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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.
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