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Cardiovascular drugs


Essentials

  • 1

    Calcium channel blockers, β-blockers, digoxin and sodium channel blocker poisonings are associated with potentially life-threatening toxicity.

  • 2

    The key to the management of calcium channel blocker and β-blocker toxicity rests with aggressive supportive care of the circulation including early use of hyperinsulinaemia euglycaemic therapy.

  • 3

    The onset of toxicity following overdose with slow-release formulations of calcium channel blockers may be delayed.

  • 4

    Early aggressive decontamination with whole-bowel irrigation is important in the management of slow-release calcium channel blocker overdose.

  • 5

    The key to management of sodium channel blockers is sodium bicarbonate therapy and hyperventilation.

  • 6

    Early identification of patients presenting with potentially severe digoxin toxicity and appropriate use of the specific Fab fragment antibody is lifesaving.

  • 7

    The management of clonidine poisoning is largely supportive.

  • 8

    Intravenous lipid emulsion therapy should be reserved for the treatment of severe local anaesthetic toxicity. It is not standard treatment in other overdoses.

Calcium Channel Blockers and β-Blockers

Introduction

In overdose, calcium channel blockers (CCBs) and β-blockers present with similar clinical pictures of potentially life-threatening impairment of cardiac function. The management of both types of overdose is similar and they are discussed together.

Pharmacokinetics

Standard CCB preparations are rapidly absorbed from the gastrointestinal tract, with onset of action occurring within 30 minutes. Pharmacokinetic parameters are shown in Table 25.2.1 . Verapamil and diltiazem undergo significant first-pass hepatic clearance. Verapamil is metabolized to norverapamil, which possesses 15% to 20% of verapamil’s pharmacological activity and is renally excreted. Diltiazem is metabolized to deacetyldiltiazem, which has half the potency of the parent compound and undergoes biliary excretion. The elimination half-lives of all CCBs may be prolonged following massive overdose. Amlodipine has a longer plasma half-life (30 to 50 hours) than other CCBs.

Table 25.2.1
Pharmacological profiles of the calcium channel blockers
Modified from Kerns W II, Kline J, Ford MD. β-Blocker and calcium channel blocker toxicity. Emerg Med Clin N Am . 1994;12:365–389.
Class Phenylalkylamines Benzothiazepines Dihydropyridines
Prototype Verapamil Diltiazem Nifedipine
Hours to peak plasma concentration (NR/SR) 1.5/5–7 2.3/5–11 0.5/5
Half-life (h) 3–7/10–12 3–5/6–7 2–5/5–7
Half-life in massive overdose (h) 10–12 8–9 7–8
Absorption (%) >90 >90 >90
V d (L/kg) 4 5 1.2
Protein binding (%) 90 80–90 90
Predominant excretion route (1) Hepatic (2) Renal Hepatic Renal
Active metabolite Yes (20%) Yes (25%–50%) No
Heart rate (%) –10 –15 +10
Systemic vascular resistance (%) –10 –10 –20
Atrioventricular node conduction velocity (%) –20 –25 +10
NR , Normal release; SR , slow release.

Importantly, slow-release preparations of both verapamil and diltiazem are associated with much longer times to peak plasma concentration and clinical effect. Absorption of β-blockers is rapid, with peak clinical effects occurring within 1 to 4 hours. Pharmacokinetic parameters of the principal β-blockers are detailed in Table 25.2.2 . Agents with high lipid solubility, such as propranolol, penetrate the blood–brain barrier better than the water-soluble agents and hence cause greater central nervous system (CNS) toxicity.

