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Antiarrhythmic drugs. Part III. Quinidine toxicity
Appraisal therapy
and reappraisal Edited
of cardiac
b y A r th ur C. DeGraff
and
Alan
F. Lyon
Antiarrhythmic drugs. Part III. Quinidine toxicity Alan F. Lyon, M.D.* Arthur C. DeGraff, M.D.** New York, N. Y.
T
he use of quinidine in the treatment and control of arrhythmia has always been associated with significant morbidity and a definite mortality risk, despite the most conscientious and informed control of dosage. The wide range in individual dose requirements and drug tolerance makes this unavoidable. In a series which included desperately ill patients in shock and patients in whom (in the absence of any alternative therapy) very high doses were used, the mortality was reported as 2 per cent. The risk under usual circumstances, with a smaller dose, would be considerably less. The toxic manifestations of qunidine are of several types and involve many organs. Toxicity due to allergy. True allergic reactions, reflecting sensitization after prior exposure to the drug, are not uncommon, although usually not life threatening. Skin eruptions have been reported, as well as drug fever both with and without associated skin eruptions. Serious episodes of thrombocytopenic purpura have been produced by quinidine. In this instance, quinidine acts as a hapten and combines with the patient’s platelets to form an antigen to which antibody is produced. When quinidine is again administered, the antibody binds to the quinidine-platelet Received for publication March *Cardiac Therapy Research N.Y., 10468. **Department of Therapeutics,
139
Unit,
22, 1965. Bronx
New
York
Veterans University
complex, and, in the presence of complement, produces lysis of platelets and clinical purpura. A hemolytic anemia has also been produced by quinidine through a similar mechanism. A test has recently been described in which quinidine can be identified as the offending agent in vitro, even during the acute episode. The test is based on the prevention of clot retraction in blood of another subject when small amounts of quinidine and the patient’s serum are added. Toxicity due to idiosyncrasy. Far more common than allergic reactions is idiosyncratic intolerance to relatively low doses of quinidine manifested by symptoms either in the gastrointestinal tract or the central nervous system. The most common reason for the discontinuance of quinidine therapy is the development of gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. Since, unlike the situation with digitalis-induced gastrointestinal symptoms, symptoms due to quinidine are not closely correlated with cardiovascular toxicity, it is reasonable to treat these reactions symptomatically when the patient’s distress is not severe and to continue the administration of quinidine if it seemsto be necessary to do so. Administration School
Hospital.
of Medicine,
130
550 First
West
Kingsbridge
Avenue.
New
York,
Road. N.Y..
Bronx. 10016.
140
Lyon and DeGra$
Less commonly, susceptible patients develop at low doses visual or aural complaints with “cinchonism.” These reactions preclude further use of quinidine, inasmuch as severe complications, such as toxic amblyopia, can develop if therapy is continued. By far the most serious complication of the central nervous system with quinidine therapy is central depression associated with respiratory arrest, convulsion, and death. It has been shown in animals that this can occur quite suddenly and at low dosage. Although sudden death in patients receiving quinidine may be due to cerebral embolism or to the development of a cardiac arrhythmia, it is likely that at least some deaths are due to sudden respiratory depression. To reduce the incidence and severity of these allergic and idiosyncratic reactions, a quinidine test dose has long been recommended. Although the administration of a single dose of 0.2 Gm. of quinidine sulfate may be helpful, it will not detect or prevent all or even many of the reactions mentioned above. The best protection against reactions is close observation and withdrawal of quinidine when reactions occur. Toxicity due to overdosage.The most important toxic responses to quinidine are not due to allergy or to idiosyncrasy to the drug, but are rather the cardiovascular responses to overdosage. Often the first clinically apparent effects of quinidine are electrocardiographic, that is, prominence of the U wave, Q-T prolongation, and QRS prolongation. These manifestations do not properly represent toxicity, but rather therapeutic effect. Clinical experience, however, has indicated that the degree of depolarization block associated with QRS prolongation will frequently be associated with toxicity. Thus, although it is, in itself, not an indication for countermeasures, it should preclude a further increase in the dose. Hypotension, on the other hand, is clearly a toxic effect. Although a depression of cardiac contractility is present at toxic levels, a reduction in peripheral resistance due to quinidine-induced vascular paralysis is the major factor causing hypotension. Direct cardiac toxicity, in addition to any
