Research in

Res Exp Med (1992) 192 : 335-343

Experimental Medicine 9 Springer-Verlag 1992

Cardiac glycosides in the treatment of experimental overdose with calcium-blocking agents M. P. Ramo 1,2, I. Grupp 1, M. K. Pesola 2, J. Heikkila 2, K. Luomanmaki 2, T. Schroder 3, and G. Grupp 1 1Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, USA 2Department of Physiology, University of Oulu, Department of Internal Medicine, University of Helsinki, Finland 3Department of Surgery, University of Oulu, Department of Surgery, University of Helsinki, Finland Received March 19, 1992 / accepted May 18, i992

Summary. The ability of digitalis compounds to counteract calcium antagonist overdose was studied in anesthetized dogs (n = 6 , 13.5 + 0 . 7 k g ) and isolated trabeculae from human hearts (n = 7). Digitalis caused by increasing intracellular cytosolic Ca 2+ concentration through Na+/Ca2+-exchange across the cell membrane, was postulated to overcome the detrimental effects of excessive slow calcium-channel blockade. In anesthetized dogs, an infusion of verapamil (40 mg/30 rain, i.v.) decreased mean arterial pressure from 88 _+ 6 to 66 _+ 6 m m H g ( P < 0 . 0 5 ) , reduced systemic vascular resistance (SVR) from 3838_+ 916 to 2200 _+ 669 dyne. s/cm5 (P < 0.05), and induced total atrio-ventricular (A-V) block in three animals. Stroke volume (SV) remained unchanged. Administration (i.v.) of NaC1 (0.9%, 200 ml) and calcium gluconate (100 rag) - to increase the availability of Na + and Ca 2+ - together with atropine (0.2rag) - to block the parasympathetic effects of digoxin on A-V conduction - increased left ventricular contractility (15%) but had no significant effects on blood pressure, SV, or A-V block. Digoxin (0.125 mg) returned sinus rhythm in all dogs and, by increasing SVR ( P < 0.05) and left ventricular contractility (P < 0.05), returned arterial pressures to baseline. Because of increased afterload, SV decreased slightly (15%) despite increased cardiac contractility. In experiments with isolated trabeculae from diseased human hearts, TA 3090 (Clentiazem) depressed contractile force and ouabain, another glycoside, restored contractile force within 30rain. Ouabain also counteracted the depression produced by anipamil, nifedipine, and amlodipine. In conclusion, these experimental results indicate that administration of digoxin, combined with atropine, may be beneficial in the treatment of verapamil overdose. Key words: Ca e+ antagonists - Poisoning - Cardiac glycosides - Atropine Correspondence to: M. P. Ramo

336 Introduction

The wide clinical use of verapamil has been paralleled by an increase in the incidence of deliberate and accidental poisonings with the drug. Verapamil overdose is associated with bradycardia, hypotension, and atrioventricular dissociation. Hyperglycemia can also occur. The therapeutic plasma concentration of verapamil is about 0.2 mg/1 [15]. In case of verapamil intoxication, there is wide individual variation between measured plasma concentration and hemodynamic manifestations - one patient has survived an oral dose of 4.0 mg/1 [18], but a verapamil dose of 3.0 mg/1 was lethal in another [17]. Major calcium antagonists, verapamil (phenylalkyl amine type), nifedipine (dihydropyridine type), and diltiazem (benzodiazepine type), share common properties despite their diversitv of action. In appropriate experimental conditions, they can all inhibit the slow inward current of calcium ions through the Ca 2+ channels. They depress the sinus node and atrioventricular (A-V) conduction and limit the amount of calcium available for interaction with contractile proteins, producing a slight negative inotropic effect with normal clinical doses [3, 15]. They are also known to relax vascular smooth muscle, resulting in peripheral and coronary vasodilation [21]. It is generally agreed that the sodium pump ( N a + , K + ATPase) represents the tissue receptor for digitalis. There are. however, several proposals for the positive inotropic effects of digitalis. The mechanism most commonly accepted suggests that glycosides induce intracellular N a + retention by inhibiting the sarcolemmal N a + pump. This, in turn, leads to the rise in intracellular Ca ~-+ due to the competition of N a + with Ca 2+ for the N a + / C a 2+ exchange mechanism on the sarcolemma [16]. Digitalis has also been proposed to have a direct interaction between sarcolemmal phospholipids, which results in an increased amount of intracellular Ca 2+ [10]. Digitalis-induced sinus bradycardia and the inhibition of A-V conduction due to reflexly stimulated vagal nucleus depends on the degree of parasympathetic activation [9, 16]. These parasympathetic actions can be inhibited by anticholinergic drugs, such as atropine [16]. Some experimental work has suggested that positive inotropic effects of cardiac glycosides are attenuated but not nullified by calcium antagonists [12, 19]. This may indicate that digitalis compounds can at least partly reverse the depressant effects of calcium antagonist overdose bv increasing intracellular calcium through N a + / C a 2+ exchange. The present experimental study was, therefore, designed to test the ability of digitalis to attenuate the cardiotoxic effects of overdose of slow channel blockers in atropine pre-treated animals and in isolated trabeculae from human tissue.

