J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.49 on 1 January 1989. Downloaded from Randy Easterling, M.D., and Paul E. Tietze, M.D.

Abstract: Digitalis toxicity is a frequently encoun­ bodies represents a significant advance in the treat­ tered clinical problem. Drug interactions leading to ment of this problem and can be lifesaving in digitalis toxicity are very common. Within this the setting of massive overdose. A case report of digi­ group, the interaction of digitalis and is talis toxicity and a review of this problem and its increasingly recognized as an important \:ause of treatment are presented. (J Am Bd Fam Pract 1989; digitalis toxicity. The use of -binding anti- 2:49-54.)

Digitalis preparations are frequently prescribed, ble and had miotic pupils. The physical examination and a significant number of patients, especially was otherwise unremarkable. the elderly, take them regularly. Because of the A 12-lead electrocardiogram showed atrial fi­ ubiquitous use of this drug and the increased fre­ brillation with a high-grade delay in AV conduc­ quency of digitalis toxicity, the rapid diagnosis of tion. The Q-T interval was markedly shortened. digitalis toxicity is essential. Results from measur­ The ventricular rate was 31, and there were long ing digitalis blood levels can help the physician asystolic intervals in V4-V6. There was sagging of provide optimal care to patients. Where digitalis the SoT segments in leads II, III, and aVF and up­ levels are not available, the physician must de­ ward sloping SoT segments in aVR. There were pend on the signs, symptoms, and typical EKG peaked T waves in V2 and V3, suggestive of hy­ and laboratory findings of digitalis intoxication to perkalemia (Figure 1). confirm the diagnosis. Other pertinent laboratory findings were: serum Several factors contribute to digitalis toxicity. potassium, 6.1 mEq/L (6.1 mmoIlL); BUN, Among these, drug interactions (especially verapa­ 18 mg/dL (3.0 mmollL); and creatinine, 1.1 mg/dL mil-digoxin) are common. While mortality from (97f.LmollL). Cardiac enzymes were normal. Serum digitalis toxicity is still high, an important advance level was 9.4 mg/dL (2.3 mmollL). in its treatment has been made with the clinical use and serum drug screens were negative for narcotics. of digitalis-binding . The purpose of this A serum digoxin level of 30.80 ng/mL (39.44 paper is to present a brief case report of digitalis nmollL) was reported and confirmed. toxicity and to review the problem and treatment of The patient received doses of , 0.5 mg http://www.jabfm.org/ digitalis toxicity. Special emphasis on the verapa­ intravenously, to increase the rate ade­ mil-digoxin interaction and the clinical use of digi­ quately to maintain a blood pressure, 100 mmHg talis-binding antibodies is made. systolic. After the digoxin level was reported, the patient was given , 600 mg intrave­ nously for approximately 45 minutes. Case Report Arrangements were made to transport the pa­ A white middle-aged man came to the emergency tient to a referral hospital for treatment with on 27 September 2021 by guest. Protected copyright. department in the early morning with complaints of digitalis-binding antibodies. At the referral chest pain, , and . His only medi­ center, while awaiting a repeat digoxin level in cations were digoxin 0.25 mg daily and veraparnil order to calculate the correct dose of digitalis­ 80 mg three times daily. He was tachypneic, mark­ binding antibodies, the patient developed a refrac­ edly bradycardic (heart rate was 36 beats per min­ tory ventricular , which degenerated ute), and hypotensive (blood pressure was 96/60 to . He could not be resusci­ mmHg). In addition, he was somnolent but arousa- tated and died approximately 10 hours after initial presentation.

