Calcium channel blockers (CCBs) are among the most commonly used cardiovascular drugs in the adult population. They are used to treat a wide array of clinical conditions including hypertension, supraventricular tachycardia, vasospasm, and migraine headaches.
Accidental over-ingestion, suicidal ingestion, and exploratory ingestion in children can all lead to severe toxicity. Therapeutic use can lead to toxicity through drug interactions with other cardiac medications or increased drug exposure because of interference with metabolism or elimination. Poisoning with these agents can have severe hemodynamic effects and be fatal.
American Poison Control Centers have reported cardiovascular drugs as the third fastest growing category of substance exposures. The American Association of Poison Control Centers (2011) reported 11,764 CCB overdoses in adults, second only to beta-blockers in several overdose deaths from cardiovascular medications (reported at 78 deaths). Calcium channel blockers and beta blockers accounted for most deaths. Verapamil and propranolol were the most commonly implicated agents. However, cases may be under-reported.
Calcium channel blockers in all their subtypes target the L type voltage-gated calcium channels. L type voltage-gated calcium channels are predominant in the following sites and roles:
Depolarization of the sinoatrial node (SA) and impulse propagation through the atrioventricular node (AV). Calcium entry during the plateau phase of the action potential in myocardial cells releases calcium from sarcoplasmic reticulum to the cytosol, triggering myocardial contraction. Contraction strength is directly proportional to intracellular calcium concentration, allowing actin and myosin to interact. Cytosolic calcium concentration mediated by membrane gated influx of calcium is responsible for maintenance of vascular smooth muscle tone. The influx of calcium is also responsible for insulin secretion. Across the subtypes, all CCBs are very well absorbed orally, undergo extensive hepatic first-pass metabolism, are lipophilic, bind readily to plasma proteins and have a large volume of distribution ( > 2 liters/kg). Elimination by hemodialysis or hemofiltration is ineffective.
At higher doses clearance slows, because hepatic clearance changes from first-order to zero-order kinetics.
Conventionally used CCBs belong to three main chemical classes, with each subclass having differing affinities for cardiac tissue and vascular smooth muscle:
Verapamil has a strong affinity for both myocardium and vascular smooth muscle. It suppresses cardiac contractility, SA nodal automaticity, AV nodal conduction, and causes potent vasodilation. Diltiazem has a similar range of effects as verapamil with less vasodilation; its effect is more potent on chronotropic action. Dihydropyridines are very effective vasodilators but exert less influence on cardiac pacemakers and myocardial contractility.
With significant overdoses, the serum and tissue concentration of these drugs are in such excess that the pharmacological difference in affinity and action between subclasses is overwhelmed. Thus, both verapamil and diltiazem causes significant bradycardia, hypotension, conduction disturbances, and escape rhythms. Nifedipine triggers hypotension and reflex sinus tachycardia. Calcium channel blockers of all subclasses reduce pancreatic insulin secretion and induce end-organ insulin resistance causing hyperglycemia. Additionally, CCBs interfere with calcium-stimulated mitochondrial action and glucose catabolism; this results in lactate production and ATP hydrolysis contributing to acidosis.
Depending on age, health, co-ingestion of other cardiovascular medications and the magnitude of toxic ingestion, the presentation may vary from asymptomatic to sudden cardiovascular collapse and death. Ingestion of toxic immediate release CCB formulations is expected to have an onset of effect within 2 to 3 hours of ingestion with all patients manifesting some symptoms within 6 hours. Toxicity can be delayed up to 16 hours after ingestion of sustained-release formulations.
Initial symptoms may be as nonspecific as dizziness, fatigue, and lightheadedness, and in severe toxicities may rapidly decline to alteration of mental status, coma, and fatal shock.
The most common ECG abnormalities involving calcium channel blockers other than dihydropyridines are sinus bradycardia, variable degrees of atrioventricular blocks, bundle branch block, QT prolongation, and junctional rhythms. Dihydropyridines maintain normal sinus rhythm and can cause reflex sinus tachycardia.