Materials and methods

Animal experiments" Six beagle dogs (13.5 _+0.7 kg) of both sexes were anesthetized (morphine 4 mg/kg, atropine sulfate 0.05 mg/kg i.m., and pentobarbital sodium 20-25 mg/kg i.v.), intubated, and artificially ventilated (200ml/kg per min, Mark 8, Medishield, England). Throughout the experiment, body temperature was maintained within _+0.5~ of baseline with an infrared warming lamp. The standard limb lead II or iII was used for ECG recordings. Left ventricular and proximal aortic pressures were monitored with catheter tip manometers (Millar 4F or 5F), which were

337 introduced into their locations via femoral and right-lingual artery (a branch of carotid artery) under fluoroscopic guidance. Pressure manometers were connected via a control unit (TBC 100, Millar) to an amplifier (Kyowa DA-110) and a display monitor (Wavetek). A 5-F catheter with six side-holes (Lehman, USCI) was placed into the left ventricle through another femoral artery for thermal dilution indicator injection (Ringersteril 1.6 ml, room temperature). Indicator was injected within one diasole with the aid of a pressure injector (Columbus Instruments 500) controlled by an E C G synchronizer (Columbus Instruments). Left ventricular thermal washout curves were recorded with a thermal probe catheter (4F, Edwards) placed into the proximal aorta and connected to a Wheatstone bridge (Wilton-Webster, CBA 210), amplifier (Kyowa), and recorder (Goertz). Drugs and infusion fluids were administered through a Cournard catheter (6 F, USCI) into the superior caval veins. All signals were recorded online with a digital computer (PDP-11/10). The ECG and pressure signals were recorded simultaneously by taking digital samples of 5 s duration at a rate of 500 Hz. The signals were filtered with a low-pass cut-off frequency of 300 Hz. A resolution better than 0.4 m m H g was obtained. The left ventricular thermal washout curves were recorded as digital samples of 12 s duration at a rate of 250 Hz. The sampling rate of calibration recordings was 25 Hz and a resolution better than 0.002~ was obtained. The quality of the thermal curves was checked with an ink writer, that of pressure signals with an oscilloscope, and that of the digital-analog conversion with another oscilloscope.

Data processing Pressure data. Digital-pressure recordings were split into cardiac cycles with the aid of the Q waves of the E C G signal. Detection of QRS complexes of the E C G signal was carried out using a 5-step algorithm [14]. Premature beats and subsequent potentiated beats were omitted. Thereafter, all the subsequent parameters were computed from every individual cycle included in the sample and their mean values were used as the result. The left end-diastolic ventricular pressure (EDP, mmHg) was defined as the pressure value at the onset of the ventricular systolic pressure rise. Maximum value of the first-time derivative of the ventricular-pressure curve (dP/dt max, mm Hg/s) was determined using the fivepoint, second-order, data-fit derivation [11].

