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Calcium channel blockers
DRUGS INCLUDED
There are three types of calcium antagonists in common use. These three types are from three distinct chemical classes.
- The phenyl alkylamines, e.g. verapamil
- The benzothiazepines, e.g. diltiazem
- The dihydropyridine derivatives, e.g. nifedipine, felodipine, nimodipine, nicardipine, amlodipine, lercanidipine
OVERVIEW
Self-poisoning from calcium channel blockers (CCBs) is the most common cause of in-hospital death from self-poisonings in Australia (Buckley et al 1995). Morbidity and mortality is generally due to cardiovascular collapse resulting from a combination of extreme peripheral vasodilatation, myocardial depression and impaired myocardial conduction. Extra-cardiac toxicity such as hyperglycaemia, lactic acidosis, seizures, and non-cardiogenic pulmonary oedema are less common but imply a poorer prognosis.
Sustained release preparations are available and produce both delayed and prolonged toxicity.
Individuals vary considerably in their response to CCBs dependent on underlying diseases and other medication. However, doses only 2-3 times the normal dose may cause profound toxicity in susceptible individuals.
MECHANISM OF TOXICITY
All act by preventing the opening of voltage-gated calcium channels (the L type). The major actions are vasodilatation (inhibiting contraction of vascular smooth muscle) and block of cardiac conduction, particularly the SA and AV nodes where there are no sodium gated channels and conduction is totally dependent on calcium flux.
Binding of the various calcium antagonists to these channels may be both use dependent and voltage dependent.
At therapeutic doses nifedipine and other CCBs of the dihydropyridine class are predominately peripheral vasodilators with little direct cardiac effect. Both verapamil and, to a lesser extent, diltiazem have direct cardiac effects in addition to peripheral vasodilatation. The direct cardiac effects include decreased sinus node activity, AV conduction and myocardial contractility.
KINETICS IN OVERDOSE
Absorption
All calcium antagonists are rapidly absorbed from the small intestine. Peak concentrations of standard formulations of these drugs occur in therapeutic use within 1-2 hours. Peak concentrations can be delayed in overdose to up to 6 hours for standard preparation and 22 hours for controlled release. All of these drugs have a significant first pass effect with bioavailability being as low as 10 - 40% for verapamil and diltiazem. Increased bioavailability has been demonstrated for some CCBs in overdose suggesting that the first pass effect is saturable.
Verapamil has two enantiomers with different kinetics and activity. The S isomer is more active but has a shorter half-life and lower bioavailability than the R isomer. The higher proportion of S isomer that is available is the major reason why IV verapamil has more cardiac effects for a given serum concentration than oral verapamil.
Distribution
All CCBs have large volumes of distribution and moderate CNS penetration. The free fraction of verapamil may increase in overdose.
Metabolism - Elimination
All CCBs are metabolised in the liver to less active or inactive metabolites.
The half-life of nifedipine, verapamil and diltiazem in therapeutic use is short (3-8 hours). Newer dihydropyridine drugs have considerably longer half-lives. The apparent half-life of many CCB appears to be longer following overdose but is generally thought to reflect a rate limited absorption.
There may be significant
enterohepatic circulation.
Controlled release medication
Due to their short half-lives, the older CCBs (verapamil, diltiazem, and nifedipine) are frequently sold in controlled release preparations. The kinetics of drugs in these preparations are quite different and alter in overdose. Peak levels of verapamil were seen at 22 hours following ingestion of 2.3 grams of a sustained release preparation with the onset of toxic effects of being delayed until 16 hours after ingestion. Further delays in absorption can occur with the formation of pharmacobezoars of sustained-release preparations. This also alters the clinical presentation (i.e. causes delayed presentation and toxicity) and the optimal method of
gastrointestinal decontamination.
See also
controlled release drugs in overdose.
CLINICAL EFFECTS
Cardiac effects
Hypotension, due to a combination of vasodilatation (relative volume depletion), heart block and myocardial depression develops over the first few hours if a standard preparation has been ingested or may be delayed in onset for up to 24 hours if a controlled release preparation has been ingested. Both cardiac and non-cardiogenic pulmonary oedema are reported. Non-cardiogenic pulmonary oedema can occur relatively late at a time when other cardiac parameters are improving. Intractable hypotension and/or asystole is the usual mode of death.
