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Home , Calcium channel opener, Digoxin

European Review for Medical and Pharmacological Sciences 2005; 9: 241-246 channel blockers, beta-blockers and poisoning: management in the emergency room

V. OJETTI, A. MIGNECO, F. BONONI, A. DE LORENZO*, N. GENTILONI SILVERI

Department of Emergency , Catholic University – Rome (Italy) *Human Nutrition Unit, University of Tor Vergata – Rome (Italy)

Abstract. – 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 , causing dependent channels3, whereas BB lower in- severe clinical symptoms refractory to standard tracellular cyclic AMP and thereby reduce in- . The most serious poisonings are 4 those resulting from 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 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, . 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 () 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 (, tential unstable and critical ill patients. , felopidine) is characterized particularly by vasodilatation, while con- tractility, conductivity and chronotropicity Calcium and remain relatively undisturbed because these 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 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, overdose, in addi- – Activation tion to bradycardia and hypotension, can cause torsade de pointes10, while lipophilic Phosphodiesterase BB (, 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 , 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 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 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 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. (, sotalol, , 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 Bicarbonate intracellular cyclic AMP levels (Figure 1) and Administration of sodium bicarbonate in calcium influx, inducing a 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. of glucagon New antidotes for verapamil poisoning, administration are , vomiting, hyper- like 4 aminopyridine, a 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 are the most impor- by cardiac contractility. tant digitalis , steroid compounds present in many plants ( 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 acute calcium administration should ma link, onset of action in 15-30 not exceed 45 mEq to avoid superimposed minutes, peak effect reached in 90-300 min- hypercalcemia induced arrhythmias7. The ad- utes, an average half life of 36 to 48 hours ministration route should be a central vein to and a predominantly renal excretory path- avoid the risk of skin necrosis. way31. Digitoxin exhibits a higher gastroin- However, in severe verapamil acute poi- testinal absorption (90%), a lower distribu- soning, calcium administration may be less tion volume, onset of action in 25-120 min- effective because calcium channels are totally utes, a peak effect reached in 4 to 12 hours, blocked, and increasing the extracellular cal- an average half life of 4 days and a predomi- cium concentration does not contribute sig- nantly hepatic pathway with en- nificantly to increase the calcium intracellular terohepatic cycle and renal excretion of content. Some studies show that adrenaline metabolites31.

243 V. Ojetti, A. Migneco, F. Bononi, A. De Lorenzo, N. Gentiloni Silveri

Digitalis glycosides inhibit the active trans- (VF)35. Hypokalemia port protein Na+, K+ ATPase, the enzymatic increases the cardiac tissue automaticity equivalent of the sodium pump. Inhibition of during digoxin poisoning while hyper- active Na+ transport results in increased in- kalemia seems to interfere particularly with tracellular Na+ content, which promotes the cardiac conductivity abnormalities31. Hy- transmembrane Na+-Ca++ exchange, resulting percalcemia may worsen the risk of fatal ar- in augmentation of myocyte Ca++ content32). rhythmias. Digitalis induces also an increased Ca++ influx Systemic glycoside poisoning symptoms through sarcolemmal Ca++ channels33. This in- and signs include nausea, vomiting, diar- tracellular Ca++ increase produces a positive rhoea, visual disturbances, disorientation, inotropic response in atrial and ventricular mental confusion and hallucinations34. myocytes. On the other hand, inhibition of the sodium transmembrane transport induces a series of electrophysiological effects rang- ing from decreased sinus automaticity, de- Supportive Therapy creased AV node conduction velocity and a decrease of atrial and ventricular effective re- As for CCB and BB intoxications, digoxin fractory period31. poisoning may lead to fatal ventricular ar- Digitalis glycosides exert also indirect car- rhythmias and cardiac arrest. diac effects through vagal activation, proba- Liver and renal function test, determina- bly enhancing baroceptor sensitivity and tion of electrolytes, blood gases and plasma through central stimulation. The action of level of glycosides and a 12 leads ECG must digoxin on AV conduction and on the AV be performed at the arrival in the Emergency node refractory period, which it prolongs, is Department. primarily dependent on increased vagal tone Monitoring of vital parameters, ventilatory and only to a minor extent on the direct ef- and hemodynamic support and fluid resusci- fect of glycosides31). tation should immediately be undertaken, if Digoxin intoxication can be acute (suicide, necessary. accidental ingestion, contact with plants) or The flow-charts of the advanced life sup- chronic (patients who take accidentally high- port must be applied in cases of cardiac arrest er dose of digoxin or develop renal failure). or life threatening arrhythmias14. In particu- Acute digitalis intoxication is characterized lar, bradycardia and AV block should be by high electric instability and it is associated managed with atropine and transthoracic with high mortality. Acute poisoning be- pacing if necessary, as described before36. comes clinically evident when digoxin plasma Ventricular with signs of cardiac concentration exceeds 2 ng/ml or digitoxin failure should be treated with DC shock. First exceeds 3.5 ng/ml. In chronic intoxications, line pharmacological approach in these cases cardiotoxicity may be evident even when is (50 mg iv in 2 min, every 5 min digoxinemia ranges within therapeutical lim- for VT, 100 mg or 1-1.5 mg/kg in VF or pulse- its2. Symptoms emerge within 12 h after drugs lessness VT)37. Alternative to lidocaine is ingestion, but may be very precocious in se- 100 mg by slow intravenous infu- vere poisoning. sion every 5 min 37. As the glycosides influence every ex- Electrolyte disturbances should be prompt- citable tissue, including gastrointestinal and ly treated as necessary. central nervous systems, poisoning with these compounds may cause cardiac and sys- temic symptoms34. Cardiac toxicity is mainly related to the decrease of potential action Decontamination and the arising of oscillatory afterpotentials, associated with high intracellular calcium Decontamination therapy with cautious levels31. ECG signs of glycoside intoxication gastric lavage should be performed within 1 are extrasystolic bigeminism, junctional ar- hour after drug ingestion; these procedures rhythmias, bradycardia, various degrees of may worsen the bradycardia because of addi- AV block, (VT) and tional vagal stimulation. Activated charcoal