Volume data. Cardiac output (CO, 1/min), left ventricular enddiastolic volume (EDV, ml), end-systolic volume (ESV, ml) and ejection fraction (EF) were determined by the thermal dilution technique from the left ventricular washout curves according to Holt [5, 8]. Stroke volume (SV, ml) was obtained by dividing cardiac output by heart rate. Pressure-volume data. Systemic vascular resistance (SVR, dyne. s/cm 5) was determined as a ratio between the mean aortic pressure and the cardiac output [22].

Protocol for closed-chest canine experiments' After instrumentation and baseline hemodynamic measurements, verapamil overdose was induced by an i.v. infusion of verapamil (4 mg/kg per 30 rain). The infusion was continued by a 30-min follow-up period. Thereafter, animals received at 5-min intervals NaC1 0.1% 50ml (3.5 ml/kg), CaC2 100 mg (7.5 mg/kg), atropine 0.2rag (0.014mg/kg), and digoxin 0.125 mg i.v. (0.009 mg/kg). Hemodynamic measurements were taken at the end of each 5-min period. After the administration of digoxin, cardiovascular variables were monitored for 1 h.

Human trabeculae experiments" Human hearts were obtained from the Human Transplant Service of the University of Cincinnati Medical Center. Each heart was received in the operating room immediately after removal from the chest of the transplant patient. The hearts were placed in ice-cold Krebs-Henseleit solution containing 5000IU heparin. About 10 each of mural trabeculae, maximal length 10 mm, thickness less than 1 mm, were removed from the inside walls of the right and left atria

338 95% 02 5% CO2

Stimulator ,

i/"

!

J Muscle --

Punctate Electrodes

Reservoir

Strip

I'r'~ ~--'i'l ~ Hinged I~ I Clamp Spring Force Trenlducet

~L~

7o ml

Fig, 1. Schematic drawing of a setup for two muscle chambers accomodating two strips each. Left upper corner, magnification of the muscle holder

T a b l e 1. Contents of Krebs-Henseleit solution (mM)

NaC1 KC1 CaC2 MgSO4 KH2POa NaHCO3 Glucose NaEDTA Total K + Total Mg 2+ Total Ca 2+ pH

118 4.7 2.5 1.2 1.2 25.0 5.5 0.5 5.9 1.2 2.0 7.4

and right and left ventricles and incubated in cold Krebs-Henseleit solution until they were suspended in the assay bath at 35~ The trabeculae were placed in a muscle holder constructed to accommodate two preparations in contact with two pointed platinum electrodes, which were used for stimulation. The other ends of the preparations were connected via a nylon suture (6 : 0) to a calibrated displacement force transducer (Grass FTv 0.03). The muscle holder was inserted into a bath chamber of 70ml volume, which was jacketed for heating (Fig. 1). Krebs-Henseleit solution (Table 1), stimulation, oxygenation, temperature, and pH were identical to those in the other isolated preparations in our laboratory: pH 7.4, temperature 35~ and 95% 0 2 : 5 % CO2 oxygenation. The trabeculae were studied under isometric conditions with an initial load of 1 g, stimulated through needle electrodes at 1.0 Hz (Grass $8 stimulator), stimulus duration of 2 to 5 ms, and voltage 30% above threshold. Contractile force and its first derivative dF/dt (Grass 7 P20C differentiator) were recorded for all muscles on a Grass P7 polygraph.

339

Protocol for experiments on human trabeculae The preparations were equilibrated for 60-120min. Dose-response curves with TA 3090 (Clendiazem, a benzodiazepine calcium blocker) was obtained on a cumulative basis, adding increasing concentrations of TA 3090 (1 nM-10 gM) every 40 and 60 min. After a 30-min washout of TA 3090, a oubain dose-response curve was obtained.

