Clinical Pharmacokinetics 3: 97-107 (1978) © ADIS Press (1978)

Clinical Pharmacokinetics of Procainamide Erling Karlsson Department of Internal Medicine. Division of Cardiology. Linkoping University. Linkoping

Summary

Procainamide is almost completely absorbed after oral administration and peak plasma concentrations are generally reached within 1 to 2 hours. Upon intravenous administration there is a rapid initial distribution phase, which is completed after about 30 minutes. The pharmacokinetics can be described by a 2-compartment open model. The plasma half-life during the ~-phase averdges 3 hours. The apparent volume of distribution is about 2LI kg body weight. A t therapeutic plasma levels about J5 % is bound to plasma proteins. Approximately 50 % of administered procainamide is eliminated as unchanged drug via the kidneys. N-Acetylprocainamide is the main metabolite and is pharmacologically active. with a recovery in urine of about 15 % (range 7 to 34 % in healthy subjects). The acetylation of procainamide seems to be under the same monogenic control as that of isoniazid. A t least 2 more metabolites have been found but are not yet identified. The renal clearance of procainamide ranges from 179 to 660mll min. Glomerular filtration and active tubular secretion seem to be the most important mechanisms. In patients with low-output cardiac failure andlor renal impairment, the absorption. distribution and elimination of the drug may be significantly altered. Determination of plasma levels is of particular value in these cases and will contribute to more safe and effective therapy in the majority of patients. As N-acetylprocainamide seems to have pharmacological effects comparable with those of procainamide, both agents should be monitored simultaneously ill order to optimise therapy.

Although procainamide has been used widely as an antiarrhythmic drug for more than 2 decades, details of its pharmacokinetics and pharmacodynamic effects have been established only during the last few years. As its properties have been elucidated, interest in both the unchanged drug and its main metabolite, N-acetylprocainamide, has increased markedly. This article will discuss some of the pharmacokinetic factors which may influence the therapeutic effect of the drug. as well as discussing some of its adverse effects. The first section of the review deals with data obtained from healthy subjects and this is followed by

information applicable to the treatment of patients in various clinical situations.

I. Fundamental Pharmacokinetic Properties 1.1 Absorption from the Gastrointestinal Tract Procainamide, a basic drug with a pKa of 9.23, is almost completely ionised in the acid milieu of the stomach and therefore is not absorbed until it reaches the small intestine. After oral administration to fast-

Clinical Pharmacokinetics of Procainamide

ing healthy volunteers there is a delay of about 20 to 30 minutes before the drug appears in plasma (KochWeser and Klein, 197 I). Absorption is almost complete (Koch-W eser. 1971; Graffner et aI., 1975), and. by introducing procainamide solutions at different levels of the small intestine, absorption has been shown to be equally good throughout the entire small intestine (Weliky and Neiss, 1975). The recently developed sustained release preparations of procainamide (Fremstad et aI., 1973; Karlsson, 1973; Arstila et aI., 1974) have an oral bioavailability similar to that of ordinary tablets (Graffner et aI., 1975). However, the time over which each dose would be absorbed is prolonged, resulting in lower peak plasma levels. In this way it is possible to administer larger maintenance doses without achieving toxic plasma concentrations.

1.2 Distribution in the Body After intravenous administration the drug is rapidly distributed in body tissues (Koch-W eser, 1971; Graffner et aI., 1975; Graffner et al., 1977) and the pharmacokinetics can be described by a 2compartment open model. The average half-life of the a-phase, i.e. the .initial rapid decline of the plasma curve, corresponds to about 5 minutes and the initial distribution phase is completed after about 30 minutes (Koch-Weser and Klein, 1971; Graffner et aI., 1975). This rapid initial distribution indicates that the drug is most extensively bound to heart, kidney, liver and lungs, i.e. organs which are well-perfused. The apparent volume of distribution of procainamide is about 2L1kg body weight (Koch-Weser and Klein. 1971; Graffner etal., 1975; Graffner et aI., 1977).

