- Email: [email protected]
Pharmacologic and clinical control of antiarrhythmic drugs
Pharmacologic and Clinical Control of Antiarrhythmic
J. THOMAS
Drugs
BIGGER, Jr., M.D.
New York, New York
From the College of Physicians and Surgeons of Columbia University, New York, New York. This study was supported in part by a Grant-in-Aid from the New York Heart Association and by U.S. Public Health Service Grant HL 12738. Requests for reprints shoukf be addressed to Dr. J. Thomas Bigger, Jr., College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, New York 10032. Presented at the New York Heart Association Conference on Pharmacological and Clinical Control of Cardiovascuhr Drugs-Controversies in Cardiology, The Waldorf-Astoria, New York, New York, January 22, 1974.
Knowledge of pharmacokinetics and pharmacodynamics is a powerful tool for controlling cardiac arrhythmias with drugs even though antiarrhythmlc drugs are potentially quite toxic. If the diagnosis and drug selection are correct at the outset of therapy, the clinician can use his knowledge of pharmacokinetics to achieve arrhythmia control with a minimum of personal effort and risk to his patient. I intend to discuss here the pharmacokinetic principles which underlie effective, safe antiarrhythmic drug therapy. This discussion presumes that a decision has been made to treat an arrhythmia with an antiarrhythmic drug. This is a complex decision which must be made on the basis of (1) precise electrocardiographic diagnosis of the arrhythmia, (2) a judgment of the risks posed by the arrhythmia, (3) the risks posed by antiarrhythmic therapy, and (4) the decision that some alternate form of therapy is not preferable [I]. This decision also presumes that the particular antiarrhythmic drug to be used for therapy is appropriate and has been selected with due consideration to the antiarrhythmic spectrum of the drug, its cardiovascular effects and its general pharmacology. The thrust of this discussion is to present pharmacokinetic principles which allow the clinician to conduct safe, effective therapy, and to describe simple pharmacokinetic models which predict with considerable accuracy the plasma drug concentration at any given time on any dosing scheme. With the antiarrhythmic drugs currently in use, there is a very high correlation between plasma drug concentration and the cardiac drug actions in the steady state. Furthermore, after rapid drug administration, there is very rapid equilibration between plasma concentration and the cardiac site of drug action. These facts underlie the utility of using pharmacokinetic models to compute effective, safe drug regimens and of measuring plasma drug concentrations to monitor therapy with these drugs. The performance of pharmacokinetic models must be good if they are to be used as tools in antiarrhythmic drug therapy because the therapeutic ratio of all antiarrhythmic drugs is fairly low, i.e., the plasma concentrations which cause significant undesirable effects are not much higher than the concentrations required for effective drug action. First I will discuss the pharmacokinetic models and principles and then illustrate their utility in cardiovascular therapy. Although, currently used antiarrhythmic drugs are used to illustrate these princi-
April 1975
The American Journal of Medicine
Volume 58
479
ANTIARRHYTHMIC DRUGS-BIGGER
A. k,
ke_
I
I
Figure 1. Simple compartmental models useful in planning therapeutic regimens. A, one compartment model. The body is represented by a single homogeneous compartment into which drug enters and from which it leaves. 6, two compartment model. The body is represented by two compatiments-a central compartment (1) and a peripheral comparfment (2). All drug is administered into the central compartment and all elimination takes place from the central compartment. This model is required for predicting plasma concentration when the rate of drug administration exceeds the rate of drug distribution in the body,
ples, it should be pointed out that skill in the use of pharmacokinetic principles is as applicable to new drugs as old. SIMPLE ONE COMPARTMENT MODELS
One Compartment Model. In the one compartment model (Figure l), the entire body is represented as a single, homogeneous compartment into which drugs enter and from which they leave [2,3]. When drugs enter the compartment they are considered to be instantaneously distributed throughout the volume of the compartment so that drug concentration is always given by the amount of drug in the compartment divided by the compartment volume. Experimentally, the apparent volume of distribution of a drug is estimated by dividing the amount of drug in the body by its plasma concentration. For example, if 1,000 mg of a drug is in the body at the time a plasma concentration of 10 mg/liter is measured, the apparent volume of distribution (V,) is 100 liters. The Vd varies directly with body weight and is often expressed as liters per kilogram body weight. The antiarrhythmic drugs have relatively large volumes of distribution in the range of 1.5 to 3.0 liters/kg body weight. In the therapeutic plasma concentration range,
480
April 1975
The American Journal of Medicine
Volume 58
most antiarrhythmic drugs are eliminated from the compartment with first order kinetics, i.e., the amount of drug elimination per unit time is proportional to the amount of drug in the body (elimination is exponential). As noted elsewhere in this symposium, the characteristic first order elimination of a drug is usually expressed as the half-time-the time required for the amount of drug in the body to half itself. For example, if a drug has an elimination halftime of 3 hours, and, if no further drug is administered, plasma drug concentration will fall by half every 3 hours (Figure 1D). During this process, the amount of drug eliminated will also be halved with each succeeding 3 hour period. Administration of drugs commonly takes a number of forms. Figure 2 shows the time course of drug concentration in a 100 liter compartment when 1,000 mg of drug is given in different ways. In the upper row, administration takes place in the absence of elimination; in the lower row, elimination occurs simultaneously. In the absence of elimination, sudden injection of 1,000 mg of drug would lead instantaneously to a concentration of 10 mg/liter in the compartment (Figure 1A) and this concentration would be maintained for an infinite period of time. Figure 2D shows the time-concentration curve if the drug is eliminated with a half-time of 3.0 hours; the drug concentration is halved every 3 hours (see x’s in Figure 2D). In Figure 2B, the 1,000 mg of drug is infused at a constant rate over a 6 hour period (166.7 mg/hour). During constant infusion, in the absence of elimination, the drug concentration rises linearly in the compartment and, after drug administration is discontinued at 6 hours, the concentration remains constant at 10 mg/liter (Figure 2B). Figure 2E shows the same infusion given in the presence of drug elimination (tl/2e = 3.0 hours). Under these circumstances, the steady state concentration in the compartment is given by: [SS] = =
IR (mg. hr-‘) V,(liter)
X K, (hr-‘)
166.7 mg. hr-’ lOOliters
X 0.231 hr-’
= 7.2 mg/liter where [SS]
= steady-state
drug concentration
IR = infusion rate Vd = apparent volume
of distribution
and K, = rate constant ( - 0.693 /t ‘Ize)
for elimination
(1)
DRUGS-BIGGER
ANTIARRHYTHMIC
IO
mglliter 5
I
I
I
I
I
I
2
4
6
6
IO
12
2
4
6
6
IO
12
L
0
I
2
4
6
6
IO
12
2
4
6
6
IO
I2
0
I 2
I 4
0
2
4
I 6
I 6
I IO
I 12
6
6
IO
I2
mglliter
~:jb>h
I//\-,
0
IL
0
HOURS
HOURS
HOURS
Time concentration curves for injection (A and D), infusion (6 and E), and oral Figure 2. (exponential) (C and F) administration of drug in the one compartment model. The volume of the compartment is 100 liters (V, = 100 liters); the amount of drug administered in each instance is 1,000 mg. In the upper row, drug elimination has been set to zero so that the time concentration curve for each mode of administration can be examined without the complication of simultaneous elimination. In the lower row, administration rate and duration are identical to the upper row but drug elimination is taking place (t%e = 3 hours). The drug concentration at any given time during a constant rate infusion is given by: [SS]
X (1 - e-K”)
(2)
where [SS] = steady-state e =
base
drug
of natural
K, = elimination
rate
concentration logarithms constant
t = time Thus, the steady-state concentration of 7.2 mg/liter is approached asymptotically and 90 per cent of the value is achieved in 3.3 elimination half-times. In this instance, 90 per cent of the plateau concentration would be reached at 9.9 hours (3.3 X 3.0 hours). Since the infusion in Figure 2E was discontinued at 6 hours (two half-lives), the plasma concentration only reaches 75 per cent of the steady-state concentration, 5.4 mg/liter. As soon as infusion ceases, the concentration falls exponentially. Figure 2C shows the time-concentration curve for a circumstance in which the drug is administered to an adjacent compartment, e.g., the gut for oral drug administration: the amount of drug falls exponentially in the gut as it moves into the compartment representing the body. The half-time for absorption (t’ha) is 0.33 hour (absorption rate constant, K,, is 2.08 hr-‘), so that 90 per cent of absorption is virtually complete by 1 hour.