From the Tuscaloosa Practice Residency and the De­ partment of Family , College of Community Health Digitalis Sciences, University of Alabama School of Medicine, Tusca­ loosa, AL. Address reprint requests to Paul E. Tietze, M.D., Digitalis is most frequently prescribed for its posi­ P.O. Box 870378, Tuscaloosa, AL 35487-0378. tive inotropic effect in patients with congestive

Digitalis Toxicity 49 J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.49 on 1 January 1989. Downloaded from , I potential, leading to increased excitability of myocardial tissue.1.3 Digitalis also has clinically important effects :1 II on heart rate and impulse conduction in the heart. The slowing of the heart rate is due prima­ rily to increased vagal tone, which decreases the i Q I rate of sinoatrial node depolarization. Digitalis increases the refractory period in the atrioven­ tricular (A V) node and ventricular conducting system. At the same time, the refractory period

'II, of the myocardium is decreased, leading to im­ proved impulse conduction. Digitalis also de­ Figure 1. Electrocardiogram showing creases conduction velocity through a direct ef­ with high-grade AV conduction delay and long asys­ fect on the AV node.1.3 tolic interval in the lateral chest leads. Note the sag­ ging SoT segments in leads II, III and aVF consistent with digitalis effect. The Q-T interval is shortened. Digitalis Toxicity Note also tall peaked T waves in V2 and V3, sugges­ tive of . Digitalis toxicity is an extremely common and po­ tentially lethal problem that often is not recog­ nized.3.4 Mortality rates as high as 50 percent at serum digoxin levels of 6.0 nglmL (7.68 nmolJL) and for slowing the ventricular rate and above have been reported.4 The liability to digi­ in patients with atrial fibrillation or flutter. The talis toxicity is primarily due to the narrow margin most frequently used cardiac are di­ between therapeutic and toxic levels of the drug. 1,4 goxin and (less commonly) . Digitoxin is The most frequently asso­ primarily metabolized by the liver and has a much ciated with digitalis toxicity are perhaps best longer half life (approximately 7 days) than does described by Withering in 1785, who wrote of digoxin (approximately 1.5 days), which is prima­ this drug: rily excreted by the . Both drugs are ex­ creted in the bile, and enterohepatic recircula­ The foxglove when given in very large and quickly re­ tion plays a role in their metabolism. 1 Because peated doses, occasions sickness, vomiting, purging, digitalis toxicity represents an exaggeration of its giddiness, confused vision, objects appearing green or yellow; increased secretion of urine, with frequent mo­ pharmacologic actions, a review of these actions tions to part with it, and sometime inability to retain it; http://www.jabfm.org/ is in order. slow , even as slow as 35 beats in a minute, cold Most of the pharmacologic action of digitalis sweats, convulsions, syncope, death.5 occurs through its effect on the cell-membrane­ bound -potassium ATPase pump. The majority of these signs and symptoms are due Through inhibition of this system, there is an to the effect of digitalis directly on the central intracellular loss of the potassium ions and an nervous system. 1

