European Review for Medical and Pharmacological Sciences 2005; 9: 241-246 Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room V. OJETTI, A. MIGNECO, F. BONONI, A. DE LORENZO*, N. GENTILONI SILVERI Department of Emergency Medicine, Catholic University – Rome (Italy) *Human Nutrition Unit, University of Tor Vergata – Rome (Italy) Abstract. – Calcium channel blockers and fect are similar. In fact, CCB interfere with beta-blockers intoxications account for up to calcium cell influx blocking “L” type voltage 65% of deaths for cardiovascular drugs, causing dependent channels3, whereas BB lower in- severe clinical symptoms refractory to standard tracellular cyclic AMP and thereby reduce in- medications. The most serious poisonings are 4 those resulting from verapamil and propanolol tracellular calcium contents (Figure 1). Since ingestion. Both support and antidotic therapy intracellular calcium plays a key role in car- are necessary for these potentially unstable pa- diac automaticity, conductivity and contractil- tients. Supportive measures and the use of ity, intoxication from these drugs leads to an digoxin-specific antibody fragments are first line inhibition of sinus and atrio-ventricular (AV) treatment for digitalis glycoside poisoning. node depolarization and to a depression of Key Words: myocardial cell contractility5. Calcium channel blockers, Beta-blockers, Digitalis, Clinically patients with CCB or BB poison- Glucagon, Digoxin-specific antibody fragments, Sup- ing present profound bradycardia, possible port therapy, Antidotes. AV block, severe ventricular dysfunction leading to acute impairment of cardiac output and cardiac arrest1. Introduction Effects of CCB and BB differ as regards the peripheral vessels. CCB determine va- sodilation by lowering smooth muscle intra- Calcium channel blockers (CCB) and beta- 6 blockers (BB) intoxications represent 40% of cellular calcium content , whereas most BB the pharmacological poisoning cases in the USA cause vasoconstriction diverting cate- and account for 65% of deaths determined by cholamines on constricting alfa adrenocep- cardiovascular drugs1. Treatment is often diffi- tors. cult because of the unresponsiveness to standard However differences exist also among the supportive medications. The therapeutic ap- various classes of CCB. Benzothiazepines proach for digitalis glycoside poisoning has been (diltiazem) and especially phenilalchil- radically modified since the introduction of amines (verapamil) intoxications cause a digoxin-specific antibody fragments (Fab)2. The more severe clinical picture, characterized knowledge of the pharmacokinetic and pharma- by profound bradycardia, conduction distur- codynamic properties of these compounds is bance (sinus arrest, asystole, AV block), va- pivotal for a rational choice of supportive and sodilation and hypotension7. Poisoning by antidotal therapy in the treatment of these po- derivates of dihydropyridine (nifedipine, tential unstable and critical ill patients. amlodipine, felopidine) is characterized particularly by vasodilatation, while con- tractility, conductivity and chronotropicity Calcium Channel Blocker and remain relatively undisturbed because these Beta Blocker Intoxication drugs show a high vessel selectivity8. Some patients show even sinus tachycardia be- Although CCB and BB have different cause of sympathetic overdrive secondary to mechanisms of action, their cardiovascular ef- vasodilation1. 241 V. Ojetti, A. Migneco, F. Bononi, A. De Lorenzo, N. Gentiloni Silveri CCB toxicity presents often with hypergly- caemia because of insulin secretion impair- Ca++ Calcium channel ment and peripheral enhanced insulin-resis- tance, worsening thereby metabolic acidosis secondary to cardiovascular shock9. ENOXIMONE As regards BB, sotalol overdose, in addi- – Activation tion to bradycardia and hypotension, can cause torsade de pointes10, while lipophilic Phosphodiesterase BB (metoprolol, carvedilol, timolol and in Metabolites Cyclic particular propanolol), easily pass through AMP ATP the blood-brain barrier causing delirium, seizures and coma11. Exposure to a BB with membrane stabilizing activity (propanolol, GLUCAGON acebutolol, metoprolol and labetalol) is as- Activated sociated with an QRS interval prolongation + Adenilate cyclase and an increased risk of cardiovascular mor- Adenilate cyclase bidity12. Clinical symptoms of BB intoxication arise generally within 6 hours after ingestion, un- less the patients ingested slow-release prepa- rations12. Beta adrenoceptor Supportive Therapy Catecholamines Figure 1. Mechanisms of action of glucagon and enox- Patients with suspected CCB or BB intoxi- imone. cation should be immediately referred to an emergency department regardless