Figure 2F shows the same absorption process in the presence of simultaneous elimination. Here, a drug concentration of 7.6 mg/liter is obtained at 1.2 hours and then begins to fall; after absorption is complete (about 2 hours), drug concentration falls exponentially. The ratio of K, to K, determines both the peak concentration obtained and the time at which it occurs. For example, if the rate of absorption were decreased in Figure 2F, the peak concentration would not only occur later, but also be lower. In reality, it takes a finite time to distribute drug throughout its apparent volume of distribution. However, if distribution is significantly faster than the rate of administration or of excretion, then the one compartment model is a useful predictor of plasma concentration against time. Since the distribution of antiarrhythmic drugs, except digitalis, is quite rapid, the one compartment model adequately predicts the plasma concentration-time curve for many drug regimens including intravenous infusion, intramuscular injection and single or multiple oral doses. Two Compartment Model. The two compartment model is used to predict plasma concentration under circumstances when the one compartment model fails, e.g., when the rate of drug administration is rapid relative to the distribution process [4,5]. The two compartments of the model are a central compartment and a peripheral compartment. The central compartment represents the plasma and well per-
April 1975
The American Journal of Medicine
Volume 59
491
ANTIARRHYTHMIC DRUGS-BIGGER
DOSING EXAMPLES USEFUL IN THERAPY -Central ---Peripheral
Intravenous Injection. Intravenous injection is often used for its rapidity in achieving arrhythmia control. Toxic
Effective I
I 2
HOURS
Figure 3. Rapid intravenous injection of 500 mg of procaine amide. The upper panel shows the concentraafion time curve of procaine amide in the central (plasma) and peripheral compartmenfs. The minimum effective and toxic concentrations are indicated. The lower panel diagrammatically depicts the distribution of procaine amide at three times: A, at the instant afier rapid injection when all the drug molecules are in the central compartment; B, at the instant the two compartments come into equilibrium, about 35 minutes after injection; and C, 2 hours after injection when abouf 30 per cent of the dose has been eliminated by renal excretion and hepatic metabolism. Note fha t immediately after injection, toxic concentrations are produced. As procaine amide distributes into the peripheral compartment, the concentration in the plasma (central comparfment) falls into fhe therapeutic range (between minimum effective and toxic concentrations).
fused tissues, and the peripheral compartment the more slowly equilibrating tissues. In the “standard” two compartment model, drug is always administered into the central compartment; also, all elimination takes place from the central compartment, whether by renal excretion, hepatic metabolism or other mechanisms. Most of the antiarrhythmic drugs, e.g., procaine amide, lidocaine, propranolol and diphenylhydantoin, are rapidly distributed to the tissues; the half-time between the compartments of the two compartment model ranges between 5 and 15 minutes. For these drugs, the one compartment model suffices for most modes of drug administration except that of intravenous injection. Digoxin has an intercompartment (distribution) half-time of about 1 to 2 hours; for quinidine, this measurement is not available. 482
April 1975
The American Journal of Medicine
Volume 58
However, this is a relatively risky method of drug administration, and considerable morbidity attends its use. Rapid intravenous injection should only be employed when the risk from the arrhythmia clearly exceeds the risk of intravenous drug injection, and injection should always be as slow as possible. If one knows approximately the ultimate apparent volume of distribution of a drug (e.g., 100 liters) and its usual effective concentration range (e.g., 5 to 10 mg/liter), then it is a simple matter to calculate that a dose of 500 to 1,000 mg will be required in order to reach this concentration as shown in Figures 2A and 2D. If this amount of drug is injected suddenly, plasma concentrations will greatly exceed the prediction of the one compartment model in the initial minutes. The actual time course can be predicted with reasonable accuracy using the two compartment model. Figure 3 shows the plasma concentration-time curve after the sudden intravenous injection of 500 mg of procaine amide. As shown diagrammatically, all the drug is delivered rapidly into the central compartment overwhelming the distribution process and producing a very high initial plasma concentration which may cause severe toxicity. As time elapses, the central and peripheral compartments come into equilibrium (6 in Figure 3), and the plasma concentration of the drug falls to therapeutic concentrations. Note that the early, rapid decline in plasma concentration is not due to elimination from the body but to distribution of the drug into the peripheral compartment. At the time the drug level falls into the therapeutic range, virtually none of the drug has been eliminated either by renal excretion or hepatic metabolism. Several methods have been proposed to avoid the high and potentially dangerous plasma concentrations which are achieved when the effective dose of procaine amide is given as a single intravenous injection. One can simply divide the total effective dose and inject 100 mg doses every 5 minutes (Figure 4A) or infuse the total effective dose bver a 25 to 30 minute period [6,7]. These methods are useful for other antiarrhythmic drugs as well. The urge to rapidly abolish every ventricular premature depolarization (VPD) can cause the clinician to administer antiarrhythmic drugs too rapidly and is responsible for some of the morbidity which still attends the emergency use of antiarrhythmic drugs to treat patients with ventricular arrhythmias. It is encouraging to know that for ventricular arrhythmias, control by drugs is a graded process. Antiarrhythmic effect can be seen at very low drug plasma concentrations, and then a graded increase in arrthymia control proceeds as plasma drug concentration increases until VPDs are abolished at high-
ANTIARRHYTHMIC DRUGS--BIGGER
A.
B.
l+CH__---__--____---___ TOXIC
r----‘5
----------______________ ii\
IO
\
TOXIC
IO-
CT =t
L3
El-
w (3
5 6i LlJ z
4-
MEC
-
z :
2-
: O0
HOURS
2
I
3
HOURS
Two methods for rapid intravenous administration of procaine amide. A, intermittent intravenous injection. Five 100 mg injections of procaine amide were given at 5 minute intervals. A peak plasma concentration of 10.3 pg/ml was obtained. t?, rapid intravenous infusion. A dose of 500 mg was infused over a 25 minute period (20 mg/min). A peak concentration of 8.7 pg/ml was reached. Each of these two methods attains arrhythmti control quickly without the initial toxic plasma concentration seen in Flqure 3, even thocrqhdose and body weight are held constant, because administration is slower and more drug distribution takes place during administration. F&we
4.
er drug concentrations
[8,9]. Thus, these slower technics of initial intravenous drug administration do not subject the patient to significant additional risk from the arrhythmia itself but do significantly lower the morbidity due to drug administration [ 8,9]. Constant Rate Intravenous Infusion. Constant rate intravenous infusion is commonly used in intensive care units for short-term therapy when precision and stability of plasma concentration are desired. However, this means of dosing is slower than either intravenous or intramuscular injection or oral dosing. Of the currently available antiarrhythmic drugs, procaine amide and lidocaine are most often given by this method; diphenylhydantoin (DPH) cannot be given by this method because it either tends to precipitate in intravenous solutions or, if the pH is alkaline enough to solubilize the DPH, it causes phlebitis. Figure 5A shows procaine amide being infused at four different rates-20, 40, 60 and 80 pg/minlkg body weight. Notice that when the infusion rate is doubled or quadrupled, the steady-state procaine amide concentration doubles or quadruples as dictated by equation 1. Similarly, equations 1 and 2 indicate that the steady-state drug concentration will vary linearly with changes in the apparent volume of distribution; to partially compensate for this, infusion rate can be calculated on the basis of body weight (V, varies with body weight). Also, note in Figure 5A that the steadystate procaine amide concentration is reached at the same time with each infusion; 90 per cent of steadystate occurring at about 12 hours (3.3 X 3.5 hours = 11.6 hours). Lidocaine has a shorter half-time than
procaine amide (1.5 to 2.0 hours) and 90 per cent of the steady-state lidocaine concentration is reached in 5 to 7 hours during a constant rate infusion. Two points which are important in antiarrhythmic therapy should be considered here: (1) an infusion rate which will ultimately produce an ideal steady-state concentration will not produce effective concentrations for a considerable time after beginning the infusion (12 hours to minimum effective concentration during 20 pg/min/kg infusion, Figure 5A), and (2) the full therapeutic and/or toxic effect of a constant rate intravenous infusion is not exhibited for many hours after initiating the infusion (12 hours to toxicity during 80 pg/min/kg infusion, Figure 5A). The first fact may lead the impatient clinician to increase the infusion rate to achieve early arrhythmia control, but at the expense of late toxicity. The second fact means that if toxicity occurs during a constant rate infusion, it will come late when the clinician is absent or when his vigilance is low. From equations 1 and 2 it can be seen that an increase in the half-time for elimination (decrease in K,) will not only increase the steadystate drug concentration (equation 1) but also the time to reach steady-state concentrations (equation 2). Thus, constant rate infusion will produce absolutely stable concentrations after plateau has been reached but only if the patient’s physiologic state remains stable. In cardiac intensive care units, ventricular failure or circulatory failure and shock commonly occur. The reduction in regional blood flow to liver, kidney and skeletal muscle which ensues has two important effects April 1975
on the disposition of antiarrhythmic
The American Journal of Medicine
Volume 59
483
ANTIARRHYTHMIC DRUGS--BIGGER
A.
15r
B.
.