1.3 Protein Binding Protein binding of procainamide has been studied both in dogs (Mark et aI., 195 I) and in man (KochWeser and Klein, 1971; Reidenberg et aI., 1975). At plasma concentrations corresponding to proposed

98

therapeutic levels, similar values were found in these studies, with only about 15 % bound to plasma proteins.

1.4 Elimination 1.4.1 Routes qfEliminatiol1 Procainamide is mainly eliminated via the kidneys as unchanged drug. Mark et al. (1951) performing the first study of the biotransformation of procainamide, reported that 50 to 60 % was excreted unchanged. Since then, there have been several investigations of the biotransformation of procainamide, both in hea)thy subjects and in cardiac patients (Dreyfuss et aI., 1972; Giardina et aI., 1973, 1976; Elson et aI., 1975; Gibson et aI., I 975b). In all these reports, the amount of unchanged procainamide recovered in the urine has been found to average 50 %. Mark et al. (1951) also reported that 2 to 10% of administered procainamide was excreted as paminobenzoic acid or its conjugate. However, subsequent studies by Dreyfuss et al. (1972) and Giardina et al. (I 976) did not confirm these findings. In the latter study, less than 0.2 % was accounted for either as p-aminobenzoic acid or as p-acetaminobenzoic acid. It _has also been suggested that the p-aminobenzoic acid measured in the first study resulted from hydrolysis of procainamide and N-acetylprocainamide and thus was not a true metabolite (Strong et aI., 1975). Dreyfuss et al. (1972) found another metabolite which is substituted in the aromatic aminogroup in the same way as N-acetylprocainamide, but this metabolite could not be identified. Two unknown metabolites were found by Giardina et al. (1976). The first one was recoverect in the urine as 6 to 10% of the procainamide dose and the second as \2 to 4 % . 1.4.2 N-Acefylprocainamide- An Active Metabolite The most important metabolite is N-acetylprocainamide. It is not only the major identified metabolite (Dreyfuss et aI., 1972; Giardina et al.. 1973. 1976; Karlsson et aI., 1974b; Elson et al..

Clinical Pharmacokinetics of Procainamide

99

1975; Gibson et at., 1975b; Graffner et at., 1975), but also seems to have pharmacological effects comparable with those of unchanged procainamide (Atkinson et al., 1977; Karlsson and Sonnhag, 1977). The amount of recovered N-acetylprocainamide shows a large interindividual variation, even if only healthy subjects are considered. Thus, Graffner et al. (J 97S) reported a N-acetylprocainamide recovery of 10 to IS % (mean of 12 %) during the first 24 hours, Gibson et al. (J 97 Sb) 7 to 34 % (mean of 16 %) and Giardina et al. (J 976) 7 to 24 % (mean of IS %). When procainamide is administered by the intravenous route, the plasma levels of N-acetylprocainamide measured at the same time are negligible, suggesting that acetylation of procainamide takes place during the first pass circulation through the intestinal wall and/or liver (Karlsson and Sonnhag, 1977).

1.4.3 Genetically Determined Metabolism

Presumably, the most important reason for the intraindividual variation in procainamide acetylation is the genetically determined differences in metabolic rates. It has been shown that the procainamide acetylation has a genetically bimodal distribution (fig. I) and that rapid acetylators have a higher recovery of N-acetylprocainamide in urine than slow acetylators. This was first demonstrated in cardiac patients using isoniazid as a test substance (Karlsson et al., I 974b), but has subsequently been verified in both patients and volunteers and with other test substances used for phenotype determination (table I). It has also been demonstrated that rapid acetylators have higher Nacetylprocainamide : procainamide ratios in plasma than slow acetylators (Reidenberg et al., 197 S; Frislid et al., 1976).

60

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100

Percentage acetylated sulpha pyridine in urine

Fig. 1. Relationship between percentage of acetylated sulphapyridine in urine and urinary N-acetylprocainamide in percent of the sum of excreted procainamide and N-acetylprocainamide. Rapid (.) and slow (.) acetylators according to sulphapyridine test (N ~ 33). From Karlsson and Molin (1975); by permission of author and editor.