Hypotension and bradycardia when progressive, can eventually lead to cardiogenic shock. Also, hyperglycemia is common with all subclasses of CCBs and can be a useful clinical marker for the severity of poisoning. Both of these effects lead directly to metabolic acidosis. It is also common to develop mild hypokalemia and mild to severe hypocalcemia.
Profound hypoperfusion and end-organ ischemia with severe overdose can cause clinical evidence of end-organ failures like seizures, myocardial infarction, acute respiratory distress syndrome (ARDS), renal failure, bowel infarction and ischemia, and stroke.
Reports of non-cardiogenic pulmonary edema with CCB overdose are few, and the mechanism is not well defined. Sudden rapid precapillary vasodilatation causing an increase in capillary hydrostatic pressure may explain it. Overaggressive administration of crystalloids in an attempt to correct hypotension exacerbate the damage.
The basic tenets of management of any critically ill patient remain focused on initial attention to airway, breathing, and circulations. Consider endotracheal intubation in patients with worsening signs and symptoms of toxicity due to the risk of rapid hemodynamic deterioration — some advocate preadministration of atropine to offset vagally mediated hypotension and bradycardia during laryngoscopy.
If rapid deterioration is not evident, the patient should still be on a continuous cardiac monitor with close, intensive care monitoring. History should focus on underlying medical conditions, type of formulation ingested (immediate vs. sustained release), co-ingestants, and time of ingestion. Obtain an ECG to identify conduction abnormalities. Atropine is mostly ineffective in severe CCB toxicity.
Use intravenous crystalloids during initial resuscitation while remaining cognizant of the risk of fluid overload with drug-induced inotropic failure. Dynamic assessment of fluid responsiveness with pulse pressure variability or stroke volume variability may, therefore, be worthwhile.
Finally, seek early consultation with a medical toxicologist or poison control center. Cardiology consultation is also prudent considering the likelihood of transvenous pacemaker or intra-aortic balloon pump in severe overdose.
Conventional decontamination measures like urinary alkalinization, hemodialysis or hemofiltration are ineffective in CCB toxicity because of their large volume of distribution and lipophilic nature. Whole bowel irrigation is the mainstay of elimination in extended-release preparations.
Controversy exists regarding the utility of GI decontamination in early intervention patients. It should not take precedence over resuscitation and avoid it in patients who are unstable.
Administer activated charcoal in a dose of 1 gm/kg within 1-2 hours for maximum benefit. In a volunteer study, charcoal administration 2 hours after amlodipine ingestion reduced absorption by 49% when compared with controls. The preferred method of decontamination is whole bowel irrigation (WBI). In large ingestion of sustained-release formulations, consider use of activated charcoal up to 4 hours and/or WBI. Activated charcoal can continue at a dose of 0.5 mg/kg every 2-4 hours provided there is bowel sounds and no evidence of obstruction or perforation.
The rationale behind the administration of calcium is that increased extracellular concentration will promote calcium influx via unblocked L type calcium channels. However, responses are variable and suboptimal with severe toxicity. Calcium may improve hypotension, and conduction disturbances but is less effective in the management of bradycardia. The optimum dose ranges from 4.5 to 95.3 mEq/L based on reports, and there appears to be no identifiable dose-response relationship.
Calcium chloride contains triple the amount of elemental calcium in a weight to weight basis over calcium gluconate. (10% calcium chloride: 272mg elemental calcium or 13.6 mEq/1g ampule; 10% calcium gluconate: 90mg elemental calcium or 4.5 mEq/1g ampule). However, CaCl ideally should be administered via a central line because of the risk of skin necrosis on extravasation. The initial recommended dose is 10-20 ml of 10% calcium chloride (30-60 ml for calcium gluconate) with repeat boluses every 10-20 minutes for 3-4 additional doses if clinical response is inadequate. Give boluses over 5 minutes as faster administration can cause hypotension, atrioventricular dissociation, and ventricular fibrillation.
As the effect of calcium is transient, some centers recommend an infusion of calcium chloride titrating to effect and monitoring calcium levels, usually at 0.2-0.4 ml/kg/hour. Kerns et al. recommend monitoring calcium levels 30 minutes after starting infusion and every 2 hours during infusion. Calcium gluconate is safe through a peripheral IV but requires higher volumes to achieve the same calcium dose. There have been cases of multiorgan failure with acute tubular necrosis, hepatic necrosis, splenic infarcts and skin involvement from calciphylaxis related to over-aggressive use of calcium in the setting of CCB overdose. Most practitioners will administer calcium as an initial measure but if toxicity reoccurs or worsens will switch to other interventions.