Table 25.2.2
Pharmacological profiles of the β-blockers
Modified from Kerns W II, Kline J, Ford MD. β-Blocker and calcium channel blocker toxicity. Emerg Med Clin N Am . 1994;12:365–389.
Agent β 1 Selective Membrane stabilization Absorption (%) Protein binding (%) Volume of distribution (L/kg) Elimination/half-life (h) Lipophilic
Atenolol Yes No 50 <5 0.6–1.1 Renal/6–9 Weak
Carvedilol No Yes 25 98 2 Hepatic/6 Weak
Esmolol Yes No NA 55 3.4 Blood esterase 9 min Weak
Labetalol No No 90 50 5.1–9.4 Hepatic/3–4 Weak
Metoprolol Yes No 90 12 5.6 Hepatic/3–4 Moderate
Oxyprenolol No Yes 90 80 1.2 Hepatic/2–3 Moderate
Pindolol No Yes 90 57 1.2–2 Renal/3–4 Moderate
Propranolol No Yes 90 93 3.4–6 Hepatic/3–4 High
Sotalol No No 70 0 0.23–0.7 Renal/9–10 Weak
Timolol No No 90 10 1.3–3.6 Renal/4–5 Weak

Pathophysiology

CCBs antagonize the entry of extracellular calcium into cardiac and smooth muscle, but not skeletal muscle. Upon entry into cells, calcium participates in mechanical, electrical and biochemical reactions. It is involved in excitation–contraction of cardiac and smooth muscles, as well as phase 0 depolarization in the sinus and atrioventricular (AV) nodes by calcium influx through channels. CCBs affect myocardial contractility and slow conduction through the sinus and AV nodes. Contraction of smooth muscle is mediated by calcium influx, which is inhibited by CCBs. This results in vasodilatation and secondary reflex tachycardia from an increase in sympathetic activity.

Verapamil, a phenylalkylamine, produces more profound cardiac conduction defects and equal reductions in systemic vascular resistance when compared with other CCBs on a mg/kg basis. Verapamil is more likely to produce symptomatic decreases in blood pressure, heart rate and cardiac output than diltiazem, a benzothiazepine. The dihydropyridines, which include amlodipine, felodipine, lercanidipine, nifedipine and nimodipine, preferentially bind to vascular smooth muscle and predominantly decrease systemic and coronary vascular resistance.

β-Blockers prevent the binding of catecholamines to β-receptors (β 1 , β 2 ). β 1 -Receptors are located in the myocardium, kidney and eye and β 2 -receptors in adipose tissue, pancreas, liver and both smooth and skeletal muscle.

Blockade of β-receptors results in blunting of the metabolic, chronotropic and inotropic effects of catecholamines. Some β-blockers, especially propranolol, may also impede sodium entry via myocardial fast inward sodium channels, thus slowing phase 0 of the action potential. This results in a prolonged QRS duration on the electrocardiogram and produces cardiotoxicity in overdose similar to that of the tricyclic antidepressants.

The different β-blockers have slightly differing pharmacological properties, including selectivity for β-adrenoreceptors, intrinsic sympathomimetic activity and membrane-stabilizing activity. The relative affinity for β-adrenoreceptors may influence expression of toxicity. Atenolol, esmolol and metoprolol are β 1 -selective agents and therapeutic use of these drugs is less likely to produce the peripheral vasoconstriction, bronchospasm and disturbances in glucose homoeostasis that result from β 2 inhibition. However, pharmacological specificity decreases with increasing dose.

Clinical features

Calcium channel blockers

The severity of toxicity is determined by a number of factors, including the amount and characteristics of the drug ingested, the underlying health of the patient, co-ingestants and delay until treatment. The majority of serious cases and deaths result from the ingestion of verapamil or diltiazem, the most toxic of the CCBs. Ingestion of as few as 10 tablets of the higher dose formulation of verapamil or diltiazem can cause severe toxicity. Elderly patients and those with congestive cardiac failure may develop toxicity with ingestions of two to three times their normal daily dose. The principal clinical features are shown in Box 25.2.1 . Ingestion of toxic amounts of standard preparations typically produces symptoms within 2 hours, although maximal toxicity may not occur for up to 6 to 8 hours. The slow-release preparations can produce significant toxicity with onset of symptoms more than 6 hours postingestion. The major threats to life are myocardial depression and hypotension.

