Modern Concepts of Cardiovascular Disease

Published monthly by the AMERICAN HEART ASSOCIATION 44 East 23rp StrEET, New York 10, N. Y.

Editor Benepict F, Massett, M.D., Boston

Associate Editor Gorpon S. Myers, M.D., Boston

Copyright 1955 by American Heart Association

Vol. XXIV

NOVEMBER 1955

No. 11

THE USE OF QUINIDINE IN THE TREATMENT OF CARDIAC ARRHYTHMIAS*

Quinidine is of recognized value in the termi- nation and prevention of various cardiac arrhy- thmias. It is the standard agent with which newer anti-arrhythmic drugs are compared. In recent years a number of publications have re- viewed the extensive literature on the therapeutic indications for this drug.’** Of particular inter- est to the practicing physician are the exact indications and contraindications, the nature and frequency of untoward reactions, the routes of administration, and the schedules of doses for termination and prevention of arrhythmias.

Indications

Quinidine has been called the “broad spec- trum” drug for disorders of rhythm. It may be used effectively in the prevention and termina- tion of atrial fibrillation, atrial flutter, atrial extrasystoles, paroxysmal supraventricular tachy- cardia, paroxysmal ventricular tachycardia, and ventricular extrasystoles.

Contraindications

The only absolute contraindication to the use of quinidine is a history of a serious reaction, such as thrombocytopenic purpura, occurring during previous administration of the drug. Also, quinidine should not be used in patients with complete atrioventricular heart block. In the presence of such a conduction disturbance the drug may precipitate or aggravate paroxysms of ventricular tachycardia or ventricular fibrilla- tion.

Relative contraindications to quinidine which are frequently mentioned include partial atrio- ventricular block, bundle-branch block, severe cardiac failure, marked cardiac enlargement, long-standing valvular disease, subacute bacte- rial endocarditis, various acute infections, and advanced age of the patient. The evidence that

*From the Medical Research Department of the Yamins Research Laboratories of the Beth Israel Hospi- tal and the Department of Medicine, Harvard Medical School, Boston, Mass.

these factors increase the likelihood of cardiac toxicity is not conclusive, and they should not prevent the use of the drug when there is a definite indication.

Toxicity

Uncertainty about the toxicity of quinidine undoubtedly contributes to its limited use by many physicians. The experience of many clini- cians, however, indicates that serious reactions are rare.

It has been recommended that a test dose be given before starting a regular schedule of quini- dine administration. Inasmuch as reactions to the drug may be expected to occur within a few hours after a dose, a longer period of observa- tion is not necessary. The appearance of severe untoward symptoms following the first of a pro- posed series of doses will serve as indication for modifying the dosage schedule. These reactions include:

1. Severe sensitivity reactions to quinidine have been reported but are rare. Thrombocy- topenic purpura and fever have been definitely related to the drug; readministration of quini- dine even in small amounts to the sensitized in- dividual has immediately reproduced these re- actions, and such administration is dangerous.

2. Nausea, abdominal discomfort, diarrhea, ringing in the ears, and dizziness are not un- common and may occur even after small doses. If mild these symptoms do not contraindicate further administration of quinidine. Quinidine may cause a slight fall in arterial blood pressure but generally this is not significant.

3. The potentially serious toxicity of quini- dine is related to its depressing action on the heart. The controversial problem of emboliza- tion in patients with chronic atrial fibrillation will not be considered here. Clinical counter- parts of known experimental effects of quinidine have been described in patients with various arrhythmias receiving the drug. These include

sinus arrhythmia, sinus standstill, atrioventricu- lar block, bundle-branch block, ventricular ex- trasystoles, ventricular tachycardia, transient ventricular fibrillation, and death. In many cases these phenomena have been observed with moderate or large doses of quinidine and with relatively high blood concentrations. There also appears to be an important factor of individual susceptibility, and serious reactions have been described with relatively low concentrations of quinidine in the blood. It is pertinent to empha- size the rarity of serious reactions.