Am. Heart J. July, 1965
depression of contractility, may be manifested by intra-atria1 block, sinus depression, and sinus node exit block, simulating atria1 standstill. In severe toxicity, A-V nodal block develops. In animals, this is a late and irreversible sign. However, it is reversible in some patients; probably in man it occurs at a lower level of toxicity because of pre-esisting disease of the A-V node. Since quinidine is primarily a depressant, the usual clinical signs of cardiac toxicity, such as ventricular premature contractions, ventricular tachycardia, and ventricular fibrillation (rather than cardiac arrest), cannot be attributed directly to the effects of the drug on the cell membrane, but must be due to hypotension and other deleterious effects of quinidine on the cardiac muscle. Tosic levels of quinidine are associated with depression of serum sodium, and, especially, serum serum potassium, pH. The mechanism of these changes in qunidine intoxication is not understood, but it is likely that they contribute to the toxic manifestations. Treatment of overdosage. There are three potential approaches to the treatment of quinidine toxicity : (1) the administration of drugs that have an opposite effect on contractility, depolarization, and repolarization; (2) the administration of drugs designed to elevate the blood pressure by increasing peripheral resistance; (3) the administration of drugs or solutions designed to correct the electrolyte abnormalities that exist. Drugs in the first group are epinephrine, ephedrine, and isoproterenol. A decade ago it was demonstrated that epinephrine could raise the blood pressure and increase contractility in the presence of quinidine toxicity, but the effect was not striking and clinical experience was quite limited. The use of ephedrine prophylactically during the administration of quinidine has found favor in Europe, on the basis of a clinical study which reported a reduction in sudden deaths when it was used. The findings of this study have not been confirmed. Isoproterenol has been shown to reverse mild cases of quinidine toxicity and to be of prophylactic value in a narrow dose range in animal studies. It has also been reported to have been successful in
l'oi?Jmc70
Number
141
1
the treatment of an episode of quinidine toxicity in man. Clinical experience with drugs in the treatment of quinidine intoxication in the cardiac patient is very limited; the animals in which success has been reported have usually manifested hypotension and bIock; it is not clear whether the ectopic beats and tachycardias seen in human toxicity would be potentiated by these drugs with any frequency. Most of the drugs commonly used in raising the blood pressure by increasing peripheral resistance are ineffective in the presence of quinidine intoxication, apparently because of quinidine-induced paralysis of arteriolar vasoconstriction. Levarterenol, phenylephrine, and methoxamine have been shown to be ineffective in this situation. Arteriolar response to angiotensin is, on the other hand, retained to some extent, and it also favorably affects heart rate and stroke volume, Thus, this pressor drug is moderately effective in quinidine-induced hypotension. Moreover, at least in animals, the effect of angiotensin has been potentiated by the simultaneous administration of disodium calcium EDTA, which has been shown empirically to improve heart rate and stroke volume. The efficacy of molar lactate in correcting the hypotension and, to a lesser extent, the arrhythmias in some cases of moderate quinidine intoxication has been apparent for several years in the laboratory and in the clinic. The earlier experiments which suggested that quinidine causes an actual depletion of intracellular sodium provided a rational basis for the molar lactate therapy, in that it w-aspresumed that the hypertonic sodium solution drove sodium back into the cells. Since more recent studies, although supporting the concept of a delay in the transport of sodium, have failed to confirm intracellular sodium depletion, this postulated mechanism for molar lactate action can no longer be maintained. Nonetheless, there is extracellular acidosis and a lowered serum sodium, both of which the molar sodium lactate tends to correct. The recent demonstration that the organic buffer THAM has a similar favor-