Box 25.2.1
Clinical features of calcium channel blocker overdose
AV, Atrioventricular.

  • Central nervous system

    • Lethargy, slurred speech, confusion, coma

    • Respiratory arrest

    • Coma

  • Gastrointestinal

    • Nausea, vomiting

  • Cardiovascular

    • Hypotension

    • Bradycardia and other arrhythmias

    • Sinus bradycardia

    • Accelerated AV nodal rhythm

    • 2° AV block

    • 3° AV block with AV nodal or ventricular escape rhythm

    • Sinus arrest with AV nodal escape rhythm

    • Asystole

  • Metabolic

    • Hyperglycaemia

    • Lactic acidosis

Overdose of Dihydropyridines (DHPs) often produces tachycardia with normal blood pressure during the first 30 minutes, followed later by hypotension and bradycardia in large ingestions. Even though amlodipine has been reported to be less toxic than verapamil and diltiazem, it can cause severe shock in large overdoses. Vasoplegic shock is frequently observed in mixed overdoses of dihydropyridine (e.g. amlodipine) and angiotensin antagonists such as angiotensin receptor blockers or angiotensin converting enzymes inhibitors, possibly from a synergistic effect on peripheral vasodilatation. All CCBs can cause symptoms of cerebral hypoperfusion, such as syncope, lethargy, light-headedness, dizziness, altered mental status, seizures and coma.

β-Blockers

In one large series of patients with β-blocker overdose, 30% to 40% of patients remained asymptomatic and only 20% developed severe toxicity. Most of the life-threatening presentations or deaths that have been reported in the literature are due to overdoses of propranolol (>1.5 g) or sototol. Significant toxicity is also more likely to develop in patients with pre-existing cardiac disease or where there is co-ingestion of other drugs with effects on the cardiovascular system, especially CCBs and cyclic antidepressants. If β-blocker toxicity is to develop, it is usually observed within 6 hours of ingestion.

Sinus node suppression, conduction abnormalities and decreased contractility are typical. First-degree AV block, AV dissociation, right bundle branch block and intraventricular conduction delay have been reported.

Propranolol in overdose has a sodium channel blocking effect that is characterized by cardiotoxicity including prolongation of the QRS interval and ventricular arrhythmias that more closely resemble tricyclic antidepressant overdose. Sotalol has both β-blocker activity and class 3 antiarrhythmic properties. Class 3 drugs lengthen the duration of the QT interval owing to prolongation of the action potential in His–Purkinje tissue. Therefore ventricular arrhythmias, such as torsades de pointes, are more common with sotalol.

Hypotension occurs as a result of negative inotropic effect. In addition, CNS effects, such as depressed conscious level and seizures, can occur, especially with the more lipid-soluble and membrane-depressant agents, such as propranolol.

Clinical investigation

The ECG is essential in evaluating and monitoring toxic conduction defects. Serum drug levels are unhelpful. Patients with severe toxicity require monitoring of serum electrolytes and glucose. Serum calcium must be closely monitored if calcium salts are administered therapeutically.

Treatment

The primary aim in both β-blocker and CCB toxicity is to restore perfusion to vital organs by increasing cardiac output and the methods used are similar. Supportive management may include airway and ventilatory support, intravenous fluid administration, early implementation of hyperinsulinaemia euglycaemic therapy and administration of inotropes. Transcutaneous or transvenous pacing may be tried in cases with profound bradycardia, but often is of limited benefit. Severe cases may require invasive blood pressure monitor, cardiac output studies to measure cardiac index and peripheral vascular resistance using pulse-induced contour cardiac output (PiCCO) monitor.

If safe to do so, oral-activated charcoal should be administered as soon as practicable to all those presenting after ingestion of CCB or β-blocker ingestions. More aggressive decontamination, with whole-bowel irrigation, is indicated following overdose with slow-release CCBs.

