Calcium channel blockers:
Toxicity from organic calcium channel antagonists (CCAs) causes a
decrease in mechanical contraction of heart and smooth muscle. Severe
toxicity produces hypodynamic shock, characterized by bradycardia and
hypotension and often accompanied by metabolic acidosis. Because
CCAs interfere with normal signaling of stimulatory hormones in the
cardiovascular system, standard cardiotonic and vasopressor treatments
for hypotension often produce ineffective or minimal effects in patients
with severe toxicity.
Classification of Ca2+ Channel Antagonists
Chemical Class
Phenylalkylamines
Benzothiazepines
Dihydropyridines
Drug
Verapamil
Diltiazem
Amlodipine
Felodipine
Isradipine
Nicardipine
Nifedipine
Nimodipine
Nisoldipine
Bepridil
Diarylaminopropylamine esters
The sustained-release and second-generation dihydropyridine CCA
preparations are long-acting drugs, they provide a larger drug dose per
tablet (especially in children) and can extend the duration of clinical
toxicity, and can lead to a delay in clinical manifestation of toxicity.
Pathophysiology:
An increase in intracellular calcium causes smooth and cardiac muscle to
contract and accelerates impulse formation in cardiac pacemaker cells.
Conversely, a deprivation of intracellular calcium causes smooth muscle
relaxation, a decrease in cardiac contraction, and a slowing of
automaticity. Clinically, these effects are recognized as hypotension,
bradycardia, and shock.
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Verapamil is the most potent negative inotrope of all CCAs, causing
equal depression of heart contraction and increase in smooth muscle
dilation at any concentration. Dihydropyridines are selectively relax
smooth muscle at concentrations that produce less negative inotropy.
Second-generation drugs are more lipid soluble and have longer duration
of action. These drugs cause a more gradual smooth muscle relaxation,
producing less reflex tachycardia than is observed with first-generation
dihydropyridines.
Clinical presentation:
CCAs generally produce hypotension with a slow heart rate, CCAs
produce bradycardia by decreasing sinus node firing, leading to sinus
arrest. Dihydropyridines are well recognized to produce reflex increases
in heart rate with an increase in left ventricular stroke volume, leading to
an increase in cardiac output at therapeutic and moderate toxic doses.
With severe overdose, all CCAs exert a negative inotropic effect with
depressed cardiac contraction, conduction block, and hypotension with
shock. Other clinical manifestations are organ hypoperfusion, inhibition
of metabolic processes, drowsy, Altered mental status, Pulmonary edema,
Metabolic acidosis with hyperglycemia, The mechanism of
hyperglycemia is related to a suppressive effect of CCAs on pancreatic
beta cell insulin release coupled with whole-body insulin resistance.
Treatment:
Treatment of CCA overdose consists of: (1) providing supportive care,
(2) decreasing drug absorption, and (3) augmenting myocardial function
with cardiotonic agents.
1- supportive care
Supportive care consists of airway protection and management,
adequate ventilation, and hemodynamic monitoring. Endotracheal
intubation may prevent pulmonary aspiration during gastric
instillation of charcoal or if vomiting occurs during the
administration of glucagon.
2- Decontamination
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Activated charcoal should be administered after the patient’s
airway is secured. In massive overdose, sustained-release
preparations can form gastrointestinal concretions (with ileus),
which can persist for days, rendering charcoal less useful.[45][60]
In this situation, whole-bowel irrigation with polyethylene glycol
may accelerate removal of sustained-release CCA pill fragments.
CCA elimination half-life is increased in overdose, and toxicity
from massive overdose can last for days.
3- Cardiotonic Drugs
(1) provide a reasonable crystalloid bolus (10–20 mL/kg), (2)
correct acidemia (keep arterial pH above 7.30 by
hyperventilation or with sodium bicarbonate infusion), and (3)
correct hyperkalemia (>5.0 mEq/L), preferably with insulin
infusion.
Calcium salts are the first-line treatment of CCA overdose.[51] Calcium
chloride should be initiated as a 10- to 20-mg/kg bolus injection. If this
infusion improves heart rate, myocardial conduction, arterial blood
pressure, or urine production, then a constant infusion of calcium chloride
at 20 to 50 mg/kg/hr should be initiated. Ionized plasma calcium
concentrations should be maintained between 2.0 and 3.0 mEq/L.
Calcium should not be used if concomitant cardiac glycoside (e.g.,
digoxin) toxicity is possible.
If calcium produces an inadequate clinical response, glucagon should be
given in a 0.05- to 0.20-mg/kg bolus infusion. If a benefit is observed,
usually within 5 minutes, a constant infusion of glucagon should be
initiated, starting at 0.05 to 0.1 mg/kg/hr.
Atropine administration is acceptable in the patient initially presenting
with bradycardia and hypotension. Catecholamines are the next treatment
for refractory CCA overdose. Dopamine can be used in standard doses for
cardiogenic shock (10–20 μg/kg/min). Epinephrine has also shown
benefit in CCA-intoxicated humans and animals. However, it was found
recently that epinephrine worsened myocardial function and did not
improve survival compared with saline treatment.
The phosphodiesterase inhibitor amrinone has successfully treated
refractory CCA hypotension. Insulin apparently improves myocardial
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mechanical efficiency and contractility by accelerating carbohydrate
oxidation and lower plasma potassium concentrations, thereby indirectly
improving automaticity and conduction. Serum potassium and glucose
levels should be monitored during and after the insulin therapy is stopped.
For patients with cardiogenic shock that is refractory to the above
treatments, Electrical cardiac pacing may help restore heart rate and
should be considered for patients with shock and a heart rate below 40
beats per minute.
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