244 Calcium channel blockers, beta-blockers and digitalis poisoning: management in the emergency room should be administered (0.5-1 g/kg every 2-4 Effects of Fab administration are observed h for 48-72h), particularly in cases of digitox- 30-60 minutes after drug administration, with in intoxication. a peak effect reached in 4 hours. Hemodialysis and hemofiltration are not Side effects include hypokalemia and skin useful because of the high plasma protein rash. link of the glycosides.

Antidotal Treatment References The development of digoxin specific anti- 1) DEWITT CR, WAKSMAN JC. , patho- bodies fragments (Fab) has changed the man- physiology and management of calcium channel agement of both digoxin and digitoxin poi- blocker and beta-blocker toxicity. Toxicol Rev soning2. Equimolar doses of anti digoxin Fab 2004; 23: 223-238. fragments completely bind digoxin in vivo. 2) BATEMAN DN. Digoxin-specific antibody fragments: Even if the plasmatic free levels of glycosides how much and when? Toxicol Rev 2004; 23: 135- are very low, Fab administration is associated 143. with rapid improvement of cardiac symp- 3) LUFT FC, HALLER H. Calcium channel blockers in toms, in particular of AV blocks38. In patients current medical practice: an update for 1993 Clin with rapid onset of toxicity symptoms there Exp Hypertens 1993; 15: 1263-1276. are higher levels of free digoxin and digitox- 4) LUBBE WF, PODZUWEIT T, O PIE LH. Potential arrhyth- in, as the tissue distribution will not have yet mogenic role of cyclic monophosphate (AMP) and cytosolic calcium overload: implica- occurred, and Fab administration is particu- tions for prophylactic effects of beta-blockers in larly useful. myocardial infarction and proarrhythmic effects of Indications for Fab administration include phosphodiesterase inhibitors. J Am Coll Cardiol severe arrhythmias, symptomatic bradycar- 1992; 19: 1622-1633 dia, AV blocks with and digox- 5) LOVE JN, LITOVITZ TL, HOWELL JM, CLANCY CJ. Char- in levels over 10 ng/ml or digitoxin levels over acterization of fatal beta blocker ingestion: a re- 25 ng/ml39. view of the American Association of Poison Con- trol Centers data from 1985 to 1995.Toxicol Clin The approximate dose of Fab in mg is 60 Toxicol 1997; 35: 353-359. times the digoxin body burden in mg40. Practically, the amount of Fab to adminis- 6) GROSSMAN E, MESSERLI FH. Calcium antagonists Prog Cardiovasc Dis 2004; 47: 34-57. trate may be calculated from glycoside plasma concentration according to the following for- 7) MAGDALAN J. New treatment methods in verapamil × poisoning: experimental studies. Pol J Pharmacol mula: plasmatic concentration (ng/ml) 2003; 55: 425-432. 0.0056 for digoxin, 0.00056 for digitoxin (con- × 8) LUSCHER TF, COSENTINO F. The classification of calci- version factor for distribution volume in mg) um antagonists and their selection in the treat- weight in kg = total digoxin or digitoxin ment of hypertension. A reappraisal Drugs 1998; amount in the body × 60; (for instance: digoxin 55: 509-517. plasmatic levels of 20, in a patient weighting 70 9) ENYEART JJ, PRICE WA, HOFFMAN DA, WOODS L. Pro- kg: 20 × 0.0056 × 70 = 7.84 mg × 60 = 480 mg). found hyperglycemia and metabolic acidosis after If plasmatic glycosides levels are not avail- verapamil overdose. J Am Coll Cardiol 1983; 2: able, the following formula may be used: 1228-1231. ingested dose in mg × 0.80 (absorption con- 10) ASSIMES TL, MALCOLM I. Torsade de pointes with so- version factor) × 0.60. talol overdose treated successfully with lidocaine. If the ingested amount of glycosides is un- Can J Cardiol 1998; 14:753-6. known, 380 mg of Fab should be adminis- 11) REITH DM, DAWSON AH, EPID D, WHYTE IM, BUCKLEY tered. If the clinical picture does not improve, NA, SAYER GP. Relative toxicity of beta blockers in 40 overdose. J Toxicol Clin Toxicol 1996; 34: 273- administration should be repeated . 278. Fab are given intravenously over 15-30 12) LOVE JN, HOWELL JM, LITOVITZ TL, KLEIN-SCHWARTZ W. min after dilution to at least 250 ml with Acute beta-blocker overdose: factors associated plasma protein solution or 0.9 sodium chlo- with the development of cardiovascular morbidity. ride solution. J Toxicol Clin Toxicol 2000; 38: 275-281.

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