intracellular gain of sodium and, subsequently, By virtue of its action on the sodium-potassium on 27 September 2021 by guest. Protected copyright. calcium ions through the sodium-calcium ex­ ATPase pump, digitalis use leads to hyperkalemia, change mechanism. In cardiac muscle, in­ which can be significant with high serum digoxin creased intracellular calcium improves actin and levels. 3.4 myosin interaction. This leads to the increased The mechanisms involved in the expression velocity of muscle shortening and increased ve­ of digitalis toxicity are outlined by Goodman. 3 locity of developed tension, which is the positive There are: (I) depression of conduction, (2) alter­ inotropic effect of digitalis.2 The rapid influx of ation of impulse formation and increased hetero­ sodium ions into myocardial cells increases geneity of refractory periods, (3) other cardiac phase 4 depolarization and increases myocardial factors such as cardiac ischemia or inflammation, automaticity, which may lead to the appearance and (4) noncardiac factors that accentuate the oflatent pacemakers in the myocardium and the signs of toxicity. 3 conducting system. Sodium influx is also re­ Depression of conduction and alteration of im­ sponsible for lowering the resting membrane pulse function are directly responsible for the I 1 so The Journal of the Ammcan Board of Family Practice-Vol. 2 No. 1 I January - March 1989 j J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.49 on 1 January 1989. Downloaded from Table 1. Dysrythmias Seen with Digitalis Toxicity. The mechanism of increased serum digoxin levels in patients taking both verapamil and di­ Sinoatrial block goxin is decreased renal and nonrenal clearance Sinus of digitalis. The renal effect is primarily through Second-degree AV block (usually Type I) decreased active tubular secretion of digitalis.7,8 Complete AV block In the presence of renal disease, this effect is Premature depolorizations arising outside accentuated. With concomitant verapamil ad­ the cardiac conducting system ministration, the increase in serum digoxin may Supraventricular tachycardia with AV block be 70-100 percent above pretreatment levels.7 Atrial fibrillation with a regular ventricular Because both drugs slow conduction through response the AV node, pronounced suppression of AV nodal conduction could be expected in some patients using these drugs in combination.9 We recently dysrhythmias seen with digitalis toxicity. While prescribed digitalis for an elderly diabetic woman almost any dysrhythmia may be seen, some of the . with atrial fibrillation and a rapid ventricular re­ more commonly encountered are listed in Table I. sponse. When verapamil was given for hyperten­ When any degree of is seen sion, she developed complete , necessi­ in combination with excitant dysrhythmias (Le., tating placement of a temporary pacemaker. with AV block), digitalis toxicity On the other hand, verapamil seems to suppress is likely.3 certain digoxin-induced dysrhythmias so that the Digitalis uptake by abnormal or diseased cardiac cardiac conduction manifestations of digitalis tox­ tissue is different from uptake by normal tissue, icity may not be expressed.7 leading to variation in cellular recovery times. In These actions mandate the reduction in di­ patients with cardiac disease, rhythm disturbances goxin dose even in patients with therapeutic lev­ may occur at therapeutic serum digoxin levels. els or desired effect at subtherapeutic levels Resolution of these dysrhythmias after withdrawal when verapamil is begun.7 Generally, the dose of the drug is strong evidence for drug toxicity. of digoxin should be halved and the patient There are a number of other factors that lead to monitored frequently both clinically and with digitalis toxicity. The elderly are predisposed as digoxin levels to decrease the possibility of digi­ are patients with underlying heart disease, renal talis intoxication. disease, conditions associated with hypoxemia With digitalis toxicity, cardiac rhythm disturb­ and , and electrolyte abnormali­ ances are not infrequently fatal. In high doses,

ties, induding hypematremia, , hy­ however, digitalis may be directly lethaL The http://www.jabfm.org/ percalcemia, and hypomagnesemia. 1,3,6 membrane-bound sodium-potassium ATPase sys­ Drug interactions contribute significantly to the tem in all body tissues ceases to function, and rest­ production of toxic levels of digoxin. The hypoka­ ing membrane potentials are reduced. With the lemia associated with administration not myocardial cells unable to act as pacemakers, the only sensitizes the heart to digitalis effects but also result is asystole and, ultimately, complete loss of may result in elevated serum digoxin concentra­ cardiac electrical activity.lo