Increasing heart block typically occurs in a sequence from sinus bradycardia to 1st degree heart block to junctional bradycardia (with absent P waves) to a slow idioventricular rhythm to asystole. This may occur with any CCB but higher degrees of block are much more common with verapamil and diltiazem.
Gastrointestinal effects
Nausea and vomiting are common. The effect of CCBs on the gut can lead to an ileus, which may significantly interfere with
gastrointestinal decontamination of controlled release preparations.
Other effects are rarely life threatening but include hyperglycaemia, lactic acidosis, bowel ischaemia and seizures. These are less common and occur only in poisonings with significant cardiac effects. Hyperglycaemia and metabolic acidosis both require active treatment.
Late presentation
This is most likely to occur with sustained release preparations and the clinical effects will be similar. If the patient is asymptomatic, and more than 24 hours have elapsed, then no treatment is indicated. In all other circumstances, the treatment, including gastrointestinal decontamination, should be done as usual.
INVESTIGATIONS
Arterial blood gases and venous blood for electroytes, renal function, calcium and blood glucose should be taken. Renal impairment may be associated with the accumulation of active metabolites of verapamil and diltiazem.
Blood concentrations
These are unhelpful in management. A
digoxin level should be taken if there is any history of digoxin ingestion.
ECG
Repeated measures of the ECG, with continuous monitoring if available, serves as a measure of severity and is the best guide to the need for specific treatment.
DIFFERENTIAL DIAGNOSIS
There are a number of drugs that can lead to a patient presenting with profound hypotension and bradycardia. Correct diagnosis is important as these drugs have different specific treatments.
DIFFERENCES IN TOXICITY WITH IN THIS DRUG CLASS
In therapeutic use, verapamil is relatively cardioselective with more significant effects on cardiac conduction while the dihydropyridines are predominantly selective for smooth muscle and lead primarily to peripheral vasodilatation. Diltiazem's effects lie between these two groups.
In overdose all these drugs have both cardiac and vasodilating actions. However the cardiac effects of verapamil and diltiazem appear to be generally more profound and few deaths have been reported from dihydropyridine overdose alone.
DETERMINATION OF SEVERITY
Prognosis correlates best with the degree of heart block. Hypotension due to vasodilatation without heart block usual responds to fluid loading and is rarely life threatening. Other factors that increase the severity of the overdose are
- patients with underlying heart disease
- late presentation/ineffective gastrointestinal decontamination
- coingestion/regular treatment with beta blockers or digoxin (antidotes to these drugs may also be considered in this case)
- old age
TREATMENT
For a summary of management see
management of serious calcium channel blocker overdose in adults.
Supportive
IV access with
IV fluids (normal saline) should be secured as soon as possible.
Most patients who have hypotension without any evidence of conduction defect respond to volume expansion and should receive a bolus of normal saline (10-20 mL/kg). Patients whose blood pressure does not respond to such a fluid challenge should have central venous pressure monitoring.
ECG monitoring in intensive care is indicated for all but the most trivial poisonings.
GI Decontamination
Gastric lavage should be considered in sustained release verapamil or diltiazem poisonings and patients presenting within an hour of ingestion. Atropine should be given prior to lavage and in any patient who is vomiting. The aim is to prevent worsening
bradycardia due to enhanced vagal tone associated with nausea and gastrointestinal decontamination.
Oral activated charcoal should be given to all patients ingesting any overdose of a CCB. This should be followed by
repeated doses of activated charcoal, particularly in verapamil poisoning (though controlled clinical trial data supporting this approach are lacking).
Patients who have taken sustained release preparations require whole bowel irrigation.
Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is important in overdose with vasodilating drugs.
Antidotes
The following large number of drugs/treatments have been claimed to act as antidotes for CCB poisoning.
Many of these are supported only by occasional case reports. Critical reviews support calcium as first line treatment. Acidosis should be corrected.
Atropine, inotropes,
insulin-dextrose euglycaemia, and
glucagon are probably the best adjunctive treatments.
Bicarbonate
Acidosis should be corrected to a pH within the normal range. L channel function is impaired when the pH falls outside the physiological range. Acidosis enhances the effect of verapamil and decreases the effect of calcium. Sodium bicarbonate significantly improved myocardial contractility and cardiac output in a swine model of verapamil poisoning.