able effect suggests that the correction of acidosis rather than the increase in sodium is the specific mechanism of action, since THAM contains no sodium. Indeed, it has been postulated that THAM is more effective than molar sodium lactate, precisely because it does not increase the serum sodium and thus cause competition with calcium for membrane transfer. Fortunately, clinically documented quinidine overdosage is quite uncommon. This has, however, prevented the accumulation of extensive clinical esperience with any of the treatment routines outlined above. On the basis of the scanty information available, it would
seem that
the administration
of a titrated amount of intravenous angiotensin and of 40 ml. of molar sodium lactate or an equivalent amount of THAM with subsequent titration of buffer as needed is the best treatment of quinidine toxicity available. The role of disodium calcium EDTA and isoproterenol is less well established. There is presently no good clinical evidence for the prophylactic use of any drug or electrolyte during the administration of quinidine. REFERENCES 1. Rellet, S., Hamdan, G., Somlyo, A., and Lara, R.: Reversal of cardiotoxic effects on quinidine by molar sodium lactate. Experimental Study, Am. J. M. SC. 237:165, 1959. 2. Weintraub, R. M., Pechet, L., and Alexander, R.: Rapid diagnosis of drug-induced thrombocytopenic purpura. Report of 3 cases due to quinine, quinidine, and Dilantin, J.A.M.A. 180:528,1962. \3 Sierra, M. A., Keyes, M. H., Williams, R. M., Becker, D. J., Silverblatt, C. W., Gardner. M’. R., and Wasserman, F.: The effect of 2 - amino - 2 - hydroxymethyl -1,3 - propanediol (THAM) in experimental quinidine intoxication, Am. J. Cardiol. 10562, 1962. 4. Gottsegen, G., and &t8r, E.: Prevention of the cardiotoxic effect of quinidine by isoproterenol, AM. HEART J. 65:102, 1963. 5. Luchi, R. J., Helwig, J., Jr., and Conn, H. L., Jr.: Quinidine toxicity and its treatment. An experimental study, AM. HEART J. 65:340, 1963. 6. Thomson, G. W. : Quinidine as a cause of sudden death, Circulation. 14:757, 1965.
and reappraisal Edited
of cardiac
b y A r th ur C. DeGraff
and
Alan
F. Lyon
Antiarrhythmic drugs. Part III. Quinidine toxicity Alan F. Lyon, M.D.* Arthur C. DeGraff, M.D.** New York, N. Y.
T
he use of quinidine in the treatment and control of arrhythmia has always been associated with significant morbidity and a definite mortality risk, despite the most conscientious and informed control of dosage. The wide range in individual dose requirements and drug tolerance makes this unavoidable. In a series which included desperately ill patients in shock and patients in whom (in the absence of any alternative therapy) very high doses were used, the mortality was reported as 2 per cent. The risk under usual circumstances, with a smaller dose, would be considerably less. The toxic manifestations of qunidine are of several types and involve many organs. Toxicity due to allergy. True allergic reactions, reflecting sensitization after prior exposure to the drug, are not uncommon, although usually not life threatening. Skin eruptions have been reported, as well as drug fever both with and without associated skin eruptions. Serious episodes of thrombocytopenic purpura have been produced by quinidine. In this instance, quinidine acts as a hapten and combines with the patient’s platelets to form an antigen to which antibody is produced. When quinidine is again administered, the antibody binds to the quinidine-platelet Received for publication March *Cardiac Therapy Research N.Y., 10468. **Department of Therapeutics,
139
Unit,
22, 1965. Bronx
New
York
Veterans University
complex, and, in the presence of complement, produces lysis of platelets and clinical purpura. A hemolytic anemia has also been produced by quinidine through a similar mechanism. A test has recently been described in which quinidine can be identified as the offending agent in vitro, even during the acute episode. The test is based on the prevention of clot retraction in blood of another subject when small amounts of quinidine and the patient’s serum are added. Toxicity due to idiosyncrasy. Far more common than allergic reactions is idiosyncratic intolerance to relatively low doses of quinidine manifested by symptoms either in the gastrointestinal tract or the central nervous system. The most common reason for the discontinuance of quinidine therapy is the development of gastrointestinal symptoms, such as nausea, vomiting, and diarrhea. Since, unlike the situation with digitalis-induced gastrointestinal symptoms, symptoms due to quinidine are not closely correlated with cardiovascular toxicity, it is reasonable to treat these reactions symptomatically when the patient’s distress is not severe and to continue the administration of quinidine if it seemsto be necessary to do so. Administration School
Hospital.
of Medicine,
130
550 First
West
Kingsbridge
Avenue.
