Antidotes to ventricular fibrillation induced by mercurial diuretics

ANTIDOTES

B.

N.

CRAVER,

TO VENTRIC‘I1LAK BY MERC‘1’RIXL M.D.,

Ph.D., I;. F. B. Ii. KENNICK, SUMMIT,

FIBRII,LATION DIIJRETICS YOSGMAN,

iNI>.,

INDUCED

Ph.D.,

XND

M.D. N.

J.

has recently STANLEY’ to mercurial diuretics.

summarized the reported cardiac deaths attributable Presumably these resulted from the now wellestablished cardiac toxicity of this class of therapeutic agent. It has been reported for all of the commonly used drugs of this class and is a limitation therefore of the entire group and not merely of one or two representatives, as has been emphasized by DeGraff .2 Fortunately, the number of patients involved is small, as may be gathered from a recent observation of Smith” that, if the mercurials employed for diuresis were as proportionately toxic as the arsenicals employed in the therapy of syphilis, over 100 deaths a year could be expected from these agents. Nonetheless, a means of diminishing or eliminating this toxic manifestation would further enhance the usefulness of this valuable group of drugs. A suitable method was therefore devised for assaying the antidotal value of the following against ventricular fibrillation: vagotomy, atropine sulfate, 2-[~-p-tol~l-N-(m’-hydroxyphen~~lj-aminomethyl]-imidazoline HC’I (C:-7337), British anti-lewisite (BAL), and magnesium sulfate. METHODS

We chose as a typical representative of this class of compounds the sodium salt of pyridenedicarboxyl-beta-mercuri-omega-hydroxypropylamide-theophylline. We sought to establish a dose of the mercurial given by a constant route on a per kilogram basis that would suffice to produce fatal ventricular fibrillation in 100 per cent of the dogs receiving it.* All animals were anesthetized with 32 mg. per kilogram sodium pentobarbital administered intraperitoneally. We found in preliminary experiments that doses of from 10 to 12 mg. per kilogram of the mercurial injected into the jugular vein produced ventricular fibrillation in but one of six animals (17 per cent) ; 1.5 mg. per kilogram caused it in ten of twelve animals (83 per cent); and 20 mg. per kilogram induced it in nine of ten The dose of 1.5 mg. per kilogram was employed in our work dogs (90 per cent). because it was fatal in 83 per cent of the animals after the first dose and fatal in the remaining animals after the second dose. Since slightly smaller doses were seldom fatal, we believed this choice of dose would readily permit the disFrom the Research Department, Divisiorl of hIacrabiology. Ciba Pharmaceutical Products, Inc., Summit. A preliminary report of this paper was presented at t,he annual meeting of the American Industrial Hygiene Association in Chicago. 1946. Received for publication May 3, 1950. *The preparation available contained 70 mg. per milliliter of the mercury complex. This represented 21.5 mg. per milliliter of mercury. 590

CRAVER

ET

AL.

:

ANTIDOTES

TO

CARDIOTOXIC

MERCURIALS

591

cernment of even a slightly antidotal effect from the therapeutic measures employed. Variations in the rate of administration of the dose of from ten seconds to two minutes did not seem to alter the result, but injection into the femoral vein instead of the jugular required more than twice the dose to kill from ventricular fibrillation. This would have been predicted by the intensive investigations of DeGraff and Lehman,* since for practical reasons we did not prolong our injection time sufficiently to allow evidences of an increased toxicity to appear. The final route chosen was the jugular vein, and a twenty-second period was used for the injection. In attempting to assay the value of each protective measure, the agent being studied was employed prior to the administration of the first dose of the sodium salt of pyridenedicarboxyl-beta-mercuri-omegahydroxypropylamide-theophylline or was injected simultaneously. If the first dose did not prove fatal, the same dose was repeated at thirty-minute intervals until death resulted. RESULTS

