Pharmacology Notes: Toxicology: calcium channel blockers

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Toxicology: calcium channel blockers

Monday, October 3, 2011 Posted by Piscean

Toxicology: calcium channel blockers

For pharmacological information, see Calcium channel blockers in 'Getting to know your drugs'.

Indicators of toxicity

Dose ingested

The toxic dose varies in adult deliberate self-poisoning and unintentional poisoning. Toxicity may develop with just two to three times the normal daily dose in elderly patients. In children, ingestion of less than 12 mg/kg verapamil, or less than 2.7 mg/kg nifedipine, is unlikely to cause toxicity.

Other indicators of toxicity

Severity of poisoning is highly dependent on the type of calcium antagonist, with the most severe effects from cardioselective calcium antagonists, verapamil and diltiazem. Only massive ingestions of peripherally selective agents (nifedipine, felodipine, amlodipine) will result in severe poisoning.

Patients with underlying cardiac disease are likely to have more severe effects.

Clinical presentation

The main presenting features include:

cardiovascular effects: hypotension (combination of peripheral vasodilatation and myocardial depression) progressing to cardiogenic shock; bradycardia, first degree heart block progressing to junctional bradycardia (no P wave), idioventricular rhythms and asystole; pulmonary oedema

central nervous system: drowsiness, confusion, rarely seizures Coma is usually secondary to hypotension/hypoxia from cardiovascular collapse.

gastrointestinal effects: nausea, vomiting

metabolic effects: hyperglycaemia; lactic acidosis.

Key investigations

ECG: should be done in all patients

blood glucose level and electrolytes

blood gases.

Treatment

Airway and breathing

Ensure that there is an adequate airway and breathing. However, intubation and ventilation is usually only required with severe poisoning where a decreased level of consciousness is multifactorial (hypoxia, hypotension, direct drug effect).

Circulation

Hypotension should be treated with a fluid bolus of 20 mL/kg of normal saline. Use:

sodium chloride 0.9% 20 mL/kg IV over 10 to 30 minutes.

This should be repeated if there is no response, or only a partial response. Persistent hypotension will need to be treated with inotropes.

Serial ECGs and ECG monitoring should be done in all but minor poisoning with calcium channel blockers. Bradycardia can be treated initially with atropine if there is hypotension, use:

atropine 0.5 to 1.5 mg IV as a bolus, repeat after 15 minutes if necessary (child: 0.02 mg/kg to a maximum of 0.5 mg/dose IV, repeated in 5 minutes if required to a total maximum of 1 mg).

Severe bradycardia with persistent hypotension may require temporary transvenous pacing, but ventricular rather than atrial pacing will be required due to atrioventricular (AV) nodal blockade.

Inotropic support

The choice of inotrope will depend partly on the particular calcium channel blocker ingested. Hypotension will usually result from a combination of myocardial depression, heart block and peripheral vasodilatation. Calcium therapy, see Antidotal therapy should be considered early before the use of inotropes. The following inotropes are recommended based on animal studies and anecdotal experience. Use:

1	adrenaline 1 to 20 micrograms/minute IV infusion, see Box 14.4
	OR
1	short-acting insulin 1 unit/kg (see Table 5.30) IV as an initial bolus, followed by an infusion of 1 unit/kg/hour IV. The dose can be increased to 2 units/kg/hour or further but this should be discussed with a clinical toxicologist
		PLUS
		glucose 50% 50 mL (child: glucose 10% 2.5 mL/kg) IV as an initial bolus, followed by an infusion according to Box 14.26
	OR
2	dopamine 10 to 20 micrograms/kg/minute (child: 5 to 20 micrograms/kg/minute) IV infusion, see Box 14.6.

The use of a combination of inotropes such as dobutamine and noradrenaline may be an appropriate option, but should be done in consultation with a critical care specialist. Vasopressors such as metaraminol or low-dose adrenaline may be useful in the short term for hypotension. Use:

1	metaraminol 0.5 to 1 mg (child: 0.01 mg/kg) IV as a bolus; this can be repeated if there is clinical response
	OR
2	adrenaline 0.1 to 1 mg (child: 0.01 mg/kg) IV as a bolus; this can be repeated every 2 to 5 minutes depending on clinical response. An adrenaline infusion should then be commenced, see Box 14.4.