tion? It is well recognized that concurrent admin­ on 27 September 2021 by guest. Protected copyright. istration of predictably results in in­ creased serum digoxin levels, and the digoxin Table 2. Interacting with Digitalis to Increase dose should be reduced by 50 percent whenever 7 quinidine is administered concurrently.7 The Serum Digitalis Levels. association of increased serum digitalis levels Quinidine in patients receiving verapamil concurrently is emerging as a very clinically important interac­ Verapamil I 8 I tion. ,9 This interaction may now be encountered Diltiazam clinically as frequently as the above-mentioned digitalis-quinidine interaction. Drugs that com­ Triamterene I monly interact with digitalis to increase digitalis Diuretic-induced hypokalemia levels or to potentiate the effect of digitalis are Tetracycline, Erythomycin listed in Table 2. I Digitalis Toxicity 51 l J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.49 on 1 January 1989. Downloaded from Treatment of Digitalis Toxicity In patients with severe bradyarrhythmias, atro­ The diagnosis of digitalis toxicity should be con­ pine 0.5 mg should be administered intravenously sidered for patients taking digitalis who become to block the vagotonic effects of digitalis. 3 acutely ill, especially those with predisposing While treating the specific problems related to factors. Treatment should be considered from two digitalis toxicity outlined above, prevention of perspectives: (1) efforts to lower the digitalis level. further intestinal absorption of the drug is ac­ and (2) efforts to treat its direct pharmacologic complished by emesis or lavage and by the admin­ effects. istration of activated charcoal and a cathartic. In treating the pharmacologic effects of digitalis, Charcoal is most effective when given early after a life-threatening is marked hyper­ ingestion; however, repeated charcoal adminis­ kalemia. A result of the inhibition of the sodium­ tration of 1 gram per kilogram body weight every potassium ATPase pump in all tissues, profound 2 to 4 hours is beneficial because of the entero­ hyperkalemia usually occurs only in the setting of hepatic recirculation of digitalis. 3 renal disease or massive overdose. Hyperkalemia Similarly, -binding resins such as choles­ seen with digitalis intoxication usually does not tyramine can prevent further absorption from the require specific therapy; however, when marked gastrointestinal tract and reduce serum half-life by hyperkalemia develops, serum potassium should interrupting enterohepatic circulation. The useful­ be carefully lowered with insulin and glucose or ness of cholestyramine has been most impressive ion exchange resins. Mild hyperkalemia lessens in treating digitoxin toxicity, but it would also be the effect of some of the dysrhythmias seen with useful to consider in . 12 digitaiis toxicity. Hypokalemia, which tends to ac­ centuate these dysrhythmias, must be avoided. The use of intravenous calciuin, with hyperkale­ Digoxin Fragments mia in the setting of digitalis toxicity, is contra­ The most promising treatment for massive digi­ indicated because of elevated intracellular cal­ talis overdose is the use of digitalis-specific anti­ cium concentrations. After the diagnosis of acute bodies. In patients with massive overdose, con­ digitalis intoxication, serial determinations of the ventional therapy is ineffective, and survival is serum potassium levels should be obtained. unusual. Antibodies of high affinity and specificity Phenytoin and are useful in suppress­ for digoxin have been used in the laboratory to ing the increased ventricular automaticity without determine serum digoxin concentrations for many suppressing conduction through the AV node in years. In the early 1970s, these antibodies were the digitalis toxic patient. Phenytoin is particularly first considered for intravenous treatment of digi­

useful because it does not decrease the inotropic talis toxicity. The use of whole digoxin-specific http://www.jabfm.org/ effects of digitalis and does suppress some supra­ antibodies was believed to be limited by several ventricular dysrhythmias. potential problems. To avoid these problems, Phenytoin should be given intravenously at a digoxin-specific antibody fragments (Fab) were rate of 50 nig to 100 mg every 5 minutes with developed. 13, 14 close blood-pressure monitoring until the dys­ (Digibind™) has been rhythmia is conirolled, phenytoin toxicity occurs, found to be highly effective in rapidly reversing

or a maximum of 600 mg to 1000 mg is given. 3 life-threatening digoxin and digitoxin intoxica­ on 27 September 2021 by guest. Protected copyright. Lidocaine is given as a 1 mg per kg intravenous tion in a number of patients. 13,I 5 The mechanism bolus followed by an infusion of up to 4 mg per of action of these antibody fragments has been minute. 1 1 well described. Circulating digoxin is rapidly A temporary ttansvenous pacemaker may be bound by the Fab fragments, resulting in a con­ used to abolish ventricular tachyarrhythmias by centration gradient favoring movement of digoxin overdrive suppression. It should be used with from receptor sites in the heart into the circula­ great caution, however, because of the increased tion. Thus, there is a rapid reduction infree serum myocardial excitability and decreased fibrilla tory digoxin concentrations and an initial increase in threshold. For the same reason, electric cardio­ total (bound and unbound) serum digoxin due to version of dysrhythmias other than ventricular drug release from receptors in the heart and other I fibrillation should be used only as it last resort. tissues. After digoxin is bound by the circulating If cardioversion is attempted, low-energy levels antibody fragments, it is pharmacologically inac­ should be employed. 3 tive. This complex is then excreted by the kid-