In several experiments vagotomy or the administration of 0.2 mg. per kilogram of atropine sulfate apparently offered slight protection, since after these modes of treatment from two to five fatal doses of the mercurial had to be administered before ventricular fibrillation appeared. The relatively slight protection encountered is basically in agreement with the report in 1922 by Salant and Kleitman” that no protection from either atropine or vagotomy was observed. Efforts to demonstrate any protective action by the adrenolytic, C-7337, (1.0 mg. per kilogram) proved unavailing, since only one of the five animals given that treatment survived, and that 20 per cent survival is essentially the same as the survival rate in the control animals. Preliminary experiments with BAL indicated that complete protection against the cardiac toxicity was afforded by that drug. Further work with this compound was promptly abandoned when we learned that Farah” had already initiated an intensive investigation not only of this thiol derivative but of others as well. This work has since been published in detail and has been independently confirmed in respect to BAL’s inhibition of the diuretic action of mercurials by Earle and Berliner’ and Sussman and Schack.8 Farah and Mareshg studied the effects of several other thiol derivatives and found that cysteine and glutathione prevented the cardiac toxicity of the mercurial diuretic (mersalyl) but did not alter its diuretic properties. Even though it is apparent that from their studies may emerge the ultimate solution to the cardiac toxicity of mercurial diuretics, the above data have been reported for three reasons: 1. The method herein reported would appear to offer a convenient means of assaying the comparative cardiac toxicity of mercurials. 2. It helps emphasize that the protection afforded by thiol derivatives far surpasses that that can be anticipated from any hitherto reported protective agents. 3. The closer the injection is made to the heart, the more likely is a given dose to induce ventricular fibrillation, and this would commend the injection of mercurials into human beings at as peripheral a point as possible.

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Table I summarizes the results obtained in our experiments using magnesium sulfate as the antidote. We were particularly interested in the value of this salt as an antidote because of the report of Pines and his associates”’ that the salt conferred protection against the cardiac toxicity of the same mercurial we have employed in this study. We have been able to confirm this protective action, although in our experiments higher doses of the salt were required, but this is doubtless explicable on the basis of the different experimental methods employed. Pines and his associates implied in their report that the degree of protection afforded was not great, since they noted that the disturbances of cardiac conduction induced by the injected mercurial, as demonstrated electrocardiographically, were not altered by the magnesium sulfate. Nonetheless, the recommendation of Pines and his associatesthat magnesium sulfate be added to mercurial diuretics, a recommendation more recently supported by Oettle” and by Kay and Burch,l? among others, had much to commend it until the reports of the vastly greatel protection afforded by thiol derivaties appeared. Since these derivatives seemingly constitute an almost ideal solution of the problem, their use will cloubtless supplant that of any other recommended antidotes.

X0. ANIMALS

DOSE PER DOGIh'ML. OF 20yc

1

DOSE

OF &@&

I>

NO. SURVIVORS

mg./kg.t

MgSOd

~~

12 2 5

None 0.5 1.25

5

2 5

5

5

1

25; 7.9 24.5; 28.4 30.2; 27.2; 38.5;

I I1

36.2; 61.0 21.3; 84.7;53.2; 2.5 141(7); lOO(3); 106; + like dose : lOO(2); 116

IT. l5 min. ; : before ; 10 I.P. 1.5 1 308(3); 206; 408(2); min. before 213(2); 168 - - ~...

1 ..____-.

70 OF ) SIJRVIVORS

.--'pm-~--~.-

2 ::

;

O 3

I

I

~ i /

3

-I--~-

17 0 0 O 60

60 ~--

. ..~

~~

2nd in both

1 2nd, 3rd, and 1 7th / Zn;l;ind,

--. -__._-.

and _

1 In all cases 15 mg. per kilogram of mercurical were injected intrajugularly in twenty seconds. tThese varied with the w,eight of the animal, but we desired to employ the same dose recommended by Pines and associates (0.5 C.C. of 20 per cent per dog) or a multiple thereof. A figure in parentheses after the dose of magnesium sulfate in mg. per kilogram designates the dose at which the animal SWcumbed in those instances in which the first dose was not fatal.

In approximately half our experiments electrocardiograms were taken immediately after the injection of the mercurial diuretic. Fig. 1 is typical of the electrocardiogram changes that were usually observed prior to the terminal ventricular fibrillation. In dogs that did not succumb to a given injection of the mercurial, marked alterations in the electrocardiogram were nonetheless usually observed, but did not progress to ventricular fibrillation. In many of the experiments an effort was made to cause a reversion of the ventricular fibrillation to a normal rhythm. In view of the work of Chapman and Shaffer’3 demonstrating that ascorbic acid lessenedthe acute cardiac toxicity

CRAVER ET .4L.:

-4NTIDOTES TO CARDIOTOXIC MERCURIALS

593

of Mercuhydrin, although not of Mercupurin or mersalyl, we attempted in several

experimentsto lessenthe cardiac toxicity of the mercurial herein studied by both prior and simultaneous injections of vitamin C in various doses up to 100 mg. per animal, but no antidotal value was observed, nor did it prove of value in The statement by Frohlicher14 correcting established ventricular fibrillation. that electrically induced fibrillation could be corrected by large doses of acetylcholine led us to attempt that method also, but intracardiac injections of various This discrepancy might easily be attribdoses up to 10 mg. were without avail. Only two procedures uted to the different mechanisms producing the fibrillation. proved effective: (a) manual massage, which only occasionally succeeded in restoring the normal rhythm; and (b) brief electrical stimulation of the myocardium with 110 volts through broad electrodes placed on either side of the heart. This last procedure almost invariably restored a normal rhythm.*

