of vascular access, supplemental oxygen, cardiac monitoring, and frequent blood pressure measurement. Because of the rapid onset of toxicity with normal-release preparations, induction of emesis is dangerous and contraindicated. Vomiting is a powerful vagal stimulus that can exacerbate bradycardia and heart block. Gastric emptying or activated charcoal are similarly of no benefit because of the rapid absorption of these drugs. Hypotension and Bradycardia Hypotension can be caused by myocardial depression, inadequate heart rate, or peripheral vasodilation. Atropine can be administered in the usual American Heart Association's recommended doses (0.5 to 1 mg, up to 3 mg for adults, and 0.02 mg/kg for children, minimum 0.1 mg). Atropine's effect has often been disappointing and short-lived, and multiple doses risk anticholinergic poisoning.[41] If symptomatic bradycardia or heart block persists, the next step is a pacemaker or chronotrope such as isoproterenol. A bolus of crystalloid fluid, 20 mL/kg or more, should also be infused early. Intravenous calcium salts have traditionally been given to most patients. Their effect on contractility is considerable, but their effect on bradycardia, AV block, and peripheral vasodilation is often poor. The optimal dose of calcium is unknown. A reasonable dose is 6 g of calcium chloride, but some practitioners advocate aggressive calcium infusions, administering up to 30 g and raising the total serum calcium level to as high as 23.8 mg/dL.[42] Adverse effects of hypercalcemia include lethargy, coma, anorexia, nausea, vomiting, pancreatitis, polyuria, dehydration, and nephrocalcinosis. Most of these effects have been reported after weeks or months of hypercalcemia from malignancy or hyperparathyroidism. It is doubtful that hours or days of acutely induced hypercalcemia would be detrimental in the setting of massive calcium channel blockade. However, with rapid intravenous injection in animals and humans, bradycardia, AV block, AV dissociation, junctional tachycardia, ventricular ectopy, and ventricular fibrillation have been reported.[43] Extravasation of calcium salts can cause severe tissue necrosis. Administration through a central venous catheter is safer than through a peripheral intravenous line. Infiltration of calcium gluconate is less destructive than calcium chloride, but larger doses are necessary because it provides fewer calcium ions. It is prudent to raise the total serum calcium level no higher than 14 mg/dL, which the endocrine and oncology literature define as the threshold of ‘severe’ hypercalcemia. If ionized calcium levels are followed, it is probably wise not to exceed twice-normal levels. Adults should receive 10 to 20 mL of 10% calcium chloride slowly over 5 to 10 minutes, followed by a constant infusion of 5 to 10 mL/hr. Children can receive 10 to 30 mg/kg (0.1 to 0.3 mL/kg) of 10% CaCl initially. The serum calcium level can be as high as 18.2 mg/dL within 15 minutes after a bolus of just 5 mL of 10% CaCl, so levels should be measured later during the constant infusion. As with β-blocker poisoning, a monotherapeutic approach will probably succeed only for trivial overdoses. Most severely poisoned patients will require addition of catecholamines to accelerate the heart rate (chronotropy), enhance AV conduction (dromotropy), and restore tone to peripheral vessels (vasotropy). Most experience and success have been reported with isoproterenol and dopamine, often in combination.[41] Isoproterenol infusion can begin at 2 to 10 µg/min (0.1 µg/kg/min in children), but much higher rates may be needed. Unlike β-blocker overdose, however, the β-adrenergic receptor remains intact, and lower catecholamine infusion rates have generally been effective (e.g., dopamine 5 to 30 µg/kg/min). Epinephrine, norepinephrine, and dobutamine have also led to successful outcomes.[44] Isoproterenol or dobutamine alone may not reverse or may even exacerbate peripheral vasodilation; therefore, it is logical to add a vasopressor such as norepinephrine, metaraminol, phenylephrine, or high-dose dopamine. Glucagon has also been used for its inotropic and chronotropic effects, in doses similar to those advocated for β-blocker poisoning. Bailey recently reviewed 30 controlled animal studies (no controlled human studies exist) of glucagon use in β-blocker and calcium channel blocker overdose.