A number of drugs play a role in the management of significant CCB or β-blocker poisoning, although none is a completely effective antidote. Suggested doses are shown in Table 25.2.3 . Calcium, an inotropic agent, is the initial drug of choice for CCB toxicity and has also been used successfully for β-blocker poisoning. Administration must be closely monitored, with ionized calcium measured 30 minutes after commencing the infusion and then second-hourly. Catecholamines are useful in attempting to restore adequate tissue perfusion.

Table 25.2.3
Useful drugs in the management of calcium channel blocker and β-blocker toxicity
CCBs β-Blockers
Calcium 28 Calcium gluconate 10% 30 mL (child 0.6 mL/kg) IV over 10 min. OR calcium chloride 10% 10 mL (child 0.2 mL/kg) IV over 10 min. Repeat every 5 min as required. Further administration guided by serum calcium concentrations.
Catecholamines Adrenaline (epinephrine) infusion started at 1 μg/kg/min and titrate to maintain organ perfusion. Isoprenaline or adrenaline (epinephrine) infusion titrated to maintain organ perfusion.
Sodium bicarbonate for propranolol poisoning A bolus dose of sodium bicarbonate 8.4% 1–2 mmol/kg, every 3–5 min, 3 doses should see a narrowing of the QRS complex, resolution of arrhythmias. Repeat only if there is a response and recurrence of arrhythmias.
Hyperinsulinaemia euglycaemia Actrapid 1 units/kg IV bolus followed by an infusion starting at 1 units/kg/h. Give with 50% dextrose 50 mL followed by infusion to maintain euglycaemia. Actrapid 1 units/kg IV bolus followed by an infusion commencing at 1 units/kg/h. Give with 50% dextrose 50 mL followed by infusion to maintain euglycaemia.
CCB, Calcium channel blocker.

Hyperinsulinaemic euglycaemia therapy (HIET) is increasingly advocated as therapy for hypotension unresponsive to fluids and calcium salts, with many toxicologists using HIET early in the management of these poisonings when inotropes are being considered. This therapy is supported by animal work and multiple human case reports, but a randomized controlled trial is lacking. Insulin administration switches cardiac cell metabolism from fatty acids to carbohydrates. It restores calcium fluxes and improves myocardial contractility. The recommended initial dose of Actrapid is 1 units/kg IV followed by an infusion commencing at 1 units/kg/h, titrated against clinical response. In a case series of patients treated with HIET for β-blockers or CCB poisoning, the median loading dose and infusion rate were 80 and 150 units/h respectively, with a median glucose requirement of 37.5 g/h. Despite treatment, hypokalaemia and severe hypoglycaemia (<2.5 mmol/L) occurred in 80% and 41% of the patients, respectively. The duration of glucose requirement was found to be proportional to the rate and total dose of insulin administration. However, the optimal dose of insulin is still to be determined.

There are no clinical trials supporting glucagon’s efficacy in either calcium channel or β-blocker poisoning. Due to the significant doses often required, it is frequently difficult to source adequate stocks of glucagon for use as an inotropic agent. As such, its use in the treatment of calcium channel or β-blocker poisoning is not routinely recommended.

Severe propranolol toxicity is due to a combination of β-receptor and sodium channel blockade. Treatment includes intubation, ventilation, inotropic and sodium bicarbonate therapy. There are no clinically effective methods of enhancing the elimination of CCBs or β-blockers. When all else fails, extracorporeal life support has been shown to allow organ perfusion until reversal of cardiac dysfunction and elimination of the drugs.

Disposition

Following overdose of β-blockers or standard CCBs, patients should be observed in a monitored environment for at least 6 hours. Overdoses of slow-release CCBs require monitoring for at least 16 hours from the time of ingestion. All symptomatic patients should be admitted to a monitored environment until toxicity resolves.

Digoxin

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