80
(~g/min/kg)
~B;____r-__-~
20
__-_--_---se MEC
I OV
0
I
I
I
I
12
24
36
48
0
HOURS
2
4
6
8
DAYS
Intravenous infusion of procaine amide. A, effect of infusion rate on plasma procaine amide concentration. CalFigure 5. culations for a 70 kg subject with V, = 2.0 liters/kg body weight and t’/2 = 4 hours. The concentration-time curve is shown for constant infusion rates of 20, 40, 60 and 80 pg/min/kg body weight. The time at which plateau is reached is independent of infusion rate and only dependent on the elimination rate (90 per cent of plateau being reached at 3.3 times t$$e, 13.2 hours). The time between starting the infusion and achieving minimum antiarrhythmic concentrations (MEC) depends both on infusion rate and the level of MEC. B, effect of circulatory impairment of plasma procaine amide concentration during constant rate infusion. Calculations for a 70 kg subject receiving a 50 ug/min/kg infusion over an 8 day period. During the initial 3 days, V, = 2.0 liters/kg and t& = 4 hours and steady-state plasma concentration is 8.7 pg/ml. On day 3 (arrow), Vd decreases and tr/Z increases by 20 per cent as might occur due to acute ventricular failure. Plasma concentration rises into the toxic range even though the infusion rate is constant.
B.
A.
*r 6
TOXIC
2
MEC
-_------_------------~-~
0 ik 0
2
4
l 6
HOURS
HOURS
Figure 6. Combined intravenous injection and constant rate infusion of lidocaine for rapid onset, sustained antiarrhythmic action. Calculations are for a 60 kg subject with a distribution half-time (cu) of 8 minutes and a disposition half-time (@) of 120 minutes. The minimum effective concentration (MEC) is 1.5 ug/ml. A, an initial intravenous injection of 100 mg lidoCaine is given (arrow) and an infusion of 2.4 mg/min/kg body weight started simultaneously (hatched bar). A peak of 5.1 ug/ml is reached immediately, a minimum of 2.3 pg/ml at 35 minutes, and the steady state concentration of 3.6 ug/ml is reached at about 7 hours. B, the initial injection and constant rate infusion are the same as in A. However, the MEC is 2.8 @g/ml. When the arrhythmia recurs at 35 minutes, a second dose of 100 mg is given and toxic plasma concentrations result. The second injection shouM have been smaller-25 to 50 mg.
484
April 1975
The American Journal of Medicine
Volume 58
ANTIARRHYTHMIC DRUGS-BIGGER
drugs: (1) it decreases the rate of drug elimination by slowing both renal excretion and hepatic metabolism, and (2) it reduces the apparent volume of distribution of antiarrhythmic drugs. Thus, when circulatory failure and shock occur, plasma drug concentration can increase to toxic levels during a constant rate infusion (Figure 5B). Hemodynamic changes leading to excessive plasma concentrations may be subtle, and patients may slip into toxicity on the 2nd or 3rd day of infusion without impressive clinical evidence of change in their hemodynamic state. Also, if lidocaine is the antiarrhythmic drug being infused, symptoms of toxicity are often subtle and easily mistaken for anxiety and personality changes engendered by the acute situational stress. On a number of occasions, we have treated such symptoms with diazepam until measurement of plasma lidocaine revealed their true nature and a reduction in the rate of lidocaine infusion led to the abatement of symptoms. Combined Intravenous Injection and Constant Rate Intravenous Infusion. Because effective plasma concentration of antiarrhythmic drugs are maintained so briefly after sudden injections of safe doses and attained so slowly during constant rate infusion, these two methods have been combined to produce immediate and sustained arrhythmia control. For example, it is common practice to give an injection of 1 to 1.5 mg of lidocaine followed by an infusion at rates between 10 and 50 pg/min/kg body weight [6,10,11]. Figure 6A shows this drug regimen in a hypothetical patient who weighs 60 kg; 100 mg of lidocaine was given by injection followed by 40 pg/min/kg body weight by infusion. The plasma concentration reaches therapeutic levels (usually 1 to 5 pglml) almost immediately, falls to minimum at about 35 minutes, and ultimately reaches plateau at about seven hours. On such a regimen, the arrhythmia which is being treated may reassert itself near the time of minimum plasma concentration. The appropriate response to the recurrence of arrhythmia at this point in therapy is not to change drugs, add a drug or change the infusion rate, but to give an additional injection of lidocaine. I would like to introduce a note of caution here about an error which is still made and not uncommonly. If lidocaine is given when the plasma concentration approaches its minimum, a smaller dose (one-quarter to one-half) should be employed than that which initially controlled the arrhythmia. The error is to inject the same 1.5 mg/kg dose of lidoCaine at 35 minutes as initially. Figure 6B shows the result of this error-the plasma lidocaine concentration not only increases well into the toxic range, but also falls more slowly to the therapeutic range than initially. This response to the second injection results from the fact that at the time of the minimum plasma
concentration, there is more than 200 mg of lidoCaine in the body plus a considerable amount of lidoCaine metabolites. Intramuscular Injection. Several antiarrhythmic drugs are effective when given intramuscularly, e.g., quinidine, procaine amide and lidocaine. This route of administration is useful when oral medication is withheld before or after surgical procedures or in certain emergency situations. These drugs are rapidly absorbed from the site of injection giving rise to a plasma concentration-time curve much like that of oral absorption (Figure 2F). However, drug absorption begins immediately after intramuscular injection whereas absorption of orally administered quinidine and procaine amide does not begin until they encounter the small intestine. For procaine amide or quinidine, intramuscular doses are the same as those employed in oral therapy. During the past 5 years there has been considerable interest in the intramuscular use of lidocaine to treat cardiac arrhythmias. The basis of this interest is the hope that intramuscular administration of lidoCaine may have an important role in controlling arrhythmias in the prehospital phase of acute myocardial infarction. A dose of lidocaine, given in the deltoid muscle, is absorbed very rapidly; in patients hospitalized for acute myocardial infarction, doses of 4 mg/kg body weight produce therapeutic plasma concentrations in 10 to 15 minutes and maintain effective levels for lx to 2 hours [ 12- 161. Intramuscular lidocaine can effectively control the arrhythmias encountered in the hospital phase of acute myocardial infarction. Controlled clinical trials are needed to evaluate the use of lidocaine in the prehospital phase of acute myocardial infarction (1) at home or during transportation to the hospital, and (2) during transportation from the hospital emergency room to the coronary care unit. The intramuscular use of diphenyhydantoin to treat cardiac arrhythmias has been disappointing. Although arrhythmias can be controlled via this method, the plasma concentrations are erratic after intramuscular doses, and the area under the plasma concentration time curve is often less than for an identical oral dose, suggesting that some of the intramuscular dose is bound locally by proteins. Oral Administration. Although emergency and special situations may dictate arrhythmia control by parenterally administered drugs, most acute and virtually all chronic arrhythmia control is accomplished by oral drug administration. Lidocaine is not used orally to control cardiac arrhythmias because, when given by this route, effective, plasma concentrations are difficult to achieve without symptoms. As lidocaine is absorbed from the
April 1975
The American Journal of Medicine
Volume 59
495
ANTIARRHYTHMIC DRUGS-BIGGER
gastrointestinal tract, it is carried to the liver in portal vein blood and rapidly metabolized (deethylated). The nausea, vomiting and dizziness seen after oral doses may be partially attributed to lidocaine metabolites [ 171. Quinidine and procaine amide are well absorbed and are usually given orally. Both of these compounds are weak organic bases and are highly ionized at the usual pH of the stomach. For example, procaine amide with a pKa of 8.9 is virtually 100 per cent ionized at pH 1.5. Since it is the unionized form of these basic drugs which is absorbed, there is little, if any, absorption from the stomach. Thus, the onset of absorption is determined by the gastric transit time. Once absorption begins in the small intestine, it is rapid and essentially complete; the peak plasma concentration is attained between 45 minutes and 2 hours after a single oral dose of quinidine or procaine amide. Propranolol is more erratically absorbed from the gastrointestinal tract and there is great variability between patients in the fraction of a dose which is absorbed; this largely accounts for the sevenfold difference in plasma concentration found in a group of patients given an identical dose of propranolol [ 181. Also, like lidocaine, propranolol in portal vein blood is cleared during passage through the liver [ 191. As Figure 2F shows, the plasma concentration falls as a function of the elimination rate constant once absorption is completed. With the high ka:ke ratio of antiarrhythmic drugs (see Figure l), the duration of drug action is dependent primarily on the peak concentration, the minimum effective concentration and the half-time for elimination. Raising the dose of drug will increase the peak plasma concentration and prolong drug action. However, repeatedly doubling the dose will not double the duration of drug action since, at the increased plasma concentrations, elimination will initially be faster; the duration of therapeutically effective drug concentration increases as the logarithm of the amount of drug in the body [2]. The toxic concentration limits the duration of action which can be achieved by increasing the size of single doses, and multiple oral doses are used to maintain effective drug concentrations. Multiple Oral Doses. Multiple oral dosing is the most common dosing technic used in drug therapy, including antiarrhythmic drug therapy. Discussion of idealized regimens for multiple oral doses often suggest that a loading dose equal to the desired effective concentration times the apparent volume of distribution be given followed by repeated doses half this size given at intervals equal to the drug’s half-life. This regimen produces effective concentrations almost immediately and maintains them; the plasma concentration will fluctuate by 50 per cent between
