Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 3/30/2013
Definition
Calcium channel blockers (CCBs) are common agents used therapeutically for a variety of conditions, including hypertension, angina pectoris, coronary artery spasm, supraventricular arrhythmias, and prophylaxis for migraine headache. Accidental or intentional ingestion of CCB can result in toxicity, which can be life threatening, even in previously healthy individuals.
Description
- Calcium plays an essential role in cardiovascular function. Calcium flow across the cellular membrane is required for cardiac automaticity, conduction and contraction, along with maintenance of vascular tone
- Calcium flows through a voltage-gated L type channel found in cardiac myocytes, pacemaker cells, vascular smooth muscle, and on beta islet cells in the pancreas
- Calcium channel blockers inhibit this influx leading to decreased intracellular calcium and potentially cardiovascular dysfunction
- As of 3/2013, 10 CCBs are available in the U.S. These are classified based on their chemical structure:
- Diphenylalkylamines (verapamil)
- Benzothiazepines (diltiazem)
- Dihydropyridines (amlodipine, clevidipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and nisoldipine)
- Different CCBs may selectively bind to different sites of the channel leading to a selective or generalized effect. The toxic effects of CCBs can be seen as modified vascular smooth muscle tone, myocardial contractility, automaticity and atrioventricular conduction
- In general, dihydropyridines are relatively safe (as a solitary ingested drug) in overdose; whereas, verapamil is of greatest concern, followed by diltiazem
- CCBs are most commonly prescribed in a sustained release formulation which usually result in a late onset of action
- Toxic effects of CCB's may be seen after 20–60 minutes when immediate release formulations are ingested. In such cases, it is expected that toxicity will be seen within 2 hours or ingestion
- In cases where a sustained release formulation is ingested, it is critical that the health care professional be aware that life threatening toxicity may occur as late as 16 hours after ingestion
- The emergency treatment of CCB overdose includes:
- Supportive therapy (ABCs)
- Gastric decontamination using activated charcoal (immediate release) or activated charcoal followed by whole bowel irrigation (sustained release) to avoid the further absorption of the drug into systemic circulation
- Provision of specific pharmacological therapies such as calcium intravenously, high dose insulin and dextrose, catecholamines, and/or lipid infusion to treat cardiotoxicity
Epidemiology
- Incidence/Prevalence
- In 2010, the American Association of Poison Control Centers (AAPCC) reported 11,194 exposures to CCBs resulting in 13 deaths, and 65 major poisonings
- 1369 of the 11,194 exposures occurred in children aged <5 years
- Age
- Toxicity can occur at any ages
- The most common age groups affected are children aged <5 years, and adults > 20 years of age
- Risk factors
- CCB toxicity can occur in healthy individuals, generally only with diltiazem or verapamil (unless in combination with other agents such as beta-blockers)
- CCB toxicity occurs at lower doses in patients who have a compromised cardiovascular status
- Concomitant use of beta blockers increases the risk of toxicity
Etiology
Toxicity from CCBs may occur due to single acute ingestion (unintentional or intentional) or with therapeutic use. Severe toxicity is generally due to supratherapeutic ingestion of a non- dihydropyridine CCB (e.g. diltiazem, verapamil). Acute toxic exposure may occur due to the following:
- Unintentional intake of additional therapeutic doses in a patient on CCB's
- Unintentional intake of another person's therapeutic CCB by a patient who is naive to CCBs
- Unintentional pediatric intake
- Intentional intake with attempting suicide
History
- Obtain a history pertaining to the time of ingestion, name of the medication, the number of pills ingested, formulation and dose of the tablet taken by the patient
- Obtain information about concomitant ingestion of other drugs if any
- Monitor all patients closely as asymptomatic patients may have a rapid decompensation
- Patient may present with dizziness, nausea, seizure, syncope, decreased or altered mental status
Physical findings on examination
- Cardiac effects (bradycardia, congestive
- CCB overdose primarily results in cardiovascular toxicity
- Initial signs include myocardial depression, hypotension, and bradycardia
- Junctional escape rhythms are common in cases of CCB toxicity
- Conduction disturbances such as sinus bradycardia and varying degrees of atrioventricular block are commonly present
- Pulmonary edema is a common finding in patients with significant CCB poisoning
- CCB's in overdose can exert a strong negative inotropic effect due to poor pumping of myocardium, with peripheral vasodilation leading to cardiogenic shock and death
- Central nervous system (CNS) effects
- Drowsiness, confusion, agitation, and seizures may occur, but are rare, and often relate to unstable vital signs leading to such symptoms rather than a primary effect of the given drug
- Metabolic effects
- CCB overdose affects the influx of calcium channel sensitive cells in the pancreas. The pancreatic islet cells significantly decrease insulin release
- When CCB overdose occurs, this effect on the pancreas leads to a decrease in cardiac carbohydrate metabolism by inhibiting glucose uptake by cardiac muscle
- Hyperglycemia may also result in non-diabetic patients
- Metabolic acidosis may develop due to decrease in tissue perfusion
Blood tests findings
Other laboratory test findings
ECG findings- An electrocardiogram may show typical findings of toxicity such as:
- Bradycardia
- 1st, 2nd, or 3rd degree AV block
- Findings on ECG different from this can provide hints toward other co-ingestants that have cardiac toxicity
General treatment items
- Avoid pitfalls such as late or poor recognition of a critically ill patient. Patients with hypotension (despite a single 20 mL/kg bolus of normal saline) are significantly at risk, as are those with significant AV blocks