52 The Journal of the American Board of Family Practice-Vol. 2 No. 1 I January - March 1989

_---II J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.49 on 1 January 1989. Downloaded from ney.13-15 It is important that a digoxin level be de­ between verapamil and digoxin. Because both of 1 tennmed before administration of the digoxin anti­ the drugs are used commonly now, increased fre­ 1 body fragments. A standard serum digoxin concen­ quency of concurrent use and increased frequency tration after the antibody is given will not give an of the production of digitalis toxicity by this inter­ accurate assessment of free (active) digoxin but will action is anticipated. Some cases of toxicity may measure bound (inactive) digoxin as well. IS be prevented by prophylactically lowering the In a recent multicenter study of 63 patients with digitalis dose when verapamil is added and by severe digitalis toxicity, 53 of 56 patients included in closely monitoring for toxicity. the final analysis were safely and effectively treated Digitalis-binding antibody fragments offer a with Digibind™. They generally responded within major advance in our ability to deal with a signifi­ 30 minutes of administration. This 95 percent re­ cant clinical problem. As this therapy becomes sponse rate was achieved in patients with life­ available outside of major medical centers, physi­ threatening cardiac rhythm disturbances, hyper­ cians prescribing digitalis preparation should be­ kalemia, or both, many of whom had failed to come knowledgeable in the use of the digitalis­ respond to conventional measures. There were no binding antibody fragments. The appropriate role obvious allergic or systemic reactions. There was of this therapy currently is in the setting of mas­ no evidence of renal deterioration, nor was there a sive, life-threatening digitalis overdose. As more significant difference in the response of patients clinical experience is gained, this role may be re­ with or without preexisting renal impairment. 16 defined. Familiarity with the use of digitalis-bind­ The therapeutic effects of digitalis are also re­ ing antibodies will enhance our ability to deal versed with the use of digitalis antibody frag­ with this common problem. ments. Reappearance of a rapid ventricular re­ sponse to atrial fibrillation or heart failure may occur. Similarly, a rapid fall in serum potassium concentration occurs as a consequence of revers­ References 1. Gilman AG, Gilman LS, Rail TW, Murad F, eds. ing the effects of digitalis. Potassium concentra­ Goodman and Gilman's the phannacological basis tions should be monitored closely during therapy of therapeutics. 7th ed. New York: MacMillan with Fab fragments to avoid hypokalemia. 16•17 Publishing Company, 1985:716-47. To determine the appropriate dose, two simple 2. Fozzard HA, Sheets MF. Cellular mechanisms of calculations are necessary. The body load (BL) of action of cardiac glycosides. J Am Coil Cardiol 1985; 5(Suppl):lOA-15A. digoxin is the serum digoxin concentration (di­ 3. Haddad LM, Winchester J. Clinical management goxin) in nanograms per milliliter multiplied by of and . Philadelphia: the patient's weight (wt) in kilograms and the vol­ W.B. Saunders Company, 1983:813-28. ume of distribution of digoxin in the body (5.6 in 4. Ordog GJ, Benaron S, Bhasin V, Wasserberger J, http://www.jabfm.org/ liters per kilogram) divided by 1000. Balasubramanium S. Serum digoxin levels and mortality in 5100 patients. Ann Emerg Med 1987; BL(mg) = (digoxin x wt x 5.6)/1000 16:32-9. Each 4 mL vial contains 40 mg of purified di­ 5. Withering W. An account of the foxglove and goxin antibody fragments, which will bind ap­ some of its medical uses; with practical remarks on proximately 0.6 mg of the body load of digoxin. dropsy, and other diseases. Facsimile reprint of Thus, one can calculate the total number of vials 1785 ed. Binningham, AL: The Classics of Medi­ cine Library. Gryphon Editions Ltd, 1979: 184. on 27 September 2021 by guest. Protected copyright. required by dividing the total body load of digoxin 6. Lee TH, Smith TW. Serum digoxin concentration in mg by 0.6 mg/vial. and diagnosis of digitalis toxicity. Current con­ Vials = BL(mg)/0.6(mg) cepts. Clin Pharmacokinet 1983; 8:279-85. In clinical trials, an average of 10 vials was 7. Marcus FL. Phannacokinetic interactions between used. If the digoxin level is unknown, the manu­ digoxin and other drugs. J Am Coil Cardiol1985; 5(Suppl):82A-90A. facturer recommends 20 vials be given. The cost of 8. Zatuchni J. Verapamil-digoxin interaction. Am digoxin immune Fab fragments to a hospital is Heart J 1984; 108:412-3. approximately $175 per vial. 17 9. Pedersen KE, Dorph-Pedersen A, Hvidt S, Klit­ gaard NA, Nielsen-Kudsk F. Digoxin-verapamil interaction. Clin Pharmacol Ther 1981; 30: 311-6. Summary 10. Reza MJ, Kovick RB, Shine KI, Pearce ML. Mas­ A case report of lethal digitalis poisoning has been sive intravenous digoxin overdose. N Engl J Med presented, which has highlighted the interaction 1974; 291:777-8.