488
April 1975
The American Journal of Medicine
Volume 58
doses. Such a regimen is only practical for quinidine which has a half-life around 6 to 7 hours. For example, if quinidine’s apparent volume of distribution is about 125 liters and a plasma concentration of 4 yglml is desired, an initial dose of 500 mg could be given and followed by 250 mg every 6 hours. With antiarrhythmic agents having shorter half-lives, e.g., propranolol or procaine amide, this technic of dosing becomes impractical because of the inconvenience of a chronic regimen which requires the patient to take the drug every 2x to 4 hours. If these drugs are given at convenient intervals, such as every 6 to 8 hours, the fluctuation in plasma concentration between doses will be much greater than 50 per cent. Since the therapeutic ratio of these drugs is narrow, wide fluctuations run the risk either of causing toxicity at peak concentrations or of losing arrhythmia control at the minimum concentration. These events can easily be checked during quinidine or procaine amide therapy by observation of the blood pressure and, more importantly, the electrocardiogram. For optimum results, observations should be made rather precisely at the peak and valley of concentration, i.e., 1 to 1 yZ hours after a dose and just before the next dose. Observations made at other times are not as useful and may be misleading. At the peak, one looks for toxic manifestations; with quinidine and procaine amide the primary toxic effect being sought is excessive QRS widening. At the time of minimum concentrations, one should look for return of the arrhythmia or loss of the drug effect on the QRS [ 201. Repeated observations as the drug regimen is adjusted provides immediate feedback and usually allows the therapist to arrive rapidly at a safe, effective regimen without measuring plasma drug concentrations. For quinidine, procaine amide and propranolol, loading doses are not usually required because of their short half-life; steady-state concentration is achieved at 3.3 times the half-life-within 1 day. DPH has a “half-life” of 20 to 40 hours so that it may require a week or more to reach steady-state concentrations when giving constant doses at constant intervals. Therefore, an initial loading dose is useful when initiating therapy with this agent [8]. It should be remembered that oral absorption is rapid. To forget this may cause problems when changing from intravenous infusion to oral dosing. Figure 7 shows an example, the patient has received procaine amide by constant rate intravenous infusion for several days at the rate of 1,000 mg every 6 hours. Intravenous therapy is discontinued and oral therapy, 1,000 mg every 6 hours, is begun immediately. Although oral therapy with this dose and dosing interval will ultimately be satisfactory, it causes initial toxicity because the orally administered drug is entering the body much
ANTIARRHYTHMICDRUGS--BIGGER
more rapidly than the previous intravenous infusion. To avoid this problem, the drug plasma concentration should be allowed to fall below the mean desired concentration before beginning oral doses (Figure 7, bottom). Long-term oral therapy presents many problems: lack of compliance to the drug regimen, changes in the underlying arrhythmic process, insufficient plasma drug concentrations and drug toxicity are all important problems. Drug toxicity may come about due to either excess plasma concentration or immunologic reactions in the presence of the drug. The latter reactions, such as the procaine amide-induced lupus erythematosus-like syndrome or quinidine-induced thrombocytopenia, can only be combatted by the physician’s awareness of the syndromes and careful monitoring of patients for early signs of toxicity. Toxicity due to excessive drug concentrations can be avoided in most instances by a clear understanding of the processes responsible for absorption, distribution and elimination of the drugs being employed, and frequent reevaluation of factors which would alter the body’s handling of drugs. As discussed under constant rate infusion, the elimination of antiarrhythmic drugs will be slowed if congestive heart failure develops or worsens due to reduced hepatic and renal blood flow (Figure 5B). Changes in cardiac compensation are often subtle. Drug interactions may alter the plasma concentration of drugs. For example, institution of therapy which produces an alkaline urine, e.g., sodium bicarbonate or acetazolamide will slow the elimination of the organic bases quinidine and procaine amide. Also, changes in the physiologic state may increase the cardiac effect of a given plasma concentration. Advancing renal failure may not only slow the elimination of some drugs but also when hyperkalemia occurs, the increased potassium ion concentration augments the cardiac action of antiarihythmic drugs. Of course, the problem of inadequate plasma concentration of drugs for arrhythmia
0
’
I
0
6
I2
6
24
TIME IN HOURS Figure 7. changing from constant rate intravenous infusion (1,000 mg every 6 hours) to oral dosing regimen of procaine amide (1,000 mg every 6 hours) tv# = 4.0 hours; V, = 140 liters. Top, first oral dose given immediate/y after discontinuing intravenous infusion. Bottom, first oral dose given 4.0 hours (one half-life) after discontinuing infusion. From Bigger and Giardina [ 151.
control is also a serious problem in chronic oral therapy. Here, lack of patient compliance to drug regiment is the most common problem. A major contributing factor to lack of compliance is the inconvenience of most antiarrhythmic regimens which require many doses a day due to the short half-life of the drugs. There is an urgent need for antiarrhythmic drugs with longer half-lives for use in long-term theraPY.
REFERENCES 1. 2.
3. 4.
5.
6.
and lidocaine in the treatment of cardiac arrhythmias. Prog Cardiovasc Dis 6: 5 15, 1969. Giardina EGV, Heissenbuttel RH, Bigger JT Jr: Intermittent intravenous procaine amide to treat ventricular arrhythmias. Correlation of plasma concentration with effect on arrhythmia, electrocardiogram, and blood pressure. Ann Intern Med 78: 183, 1973. Bigger JT Jr, Schmidt DH, Kutt H: Relationship between the plasma level of diphenylhydantoin sodium and its cardiac antiarrhythmic effect. Circulation 38: 363, 1968. Giardina EGV, Bigger JT Jr: Procaine amide against reentrant ventricular arrhythmias. Lengthening R-V intervals of coupled ventricular premature depolarizations as an insight into the mechanism of action of procaine amide. Circulation 48: 959, 1973.
Bigger JT Jr: Arrhythmias and antiarrhythmic drugs. Adv Intern Med 18: 251. 1972. Goldstein A, Aronow L, Kalman SM: The time course of drug action, chap 4. Principles in Drug Action: The Basis of Pharmacology, New York, John Wiley 8 Sons, 1974. Wagner JG: Pharmacokinetics. Ann Rev Pharmacol 8: 67, 1968. Riegelman S, Loo J: Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J Pharm Sci 57: 117, 1968. Riegelman S. Loo J, Rowland M: The concept of a volume of distribution and possible errors in evaluation of this. parameter. J Pharm Sci 57: 128, 1968. Bigger JT Jr, Heissenbuttel RH: The use of procaine amide
April 1975
The American Journal of Medicine
Volume 59
487
ANTIARRHYTHMICDRUGS-BIGGER
10.
11.
12.
13.
14.
15.
488
Gianelly R, von der Groeben JO, Spivak AP. Harrison DC: Effect of lidocaine on ventricular arrhythmias in coronary heart disease. N Engl J Med 277: 1215, 1967. Kimball JT. Killip T: Aggressive treatment of arrhythmias in acute myocardial infarction. Procedure and results. Prog Cardiovasc Dis 10: 483, 1968. Bell& S, Roman L, Kostis JB, Fleischmann D: Intramuscular lidocaine in the therapy of ventricular arrhythmias. Am J Cardiol 27: 291. 1971. Cohen L, Rosenthal J, Horner D, Atkins J, Matthews 0, Sarnoff S: Plasma levels of lidocaine after intramuscular administration. Am J Cardiol 29: 520, 1972. Fehmers M. Dunning A: Intramuscularly and orally administered lidocaine in the treatment of ventricular arrhythmias in acute myocardial infarction. Am J Cardiol 29: 514.1972. Bigger JT Jr, Giardina EGV: The pharmacological and clini-
April 1975
The American Journal of Medicine
Volume 58
16.
17. 18.
19.
20.
cal use of lidocaine and procaine amide. Va Med Q 9: 65, 1973. Zener JC, Kerber RE, Spivak AP, Harrison DC: Blood lidoCaine levels and kinetics following high dose intramuscular administration. Circulation 47: 984, 1973. Scott DB, Jebson PJ. Godman MJ, Julian DG: Oral lignoCaine. Lancet 1: 93, 1970. Shand DG, Nuckolls EM, Oates JA: Plasma propranolol levels in adults with observations in four children. Clin Pharmacol Ther 11: 112, 1970. Paterson JW, Conally ME= Dollery CT, Hayes A, Cooper RG: The pharmacodynamics and metabolism of propran0101in man. Pharmacol Clin 2: 127, 1970. Heissenbuttel RH, Bigger JT Jr: The effect of oral quinidine on intraventricular conduction in man. Correlation of plasma quinidine with changes in intraventricular conduction time. Am Heart J 80: 453, 1970.