- It is important that the treating clinician be aware of the high likelihood of need for airway management, early in such cases where these is refractory hypotension and/or evidence of significant cardiotoxity
- The treatment approach for CCB overdose must focus on stabilizations of A,B, C's, but also a focused effort toward the restoration of cardiac function and systemic vascular tone
- In cases where full absorption of a CCB overdose is incomplete, steps should be taken to decrease further absorption. These may include gastrointestinal decontamination using activated charcoal, orogastric lavage, or whole bowel irrigation:
- Activated Charcoal: Oral activated charcoal administration may be given within two hours of ingestion however it may be given up to 4 hours after ingestion in cases of extended-release medications
- Gastric lavage: Detoxification using lavage is carried out when a patient presents within 1–2 hours of ingestion of a life threatening dose of CCB. This treatment modality is generally not used as charcoal and whole bowel irrigation are less invasive and just as effective
- Whole bowel irrigation: Whole bowel irrigation with polyethylene glycol solution may be used in some cases of ingestion of extended-release formulation capsules or tablets. However, adverse outcomes are possible especially in hemodynamically unstable patients or patients with ileus
- In patients presenting with hypotension and bradycardia, a 20 mL/kg bolus of normal saline (0.9%) intravenous (IV) should be administered as first line therapy
- Bradycardia should be treated, with the first agent recommended, being IV atropine. In cases of significantly symptomatic bradycardia, non-responsive to atropine, other measures such as transvenous pacing, intra-aortic balloon pump, cardiopulmonary bypass or extracorporeal membrane oxygenation may be required
- Pharmacological antidotes aim to increase the transmembrane calcium flow either by increasing calcium concentration (calcium salts) or by increasing intracellular cyclic adenosine monophosphate (cAMP) concentration (adrenaline or glucagon), phosphodiesterase inhibition (inamrinone or milrinone), or CCA binding to channels (sodium bicarbonate):
- Calcium salts intravenously
- IV calcium gluconate or calcium chloride are a reasonable first line agent to overcome the blockade of calcium influx. This is generally only a temporizing measure and not full treatment
- Improves conduction, inotropy, and blood pressure
- Glucagon – little evidence for use (not first line)
- Glucagon infusion stimulates muscle contraction through stimulation of adenyl cyclase via G proteins and thus increasing the intracellular cAMP level
- Although glucagon has been used in CCB overdose, it is not a first line therapy, and does not have any adequate evidence supporting its value in CCB overdose
- Sodium bicarbonate
- Sodium bicarbonate may be utilized in cases of academia. In such cases, it is expected that a lowering of the CCA binding to L-type calcium channel might result in improved hemodynamics
- Inamrinone (amrinone) and milrinone are commonly used for phosphodiesterase inhibition thereby increasing the intracellular concentration of cAMP, independent of beta-adrenergic receptor stimulation
- Adrenergic agents
- Drugs belonging to this class, such as dopamine, epinephrine, and norepinephrine, are reasonable in cases where bradycardia and hypotension are not relieved by atropine and IV fluids
- Hyperinsulinemia-euglycemia therapy (HIE)
- CCB toxicity induces hypoinsulinemia due to blockade of calcium flow into pancreatic beta-islet cells
- Insulin is an important factor in energy supply from glucose to myocardial muscles during stress and also has an inotropic effect
- Hypoinsulinemia prevents glucose uptake by myocytes leading to loss of inotropy and peripheral vascular resistance
- HIE therapy improves inotropy and peripheral vascular resistance and reverses acidosis, possibly by improving carbohydrate uptake and utilization by myocytes
- HIE includes use of high dose insulin with concurrent glucose infusion to maintain euglycemia. The recommended dose is
- 1 U/kg regular insulin bolus followed by 0.5 U/kg per hour regular insulin infusion
- The infusion can be titrated upward every 30 minutes to achieve the desired result
- Dextrose is given as a 25 mg IV bolus followed by 0.5 gm/kg/hr infusion, unless patient shows marked hyperglycemia
- Potassium supplemention should routinely occur to prevent severe hypokalemia
- This therapy also limits the metabolism of lactate thus limiting the metabolic acidosis in CCB toxicity
- Levosimendan may be useful in severe CCB overdose. This drug acts as calcium sensitizer and improves contraction without increasing intracytosolic calcium concentration
- Lipid emulsion therapy: Lipid emulsion such as Intralipid, may be life saving in cases where standard therapy is ineffective. It is yet to be determined it this is a treatment consistently expect to result in improvement; however, in critical cases, it is reasonable to administer
Medications indicated with specific doses
Gastrointestinal decontamination
- Activated charcoal (Actidose-Aqua)
- Atropine [Injectable]
- Sodium bicarbonate [IV]
Calcium salts- Calcium gluconate 10%
- Calcium chloride 10%
Phosphodiesterase inhibitorsAdrenergic agents- Dopamine [IV]
- Epinephrine [Injectable]
- Norepinephrine [IV] (Levophed)
Lipid emulsion 20% Dietary or Activity restrictions
- CCB toxicity patients should not be allowed to eat or drink until it is established that they are not unwell enough to require intubation
- Complete bed rest is advised for patients with CCB toxicity due to risk of orthostatic hypotension
Disposition
- Admission criteria
- All symptomatic patients should be admitted to an intensive care unit (ICU) for hemodynamic monitoring
- Patients who have ingested extended release CCBs should be admitted for 24 hours of observation due to risk of delayed symptoms
- Discharge criteria
- Patients without evidence of symptoms after 2 hours of ingestion of immediate release CCBs or 16 hours after ingestion of sustained release preparations may be medically cleared
- Such patients may require psychiatric evaluation before discharge