New
York,
Road. N.Y..
Bronx. 10016.
140
Lyon and DeGra$
Less commonly, susceptible patients develop at low doses visual or aural complaints with “cinchonism.” These reactions preclude further use of quinidine, inasmuch as severe complications, such as toxic amblyopia, can develop if therapy is continued. By far the most serious complication of the central nervous system with quinidine therapy is central depression associated with respiratory arrest, convulsion, and death. It has been shown in animals that this can occur quite suddenly and at low dosage. Although sudden death in patients receiving quinidine may be due to cerebral embolism or to the development of a cardiac arrhythmia, it is likely that at least some deaths are due to sudden respiratory depression. To reduce the incidence and severity of these allergic and idiosyncratic reactions, a quinidine test dose has long been recommended. Although the administration of a single dose of 0.2 Gm. of quinidine sulfate may be helpful, it will not detect or prevent all or even many of the reactions mentioned above. The best protection against reactions is close observation and withdrawal of quinidine when reactions occur. Toxicity due to overdosage.The most important toxic responses to quinidine are not due to allergy or to idiosyncrasy to the drug, but are rather the cardiovascular responses to overdosage. Often the first clinically apparent effects of quinidine are electrocardiographic, that is, prominence of the U wave, Q-T prolongation, and QRS prolongation. These manifestations do not properly represent toxicity, but rather therapeutic effect. Clinical experience, however, has indicated that the degree of depolarization block associated with QRS prolongation will frequently be associated with toxicity. Thus, although it is, in itself, not an indication for countermeasures, it should preclude a further increase in the dose. Hypotension, on the other hand, is clearly a toxic effect. Although a depression of cardiac contractility is present at toxic levels, a reduction in peripheral resistance due to quinidine-induced vascular paralysis is the major factor causing hypotension. Direct cardiac toxicity, in addition to any
Am. Heart J. July, 1965
depression of contractility, may be manifested by intra-atria1 block, sinus depression, and sinus node exit block, simulating atria1 standstill. In severe toxicity, A-V nodal block develops. In animals, this is a late and irreversible sign. However, it is reversible in some patients; probably in man it occurs at a lower level of toxicity because of pre-esisting disease of the A-V node. Since quinidine is primarily a depressant, the usual clinical signs of cardiac toxicity, such as ventricular premature contractions, ventricular tachycardia, and ventricular fibrillation (rather than cardiac arrest), cannot be attributed directly to the effects of the drug on the cell membrane, but must be due to hypotension and other deleterious effects of quinidine on the cardiac muscle. Tosic levels of quinidine are associated with depression of serum sodium, and, especially, serum serum potassium, pH. The mechanism of these changes in qunidine intoxication is not understood, but it is likely that they contribute to the toxic manifestations. Treatment of overdosage. There are three potential approaches to the treatment of quinidine toxicity : (1) the administration of drugs that have an opposite effect on contractility, depolarization, and repolarization; (2) the administration of drugs designed to elevate the blood pressure by increasing peripheral resistance; (3) the administration of drugs or solutions designed to correct the electrolyte abnormalities that exist. Drugs in the first group are epinephrine, ephedrine, and isoproterenol. A decade ago it was demonstrated that epinephrine could raise the blood pressure and increase contractility in the presence of quinidine toxicity, but the effect was not striking and clinical experience was quite limited. The use of ephedrine prophylactically during the administration of quinidine has found favor in Europe, on the basis of a clinical study which reported a reduction in sudden deaths when it was used. The findings of this study have not been confirmed. Isoproterenol has been shown to reverse mild cases of quinidine toxicity and to be of prophylactic value in a narrow dose range in animal studies. It has also been reported to have been successful in