Clinical Pharmacokinetics of Procainamide

100

Table I. Urinary f\J-acety!procainamide as % of the sum of excreted procainamide and N-acetylprocainamida (mean ± SD) in slow and rapid acetylators Test substance

No. tested

Subjects

N-Acetylprocainamide recovery Rapid acetylators

Slow acetylators

Reference

Isoniazid

15

Patients

43.1 ± 10.3

23.8 ± 4.7

Karlsson et al. (1974b)

Isoniazid

14

Volunteers

31.7± 2.8

19.0 ± 2.0

Gibson et al. (1975b)

Sulpha pyridine

33

Volunteers

19 ± 4

9 ± 1

Karlsson and Molin (1975)

Dapsone

16

Patients (n = 12) Volunteers (n = 4)

47.7

30.3

Reidenberg et al. (1975)'

Volunteers

43 ± 5

22 ± 3

Frislid et al. (1976)

Sulphadimidine 1

20

Calculated from available data.

1.4.4 Urinary Excretion Rate and Renal Clearance Koch-Weser and Klein (1971) found the renal clearance of procainamide to range from 179 to 309ml/min in healthy subjects while GrafTner et a!. (J975), reported values from 390 to 600ml/min. The renal excretion of procainamide has been shown to be directly related to creatinine clearance (Koch-Weser and Klein, I 971). However, the high renal clearance values of procainamide indicate an active secretion in the tubules or a passive reabsorption, or a combination of the two mechanisms. Weily and Genton () 972) found a linear relationship between urine pH and procainamide clearance in dogs, with a marked decrease in clearance when the urine was alkalinised. The authors proposed from these findings that both active secretion and passive reabsorption of the drug were of importance. However, 2 subsequent comprehensive studies in man revealed no changes in procainamide clearance, despite marked variation of the urine pH (Meyer et aL 1974~ Galeazzi et a!., 1976). In neither of the studies has any relationship between urine flow rate and procainamide clearance been found. Therefore, it seems most likely that glomerular filtration and active secretion in the tubules are the most important mechanisms in the

renal clearance of procainamide, and passive reabsorption probably is of no, or at least of very small, clinical importance.

1.4.5 Total Body Clearallceand Eliminatioll HalfLife The total body clearance. is.a product of the apo parent volume of distribution and the elimination rate constant of the drug and expresses the volume of whole blood completely cleared of drug per unit time (Rowland et aL 1973). In healthy subjects, the total body clearance of procainamide varied between 396 and 715 ml / min (Koch-W eser and Klein, I 9 71 ~ Graffner et aL 1977). The overall elimination rate of pro cainamide in the ~-phase has been found to correspond to a plasma half-life of roughly 3 hours in several studies in healthy subjects (Koch-Weser and Klein, 1971; Weily and Genton, 1972~ Graffner et al., 1975 ~ Graffner et a!., 1977). The plasma half-life during the ~-phase seems to be unaffected by either route and length of administration, or by. plasma concentration of procainamide (Koch-Weser and Klein, 1971 ~ GrafTner et aL 1977).

Clinical Pharmacokinetics of Procainamide

2. Pharmacokinetics ill Various Age Groups and Disease States 2.1 Children There are almost never any indications for procainamide therapy in children which explains the complete lack of pharmacokinetic data on procainamide in this age group.

2.2 Elderly Patients Procainamide is almost exclusively used for serious ventricular arrhythmias and usually in patients with coronary artery disease, e.g. acute myocardial infarction. Most of these patients are elderly and therefore a great deal of pharmacokinetic data from this age group has been reported. However, it is difficult to decide when a physiological impairment of function of the kidney, liver or other organs proceeds to a pathological disturbance. Therefore, the influence on the pharmacokinetic profile of such an impairment or disturbance will be discussed in more detail below in connection with the different organ systems.