Calcium loading
This is the most logical and appears to be the most effective treatment in CCB poisoning. It is primarily indicated in patients with heart block (who have usually taken verapamil or diltiazem).
The initial dose for treatment of CCB toxicity in adults is 10% calcium chloride, 5–10 mL, or calcium gluconate solution, 10–20 mL. The dose in children is 10% calcium chloride, 0.2 mL/kg, or 10% calcium gluconate, 0.7 mL/kg. Calcium chloride should be infused at a rate no faster than 1–2 mL/minute, with the patient on a monitor. The initial dose can be followed by further doses every 3–5 minutes if there is no response in blood pressure or pulse rate. Large doses may be required (up to 10 g as initial treatment and 30 g in total have been used successfully without evidence of calcium toxicity).
If there is an initial response to calcium, a continuous infusion may be warranted; this may be given as 10% calcium chloride, 1–10 mL/hour. Serum calcium should be measured, but note that hypercalcaemia is the aim of treatment. A doubling of serum calcium was associated with significant haemodynamic improvement in animals and in humans. An ionised serum calcium of 2 mmol/L was effective in severe nifedipine toxicity and has been suggested as a target concentration.
The treatment of hypotension without heart block should not usually require calcium or any cardioactive medication. It is possible that calcium will be cardiotoxic in patients in this situation (particularly those who have ingested dihydropyridines (e.g. nifedipine)) and may induce ventricular arrhythmias. Hypotension alone should initially be treated with volume expansion and pressor agents.
Glucagon
Glucagon is a well-accepted antidote for beta-blocker poisoning. The rationale for its use in CCB poisoning is that it activates myosin kinase independent of calcium flux. Clinical experience suggests it is less effective than in beta-blocker poisoning. Typically, a 5–10 mg intravenous bolus followed by the same amount as an hourly infusion may reverse hypotension and bradycardia in some CCB overdoses. The solvent provided in some glucagon injection kits should not be used when reconstituting glucagon for use at these doses, because it may be toxic; use water for injection instead.
Insulin-dextrose euglycaemia
Insulin-dextrose euglycaemia appears to be a very promising technique that has been more effective in animal models than calcium, epinephrine or glucagon. Efficacy has been demonstrated in a case series of clinically serious poisonings. Insulin infusions should be used to treat hyperglycaemia or hyperkalaemia. Patients with hypotension that is refractory to volume loading, correction of acidosis and calcium salts should receive insulin-dextrose euglycaemia.
Atropine
Atropine should be tried in all patients with bradycardia. The aim is to reverse enhanced vagal tone associated with nausea and gastrointestinal decontamination. A response may only occur after calcium loading.
Inotropic agents
Dopamine is an initial pressor of choice for diltiazem overdose (75% response), it should be used in high doses (10-20 microgram/kg/min). Isoproterenol produces a therapeutic response in 50% of patients. These agents are often ineffective as a chronotropic agent when there is a high degree of conduction block as their action is predominantly through increasing the frequency of impulses originating in the SA node.
Cardiac pacing
Cardiac pacing can be done to increase heart rate. Ventricular rather than atrial pacing should be performed as the AV node is usually blocked. However, in severe poisoning the heart may fail to capture and therefore this is not a substitute for pharmacological therapy.
Calcium channel agonist (eg Bay K 8644)
This is a logical antidote but it is not commercially available or licensed for use in humans for any indication. Animal studies using calcium channel agonists have not been very promising.
Elimination enhancement
High biliary concentrations of verapamil have been found following overdose. However, multiple dose activated charcoal (although theoretically attractive) has not been demonstrated to enhance elimination.
LATE COMPLICATIONS, PROGNOSIS -FOOW UP
Late complications/deterioration have been reported with controlled release preparations of verapamil and diltiazem. These may occur as late as 24 hours in asymptomatic patients and life threatening cardiovascular collapse and death can occur as late as two to three days post ingestion (in patients who were symptomatic within 24 hours).
REFERENCES
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Buckley NA, Dawson AH, Whyte IM, McManus P & Ferguson N. Six years of self-poisoning in Newcastle: 1987-1992. Med J Aust 1995;162:190-193.
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