Hyperinsulinemic euglycemia (HIE) has emerged as a potent therapy for severe calcium channel blocker toxicity. Experimental models show that CCB toxicity shifts myocardial substrate preference to carbohydrates from free fatty acids; thus cardiac substrate delivery is impaired. CCBs also reduce insulin secretion, creates tissue insulin resistance, and interfere with glucose catabolism leading to lactic academia and metabolic acidosis. Insulin administered in such a setting helps to reverse all of those derangements of metabolism. Insulin has a direct positive inotropic effect that contributes to its clinical role here.
The foundation of insulin use in CCB toxicity stems from several canine studies which showed an improvement in cardiac function and survival rate when compared with placebo, epinephrine, glucagon, and calcium in verapamil overdose. A high dosage is usually necessary, and that leads to the obvious challenge of hypoglycemia and hypokalemia from the intracellular shift of potassium.
Current insulin dosing recommendation is 1 Unit/kg regular insulin intravenous bolus followed by 1-10 U/kg/hour continuous infusion. Higher doses are permissible in refractory cases. The goal of therapy is to achieve hemodynamic stability and withdrawal of vasoactive agents.
Before the initiation of insulin therapy, check blood glucose and potassium. If less than 200 mg/dl and 2.5 meq/L respectively, then dextrose and potassium supplementation are necessary.
Methylene can counteract post coronary artery bypass vasoplegia (low systemic vascular resistance) by inhibiting guanylate cyclase, thus decreasing cyclic guanosine monophosphate (cGMP), and inhibiting nitric oxide synthesis. It has successfully treated refractory cases of CCB overdose as an adjuvant to vasopressors and HIE therapy. Bluish discoloration of urine, saliva, and skin is transient, lasting only 24 hours.
LIPID EMULSION THERAPY
Intravenous lipid emulsion is an oil-in-water emulsion which creates a lipid phase within the plasma and thus pulls a lipid-soluble drug into the lipid phase in blood. Lipid emulsion infusion can sequester intensely lipophilic drugs like verapamil and diltiazem and thus reduce their volume of distribution.
There is also an enhanced metabolism theory which argues that the infusion of lipid emulsion provides a sustained fatty acid energy source to the myocyte under toxic metabolic milieu.
The role and efficacy of lipid emulsion therapy in CCB toxicity has its basis mostly from animal studies and case reports and is therefore recommended only in refractory shock or severe toxicity unresponsive to conventional treatments.
American Society of Regional Anesthesia recommends an initial bolus of 1.5 ml/kg of 20% lipid emulsion followed by 0.25-0.5 ml/kg/min over 30 minutes. It can interfere with the analysis of blood glucose and magnesium, and therefore collect blood samples should before its infusion along with monitoring of serum triglyceride levels.
Reported adverse effects of therapy in high doses and multiple administrations include acute pancreatitis, ARDS, interference with vasopressors and fat overload syndrome inducing hepatosplenomegaly, seizures, fat embolism, and coagulopathy.
Glucagon secreted from alpha cells of pancreas act through activation of adenylate cyclase via G proteins resulting in a positive chronotropic and inotropic effect. Bailey et al. showed an improvement in heart rate, cardiac output, and reversal of AV blocks in animal models of CCB overdose with use of glucagon. A bolus of 5-10 mg over 1-2 minutes is an appropriate initial dose. Effects of administration are clear within 1-3 minutes and last 10-15 minutes. Because of the short duration of action, an intravenous infusion of 2-10 mg/hour should follow the initial bolus.
It is an emetic and nausea vomiting can occur with bolus doses above 50 micrograms/kg. It can also induce hyperglycemia, hypokalemia, and ileus.