l'oi?Jmc70
Number
141
1
the treatment of an episode of quinidine toxicity in man. Clinical experience with drugs in the treatment of quinidine intoxication in the cardiac patient is very limited; the animals in which success has been reported have usually manifested hypotension and bIock; it is not clear whether the ectopic beats and tachycardias seen in human toxicity would be potentiated by these drugs with any frequency. Most of the drugs commonly used in raising the blood pressure by increasing peripheral resistance are ineffective in the presence of quinidine intoxication, apparently because of quinidine-induced paralysis of arteriolar vasoconstriction. Levarterenol, phenylephrine, and methoxamine have been shown to be ineffective in this situation. Arteriolar response to angiotensin is, on the other hand, retained to some extent, and it also favorably affects heart rate and stroke volume, Thus, this pressor drug is moderately effective in quinidine-induced hypotension. Moreover, at least in animals, the effect of angiotensin has been potentiated by the simultaneous administration of disodium calcium EDTA, which has been shown empirically to improve heart rate and stroke volume. The efficacy of molar lactate in correcting the hypotension and, to a lesser extent, the arrhythmias in some cases of moderate quinidine intoxication has been apparent for several years in the laboratory and in the clinic. The earlier experiments which suggested that quinidine causes an actual depletion of intracellular sodium provided a rational basis for the molar lactate therapy, in that it w-aspresumed that the hypertonic sodium solution drove sodium back into the cells. Since more recent studies, although supporting the concept of a delay in the transport of sodium, have failed to confirm intracellular sodium depletion, this postulated mechanism for molar lactate action can no longer be maintained. Nonetheless, there is extracellular acidosis and a lowered serum sodium, both of which the molar sodium lactate tends to correct. The recent demonstration that the organic buffer THAM has a similar favor-
able effect suggests that the correction of acidosis rather than the increase in sodium is the specific mechanism of action, since THAM contains no sodium. Indeed, it has been postulated that THAM is more effective than molar sodium lactate, precisely because it does not increase the serum sodium and thus cause competition with calcium for membrane transfer. Fortunately, clinically documented quinidine overdosage is quite uncommon. This has, however, prevented the accumulation of extensive clinical esperience with any of the treatment routines outlined above. On the basis of the scanty information available, it would
seem that
the administration
of a titrated amount of intravenous angiotensin and of 40 ml. of molar sodium lactate or an equivalent amount of THAM with subsequent titration of buffer as needed is the best treatment of quinidine toxicity available. The role of disodium calcium EDTA and isoproterenol is less well established. There is presently no good clinical evidence for the prophylactic use of any drug or electrolyte during the administration of quinidine. REFERENCES 1. Rellet, S., Hamdan, G., Somlyo, A., and Lara, R.: Reversal of cardiotoxic effects on quinidine by molar sodium lactate. Experimental Study, Am. J. M. SC. 237:165, 1959. 2. Weintraub, R. M., Pechet, L., and Alexander, R.: Rapid diagnosis of drug-induced thrombocytopenic purpura. Report of 3 cases due to quinine, quinidine, and Dilantin, J.A.M.A. 180:528,1962. \3 Sierra, M. A., Keyes, M. H., Williams, R. M., Becker, D. J., Silverblatt, C. W., Gardner. M’. R., and Wasserman, F.: The effect of 2 - amino - 2 - hydroxymethyl -1,3 - propanediol (THAM) in experimental quinidine intoxication, Am. J. Cardiol. 10562, 1962. 4. Gottsegen, G., and &t8r, E.: Prevention of the cardiotoxic effect of quinidine by isoproterenol, AM. HEART J. 65:102, 1963. 5. Luchi, R. J., Helwig, J., Jr., and Conn, H. L., Jr.: Quinidine toxicity and its treatment. An experimental study, AM. HEART J. 65:340, 1963. 6. Thomson, G. W. : Quinidine as a cause of sudden death, Circulation. 14:757, 1965.