of the in- gested dose13. Ambulance transportation is Unfortunately, these measures are often in- recommended because of potential life sufficient to restore hemodynamic stability and threatening complications13. in most serious cases transthoracic or transve- Supportive treatment of CCB and BB nous temporary cardiac pacing is necessary15. poisoning is nearly identical. Initial treat- Cristalloids and vasopressors (isopro- ment includes vital parameters monitoring, terenol, dopamine, dobutamine, epinephrine airways management, ventilatory and circu- and norepinephrine) are first line treatment latory support, if needed14. Even apparently for hypotension and shock16,17. stable patients can rapidly develop fatal ar- rhythmias and cardiac arrest during treat- ment. A 12 leads ECG, blood drawings for renal Decontamination and liver function, determination of gly- caemia, electrolytes and blood gases should Gut decontamination procedures with gas- be performed. tric lavage should be performed within 1-2 An intravenous access for fluid resuscita- hours after drug ingestion18,19. Repeated acti- tion and drug administration should be im- vated charcoal administrations (0.5-1 g/kg mediately placed. every 2-4 h for 48-72 h) are useful because Sinus bradycardia, AV block and cardiac CCB and BB have a prevalent liver metabo- arrest should be treated according to the ad- lism with recycling in the bowel19. Hemodialy- vanced life support algorithmsl4. In particular sis and hemoperfusion techniques cannot be boluses of atropine 0.5 mg, repeated if need- used for CCB because of their high volume ed up to 3 mg, associated with adrenalin ev 2- distribution and their lipophilic properties7. 10 microg/min are commonly used for brad- These techniques are beneficial for some BB yarrhythmias. (atenolol, sotalol, nadolol, acebutolol)19,20. 242 Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room Antidotal treatment proves to be a more effective drug than calci- um compounds in this setting, probably act- Glucagon ing as calcium channel “opener”28. The effec- Glucagon is usually accepted as first line tiveness of verapamil poisoning treatment treatment in the management of BB and ver- could be further improved administering the apamil overdose21. Glucagon is secreted by calcium preparation prior to adrenaline29. the alfa pancreatic cells and is able to en- hance adenylate cyclase activity, increasing Sodium Bicarbonate intracellular cyclic AMP levels (Figure 1) and Administration of sodium bicarbonate in calcium influx, inducing a chronotropic and membrane stabilizing drug intoxications inotropic response22. Initial dosage is 5-10 mg (propanolol, metoprolol, acebutolol and la- ev (150 microg/kg) in rapid bolus. The effect betalol) may be helpful in increasing intracel- is evident after 1-3 min reaching a peak in 5-7 lular sodium content, antagonizing thereby min and ending after 10-15 min. Repeated cardiac toxicity30. boluses every 10 min or a continuous infusion at a rate of 2-10 mg/h (50-100 microg/kg/h) New Antidotes may be necessary23. Side effects of glucagon New antidotes for verapamil poisoning, administration are nausea, vomiting, hyper- like 4 aminopyridine, a potassium channel in- glycaemia, hypocalcemia24. hibitor, and Bay K 8644, a calcium channel activator, have been extensively studied in Phosphodiesterase Inhibitors animal models7. Their introduction in clinical Phosphodiesterase III inhibitors (enoxi- practice may improve the effectiveness of mone) represent possible alternatives to CCB intoxication treatment. glucagon in CCB and BB poisoning, as their Patients must be always admitted in an in- inotropic effect is not mediated by beta tensive care unit. adrenoceptors (Figure 1)25. Asymptomatic patients should be moni- tored for at least 6 h after drug ingestion if Insulin they took a sustained-release preparation and The inotropic effect of insulin has been 12 h if they took sotalol. long established26. In the CCB and BB intoxi- cation insulin has been proposed at high dosages (0.5-1 IU/kg/h) with a continuous glucose infusion to maintain euglycaemia27. Insulin administration in fact switches cell Digoxin Intoxication metabolism from fatty acid to carbohydrates and restores calcium fluxes, improving there- Digoxin and digitoxin are the most impor- by cardiac contractility. tant digitalis glycosides, steroid compounds present in many plants (digitalis purpurea Calcium and lanata, oleander). The pharmacokinetic Treatment of choice in CCB poisoning is properties of digoxin after oral administra- calcium administration1. Repeated boluses of tion are a gastrointestinal absorption of 55- 10 mEq every 10-15 minutes may be given, 75%, a large distribution volume, low plas- but total