Fig. I.-These eiectrocardiogram records are of Lead I. The top to the injection of the mercury. The second was taken twenty seconds complex and the ST segments are depressed. The third was taken The ventricular tachycardiais and the fourth ten seconds after the third. t,he onset of ventricular fibrillation.

one is the control taken just prior The QRS after the injection. fifteen seconds after the second, now evident. The Rfth shows

SUMMARY

1. 15 mg. per kilogram of the sodium salt of pyridenedicarboxyl-betamercuri-omega-hydroxypropylamide-theophylline injected into the jugular vein in dogs was shown in over 80 per cent of the cases to cause fatal ventricular fibrillation after the first dose, and in 100 per cent after the second dose. 2. Magnesium sulfate offered some protection against the cardiac toxicity of the mercurial diuretic studied, but by the method employed herein somewhat larger doses were required than Pines and his associates had found necessary. The degree of protection afforded was not great and in no way comparable to that afforded by thiol derivatives. *The

authors

thank

Professor

Alfred

Gilman

for

this

valuable

suggestion.

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3. Atropine sulfate or vagotomy appeared to offer ver)’ weak protection, if any. 4. BAL seemingly offered complete protection against the cardiac toxicit!. of the mercurial studied. 5. Ascorbic acid and acetylcholine in the doses employed did not restore ventricular fibrillation to a normal rhythm, but manual manipulation occasionally, and electrical stimulation usually, did restore a normal rhythm. The authors thank Dr. Mr. and Mrs. James Smith for his kindness in interpreting

Harry Hays for his valuable suggestions in the early part of this work, for their technical assistance, the electrocardiogram.

and

Professor

Gordon

Myers,

M.D..

REFERENCES

1. 2. 3.

4. 5. 6. 7. 8. 9.

10.

11. 12. 13.

14.

Stanley,

T. E.: An Analysis of 27 Reported Fatalities Immediately Following the Injection of a Mercurial Diuretic, Virginia M. Monthly 8:416, 1949. J. A. M. A. 136:1025, 1948. DeGraff, A. C. : Diuretics, Smith, F. J.: The Use of Diuretics in the Treatment of Congestive Heart Failure; Presented at the Midwest Regional Meeting of the American College of Physicians, Indianapolis, Nov. 19, 1949. DeGraff, A. C., and Lehman, R. A.: The ;\cute Toxicity of Mercurial Diuretics, J. A. M. 1-l. 119:998. 1942. Salant, W., and Kleitman, N.: Some Observations on the Action of Mercury, J. Pharmacol. & Exper. Therap. 19:315, 1922. Farah, A.: Personal communication. Earle, D. P., Jr., and Berliner, R. W.: Effect of 2,3-Dimercaptopropanol on Diuresis, Am. J. Physiol. 151:215, 1947. Sussman, R. M., and Schack, J. A.: BAL Inhibition of Mercurial Diuresis in Congestive Heart Failure, Proc. Sot. Exper. Biol. & Med. 66:247, 1947. The Influence of Sulfhydryl Compounds on Diuresis and Renal Farah, A., and Maresh, G.: and Cardiac Circulatory Changes Caused by Mersalyl, J. Pharmacol. & Exper. Therap. 92:73, 1948. Pines, I., Sanabria, A., Hernandez, Arriens, R. T.: Mercurial Diuretics: Addition of Magnesium Sulfate to Prevent Toxic Effects of Their Intravenous A\dministration, Brit. Heart J. 6:197, 1944. Oettle, A. G.: Sudden Death After Intravenous Injection of a Mercurial Diuretic (“neptal”), Brit. Med. J. 2530, 1947. Ray, C. T., and Burch, G. E.: The Mercurial Diuretics, Am. J. M. SC. 217:96, 1949. The Mercurial Diuretics: A Comparison of Acute Chapman, D. W., and Shaffer! C. F.: Cardiac Toxicity in Ammals and the Effect of Ascorbic Acid on Detoxification in Their Intravenous Administration, J. Lab. & Clin. Med. 32:313, 1947. Friihlicher, R.: Effect of Acetylcholine on Electrically Induced Fibrillation in Isolated Mammalian Hearts, Helv. Physiol. Pharmacol. Acta 3:231, 1945.