Toxicokinetics
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 the 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 maintaining vascular smooth muscle tone. The influx of calcium is also responsible for insulin secretion. All CCBs are very well absorbed orally across the subtypes, 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:
- Phenylalkylamines (verapamil)
- Benzothiazepines (diltiazem)
- Dihydropyridines (nifedipine, amlodipine, felodipine, isradipine, nicardipine, nimodipine)
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.[4][5][6]
With significant overdoses, the serum and tissue concentration of these drugs are so excessive 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.[7] 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.[8]
History and Physical
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.[9] Toxicity can be delayed up to 16 hours after the ingestion of sustained-release formulations.
Initial symptoms may be as nonspecific as dizziness, fatigue, and lightheadedness, and in severe toxicities, it may rapidly decline to alter mental status, coma, and fatal shock.
Evaluation
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 poisoning severity. Both of these effects lead directly to metabolic acidosis.[10][11][12] It is also common to develop mild hypokalemia and mild to severe hypocalcemia.[13][2]
Profound hypoperfusion and end-organ ischemia with a 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 exacerbates the damage.[14][15]
Treatment / Management
The basic tenets of critically ill patient management 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.[16]
Use intravenous crystalloids during initial resuscitation while remaining cognizant of the risk of fluid overload with drug-induced inotropic failure. Therefore, dynamic assessment of fluid responsiveness with pulse pressure variability or stroke volume variability may be worthwhile.
Finally, seek early consultation with a medical toxicologist or poison control center. Cardiology consultation is also prudent considering the likelihood of a 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.
Gastrointestinal Detoxification
Controversy exists regarding the utility of GI decontamination in early intervention patients. It should not take precedence over resuscitation and avoid it in unstable patients.[5]
Administer activated charcoal in a dose of 1 gm/kg within 1 to 2 hours for maximum benefit.[16] In a volunteer study, charcoal administration 2 hours after amlodipine ingestion reduced absorption by 49% compared with controls.[17] The preferred method of decontamination is whole bowel irrigation (WBI). In large ingestion of sustained-release formulations, consider the use of activated charcoal for up to 4 hours and/or WBI. Activated charcoal can continue at a dose of 0.5 mg/kg every 2 to 4 hours, provided there are bowel sounds and no evidence of obstruction or perforation.[18]
Pharmacological Therapies
Calcium
The rationale behind calcium administration 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.[9]
Calcium chloride contains triple the amount of elemental calcium on 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 to 20 ml of 10% calcium chloride (30 to 60 ml for calcium gluconate) with repeat boluses every 10 to 20 minutes for 3 or 4 additional doses if clinical response is inadequate.[18] Give boluses over 5 minutes as faster administration can cause hypotension, atrioventricular dissociation, and ventricular fibrillation.[19][20]
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 to 0.4 ml/kg/hour. Kerns et al. recommend monitoring calcium levels 30 minutes after starting infusion and every 2 hours during infusion.[19] 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.
Insulin
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.[21][22]
The foundation of insulin used in CCB toxicity stems from several canine studies that showed an improvement in cardiac function and survival rate compared with placebo, epinephrine, glucagon, and calcium in verapamil overdose.[23] A high dosage is usually necessary, leading to the obvious challenge of hypoglycemia and hypokalemia from the intracellular shift of potassium.
The current insulin dosing recommendation is 1 Unit/kg regular insulin intravenous bolus followed by 1 to 10 U/kg/hour continuous infusion.[24] 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.[24]
Methylene Blue
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.[25] 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 that creates a lipid phase within the plasma and 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 that argues that the infusion of lipid emulsion provides a sustained fatty acid energy source to the myocyte under a toxic metabolic milieu.[26]
The role and efficacy of lipid emulsion therapy in CCB toxicity are mostly based on 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 to 0.5 ml/kg/min over 30 minutes.[27] It can interfere with the analysis of blood glucose and magnesium, and therefore collect blood samples should before its infusion and monitor serum triglyceride levels.[28]
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.[13][29]
Glucagon
Glucagon secreted from alpha cells of the pancreas act through activation of adenylate cyclase via G proteins resulting in a positive chronotropic and inotropic effect.[30] Bailey et al. showed an improvement in heart rate, cardiac output, and reversal of AV blocks in animal models of CCB overdose using glucagon.[31] A bolus of 5 to 10 mg over 1 to 2 minutes is an appropriate initial dose. The effects of administration are clear within 1 to 3 minutes and last 10 to 15 minutes. Because of the short duration of action, an intravenous infusion of 2 to 10 mg/hour should follow the initial bolus.[31][32]
It is an emetic and nausea; vomiting can occur with bolus doses above 50 micrograms/kg. It can also induce hyperglycemia, hypokalemia, and ileus.
Catecholamines
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 using norepinephrine or epinephrine, with preferential use of norepinephrine in the presence of vasodilatory shock. (Level 1D recommendation).[33] Because of inconsistent hemodynamic improvement in the case series, the workgroup suggested against the use of dopamine.[16][9]
Other Agents
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.
Consider incremental increases in the dose of high dose insulin infusion therapy and veno-arterial extracorporeal membrane oxygenation (VA–ECMO) for the patient with refractory shock.[34][35]
Once stabilized, arrangements for appropriate psychiatric evaluation and behavioral health consultation may be appropriate.
Enhancing Healthcare Team Outcomes
Between 2000 to 2010, US residents in the age group of 50 to 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 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. The presence of certain risk factors even in asymptomatic individuals should prompt an aggressive approach to care. That includes:
- Pediatric or geriatric age groups
- Poor cardiac health
- A suspected overdose of multiple medications, particularly another cardio depressant drug
- Large dose
- Diabetes
- Ingestion of sustained-release tablets
The management of CCB toxicity is with an interprofessional 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. This approach will lead to improved patient outcomes. [Level 5]
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.
Calcium Channel Blocker Toxicity