When quinidine is being administered, par- ticularly in large doses, it is important to have some guide that will warn of approaching car- diac toxicity. It has been suggested that QRS lengthening of more than 25% of the control value is not safe, but more marked prolongation of the QRS complex has been observed without untoward effect when the situation required larger amounts of the drug. When quinidine administration is associated with sinus standstill, atrioventricular block, bundle-branch block, a rise in ventricular rate, ventricular extrasystoles, ventricular tachycardia, or transient ventricular fibrillation, the drug should be stopped. Fre- quent electrocardiograms are helpful in control- ling the administration of quinidine and in pre- venting serious toxicity.

Routes of Administration

Quinidine is generally administered by mouth since it is promptly and almost completely ab- sorbed from the gastrointestinal tract. Quinidine sulfate is available in 0.1, 0.2, and 0.3 gm. tablets for oral use. Enteric-coated tablets (0.2gm.) may be used to minimize gastric irritation or to delay absorption when given at bedtime.

Parenteral administration of quinidine may be necessary when an acute arrhythmia is asso- ciated with collapse, unconsciousness, vomiting, or other factors that make oral use impossible or absorption from the gastrointestinal tract un- certain. Solutions of quinidine gluconate (0.08 gm. per ml.) or quinidine hydrochloride (0.15 gm. per ml. with antipyrine and urea) are read- ily available. Quinidine acts more quickly by the intramuscular than by the oral route, is at least as effective, and causes even fewer gastrointes- tinal reactions. Quinidine solutions also have been used intravenously in extremely urgent situations; careful control of the rate of infusion is essential to minimize the likelihood of serious toxicity. In general, the intramuscular route is the one of choice for parenteral administration.

Dosage Schedules

Measurements of quinidine blood concentra- tions have provided information necessary for the rational use of the drug. Within fifteen min- utes of a single oral dose of 0.2 to 1.0 gm. of quinidine sulfate, the alkaloid can be detected

300

in the plasma. Maximum levels are reached in one to three hours and may be maintained for two or three hours. The subsequent fall is at first fairly rapid and then slower. Approximately 50% of the peak value remains after eight hours

and 25% after twelve hours. At the end of twenty-four hours only a trace of quinidine can be demonstrated in the plasma. When the same dose of quinidine is administered at two-hour intervals, the plasma concentration increases, but the increase becomes smaller and smaller with each successive dose and the curve levels off after four or five doses. When the same dose is repeated at intervals of four, six, eight or twelve hours, the peak level after several days is not significantly greater than after the first few doses. The maximum concentration is slightly lower when the doses are given every twelve hours than when they are given every six hours; with the more frequent administration the con- centration is maintained at a higher level in the periods between the peaks. When the size of the dose is increased, the height of the peak level is raised appreciably. The size of the individual dose is the most important factor in obtaining a high plasma level of quinidine. Cumulation is minimized by rapid excretion and, therefore, the total daily dose and the total weekly dose are of little significance.

Electrocardiographic studies have related dos- age schedules of quinidine to the action of the drug on the heart. The time of onset of drug action, the time of maximum effect, and the duration of action closely parallel the change in plasma concentration. This close correlation be- tween plasma concentration of quinidine and cardiac action indicates the value of information derived from plasma levels in determining ra- tional dosage schedules.

Dosage schedules must be established in ac- cordance with the requirements of the particular case. Factors which influence the manner in which the drug is given include: the purpose of quinidine administration (whether to terminate or to prevent an arrhythmia), the urgency of the clinical situation, and the estimated risk of toxicity. These considerations influence the deci- sion as to the size of the initial dose and the frequency and size of subsequent doses. Graded doses are administered at appropriate intervals in order to achieve the greatest beneficial effect of the drug at the desired time without the de- velopment of serious toxicity.

An initial dose of 0.2 to 0.6 gm. of quinidine sulfate is commonly used to terminate an arrhy- thmia, the larger amount being used in the more urgent situation. In most cases doses are re- peated at intervals of about two hours; this per- mits observation of the maximum beneficial and untoward effects of each dose. When a more rapidly increasing action is required, the drug may be given every hour, but one must accept the greater risk of untoward effects.