Results

Animal experiments: closed-chest dog studies V e r a p a m i l infusion d e c r e a s e d m e a n a r t e r i a l a n d d i a s t o l i c p r e s s u r e s significantly ( f r o m 80 + 5 to 60 _+ 4 m m H g a n d 65 + 5 to 41 _+ 6 m m H g , r e s p e c t i v e l y ; see T a b l e 2). A l s o e n d - d i a s t o l i c a n d s t r o k e v o l u m e s w e r e r e d u c e d ( P < 0.05). F o u r o u t o f six dogs d e v e l o p e d t o t a l A - V b l o c k (Fig. 2 a , b). A f t e r NaC1 a n d CaC12 adm i n i s t r a t i o n , e j e c t i o n f r a c t i o n i n c r e a s e d significantly w h e n c o m p a r e d with t h e b a s e l i n e v a l u e b e f o r e v e r a p a m i l infusion ( T a b l e 2). M e a n a r t e r i a l a n d diastolic p r e s s u r e s r e m a i n e d the s a m e as a f t e r v e r a p a m i l infusion. CaCI2 also i n c r e a s e d s t r o k e a n d e n d - d i a s t o l i c v o l u m e s while d e c r e a s i n g t h e h e a r t r a t e slightly. A t r o p i n e t r e a t m e n t i n c r e a s e d t h e h e a r t r a t e b a c k to the p o s t - v a r a p a m i l level ( T a b l e 2), a l t h o u g h b l o o d p r e s s u r e s w e r e still low (systolic p r e s s u r e 101 + 7 m m H g a n d diastolic p r e s s u r e 40 + 8 m m H g ) . N o significant c h a n g e s w e r e obs e r v e d in t h e c o n t r a c t i l e force of the h e a r t . A t r o p i n e h a d n o effect on t h e prese n c e of A V b l o c k . D u r i n g t h e first 30 rain a f t e r a d m i n i s t r a t i o n o f digoxin, sinus r h y t h m r e t u r n e d in t h r e e o f t h e f o u r dogs. A l s o by 30 rain after d i g o x i n t r e a t m e n t , h e a r t r a t e a n d b l o o d p r e s s u r e s r e t u r n e d to b a s e l i n e level ( T a b l e 2). D i g o x i n i n c r e a s e d S V R significantly ( P < 0.01), b u t r e d u c e d E D V a n d SV. C a r d i a c c o n t r a c t i l i t y i n c r e a s e d significantly c o m p a r e d with b o t h b a s e l i n e ( d P / d t m a x f r o m 2015 + 257 to 3138 _+ 794 m m H g / s ) a n d p o s t - v e r a p a m i l ( E F f r o m 0.43 + 0.02 to 0.49 + 0.04) values. Table 2. Hemodynamic effects of NaC1 (0.1% 50 ml), CaC12 (100 mg), atropine (0.2 mg), and digoxin (0.125 mg) on verapamil overdose (3 mg/kg) (n = 6, mean -+ SEM)

Parameter

Baseline

Verapamil

NaCl and CaC12

Atropine

Digoxin

HR SV EF % SAP DAP SVR LVEDV dP/dtmax

76 + l0 36 + 7 0.44 _+ 0.01 110 + 10 65 + 5 3 838 _+ 916 80 _+ 15 2015 "+ 257

101 + 13 24_+ 3a 0.43 • 0.02 98 _+ 7 41 _+ 6a 2953 _+ 697 59 ,+ 8a 2460 "+ 391

86 + 15 34_+ 8 0.50 _ 0.03 b 101 • 8 41 • 6 3151 + 1054 70 _+ 17 2683-+ 465

96 -+ 12 35 • 8 0.45 • 0.02 101 • 7 40 • 8 2466 • 905 79 _+ 16 2713 -+ 476

82 _+ 20 24_+ 5 0.49 _+ 0.04 b-c 120 _+ 14 63 _+ 12c 6362 _+ 21521' c 53 _ 15 3138 -+ 794

a p < 0.05 versus baseline; A p < 0.01 versus baseline; b p < 0.05 versus verapamil; c p < 0.05 versus atropine; c p < 0.01 versus atropine HR, heart rate (beats/min); SV, stroke volume (ml); EF %, ejection fraction; SAP, systolic arterial pressure (mmHg); DAP, diastolic arterial pressure (mmHg); SVR, systemic vascular resistance (dyne. s/cmS); LVEDV, left ventricular end-diastolic volume (ml); dP/dtmax, first time derivate of left ventricular pressure curve (mm Hg/s)