2.3 Heart Disease In cardiac failure there is usually a reduced cardiac output leading to a general reduction of the blood flow but also to a change in the distribution of the flow. ThUS, there will be a relatively smaller perfusion of the musculoskeletal system and in severe congestive heart failure also of the kidney and the liver, and instead a higher perfusion of the brain and the heart. These changes in the blood circulation will have many effects on drug kinetics by changing both the absorption, distribution and elimination of the agent (Benowitz and Meister, 1976). There are few reports in the literature on the specific effects of cardiac failure on the pharmacokinetics of procainamide. Most of the available

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data derive from studies on patients with acute myocardial infarction. The interpretation of these data is complicated, as not only the cardiac disease per se but also commonly associated autonomic function disorders as well as other primary organ disease might influence the kinetics of the drug. The complete and rapid absorption of procainamide after intramuscular administration seems to be reduced only after a marked decrease in cardiac output (Koch -W eser, I 971). On the other hand, there is a large interindividual variability of the time course of absorption in patients with acute myocardial infarction after oral administration of the drug (KochWeser and Klein, 1971; Collste and Karlsson, 1973; Hansteen et a!., 1976). In patients with acute myocardial infarction, Koch-W eser (1971) reported that about 10% of the patients not only had a delayed but also less complete absorption and, in fact, 4 patients absorbed less than 50 % of the oral administered dosage of procainamide. This finding was confirmed by Shaw et a!. (1975). The apparent volume of distribution has also been found to be smaller in patients with congestive heart failure. Thus, Koch-Weser and Klein (t 971) found the apparent volume of distribution of procainamide to average 1.51 L/kg in 5 patients with cardiac failure as compared with 20 I L/kg in 8 subjects with normal cardiac function. A reduction of renal clearance will have the same influence on the kinetics of the drug in the body, whether it depends on a primary renal disease or if it is secondary to a low output state. Therefore, this aspect will be further discussed in connection with the general effects of renal failure (section 2.5).

2.4 Liver Disease Usually, only severe and diffuse hepatic diseases, e.g. acute hepatitis, will cause any impairment of the biotransformation of drugs (Kutt and McDowell, 1968; Breckenridge, 1971; Kutt, 1971). As only approximately 50 % of a given dose of procainamide is eliminated after biotransformation, the effect of

Clinical Pharmacokinetics of Procainamide

moderate hepatocellular damage might consequently be of minor importance for this drug. Procainamide is only little bound to plasma proteins and therefore a reduction of the protein binding of the agent secondary to liver disease is unlikely. However. in I study on patients with hepatic disease, the ratio of Nacetylprocainamide in urine to procainamide plus Nacetylprocainamide was found to be 6.4 ± 1.1 % as compared with 10.6 ± 1.3 % in a control group (p < 0.0 I), indicating an impairment of the acetylation of procainamide in the patient group (du Souich and Erill, 1976). The severity of the liver disease was not defined in this report, but at least some patients had concomitant ascites indicating a rather high degree of liver damage.

2.5 Renal Failure As procainamide is mainly eliminated via the kidneys it could be expected that impairment of renal function should have a pronounced effect on the pharmacokinetics of this drug. Several investigations have confirmed this assumption. Thus, Koch-Weser and Klein (1971) found a marked decrease of the rate of elimination in 5 patients with renal insufficiency and a good correlation between the plasma procainamide concentration and creatinine clearance. These findings were confirmed by Weily and Genton (1972), who in 8 patients with renal disease found a mean plasma half-time of 5.85 ± 0.62 hours as compared with 2.85 ± 0.25 hours in 6 normal human controls. Also, Giardina et al. (1976) found the same magnitude of prolongation of the plasma half-time in 5 patients with only moderate decrease of creatinine clearance. Gibson et al. (I 97 Sa) investigated 20 patients with severe end stage renal insufficiency (10 patients were anephric). The plasma half-time was considerably prolonged: 12.5 ± 1.4 hours in anephric and 10.1 ± 1.5 hours in nephric patients. The apparent plasma half-time for the whole group showed a great variation, with a range from 5.3 to 20.7 hours. Dialysis clearance studies performed in these patients showed

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a procainamide clearance of 67ml/min and a significant decrease of plasma half-time, indicating that dialysis should be an effective way to treat serious toxicity. Atkinson et a\. (J 976) have also reported successful management of a patient with severe procainamide intoxication using haemodialysis. In this case, haemodialysis was found to double the rate of procainamide elimination and also increased 4-fold the clearance of N-acetylprocainamide. This last finding is very important as N-acetyJprocainamide elimination has been shown to be impaired to a far greater extent than procainamide elimination in patients with renal insufficiency, thus resulting in accumulation of N-acetylprocainamide in plasma (Karlsson et al.. 1974b; Atkinson et al.. 1976; Giardina et a\., 1976). 2.6 Gastrointestinal Disease No reports have been found in the literature where the influence of gastrointestinal disease on the pharmacokinetics of procainamide has been studied.