Some evidence of improvement may be noted after the first dose: definite cardiac slowing, rise in blood pressure, decrease in symptoms, or improvement in the patient’s general condition. In such an event the same dose may be repeated every two hours. If normal sinus rhythm has not been restored after three or four equal, two- hourly doses, the size of the dose is increased by 0.1 or 0.2 gm. This dose may then be given three or four times at two-hourly intervals be- fore it is increased further.

In an urgent situation, if a favorable response is not seen two hours after the first dose, the second dose may be 0.1 or 0.2 gm. larger than the first, and subsequent doses may be similarly increased. There is, of course, a greater risk of toxicity with such a schedule. In most cases individual doses do not often need to be raised above 1.2 gm. before normal sinus rhythm is restored.

Four-hourly administration is often utilized for the termination of a mild arrhythmia or for prophylactic purposes. For example, in the con- version of chronic atrial fibrillation quinidine may be administerd every four hours and the size of the individual dose increased by 0.2 gm. every twelve to twenty-four hours. Ample time is thereby afforded to observe the effect of a particular level of quinidine. In the past the drug has too often been declared ineffective in this disorder after inadequate trial because arbi- trarily fixed schedules had been followed.

Quinidine administration at intervals of four to twelve hours is generally utilized to prevent paroxysmal arrhythmias which frequently recur or which, as in the case of ventricular tachy- cardia, are potentially very serious. Initial ad- ministration of 0.2 gm. two or three times a day, if inadequate to prevent recurrent paroxysms, may be followed by larger and more frequent doses; 1.0 gm. doses have been given repeatedly for long periods. Enteric-coated tablets with de- layed absorption may be given at bedtime in cer- tain patients to control paroxysms occurring during the night. Because of the rapidity with which quinidine is eliminated from the body, long-continued administration carries no danger of cumulative toxicity, and the drug has been used prophylactically for years without ill effects.

Continuous rather than intermittent administra- tion is desirable in order to minimize the danger of sensitization. Quinidine may be used to pre- vent arrhythmias which may develop soon after acute myocardial infarction. For this purpose 0.2 to 0.4 gm. is administered three or four times a day. In view of the unpredictability of the occurrence of these arrhythmias the efficacy of such prophylaxis is difficult to evaluate. Routine administration is not advocated, but the appear- ance of ventricular premature beats, for example, is an indication for the use of quinidine to pre- vent more serious disturbances.

In patients undergoing surgery, particularly in the thorax and on the heart, quinidine has been used prophylactically during the operation and the early post-operative period. A dose of 0.4 to 0.6 gm. is given intramuscularly one to two hours before operation and is continued intramuscularly or by mouth every six or eight hours for a few days post-operatively.

SUMMARY

Quinidine is a useful drug in the management of many cardiac arrhythmias. Dosage schedules for the treatment and for the prevention of arrhythmias must be individualized in accord- ance with the requirements of the particular patient and the known facts of the pharmacology of the drug. Serious toxicity is rare.

Arthur J. Linenthal, M.D.

Clinical Associate in Medicine

Harvard Medical School;

Associate in Medicine and Associate in Medical Research

Beth Israel Hospital.

REFERENCES

1. Linenthai, A. J., and Freedberg, A. S.: Measures used in the prevention and treatment of cardiac arrhythmias. N.E.J.Med. 241: 570, 612, 1949.

2. Gold, H.: Quinidine in disorders of the heart. 1950.

P. B. Hoeber, Inc., N. Y.,

3. Sokolow, M.: The present status of therapy of

the cardiac arrhythmia with quinidine. Am. Heart J. 42: 771, 1951.

Love, W. D.: The basis of quinidine therapy. Am.J.Med. Sci 229: 89, 1955.

The opinions and conclusions expressed herein are those of the author and do not neces-

sarily represent the official views of the Scientific Council of the American Heart Association.

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