,5o[

340

100

r

I

~= ==

so

== 0

-50

0

1

2

3

4

8 TIME (see)

150

(~176f'

0

F

1

r

2

3

4

5 TIME (sic)

Fig. 2a, b. Example of left ventricular pressure, aortic pressure, and ECG a before and b after verapamil infusion in one dog

Studies on isolated human trabeculae

T A 3090 in isolated trabeculae from the walls of diseased h u m a n hearts produced negative inotropic effects beginning at concentrations of i nM. Calculated on the basis of a 50% inhibitory effect on contractility, i.e., the concentration required to reduce contractility by one-half between maximal and minimal effect (IC 50), T A 3090 in three different trabeculae had an IC50 of 26, 36, and 38 nM, respectively. The m e a n effect was 33.3 + 5.3 nM T A 3090. When we exposed seven h u m a n trabeculae to 1 laM T A 3090 for 130 min (Fig. 3), myocardial contractile force was reduced from 200 mg to less than 50 mg tension. After a washout of T A 3090 for 110 min, contractile force did not recover in the three control trabeculae. However, addition of 300 nM ouabain in the four remaining trabeculae not only overcame the inhibitory effect of the calcium blocker, but increased contractile force to more than 300mg tension. Identical experiments with anipamil and the dihydropyridine calcium blockers nifedipine and amlodipine produced identical results to those seen with T A 3090. Therefore, the cardiac glycoside ouabaine can counteract cardiac inhibitory effects of benzodiazepine, phenylalkylalamine, and dihydropyridine-type calcium blockers.

341 Diseased Human Left Ventricular Trabeculae

400

84

A

E m

B

C

100"

g~ o

o

so

,oo

2;~

2;0

Time (mln) A. B. C.

Effect of llzM TA-3090 on 7 trabeoulae I" a "1 Washout of TA-3090 Addition of 300nM Ouabaln to 4 t r a b l m u l a e [ - ~ o - - -

Fig.3. Developed tension in diseased human left ventricular trabeculae after infusion of T A 3090 (n = 7), washout of T A 3090, and addition of 300 nM Oubain (n = 4)

Discussion

Verapamil intoxication has been treated in many different ways, but standard management, including ventricular pacing, calcium chloride, and catecholamines, is often effective [7]. Treatment of the adverse effects after oral overdosage include emptying the stomach by aspiration and lavage. Atrioventricular conduction abnormalities related to verapamil overdose have been treated by atropine or a beta-adrenoceptor agonist in addition to electrical pacing. Calcium gluconate and agents, such as dopamine and dobutamine, have been suggested to counteract heart failure and hypotension [4, 13]. Artificial ventilation has been considered an important factor in the treatment of impaired spontaneous ventilation, hypoxia, and hypercapnia caused by possible neuromuscular effects of massive verapamil overdose and in noncardiogenic pulmonary edema seen after massive diltiazem overdose [6]. There is also both experimental and clinical evidence for the beneficial effects of administering 4-aminopyridine, a potassium channel modulator, in cases of verapamil intoxication [1, 20]. In the present study, digoxin combined with atropine and calcium gluconate seemed able to overcome the hemodynamic effects of verapamil overdose. Intravenous calcium gluconate has appeared to be valuable as a first-line treatment for the adverse cardiac and hemodynamic effects following verapamil intoxication. The results of the current study support this concept. Calcium gluconate increased the contractility of the left ventricle and by doing so was able to enhance stroke volume to the original, baseline level. Neither calcium gluconate nor atropine, however, had any significant effects on verapamil-induced hypotension or on A-V block. Intravenous digoxin in the dog heart increased cardiac contractility and systemic vascular resistance significantly. Within 30 rain, blood pressure was back to normal and three dogs out of four were in sinus rhythm. It is generally known that in digitalis intoxication, intravenous verapamil is absolutely contra-indicated, because of the possible exaggeration of atrioventricular block [15]. Our experimental results demonstrate that when reflex parasympathetic vagal activation is prevented by atropine, digoxin, in pharmacological