3. Drug IlIleraclirJlls There are few reports in the literature ofclinically important specific interactions between procainamide and other drugs. Theoretically, anticholinergic drugs may cause a delay in the absorption of procainamide by decreasing motility of the stomach, but this will not affect the steady state plasma level. Aluminium hydroxide gel delays gastric emptying (H urwitz, 1977) and may similarly delay absorption. It is also unlikely that other antacids will cause interaction problems, as procainamide is absorbed at all levels of the small intestinal tract. A prerequisite for a quantitatively important displacement interaction with plasma proteins is a very high degree of binding of the interacting drug and a relatively low volume of distribution. As the protein binding of procainamide is only about 15 % at apparent therapeutic plasma levels, displacement reactions are very unlikely.

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Clinical Pharmacokinetics of Procainamide

The risk of metabolic interaction is also very small as only a minor fraction of procainamide is eliminated by biotransformation, specifically by acetylation which further reduces the risk (Rem mer, 1972). About 50% of procainamide is excreted unchanged by the kidney. Therefore, all drugs that diminish cardiac output and consequently renal blood flow may have an important influence on the elimination rate. Negative inotropic agents that decrease cardiac output may in consequence also diminish the apparent volume of distribution of the drug, further increasing the risk of plasma concentrations of procainamide reaching toxic levels. Despite the fact that procainamide is a weak base, moderate changes of the urine pH by concomitantly administered drugs seem to be without important clinical effect on the renal elimination rate of procainamide (Meyer et al., 1974; Galeazzi et a\., 1976). Pharmacodynamic interaction between procainamide and other antiarrhythmic drugs probably plays a more important role than pharmacokinetic interaction. Indeed, many of the pharmacodynamic interactions are planned in order to add specific antiarrhythmic properties of 2 or more drugs. However, there is also a risk of adding side-effects with such concomitant therapy, as most antiarrhythmic drugs not only have beneficial but also adverse effects in common, e.g. negative inotropic effect, vasodilating effect, etc. In a study in patients with acute myocardial infarction and in dogs, no changes were observed after combination treatment with procainamide and lignocaine/lidocaine (Karlsson et al., I 974a). However, in some patients a minor, transient hypotension was seen after the loading dose of procainamide. As combined antiarrhythmic treatment seems to be more common, further studies are needed to elucidate clinically important interactions during such treatment.

4. Plasma Level Monitoring A previous article in the journal has discussed monitoring of procainamide plasma levels in detail

(Koch-Weser, 1977). The following summarises essential information.

4.1 Methods The first method for determination of procainamide was described in 1951 (Mark et a\., 195 t) and was a colourimetric method. 20 years later KochWeser and Klein ( 1971) compared this method with a spectrophotofluorometric method and found close agreement between the 2 methods. In order to increase the selectivity, gas chromatographic methods have been developed, which have also facilitated simultaneous determination of procainamide and Nacetylprocainamide (Atkinson et a\., 1972; Karlsson et aI., 1974b; Frislid et aI.. 1975). Recently, a highly sensitive method based on liquid chromatography for determination simultaneously of both procainamide and N-acetylprocainamide has been described (Graffner et aI., 1977). With this method concentrations down to O.4n mol/ml (lOOng/m!) can be determined and by concentration of the extract before injection, the sensitivity can be further increased.