J. THOMAS
Drugs
BIGGER, Jr., M.D.
New York, New York
From the College of Physicians and Surgeons of Columbia University, New York, New York. This study was supported in part by a Grant-in-Aid from the New York Heart Association and by U.S. Public Health Service Grant HL 12738. Requests for reprints shoukf be addressed to Dr. J. Thomas Bigger, Jr., College of Physicians and Surgeons of Columbia University, 630 West 168th Street, New York, New York 10032. Presented at the New York Heart Association Conference on Pharmacological and Clinical Control of Cardiovascuhr Drugs-Controversies in Cardiology, The Waldorf-Astoria, New York, New York, January 22, 1974.
Knowledge of pharmacokinetics and pharmacodynamics is a powerful tool for controlling cardiac arrhythmias with drugs even though antiarrhythmlc drugs are potentially quite toxic. If the diagnosis and drug selection are correct at the outset of therapy, the clinician can use his knowledge of pharmacokinetics to achieve arrhythmia control with a minimum of personal effort and risk to his patient. I intend to discuss here the pharmacokinetic principles which underlie effective, safe antiarrhythmic drug therapy. This discussion presumes that a decision has been made to treat an arrhythmia with an antiarrhythmic drug. This is a complex decision which must be made on the basis of (1) precise electrocardiographic diagnosis of the arrhythmia, (2) a judgment of the risks posed by the arrhythmia, (3) the risks posed by antiarrhythmic therapy, and (4) the decision that some alternate form of therapy is not preferable [I]. This decision also presumes that the particular antiarrhythmic drug to be used for therapy is appropriate and has been selected with due consideration to the antiarrhythmic spectrum of the drug, its cardiovascular effects and its general pharmacology. The thrust of this discussion is to present pharmacokinetic principles which allow the clinician to conduct safe, effective therapy, and to describe simple pharmacokinetic models which predict with considerable accuracy the plasma drug concentration at any given time on any dosing scheme. With the antiarrhythmic drugs currently in use, there is a very high correlation between plasma drug concentration and the cardiac drug actions in the steady state. Furthermore, after rapid drug administration, there is very rapid equilibration between plasma concentration and the cardiac site of drug action. These facts underlie the utility of using pharmacokinetic models to compute effective, safe drug regimens and of measuring plasma drug concentrations to monitor therapy with these drugs. The performance of pharmacokinetic models must be good if they are to be used as tools in antiarrhythmic drug therapy because the therapeutic ratio of all antiarrhythmic drugs is fairly low, i.e., the plasma concentrations which cause significant undesirable effects are not much higher than the concentrations required for effective drug action. First I will discuss the pharmacokinetic models and principles and then illustrate their utility in cardiovascular therapy. Although, currently used antiarrhythmic drugs are used to illustrate these princi-
April 1975
The American Journal of Medicine
Volume 58
479
ANTIARRHYTHMIC DRUGS-BIGGER
A. k,
ke_
I
I
Figure 1. Simple compartmental models useful in planning therapeutic regimens. A, one compartment model. The body is represented by a single homogeneous compartment into which drug enters and from which it leaves. 6, two compartment model. The body is represented by two compatiments-a central compartment (1) and a peripheral comparfment (2). All drug is administered into the central compartment and all elimination takes place from the central compartment. This model is required for predicting plasma concentration when the rate of drug administration exceeds the rate of drug distribution in the body,
ples, it should be pointed out that skill in the use of pharmacokinetic principles is as applicable to new drugs as old. SIMPLE ONE COMPARTMENT MODELS
One Compartment Model. In the one compartment model (Figure l), the entire body is represented as a single, homogeneous compartment into which drugs enter and from which they leave [2,3]. When drugs enter the compartment they are considered to be instantaneously distributed throughout the volume of the compartment so that drug concentration is always given by the amount of drug in the compartment divided by the compartment volume. Experimentally, the apparent volume of distribution of a drug is estimated by dividing the amount of drug in the body by its plasma concentration. For example, if 1,000 mg of a drug is in the body at the time a plasma concentration of 10 mg/liter is measured, the apparent volume of distribution (V,) is 100 liters. The Vd varies directly with body weight and is often expressed as liters per kilogram body weight. The antiarrhythmic drugs have relatively large volumes of distribution in the range of 1.5 to 3.0 liters/kg body weight. In the therapeutic plasma concentration range,
480
April 1975
The American Journal of Medicine
Volume 58
most antiarrhythmic drugs are eliminated from the compartment with first order kinetics, i.e., the amount of drug elimination per unit time is proportional to the amount of drug in the body (elimination is exponential). As noted elsewhere in this symposium, the characteristic first order elimination of a drug is usually expressed as the half-time-the time required for the amount of drug in the body to half itself. For example, if a drug has an elimination halftime of 3 hours, and, if no further drug is administered, plasma drug concentration will fall by half every 3 hours (Figure 1D). During this process, the amount of drug eliminated will also be halved with each succeeding 3 hour period. Administration of drugs commonly takes a number of forms. Figure 2 shows the time course of drug concentration in a 100 liter compartment when 1,000 mg of drug is given in different ways. In the upper row, administration takes place in the absence of elimination; in the lower row, elimination occurs simultaneously. In the absence of elimination, sudden injection of 1,000 mg of drug would lead instantaneously to a concentration of 10 mg/liter in the compartment (Figure 1A) and this concentration would be maintained for an infinite period of time. Figure 2D shows the time-concentration curve if the drug is eliminated with a half-time of 3.0 hours; the drug concentration is halved every 3 hours (see x’s in Figure 2D). In Figure 2B, the 1,000 mg of drug is infused at a constant rate over a 6 hour period (166.7 mg/hour). During constant infusion, in the absence of elimination, the drug concentration rises linearly in the compartment and, after drug administration is discontinued at 6 hours, the concentration remains constant at 10 mg/liter (Figure 2B). Figure 2E shows the same infusion given in the presence of drug elimination (tl/2e = 3.0 hours). Under these circumstances, the steady state concentration in the compartment is given by: [SS] = =
IR (mg. hr-‘) V,(liter)
X K, (hr-‘)
166.7 mg. hr-’ lOOliters
X 0.231 hr-’
= 7.2 mg/liter where [SS]
= steady-state
drug concentration
IR = infusion rate Vd = apparent volume
of distribution
and K, = rate constant ( - 0.693 /t ‘Ize)
for elimination
(1)
DRUGS-BIGGER
ANTIARRHYTHMIC
IO
mglliter 5
I
I
I
I
I
I
2
4
6
6
IO
12
2
4
6
6
IO
12
L
0
I
2
4
6
6
IO
12
2
4
6
6
IO
I2
0
I 2
I 4
0
2
4
I 6
I 6
I IO
I 12
6
6
IO
I2
mglliter
~:jb>h
I//\-,
0
IL
0
HOURS
HOURS
HOURS
Time concentration curves for injection (A and D), infusion (6 and E), and oral Figure 2. (exponential) (C and F) administration of drug in the one compartment model. The volume of the compartment is 100 liters (V, = 100 liters); the amount of drug administered in each instance is 1,000 mg. In the upper row, drug elimination has been set to zero so that the time concentration curve for each mode of administration can be examined without the complication of simultaneous elimination. In the lower row, administration rate and duration are identical to the upper row but drug elimination is taking place (t%e = 3 hours). The drug concentration at any given time during a constant rate infusion is given by: [SS]
X (1 - e-K”)
(2)
where [SS] = steady-state e =
base
drug
of natural
K, = elimination
rate
concentration logarithms constant
t = time Thus, the steady-state concentration of 7.2 mg/liter is approached asymptotically and 90 per cent of the value is achieved in 3.3 elimination half-times. In this instance, 90 per cent of the plateau concentration would be reached at 9.9 hours (3.3 X 3.0 hours). Since the infusion in Figure 2E was discontinued at 6 hours (two half-lives), the plasma concentration only reaches 75 per cent of the steady-state concentration, 5.4 mg/liter. As soon as infusion ceases, the concentration falls exponentially. Figure 2C shows the time-concentration curve for a circumstance in which the drug is administered to an adjacent compartment, e.g., the gut for oral drug administration: the amount of drug falls exponentially in the gut as it moves into the compartment representing the body. The half-time for absorption (t’ha) is 0.33 hour (absorption rate constant, K,, is 2.08 hr-‘), so that 90 per cent of absorption is virtually complete by 1 hour.