Digitalis Toxidty 5) J Am Board Fam Pract: first published as 10.3122/jabfm.2.1.49 on 1 January 1989. Downloaded from II. Greenblatt OJ, Bolognini V, Koch-Weser J, Har­ of digoxin toxicity by digoxin-specific IgG and Fab matz JS. Pharmacokinetic approach to the clin­ fragments. Circulation 1978; 58:280-3. ical use of lidocaine intravenously. JAMA 1976; 15. Smith TW, Haber E, Yeatman L, Butler VP Jr. Re­ 236:2737. versal of advanced digoxin intoxication with Fab 12. Pieroni RE. Fisher JG. Use of cholestyramine resin fragments of digoxin-specific antibodies. N Engl J in digitoxin toxicity. JAMA 1981; 245:1939-40. Med 1976; 294:797-800. 13. Smith TW. Butler VP Jr, Haber E, et al. Treat­ 16. Wenger TL, Butler VP Jr, Haber E, Smith TW. ment of life-threatening digitalis intoxication Treatment of 63 severely digitalis-toxic patients with digoxin-specific Fab antibody fragments: with digoxin-specific antibody fragments. J Am experience in 26 cases. N Engl J Med 1982; Coll Cardiol 1985; 5(Suppl): 118A-123A. 307: 1357-62. 17. Digoxin antibody fragments in digitalis toxicity. 14. Lloyd BL, Smith TW. Contrasting rates of reversal Med Let 1985; 28:87-8.

ANNOUNCEMENT The International Center for Family Medicine (ICFM) will hold its regional meeting in Puerto Rico on March 28-April 2, 1989. The Director General, Dr. julio Ceitlin, tells us that this meeting will be co­ hosted by the Puerto Rico Chapter of the American Academy of Family Physicians and will be of interest to all family physicians. He also tells us that members of the ICFM will get a discounted registration fee ($150 for ICFM members and $250 for nonmembers).

The venue is most attractive and at a decent time of the year at the San juan Hotel in San juan, Puerto Rico. Those physicians interested either in joining the ICFM or attending the regional meeting, please get in touch with the Secretary, Nicholas J. Pisacano, M.D., 2228 Young Drive, Lexington, Kentucky

40505. http://www.jabfm.org/ on 27 September 2021 by guest. Protected copyright.

54 The Journal of the American Board of Family Pradice-Vol. 2 No. I / January - March 1989