‫ إحسان صالح‬.

‫د‬
Calcium Channel Antagonists
Introduction

Toxicity from organic calcium channel antagonists (CCAs) causes hypodynamic shock that 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.

Pharmacology

CCAs are characterized by their chemical structure, which confers selectivity regarding tissue binding and
clinical effects of toxicity. At therapeutic concentrations, organic CCAs bind to the α-subunit of the L-type
calcium channel, causing the channel to favor the closed state, thereby decreasing calcium entry during
phase II depolarization. At very high concentrations, some CCAs (verapamil) may occupy the channel canal
and prevent calcium from entering the L-channel altogether. Verapamil and deltiazem have the lowest ratio of
per cent vasodilation/ negative inotropy.

 Pharmacokinetics of Calcium Channel Antagonists

Time to Peak
Name Absorption * Elimination
Toxicity
Renal: 60% (about 5% unchanged)
Bioavailability 60–65%. 6–12 hr
Amlodipine Biliary/fecal: 20–25%
Not removed by hemodialysis
Well absorbed. Renal: 60% (less than 50% unchanged)
Nicardipine Bioavailability 35%. Biliary/fecal: 35%

Regular release 1
Renal: 80% (as metabolite traces
Well absorbed. hr; extended release
unchanged)
3–10 hr
Nifedipine Bioavailability 60–75%. Biliary/fecal: 20% (as metabolites)
Does not appear to be removed by
hemodialysis or CAPD; however,
plasmapheresis may be beneficial
Rapidly absorbed. Renal (less than 1 unchanged)
Bioavailability 13% (peak can
be doubled in hepatic Biliary/fecal
Nimodipine
impairment).
Unlikely to be removed by
hemodialysis (over 95% protein bound)
Diltiazem Regular release 1–2
Well absorbed. hr; extended release Biliary and renal (2–4% unchanged)
3–5 hr
Bioavailability 40% Does not appear to be removed by
 ‫ إحسان صالح‬.‫د‬
Time to Peak
Name Absorption * Elimination
Toxicity
hemodialysis or peritoneal dialysis
Oral bioavailability nonlinear,
increases with chronic use and
increasing dose.
Regular release 1–2 Renal: primarily as conjugated
Absorption 90%.
hr metabolites; 3% unchanged
Extended release 2–
Bioavailability 20–35%. Biliary/fecal: 9–16%
Verapamil 7hr (can be longer)
Bioavailability nonlinear,
increased with chronic use and Not removed by hemodialysis
increasing dose.

Many calcium channel blockers are well absorbed but have a lower bioavailability because of first-pass
*

metabolism.
Biotransformation of current calcium channel blockers is hepatic, extensive, and rapid.
†

Pharmacokinetics of Long-Acting Preparations

The use of sustained-release and second-generation dihydropyridine CCA preparations is common. These
preparations provide a larger drug dose per tablet (especially in children), can extend the duration of clinical
toxicity, and can lead to a delay in clinical manifestation of toxicity.

Clinical Presentation

Pathophysiology

A deficiency 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. Verapamil is the most potent negative inotrope of all CCAs.

CCAs do cause a decrease in systemic vascular resistance at all degrees of toxicity. 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.

 Clinical Presentation of Calcium Channel Antagonist Toxicity

Bradycardia with hypotension (45 to 55 beats per minute)

Altered mental status (Mental function is often altered, with behavior ranging from agitation to coma. With
shock, cerebral hypoperfusion can cause seizure activity or stroke)
Pulmonary edema frequently complicates CCA overdose
Metabolic acidosis with hyperglycemia (important differentiation). The mechanism of hyperglycemia is
likely related to a suppressive effect of CCAs on pancreatic beta cell insulin release coupled with whole-
body insulin resistance
Sinus arrest on electrocardiogram
Refractory shock
 ‫ إحسان صالح‬.‫د‬

Differential Diagnosis

The combination of hypotension and bradycardia can help differentiate CCA toxicity from hypovolemia,
sepsis, cyclic antidepressant toxicity, and structural causes of shock such as pulmonary embolism or cardiac
tamponade. All of these cause hyperdynamic shock in early stages.

The toxicologic differential diagnosis of CCAs includes those pharmaceutical agents that also produce
bradycardia and hypotension in an overdose setting. Examples include digoxin and other cardioglycoside-
containing agents, β-adrenergic receptor agonists, clonidine, organophosphates, and the type Ia
antidysrhythmic agents such as procainamide and quinidine. Differential diagnosis for hypotension with
normal or decreased heart rate as cellular hypoxia (Poisoning with carbon monoxide (severe) or cyanide)

Laboratory Studies:
EKG and venous blood drawing for electrolyte and renal function determinations. In the symptomatic
patient, serum calcium and potassium levels should be serially monitored. Hyperkalemia suggests severe
cellular poisoning and marked negative inotropy can be expected with hyperkalemia in CCA overdose.
Transthoracic echocardiography can estimate the left ventricular ejection fraction as an index of contractile
function.

Treatment

Treatment of CCA overdose consists of three basic objectives: (1) providing supportive care, (2) decreasing
drug absorption, and (3) augmenting myocardial function with cardiotonic agents..

Treatment of Calcium Channel Antagonist Toxicity

Activated charcoal but with sustained-release preparations is less useful. In this situation, whole-bowel
irrigation with polyethylene glycol may accelerate removal of CCA pill fragments. Drug elimination can be
enhanced by extracorporeal removal
Ensure airway protection and adequate ventilation and oxygenation, preferably via endotracheal intubation
(prevent pulmonary aspiration during gastric instillation of charcoal) and mechanical ventilation.
Insert a 7 F central venous “cordis” catheter. Administer a 10- to 20-mL/kg normal saline injection then
infusion for patients with a systolic blood pressure below 90 mm Hg
Keep arterial pH > 7.30 (. which, in turn, may reduce negative inotropy ) with hyperventilation and
potassium level < 5.0 mEq/L (particularly if considering an insulin infusion).
Begin electrical pacing for heart rate below 40 beats per minute with shock.
Administer 10 to 20 mg/kg of 1% calcium chloride solution (first line). If favorable response (improves heart
rate, myocardial conduction, arterial blood pressure, or urine production) , begin infusion at 20 mg/kg/hr
(monitor ionized calcium, not to exceed two times normal baseline level).
Bolus inject 0.05 to 0.2 mg/kg glucagon (If calcium produces an inadequate clinical response). If beneficial,
begin 0.1 mg/kg/hr infusion and titrate.
Consider beginning insulin/dextrose bolus/infusion at 1.0 U/kg IV bolus, followed by 1.0 U/kg/hr infusion
with 40 mL 50% dextrose/hr).
Begin dopamine infusion (the next treatment for refractory CCA overdose ) at 10 μg/kg/min; titrate infusion.
Bolus amrinone at 750 μg/kg and begin 10 μg/kg/min infusion.
For refractory case: 1- electrical cardiac pacing may help restore heart rate (if a heart rate below 40 beats per
minute) 2- Consider intra-aortic balloon counterpulsation treament or extracorporeal cardiopulmonary
bypass 3. 4-Aminopyridine should be considered for a patient who is dying despite all efforts.
 ‫ إحسان صالح‬.‫د‬

Note/1- Calcium chloride may be preferable to calcium gluconate because the calcium concentration is
approximately three times greater. 2- Atropine seldom produces any benefit as a sole treatment. However, its
administration is acceptable in the patient initially presenting with bradycardia and hypotension.

Sequelae

If the patient survives, it does not appear that severe CCA toxicity causes any residual cardiomyopathy or
central nervous system dysfunction from direct drug effect.