Figure 2F shows the same absorption process in the presence of simultaneous elimination. Here, a drug concentration of 7.6 mg/liter is obtained at 1.2 hours and then begins to fall; after absorption is complete (about 2 hours), drug concentration falls exponentially. The ratio of K, to K, determines both the peak concentration obtained and the time at which it occurs. For example, if the rate of absorption were decreased in Figure 2F, the peak concentration would not only occur later, but also be lower. In reality, it takes a finite time to distribute drug throughout its apparent volume of distribution. However, if distribution is significantly faster than the rate of administration or of excretion, then the one compartment model is a useful predictor of plasma concentration against time. Since the distribution of antiarrhythmic drugs, except digitalis, is quite rapid, the one compartment model adequately predicts the plasma concentration-time curve for many drug regimens including intravenous infusion, intramuscular injection and single or multiple oral doses. Two Compartment Model. The two compartment model is used to predict plasma concentration under circumstances when the one compartment model fails, e.g., when the rate of drug administration is rapid relative to the distribution process [4,5]. The two compartments of the model are a central compartment and a peripheral compartment. The central compartment represents the plasma and well per-
April 1975
The American Journal of Medicine
Volume 59
491
ANTIARRHYTHMIC DRUGS-BIGGER
DOSING EXAMPLES USEFUL IN THERAPY -Central ---Peripheral
Intravenous Injection. Intravenous injection is often used for its rapidity in achieving arrhythmia control. Toxic
Effective I
I 2
HOURS
Figure 3. Rapid intravenous injection of 500 mg of procaine amide. The upper panel shows the concentraafion time curve of procaine amide in the central (plasma) and peripheral compartmenfs. The minimum effective and toxic concentrations are indicated. The lower panel diagrammatically depicts the distribution of procaine amide at three times: A, at the instant afier rapid injection when all the drug molecules are in the central compartment; B, at the instant the two compartments come into equilibrium, about 35 minutes after injection; and C, 2 hours after injection when abouf 30 per cent of the dose has been eliminated by renal excretion and hepatic metabolism. Note fha t immediately after injection, toxic concentrations are produced. As procaine amide distributes into the peripheral compartment, the concentration in the plasma (central comparfment) falls into fhe therapeutic range (between minimum effective and toxic concentrations).
fused tissues, and the peripheral compartment the more slowly equilibrating tissues. In the “standard” two compartment model, drug is always administered into the central compartment; also, all elimination takes place from the central compartment, whether by renal excretion, hepatic metabolism or other mechanisms. Most of the antiarrhythmic drugs, e.g., procaine amide, lidocaine, propranolol and diphenylhydantoin, are rapidly distributed to the tissues; the half-time between the compartments of the two compartment model ranges between 5 and 15 minutes. For these drugs, the one compartment model suffices for most modes of drug administration except that of intravenous injection. Digoxin has an intercompartment (distribution) half-time of about 1 to 2 hours; for quinidine, this measurement is not available. 482
April 1975
The American Journal of Medicine
Volume 58
However, this is a relatively risky method of drug administration, and considerable morbidity attends its use. Rapid intravenous injection should only be employed when the risk from the arrhythmia clearly exceeds the risk of intravenous drug injection, and injection should always be as slow as possible. If one knows approximately the ultimate apparent volume of distribution of a drug (e.g., 100 liters) and its usual effective concentration range (e.g., 5 to 10 mg/liter), then it is a simple matter to calculate that a dose of 500 to 1,000 mg will be required in order to reach this concentration as shown in Figures 2A and 2D. If this amount of drug is injected suddenly, plasma concentrations will greatly exceed the prediction of the one compartment model in the initial minutes. The actual time course can be predicted with reasonable accuracy using the two compartment model. Figure 3 shows the plasma concentration-time curve after the sudden intravenous injection of 500 mg of procaine amide. As shown diagrammatically, all the drug is delivered rapidly into the central compartment overwhelming the distribution process and producing a very high initial plasma concentration which may cause severe toxicity. As time elapses, the central and peripheral compartments come into equilibrium (6 in Figure 3), and the plasma concentration of the drug falls to therapeutic concentrations. Note that the early, rapid decline in plasma concentration is not due to elimination from the body but to distribution of the drug into the peripheral compartment. At the time the drug level falls into the therapeutic range, virtually none of the drug has been eliminated either by renal excretion or hepatic metabolism. Several methods have been proposed to avoid the high and potentially dangerous plasma concentrations which are achieved when the effective dose of procaine amide is given as a single intravenous injection. One can simply divide the total effective dose and inject 100 mg doses every 5 minutes (Figure 4A) or infuse the total effective dose bver a 25 to 30 minute period [6,7]. These methods are useful for other antiarrhythmic drugs as well. The urge to rapidly abolish every ventricular premature depolarization (VPD) can cause the clinician to administer antiarrhythmic drugs too rapidly and is responsible for some of the morbidity which still attends the emergency use of antiarrhythmic drugs to treat patients with ventricular arrhythmias. It is encouraging to know that for ventricular arrhythmias, control by drugs is a graded process. Antiarrhythmic effect can be seen at very low drug plasma concentrations, and then a graded increase in arrthymia control proceeds as plasma drug concentration increases until VPDs are abolished at high-
ANTIARRHYTHMIC DRUGS--BIGGER
A.
B.
l+CH__---__--____---___ TOXIC
r----‘5
----------______________ ii\
IO
\
TOXIC
IO-
CT =t
L3
El-
w (3
5 6i LlJ z
4-
MEC
-
z :
2-
: O0
HOURS
2
I
3
HOURS
Two methods for rapid intravenous administration of procaine amide. A, intermittent intravenous injection. Five 100 mg injections of procaine amide were given at 5 minute intervals. A peak plasma concentration of 10.3 pg/ml was obtained. t?, rapid intravenous infusion. A dose of 500 mg was infused over a 25 minute period (20 mg/min). A peak concentration of 8.7 pg/ml was reached. Each of these two methods attains arrhythmti control quickly without the initial toxic plasma concentration seen in Flqure 3, even thocrqhdose and body weight are held constant, because administration is slower and more drug distribution takes place during administration. F&we
4.
er drug concentrations
[8,9]. Thus, these slower technics of initial intravenous drug administration do not subject the patient to significant additional risk from the arrhythmia itself but do significantly lower the morbidity due to drug administration [ 8,9]. Constant Rate Intravenous Infusion. Constant rate intravenous infusion is commonly used in intensive care units for short-term therapy when precision and stability of plasma concentration are desired. However, this means of dosing is slower than either intravenous or intramuscular injection or oral dosing. Of the currently available antiarrhythmic drugs, procaine amide and lidocaine are most often given by this method; diphenylhydantoin (DPH) cannot be given by this method because it either tends to precipitate in intravenous solutions or, if the pH is alkaline enough to solubilize the DPH, it causes phlebitis. Figure 5A shows procaine amide being infused at four different rates-20, 40, 60 and 80 pg/minlkg body weight. Notice that when the infusion rate is doubled or quadrupled, the steady-state procaine amide concentration doubles or quadruples as dictated by equation 1. Similarly, equations 1 and 2 indicate that the steady-state drug concentration will vary linearly with changes in the apparent volume of distribution; to partially compensate for this, infusion rate can be calculated on the basis of body weight (V, varies with body weight). Also, note in Figure 5A that the steadystate procaine amide concentration is reached at the same time with each infusion; 90 per cent of steadystate occurring at about 12 hours (3.3 X 3.5 hours = 11.6 hours). Lidocaine has a shorter half-time than
procaine amide (1.5 to 2.0 hours) and 90 per cent of the steady-state lidocaine concentration is reached in 5 to 7 hours during a constant rate infusion. Two points which are important in antiarrhythmic therapy should be considered here: (1) an infusion rate which will ultimately produce an ideal steady-state concentration will not produce effective concentrations for a considerable time after beginning the infusion (12 hours to minimum effective concentration during 20 pg/min/kg infusion, Figure 5A), and (2) the full therapeutic and/or toxic effect of a constant rate intravenous infusion is not exhibited for many hours after initiating the infusion (12 hours to toxicity during 80 pg/min/kg infusion, Figure 5A). The first fact may lead the impatient clinician to increase the infusion rate to achieve early arrhythmia control, but at the expense of late toxicity. The second fact means that if toxicity occurs during a constant rate infusion, it will come late when the clinician is absent or when his vigilance is low. From equations 1 and 2 it can be seen that an increase in the half-time for elimination (decrease in K,) will not only increase the steadystate drug concentration (equation 1) but also the time to reach steady-state concentrations (equation 2). Thus, constant rate infusion will produce absolutely stable concentrations after plateau has been reached but only if the patient’s physiologic state remains stable. In cardiac intensive care units, ventricular failure or circulatory failure and shock commonly occur. The reduction in regional blood flow to liver, kidney and skeletal muscle which ensues has two important effects April 1975
on the disposition of antiarrhythmic
The American Journal of Medicine
Volume 59
483
ANTIARRHYTHMIC DRUGS--BIGGER
A.
15r
B.
.