4.2 Relationship Between Plasma Levels and Effects The rationale of monitoring plasma levels of drugs is based upon several prerequisites. One of the most important premises is that there is a better correlation between plasma level and pharmacological effect than between administered dose and effect. This seems to be true of procainamide. In extensive clinical studies, Koch- Weser et al. (1969), Koch-Weser and Klein (t 971) and Koch-W eser (t 977) were able to correlate the plasma concentration of procainamide with therapeutic and toxic effects of the drug. In patients with different types of arrhythmias, treatment was found to be ineffective in 50 % of the cases when the procainamide plasma concentration was less than 4).1g/ ml. On the other hand, an arrhythmia which did not respond at a plasma con-

Clinical Pharmacokinetics of Procainamide

centration of less than 8).1g/ml, could be abolished at higher plasma levels only in 10% of the cases. With higher concentrations there was also a concomitant increase in both the frequency and severity of sideeffects (Koch-Weser and Klein, 1971; Koch-Weser, 1977). Other clinical studies have confirmed that procainamide plasma concentrations from 4 to 8 to I O).lg/ ml constitute the usually effective therapeutic range (Fremstad et aI., 1973; Giardina et aI., 1973; Gey et aI., 1974). These results are surprisingly unanimous when considering the very different haemodynamic and therapeutic situation in patients with various cardiac diseases and the fact that the plasma concentration of N-acetylprocainamide, which seems to have comparable potencies with respect to toxic as well as therapeutic effect (Atkinson et aI., 1977; Karlsson and Sonnhag, 1977), was not determined in these studies.

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I hour after the dose but in these patients it may be delayed up to 10 hours. Therefore, sick patients may have a poor initial arrhythmia protection. Furthermore, if such a patient suddenly improves, the plasma concentration may reach toxic levels, when absorption of all the drug accumulated in the gastrointestinal tract starts (Collste and Karlsson, 1973). Intravenous administration would appear to be preferable in such cases. However, secondary to the reduced cardiac output and increased sympathetic activity, there is often an altered blood distribution pattern and a decrease in the apparent volume ofdistribution (Koch-W eser and Klein, 1971). Therefore, both the total dose and the infusion rate must be reduced to approximately onehalf of the usual dose. In patients with more extensive myocardial damage. the haemodynamic margins are diminished. Therefore. the ordinary procainamide loading dose of about I g should be reduced or divided in order to reduce the risk of side-effects. e.g. hypotension. In these cases, it may also be necessary to reduce the 5. Implicatiolls lif Killetics I!f fmcaillamide maintenance daily dose and shorten the dosage interfor Therapeutic Use val in order to reduce the fluctuation of the plasma level. Both primary and secondary renal diseases are One of the main indications for procainamide is to replace lignocaine in the treatment and prevention of common in patients with acute myocardial infarction. active ventricular arrhythmias in the early post-in- . This will have an important influence on profarction period. Drug therapy in patients with acute cainamide clearance, but also on the clearance of the myocardial infarction may be complicated by disease- pharmacologically active main metabolite, Nrelated variability in both absorption, distribution and acetylprocainamide. In patients with impaired kidney elimination kinetics. This variability is not only in- function the plasma concentration of N-acetylproterindividual but also intraindividual. Therefore. a cainamide has been found to be 3 to 4 times higher knowledge of the pharmacokinetics of procainamide than that of procainamide (Karlsson et al.. I 974a). is valuable in achieving effective and safe arrhythmia Accumulation of both procainamide and N-acetylprocontrol. especially in this patient group. cainamide in these patients can be expected to make There are often disturbances in cardiac output and therapy with standard procainamide doses extremely in autonomic nervous system activity associated with hazardous. A major and individually adjusted reducacute myocardial infarction. These disturbances may tion in dose is required in these cases. The procainamide therapy regimen with tablet adlead to alterations, both in gastrointestinal motility and tissue perfusion. Consequently. the absorption of ministration every 3 hours proposed by Koch- W eser procainamide may be slower and also decreased. both and Klein (1971), and based upon procainamide after oral and intramuscular administration. The kinetic data, is unsuitable for long-term treatment. maximum plasma concentration of orally ad- Development of sustained-release, preparations has ministered procainamide is generally attained within reduced this problem. Several groups (Fremstad et a!..