342 concentrations and in the absence of digitalis toxicity, can p r o d u c e a clear imp r o v e m e n t of verapamil-induced A V - b l o c k . Because of the increased afterload p r o d u c e d by digoxin, stroke v o l u m e decreased despite increased contractility. Digitalis-induced elevation of total systemic arteriolar resistance and venoconstriciton has b e e n shown to be m e d i a t e d b o t h by the local action of digitalis on vascular s m o o t h muscle and indirectly t h r o u g h the sympathetic nervous system. T h e m a r k e d venoconstriction of the hepatic veins leads to pooling of the blood in the portal v e n o u s system and consequently diminishes venous return [2]. D e c r e a s e d end-diastolic v o l u m e after digoxin was also evident in the present study. O n the basis of the isolated trabeculae studies r e p o r t e d here, we conclude that calcium antagonists of all three types and digitalis c o m p o u n d s p h a r m a c o l o g ically antagonize each other, although they are not competitive. It is of interest to note that in h u m a n trabeculae in vitro, it t o o k a b o u t 30 min for o u a b a i n to o v e r c o m e the T A 3090 depression, a time similar to the duration of the effects of digoxin on verapamil depression in dogs. The results of the present experimental study d e m o n s t r a t e a clear h e m o dynamic i m p r o v e m e n t of severe verapamil intoxication after digoxin t r e a t m e n t c o m b i n e d with atropine, although beneficial effects of calcium gluconate cannot be excluded. W e h o p e the present study will encourage further experiments and give new insight into the possible t r e a t m e n t of massive verapamil intoxication in cases where conventional m a n a g e m e n t has failed.

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343 13. Meer J van der, Wall E van der (1983) Fatal acute intoxication with verapamil. Neth J Med 26 : 130-132 14. Okada M (1979) A digital filter for the QRS complex detection. IEEE Trans Biomed Eng BME-26 : 700-703 15. Opie LH (1984) Calcium antagonists (slow channel blockers). In: Opie LH (ed) The heart, physiology, metabolism, pharmacology, therapy. Grune and Stratton, New York, pp 246261 16. Opie LH (1984) Digitalis and sympathomimetic stimulants. In: Opie LH (ed) The heart, physiology, metabolism, pharmacology, therapy. Grune and Stratton, New York, pp 261276 17. Orr GM, Bodansky HJ, Dymond DS, Taylor M (1982) Fatal verapamil overdose. Lancet II 8309 : 1218-1219 18. Perkins CM (1978) Serious verapamil poisoning: treatment with intravenous calcium gluconate. BMJ 21 : 1127 19. Singh BN, Ellrodt G, Thomas Peter C (1978) Verapamil: a review of its pharmacological properties and therapeutic use. Drugs 15 : 169-178 20. Ter Wee PM, Kremer Hovinga TK, Uges DRA, Geest S van der (1985) 4-Aminopyridine and haemodialysis in the treatment of verapamil intoxication. Hum Toxicol 4 : 327-329 21. Walsh RA (1987) The effects of calcium-entry blockade on left ventricular systolic and diastolic function. Circulation 75 : [Suppl V] V-43 22. Yang SS, Bentivoglio LG, Maranhao V, Guldberg H (1978) Assessment of ventricular function. In: Yang SS, Bentivoglio LG, Maranhao V, Guldberg H (eds) From cardiac catheterization data to hemodynamic parameters. FA Davis, Philadelphia, pp 233-358