80
(~g/min/kg)
~B;____r-__-~
20
__-_--_---se MEC
I OV
0
I
I
I
I
12
24
36
48
0
HOURS
2
4
6
8
DAYS
Intravenous infusion of procaine amide. A, effect of infusion rate on plasma procaine amide concentration. CalFigure 5. culations for a 70 kg subject with V, = 2.0 liters/kg body weight and t’/2 = 4 hours. The concentration-time curve is shown for constant infusion rates of 20, 40, 60 and 80 pg/min/kg body weight. The time at which plateau is reached is independent of infusion rate and only dependent on the elimination rate (90 per cent of plateau being reached at 3.3 times t$$e, 13.2 hours). The time between starting the infusion and achieving minimum antiarrhythmic concentrations (MEC) depends both on infusion rate and the level of MEC. B, effect of circulatory impairment of plasma procaine amide concentration during constant rate infusion. Calculations for a 70 kg subject receiving a 50 ug/min/kg infusion over an 8 day period. During the initial 3 days, V, = 2.0 liters/kg and t& = 4 hours and steady-state plasma concentration is 8.7 pg/ml. On day 3 (arrow), Vd decreases and tr/Z increases by 20 per cent as might occur due to acute ventricular failure. Plasma concentration rises into the toxic range even though the infusion rate is constant.
B.
A.
*r 6
TOXIC
2
MEC
-_------_------------~-~
0 ik 0
2
4
l 6
HOURS
HOURS
Figure 6. Combined intravenous injection and constant rate infusion of lidocaine for rapid onset, sustained antiarrhythmic action. Calculations are for a 60 kg subject with a distribution half-time (cu) of 8 minutes and a disposition half-time (@) of 120 minutes. The minimum effective concentration (MEC) is 1.5 ug/ml. A, an initial intravenous injection of 100 mg lidoCaine is given (arrow) and an infusion of 2.4 mg/min/kg body weight started simultaneously (hatched bar). A peak of 5.1 ug/ml is reached immediately, a minimum of 2.3 pg/ml at 35 minutes, and the steady state concentration of 3.6 ug/ml is reached at about 7 hours. B, the initial injection and constant rate infusion are the same as in A. However, the MEC is 2.8 @g/ml. When the arrhythmia recurs at 35 minutes, a second dose of 100 mg is given and toxic plasma concentrations result. The second injection shouM have been smaller-25 to 50 mg.
484
April 1975
The American Journal of Medicine
Volume 58
ANTIARRHYTHMIC DRUGS-BIGGER
drugs: (1) it decreases the rate of drug elimination by slowing both renal excretion and hepatic metabolism, and (2) it reduces the apparent volume of distribution of antiarrhythmic drugs. Thus, when circulatory failure and shock occur, plasma drug concentration can increase to toxic levels during a constant rate infusion (Figure 5B). Hemodynamic changes leading to excessive plasma concentrations may be subtle, and patients may slip into toxicity on the 2nd or 3rd day of infusion without impressive clinical evidence of change in their hemodynamic state. Also, if lidocaine is the antiarrhythmic drug being infused, symptoms of toxicity are often subtle and easily mistaken for anxiety and personality changes engendered by the acute situational stress. On a number of occasions, we have treated such symptoms with diazepam until measurement of plasma lidocaine revealed their true nature and a reduction in the rate of lidocaine infusion led to the abatement of symptoms. Combined Intravenous Injection and Constant Rate Intravenous Infusion. Because effective plasma concentration of antiarrhythmic drugs are maintained so briefly after sudden injections of safe doses and attained so slowly during constant rate infusion, these two methods have been combined to produce immediate and sustained arrhythmia control. For example, it is common practice to give an injection of 1 to 1.5 mg of lidocaine followed by an infusion at rates between 10 and 50 pg/min/kg body weight [6,10,11]. Figure 6A shows this drug regimen in a hypothetical patient who weighs 60 kg; 100 mg of lidocaine was given by injection followed by 40 pg/min/kg body weight by infusion. The plasma concentration reaches therapeutic levels (usually 1 to 5 pglml) almost immediately, falls to minimum at about 35 minutes, and ultimately reaches plateau at about seven hours. On such a regimen, the arrhythmia which is being treated may reassert itself near the time of minimum plasma concentration. The appropriate response to the recurrence of arrhythmia at this point in therapy is not to change drugs, add a drug or change the infusion rate, but to give an additional injection of lidocaine. I would like to introduce a note of caution here about an error which is still made and not uncommonly. If lidocaine is given when the plasma concentration approaches its minimum, a smaller dose (one-quarter to one-half) should be employed than that which initially controlled the arrhythmia. The error is to inject the same 1.5 mg/kg dose of lidoCaine at 35 minutes as initially. Figure 6B shows the result of this error-the plasma lidocaine concentration not only increases well into the toxic range, but also falls more slowly to the therapeutic range than initially. This response to the second injection results from the fact that at the time of the minimum plasma
concentration, there is more than 200 mg of lidoCaine in the body plus a considerable amount of lidoCaine metabolites. Intramuscular Injection. Several antiarrhythmic drugs are effective when given intramuscularly, e.g., quinidine, procaine amide and lidocaine. This route of administration is useful when oral medication is withheld before or after surgical procedures or in certain emergency situations. These drugs are rapidly absorbed from the site of injection giving rise to a plasma concentration-time curve much like that of oral absorption (Figure 2F). However, drug absorption begins immediately after intramuscular injection whereas absorption of orally administered quinidine and procaine amide does not begin until they encounter the small intestine. For procaine amide or quinidine, intramuscular doses are the same as those employed in oral therapy. During the past 5 years there has been considerable interest in the intramuscular use of lidocaine to treat cardiac arrhythmias. The basis of this interest is the hope that intramuscular administration of lidoCaine may have an important role in controlling arrhythmias in the prehospital phase of acute myocardial infarction. A dose of lidocaine, given in the deltoid muscle, is absorbed very rapidly; in patients hospitalized for acute myocardial infarction, doses of 4 mg/kg body weight produce therapeutic plasma concentrations in 10 to 15 minutes and maintain effective levels for lx to 2 hours [ 12- 161. Intramuscular lidocaine can effectively control the arrhythmias encountered in the hospital phase of acute myocardial infarction. Controlled clinical trials are needed to evaluate the use of lidocaine in the prehospital phase of acute myocardial infarction (1) at home or during transportation to the hospital, and (2) during transportation from the hospital emergency room to the coronary care unit. The intramuscular use of diphenyhydantoin to treat cardiac arrhythmias has been disappointing. Although arrhythmias can be controlled via this method, the plasma concentrations are erratic after intramuscular doses, and the area under the plasma concentration time curve is often less than for an identical oral dose, suggesting that some of the intramuscular dose is bound locally by proteins. Oral Administration. Although emergency and special situations may dictate arrhythmia control by parenterally administered drugs, most acute and virtually all chronic arrhythmia control is accomplished by oral drug administration. Lidocaine is not used orally to control cardiac arrhythmias because, when given by this route, effective, plasma concentrations are difficult to achieve without symptoms. As lidocaine is absorbed from the
April 1975
The American Journal of Medicine
Volume 59
495
ANTIARRHYTHMIC DRUGS-BIGGER
gastrointestinal tract, it is carried to the liver in portal vein blood and rapidly metabolized (deethylated). The nausea, vomiting and dizziness seen after oral doses may be partially attributed to lidocaine metabolites [ 171. Quinidine and procaine amide are well absorbed and are usually given orally. Both of these compounds are weak organic bases and are highly ionized at the usual pH of the stomach. For example, procaine amide with a pKa of 8.9 is virtually 100 per cent ionized at pH 1.5. Since it is the unionized form of these basic drugs which is absorbed, there is little, if any, absorption from the stomach. Thus, the onset of absorption is determined by the gastric transit time. Once absorption begins in the small intestine, it is rapid and essentially complete; the peak plasma concentration is attained between 45 minutes and 2 hours after a single oral dose of quinidine or procaine amide. Propranolol is more erratically absorbed from the gastrointestinal tract and there is great variability between patients in the fraction of a dose which is absorbed; this largely accounts for the sevenfold difference in plasma concentration found in a group of patients given an identical dose of propranolol [ 181. Also, like lidocaine, propranolol in portal vein blood is cleared during passage through the liver [ 191. As Figure 2F shows, the plasma concentration falls as a function of the elimination rate constant once absorption is completed. With the high ka:ke ratio of antiarrhythmic drugs (see Figure l), the duration of drug action is dependent primarily on the peak concentration, the minimum effective concentration and the half-time for elimination. Raising the dose of drug will increase the peak plasma concentration and prolong drug action. However, repeatedly doubling the dose will not double the duration of drug action since, at the increased plasma concentrations, elimination will initially be faster; the duration of therapeutically effective drug concentration increases as the logarithm of the amount of drug in the body [2]. The toxic concentration limits the duration of action which can be achieved by increasing the size of single doses, and multiple oral doses are used to maintain effective drug concentrations. Multiple Oral Doses. Multiple oral dosing is the most common dosing technic used in drug therapy, including antiarrhythmic drug therapy. Discussion of idealized regimens for multiple oral doses often suggest that a loading dose equal to the desired effective concentration times the apparent volume of distribution be given followed by repeated doses half this size given at intervals equal to the drug’s half-life. This regimen produces effective concentrations almost immediately and maintains them; the plasma concentration will fluctuate by 50 per cent between