In patients in cardiac arrest the following should be used in addition to normal advanced life support protocols (see Figure 14.4 and Figure 14.5):

1	adrenaline 1 mg (child: 0.01 mg/kg) IV as a bolus; this can be repeated every 2 to 5 minutes depending on clinical response. An adrenaline infusion should then be commenced see Box 14.4
	PLUS EITHER [Note 1]
1	calcium gluconate 10% 60 mL (child: 1.0 mL/kg) IV; if there is no response this dose can be repeated every 2 to 5 minutes
	OR
2	calcium chloride 10% 20 mL (child: 0.2 mL/kg) IV; if there is no response this dose can be repeated every 2 to 5 minutes.

Prolonged cardiopulmonary resuscitation should be undertaken in these patients (4 to 8 hours), as prior to the overdose these patients are usually healthy individuals. Cardiac assist devices and/or extracorporeal circulatory support should be considered if available.

Decontamination

Consider an initial dose of charcoal up to 4 hours after severe poisoning with calcium channel blockers, if the patient has a protected airway. Calcium channel blockers can cause ileus, which is a contraindication to charcoal. Use:

activated charcoal 50 g (child: 1 g/kg to a maximum of 50 g) orally or via orogastric or nasogastric tube, up to 4 hours after the estimated time of ingestion. Patients must be able to protect their airway or be intubated.

Whole bowel irrigation should be considered for ingestions of slow-release preparations. However, evidence of benefit is based on single case reports and this must be weighed against the risk of aspiration in sedated patients and the availability of resources to administer whole bowel lavage. Use:

macrogol 3350 powder with electrolytes (ColonLYTELY) 2 sachets dissolved in 2 L of water, 1 to 1.5 L (child: 20 to 30 mL/kg/hour) in the first hour, then 1 L/hour (child: 20 to 30 mL/kg/hour) orally or via orogastric or nasogastric tube, if given within 2 hours of ingestion. Patients must be able to protect their airway or be intubated. [Note 2]

Specific pharmacological therapies

Antidotal therapy

A specific antidote does not exist for calcium channel blocker overdose. However, the administration of calcium to increase extracellular calcium appears to partially reverse the heart block and arrhythmias induced by calcium channel blocker overdose—usually found with verapamil or diltiazem. In patients with heart block or cardiac dysrhythmias, use [Note 1]:

1	calcium gluconate 10% 30 mL (child: 0.6 mL/kg) IV, over 10 minutes; if there is no response this dose can be repeated every 5 minutes
	OR
2	calcium chloride 10% 10 mL (child: 0.2 mL/kg) IV, over 10 minutes; if there is no response this dose can be repeated every 5 minutes.

Large doses of calcium may be required and up to 10 g has been used as an initial dose in severe toxicity. If there is a response to calcium then an infusion is recommended. Use:

1	calcium chloride 10% 1 to 10 mL/hour (0.02 to 0.2 mL/kg/hour in children) IV infusion, by a central line
	OR
2	calcium gluconate 10% 3 to 30 mL/hour (0.06 to 0.6 mL/kg/hour in children) IV infusion.

Serum calcium needs to be measured in all patients. The aim is to produce hypercalcaemia and generally patients have minimal adverse effects. It is reasonable to aim to maintain the ionised serum calcium above 2 mmol/L.

Correction of acidosis

Sodium bicarbonate should be administered to patients with severe acidosis provided they have adequate ventilation (either spontaneous or mechanical ventilation). To rapidly change blood pH, use:

sodium bicarbonate 8.4% (= 1 mmol/mL) 1 to 2 mmol/kg IV boluses every 3 to 5 minutes, titrated to a narrowing of the QRS complex or resolution of arrhythmias.

Bicarbonate infusions are not appropriate because the body will buffer the change. Repeat boluses may be required over a period of four to six hours.

Monitoring and disposition

Criteria for discharge: All patients ingesting slow-release formulations must be observed for 24 hours. If no clinical or ECG effects develop they can be discharged.

Criteria for admission: All patients who have ingested more than twice the daily dose or who have evidence of toxicity must be admitted to a critical care unit for close observation.

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