[26] The results were somewhat disappointing: although it possibly increased cardiac output in β-blocker overdose, its effect on survival was unclear; it increased heart rate and cardiac output in calcium antagonist overdose in animals, but it did not increase mean arterial pressure and appeared to have no effect on survival. Insulin (0.5 to 1 µ/kg/hr) infusion has demonstrated efficacy in both animal trials and human cases. [45] [46] Glucose is infused concurrently to maintain serum glucose at 100 mg/dL (usually 10 to 30 g/hr). Insulin euglycemia is thought to act by improving myocardial carbohydrate metabolism. Finally, phosphodiesterase inhibitors such as amrinone (5 µg/kg/min) have been used to treat both calcium antagonist and β-blocker poisoning.[47] If hypotension persists despite the preceding interventions, peripheral arterial and pulmonary arterial catheters should be inserted to precisely measure and coordinate effects on blood pressure, pulmonary capillary wedge pressure, cardiac output, and peripheral resistance. Without such measurements, the clinician risks overtreatment with fluid and undertreatment with pressors, which may be needed in doses hitherto not encountered. As long as dysrhythmias are not aroused, cardiotonic infusions should be aggressively titrated to effect ( Box 150-11 ). BOX 150-11 Treatment of Calcium Channel Blocker Intoxication Phase 1 Boluses of atropine, calcium, fluids Phase 2 Catecholamine infusions Calcium infusion Insulin glucose infusion Glucagon infusion Phosphodiesterase infusion Transcutaneous or transvenous cardiac pacing Invasive monitoring Phase 3 Consider intra-aortic balloon counterpulsation, cardiac bypass Pediatric Considerations Nifedipine, and probably other drugs in its class, joins the short list of medications that can kill a child with ingestion of a single tablet. [48] [49] Seizures may be more common in children than adults and should be treated with diazepam, lorazepam, or calcium. Recommendations for CaCl administration in children range from 10 to 30 mg/kg (0.1 to 0.3 mL/kg of 10% CaCl) over 5 to 10 minutes, followed by an infusion. Overall, death following calcium antagonist ingestion in children is uncommon. French poison centers reported 51 cases of pediatric diltiazem ingestion over 10 years without a single fatality.[50] The intravenous route of administration, as with digitalis, is much more dangerous. Even therapeutic doses of intravenous verapamil are considered contraindicated in infants with supraventricular tachycardia because of case reports of cardiovascular collapse and cardiac arrest after injection.[51] Hyperglycemia occasionally occurs in children, but the elevation is usually short lived. Although insulin has been administered in a handful of cases, it is generally not necessary, because the hyperglycemia usually resolves spontaneously within 24 to 36 hours. A small number of children in refractory shock secondary to drug toxicity have been treated with intra-aortic balloon counterpulsation or cardiac bypass. The common thread is a toxin with a reasonably short half-life that, although lethal, does not directly cause irreversible tissue damage. Circulatory support during the day or two required for hepatic or renal elimination of the drug is potentially beneficial. However, expense, invasiveness, and complications restrict its application. In summary, aside from the differences previously noted, the presentation in children is similar to the presentation in adults: rapid onset of toxicity with CNS depression, bradydysrhythmias, hypotension, and metabolic acidosis. Disposition Because the peak effect of normal-release calcium channel blockers commonly occurs in 90 minutes to 6 hours, patients who are totally asymptomatic for 6 hours after an ingestion can be safely discharged according to psychiatric needs. Symptomatic patients or those who ingested delayed-release preparations should be admitted to a medical or toxicology service for at least 24 hours of continuous cardiac monitoring. (http://www.mdconsult.com/das/book/body/139339021-5/844888487/1365/470.html#4-u1.0-B0-323-028 45-4..50155-4--cesec49_7891)