488
April 1975
The American Journal of Medicine
Volume 58
doses. Such a regimen is only practical for quinidine which has a half-life around 6 to 7 hours. For example, if quinidine’s apparent volume of distribution is about 125 liters and a plasma concentration of 4 yglml is desired, an initial dose of 500 mg could be given and followed by 250 mg every 6 hours. With antiarrhythmic agents having shorter half-lives, e.g., propranolol or procaine amide, this technic of dosing becomes impractical because of the inconvenience of a chronic regimen which requires the patient to take the drug every 2x to 4 hours. If these drugs are given at convenient intervals, such as every 6 to 8 hours, the fluctuation in plasma concentration between doses will be much greater than 50 per cent. Since the therapeutic ratio of these drugs is narrow, wide fluctuations run the risk either of causing toxicity at peak concentrations or of losing arrhythmia control at the minimum concentration. These events can easily be checked during quinidine or procaine amide therapy by observation of the blood pressure and, more importantly, the electrocardiogram. For optimum results, observations should be made rather precisely at the peak and valley of concentration, i.e., 1 to 1 yZ hours after a dose and just before the next dose. Observations made at other times are not as useful and may be misleading. At the peak, one looks for toxic manifestations; with quinidine and procaine amide the primary toxic effect being sought is excessive QRS widening. At the time of minimum concentrations, one should look for return of the arrhythmia or loss of the drug effect on the QRS [ 201. Repeated observations as the drug regimen is adjusted provides immediate feedback and usually allows the therapist to arrive rapidly at a safe, effective regimen without measuring plasma drug concentrations. For quinidine, procaine amide and propranolol, loading doses are not usually required because of their short half-life; steady-state concentration is achieved at 3.3 times the half-life-within 1 day. DPH has a “half-life” of 20 to 40 hours so that it may require a week or more to reach steady-state concentrations when giving constant doses at constant intervals. Therefore, an initial loading dose is useful when initiating therapy with this agent [8]. It should be remembered that oral absorption is rapid. To forget this may cause problems when changing from intravenous infusion to oral dosing. Figure 7 shows an example, the patient has received procaine amide by constant rate intravenous infusion for several days at the rate of 1,000 mg every 6 hours. Intravenous therapy is discontinued and oral therapy, 1,000 mg every 6 hours, is begun immediately. Although oral therapy with this dose and dosing interval will ultimately be satisfactory, it causes initial toxicity because the orally administered drug is entering the body much
ANTIARRHYTHMICDRUGS--BIGGER
more rapidly than the previous intravenous infusion. To avoid this problem, the drug plasma concentration should be allowed to fall below the mean desired concentration before beginning oral doses (Figure 7, bottom). Long-term oral therapy presents many problems: lack of compliance to the drug regimen, changes in the underlying arrhythmic process, insufficient plasma drug concentrations and drug toxicity are all important problems. Drug toxicity may come about due to either excess plasma concentration or immunologic reactions in the presence of the drug. The latter reactions, such as the procaine amide-induced lupus erythematosus-like syndrome or quinidine-induced thrombocytopenia, can only be combatted by the physician’s awareness of the syndromes and careful monitoring of patients for early signs of toxicity. Toxicity due to excessive drug concentrations can be avoided in most instances by a clear understanding of the processes responsible for absorption, distribution and elimination of the drugs being employed, and frequent reevaluation of factors which would alter the body’s handling of drugs. As discussed under constant rate infusion, the elimination of antiarrhythmic drugs will be slowed if congestive heart failure develops or worsens due to reduced hepatic and renal blood flow (Figure 5B). Changes in cardiac compensation are often subtle. Drug interactions may alter the plasma concentration of drugs. For example, institution of therapy which produces an alkaline urine, e.g., sodium bicarbonate or acetazolamide will slow the elimination of the organic bases quinidine and procaine amide. Also, changes in the physiologic state may increase the cardiac effect of a given plasma concentration. Advancing renal failure may not only slow the elimination of some drugs but also when hyperkalemia occurs, the increased potassium ion concentration augments the cardiac action of antiarihythmic drugs. Of course, the problem of inadequate plasma concentration of drugs for arrhythmia
0
’
I
0
6
I2
6
24
TIME IN HOURS Figure 7. changing from constant rate intravenous infusion (1,000 mg every 6 hours) to oral dosing regimen of procaine amide (1,000 mg every 6 hours) tv# = 4.0 hours; V, = 140 liters. Top, first oral dose given immediate/y after discontinuing intravenous infusion. Bottom, first oral dose given 4.0 hours (one half-life) after discontinuing infusion. From Bigger and Giardina [ 151.
control is also a serious problem in chronic oral therapy. Here, lack of patient compliance to drug regiment is the most common problem. A major contributing factor to lack of compliance is the inconvenience of most antiarrhythmic regimens which require many doses a day due to the short half-life of the drugs. There is an urgent need for antiarrhythmic drugs with longer half-lives for use in long-term theraPY.
REFERENCES 1. 2.
3. 4.
5.
6.
and lidocaine in the treatment of cardiac arrhythmias. Prog Cardiovasc Dis 6: 5 15, 1969. Giardina EGV, Heissenbuttel RH, Bigger JT Jr: Intermittent intravenous procaine amide to treat ventricular arrhythmias. Correlation of plasma concentration with effect on arrhythmia, electrocardiogram, and blood pressure. Ann Intern Med 78: 183, 1973. Bigger JT Jr, Schmidt DH, Kutt H: Relationship between the plasma level of diphenylhydantoin sodium and its cardiac antiarrhythmic effect. Circulation 38: 363, 1968. Giardina EGV, Bigger JT Jr: Procaine amide against reentrant ventricular arrhythmias. Lengthening R-V intervals of coupled ventricular premature depolarizations as an insight into the mechanism of action of procaine amide. Circulation 48: 959, 1973.
Bigger JT Jr: Arrhythmias and antiarrhythmic drugs. Adv Intern Med 18: 251. 1972. Goldstein A, Aronow L, Kalman SM: The time course of drug action, chap 4. Principles in Drug Action: The Basis of Pharmacology, New York, John Wiley 8 Sons, 1974. Wagner JG: Pharmacokinetics. Ann Rev Pharmacol 8: 67, 1968. Riegelman S, Loo J: Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J Pharm Sci 57: 117, 1968. Riegelman S. Loo J, Rowland M: The concept of a volume of distribution and possible errors in evaluation of this. parameter. J Pharm Sci 57: 128, 1968. Bigger JT Jr, Heissenbuttel RH: The use of procaine amide
April 1975
The American Journal of Medicine
Volume 59
487
ANTIARRHYTHMICDRUGS-BIGGER
10.
11.
12.
13.
14.
15.
488
Gianelly R, von der Groeben JO, Spivak AP. Harrison DC: Effect of lidocaine on ventricular arrhythmias in coronary heart disease. N Engl J Med 277: 1215, 1967. Kimball JT. Killip T: Aggressive treatment of arrhythmias in acute myocardial infarction. Procedure and results. Prog Cardiovasc Dis 10: 483, 1968. Bell& S, Roman L, Kostis JB, Fleischmann D: Intramuscular lidocaine in the therapy of ventricular arrhythmias. Am J Cardiol 27: 291. 1971. Cohen L, Rosenthal J, Horner D, Atkins J, Matthews 0, Sarnoff S: Plasma levels of lidocaine after intramuscular administration. Am J Cardiol 29: 520, 1972. Fehmers M. Dunning A: Intramuscularly and orally administered lidocaine in the treatment of ventricular arrhythmias in acute myocardial infarction. Am J Cardiol 29: 514.1972. Bigger JT Jr, Giardina EGV: The pharmacological and clini-
April 1975
The American Journal of Medicine
Volume 58
16.
17. 18.
19.
20.
cal use of lidocaine and procaine amide. Va Med Q 9: 65, 1973. Zener JC, Kerber RE, Spivak AP, Harrison DC: Blood lidoCaine levels and kinetics following high dose intramuscular administration. Circulation 47: 984, 1973. Scott DB, Jebson PJ. Godman MJ, Julian DG: Oral lignoCaine. Lancet 1: 93, 1970. Shand DG, Nuckolls EM, Oates JA: Plasma propranolol levels in adults with observations in four children. Clin Pharmacol Ther 11: 112, 1970. Paterson JW, Conally ME= Dollery CT, Hayes A, Cooper RG: The pharmacodynamics and metabolism of propran0101in man. Pharmacol Clin 2: 127, 1970. Heissenbuttel RH, Bigger JT Jr: The effect of oral quinidine on intraventricular conduction in man. Correlation of plasma quinidine with changes in intraventricular conduction time. Am Heart J 80: 453, 1970.