Refractory hypotension and shock may result from both cardiac depression and loss of peripheral vascular resistance in severe CCB toxicity. Catecholamine infusion may become necessary in such a setting in addition to the other pharmacological therapies. There hasn’t been a single established agent of choice between dopamine, norepinephrine, epinephrine or even dobutamine. The optimal agent of choice is therefore unclear. Thus, the mechanism of shock and assessment of cardiac performance should guide decisions. The Society of Critical Care Medicine consensus guidelines recommends the use of norepinephrine or epinephrine, with preferential use of norepinephrine in the presence of vasodilatory shock. (Level 1D recommendation). Because of inconsistent hemodynamic improvement in case series, the workgroup suggested against the use of dopamine.
Phosphodiesterase inhibitors like milrinone may provide inotropic support in decompensated cardiogenic shock. Similarly, levosimendan is an inotropic agent that enhances myofilament response to calcium and increases myocardial contraction and could, therefore, be beneficial in verapamil intoxication.
NON PHARMACOLOGICAL ASPECTS OF TREATMENT
As mentioned before, management and monitoring in an ICU setting are essential with the availability of advanced hemodynamic interventions like transvenous pacers, intra-aortic balloon pump, or extracorporeal membrane oxygenation if it is necessary.
Once stabilized, arrangement for appropriate psychiatric evaluation and behavioral health consultation may be appropriate.
Because of their similarity of end-organ affinity, pharmacological action, and target patients, beta-blockers are the most common confounders. Compared to CCBs, beta-blockers are less likely to cause hyperglycemia in adult patients.
However initial presentation with bradycardia and hypotension should prompt consideration of a wide array of pharmacological agents including tricyclic antidepressants, digoxin, antiarrhythmic agents, clonidine, sedative-hypnotics, opiates, and organophosphates.
Prognosis beyond the initial toxicity depends upon the magnitude of ingestion, the severity of toxidrome, and the extent of organ dysfunction.
Poor prognostic factors include
Complications range from the poisoning itself to the untoward effects of life-saving interventions.
COMPLICATIONS FROM TOXICITY
COMPLICATIONS FROM TREATMENT
Calcium channel blockers are a medication class used to treat a wide range of clinical conditions like high blood pressure, high and irregular heart rate, bluish discoloration and spasm of fingers, or headaches. Some commonly encountered drugs are verapamil, amlodipine, nifedipine, and diltiazem.
Like most other medications, when taken beyond the appropriate recommended dosage, they can have untoward toxicities with a wide range of complications that can even be fatal.
Sometimes preexisting derangement of metabolism or interaction with other drugs can result in toxic accumulation in the body.
Any concern for excessive ingestion or early onset of abnormal symptoms should immediately prompt a call for help.
If mildly symptomatic or asymptomatic it is always wise to ensure safety. Help is readily available through the poison control center helpline. In the US, call 800-222-1222 available 24 x 7.
If symptomatic with dizziness, lightheadedness, confusion, nausea, an immediate visit to the emergency department can save lives. Time is of the essence in this situation.
Beyond an acute episode, ensure the safety of the home environment, supervise medication administration in the elderly, and seek psychiatric help in individuals with suicidal intent or depression.
Between 2000 to 2010, US residents in the age group of 50-54 experienced the highest population growth. With this increasing shift towards more elderly Americans, it is logical to expect increased use of cardiovascular medication and hence unintended or intended drug toxicities. While home monitoring of asymptomatic patients in the setting of mild calcium channel blocker overdose may be safe, patients or caregivers need education with relevant knowledge about the drugs as well as resources for poison control center helplines. Likewise, any evidence of symptoms even early should not be neglected and promptly evaluated in the emergency room setting. Presence of certain risk factors even in asymptomatic individuals should prompt an aggressive approach to care. That includes:
The management of CCB toxicity is with an interdisciplinary team that includes an emergency department physician, cardiologist, toxicologist, nurse practitioner, pharmacologist, internist, and specialty-trained emergency and trauma nurses. Pharmacists should evaluate medications prescribed, drug-drug interactions, and patient compliance and communicate with the team. Specialty trained nurses assist with monitoring the patient and report issues to the team.
Finally, beyond the period of acute stabilization and management, the establishment of home safety parameters, social work support, and psychiatry consultation and support for intentional suicidal overdoses are critical determinants for an optimum outcome.
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