Clinical Pharmacokinetics of Procainamide

1973; Karlsson, 1973; Arstila et al., 1974; Shaw et aI., 1975) have shown that the fluctuation in plasma concentration during each dosage interval when using these new preparations is similar to that of an identical daily dose of conventional tablets given twice as often. Also, the overall bioavailability of the 2 preparations is similar. However, during long-term treatment there is still the disadvantage of the procainamide-induced SLE-Iike syndrome. The finding that the acetylation of procainamide follows the same pattern as that of isoniazid and sulphapyridine (Karlsson et ai., 1974b; Karlsson and Molin, 1975) added procainamide to the list of drugs whose acetylation is governed by the same genetic polymorphism (see Lunde et al., 1977). This has also been confirmed by several other groups (Gibson et aI.. 1975b; Reidenberg et aI.. 1975; Frislid et aI., 1976; Campbell et aI.. 1976; Giardina et al., 1977). Data have also been presented indicating that slow acetylators are at greater risk of development of toxic drug effects than rapid acetylators given similar doses of procainamide (Campbell et al., 1976) but conflicting results have been reported. Thus, Davies et al., (I975) reported a preponderance of rapid acetylators when comparing the tendency to develop antinuclear antibodies with acetylator phenotype. On the other hand, Henningsen d al. (1975) found that the SLE-like syndrome predominantly occurred in slow acetylators. In 2 other studies in patients on long-term treatment with procainamide (Lunde et ai., 1977; Sonnhag and Karlsson, 1977) no difference was found in frequency .of serological and clinical evidence of SLE between the 2 phenotype groups. In the first study, 10 patients developed the SLE-like syndrome; 6 of them were rapid and 4 slow acetylators. In the second study, 2 of 4 rapid and 7 of 24 slow acetylators developed the syndrome. One explanation of the results from the 2 latter studies may be that therapy in all these patients was guided by plasma monitoring in order to establish therapeutic plasma levels of procainamide. This could mask any difference between slow and rapid acetylators. Nevertheless, the ratio between the concentrations of procainamide and N-acetylprocainamide in plasma was in one of these studies (Son-

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nhag and Karlsson. 1977) higher in slow acetylators, who also developed antinuclear antibodies after a shorter duration of therapy than rapid acetylators. These findings agree with those of Woosley et al. (I 977), but the difference seems to be too small to be of predictive value in the individual patient (Sonnhag and Karlsson, 1977). The primary aromatic amino-group in procainamide has been suspected to be the cause of the SLE-like syndrome. The fact that N-acetylprocainamide does not have the same amino-group (fig. 2), has a long elimination half-life of about 6 hours (Strong et aI., 1975) and seems to effectively suppress ventricular arrhythmias (Lee et aL. 1976; Atkinson et al.. 1977; Karlsson and Sonnhag, 1977) would indicate that this drug is suitable for clinical use, particularly for long-term treatment. Theoretically, the risk of inducing the SLE-like syndrome would be less and preliminary data support this hypothesis (Atkinson, AJ., Jr.: Personal communication). Knowledge of the pharmacokinetics of a drug contributes to safe and effective therapy. For a drug like procainamide, commonly used in the treatment of critically ill patients, such a knowledge is particularly important and the direction of change in the kinetics can to a certain extent be anticipated. However, the

Procainamide

N-Acetylprocainamide

Fig. 2. Chemical structure of procainamide and its main metabolite, N-acetylprocainamide.

Clinical Pharmacokinetics of Procainamide

variability of the effects of the disease on procainamide kinetics and also of the effects of the drug on the disease is very different and complex. Therefore, monitoring of procainamide therapy by plasma concentration determination might be of value in all patients, but especially in patients with severe cardiac disease and associated renal disease. As recent evidence indicates that N-acetylprocainamide has comparable immediate toxic as well as therapeutic potencies as procainamide. measurement of both procainamide and N-acetylprocainamide plasma levels probably will further increase the value of plasma monitoring as a guide to therapy. Furthermore. the pharmacokinetic studies on procainamide may also contribute to the development of its major metabolite, N-acetylprocainamide, as a new and possibly also a better antiarrhythmic drug.

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Clinical Pharmacokinetics of Procainamide

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Author's address: Dr Erling Karlsson. Department of Internal Medicine. Division of Cardiology. Linkoping University. Linkoping S-58/ 85 (Sweden).