Epilepsia, 16:171-181,1976.

Raven Press, New York

Idiosyncratic Reactions to the Antiepileptic Drugs Harold E. Booker The Epilepsy Center, Department of Neurology, University of Wisconsin. Center f o r Health Sciences, Madison, Wisconsin 53706

INTRODUCTION

As many cases go unreported, the true incidence of adverse drug reactions is unknown. Recent studies have indicated, however, that the incidence is quite high. For .example, Meleney and Fraser (1969)found that 36% of 749 consecutive outpatients had experienced one or more adverse drug reactions within the preceding 3 months. While many of these are mild, enough are serious that Cluff et al. (1965) found that 1 in 20 hospital admissions were due to drug reactions. The fact that the antiepileptic drugs are usually administered for prolonged periods of time, often for the major portion of a patient’s life span, would allow for the appearance of adverse reactions dependent upon chronic use that might not be seen with drugs more typically given for limited periods (as, for example, antibiotics). Also, the chronic use would allow for a greater potential for adverse interactions between the antiepileptic drugs and any other unrelated diseases (and their treatment) that appear during the time of treatment. Fortunately, however, idiosyncratic reactions, almost by definition, are the rarest of all adverse drug effects. They are nevertheless important, as many are serious and even potentially fatal. In addition, study of idiosyncratic drug reactions has contributed not only to our knowledge of pharmacology and therapeutics in general, but also to the problems of biological variability and human genetics. We shall first define what is currently meant by idiosyncratic drug reactions in general and then discuss the problem of recognition or Key words: Idiosyncratic reactions -Antiepileptic drugs

identification of such relations at the clinical level. Then, while not adhering strictly to the definition, we shall discuss some possible mechanisms underlying such reactions to the antiepileptic drugs. Finally, we shall make a brief review of the more common and serious unusual or rare reactions to these drugs. DEFINITIONS AND THE PROBLEM OF RECOGNITION Idiosyncrasy can be defined as a peculiar or unique characteristic distinguishing an individual. In the past the term was used to describe all unusual or rare drug reactions. In order to better understand the idiosyncratic reactions and their current definitions, it will be helpful to discuss briefly drug effects in general. Drug effects can be classified in many ways, but it will suit our purposes best to divide them into the desired or therapeutic and undesired or adverse on the one hand, and on the other into the generic and the individual. By generic we mean effects seen in the majority of the exposed population, usually dose-related and reversible. Thus the generic effects characterize the general clinical pharmacologic properties of the drug. In contrast, the individual effects are seen in only a small percentage of the at-risk population, and often are not dose-related or reversible. Thus they can reasonably be attributed to the interaction of a drug with an unusual individual susceptibility or predisposition. Table 1is an attempt to combine the two classifications. We have not separated the desired effects into generic and individual, as the therapeutic use of most drugs wiU depend upon the generic effect alone. Therapeutic use

171

H.E. BOOKER

172

TABLE 1. Classification of drug effects

Desired or therapeutic Primary Secondary Undesired or adverse Generic Overdose Side effects Drug interactions Individual Allergic Drug-diseaseinteraction Idiosyncratic

of a drug dependent upon an individual effect is a theoretical possibility, but such use would be rare and exceptional. Adverse drug effects are sometimes called drug reactions. We shall use the latter term when emphasizing the clinical features, while the term adverse drug effect will be used more to indicate the mechanism of the reaction. Under generic effects, too much of the desired effects are known as overdose effects. Undesired effects present at therapeutic doses are called side effects. Effects present when two or more drugs are administered simultaneously (or sometimes in close temporal proximity), but absent when each drug is given alone, are called drug interactions. Although the ability of drugs to bind to proteins as cofactors or haptens is detepnined by the molecular structure of the drug (and is thereby generic), the ability of the complex to serve as an effective antigen in initiating a clinically significant immune reaction resides more with the individual, so that allergic reactions are considered individual drug effects here. In some cases, adverse effects result from potentiation (or inhibition) of generic effects by a preexisting disease state. If neither of these mechanisms is involved, the reactions are called idiosyncratic. Thus, historically the definition of idiosyncratic drug reactions seems to have been those left over when all other types are excluded. Under these circumstances it would be expected that multiple or diverse mechanisms would be responsible for the idiosyncratic reactions. However, as we shall see, more recent studies have suggested that this is not the case. While idiosyncratic reactions are generally rare, some occur with enough regularity that

the underlying mechanism can be established. A good example is prolonged sensitivity to the paralyzing effects of succinylcholine. Termination of the action of this drug is due to rapid hydrolysis by acylcholine acyl-hydrolase in serum and liver, the socalled pseudocholinesterase. Abnormal sensitivity to succinylcholine is due to the presence of an atypical pseudocholinesterase,whose presence itself has been shown to be hereditary (Whittaker, 1970). In similar fashion, a series of studies by many workers has established that one of the most frequent idiosyncratic reactions, drug-induced hemolytic anemia, is due to a genetically determined deficiency of glucose-6-phosphate dehydrogenase activity in erythrocytes (Beutler, 1972). Following the demonstration that several other rare and unusual drug reactions were genetically determined, pharmacologists today define idiosyncratic drug reactions as those adverse drug effects determined by the genotype of the individual. However, this definition is too inclusive, as recent studies in healthy, nonmedicated twins demonstrate that individual kinetics of absorption, metabolism, and excretion of several drugs are in major portion genetically determined (Vesell, 1972). However, distribution curves for most of these effects are continuous and approximate Gaussian distributions, suggesting that the variance is multifactorial in origin. In contrast, distribution of the sensitivity to succinylcholine is trimodal and discontinuous, suggesting control by a single pair of alleles. Thus some pharmacologists would limit the definition of idiosyncratic drug reactions to only those adverse drug effects determined by rare, single-factor genetic abnormalities. If we limit our discussion of idiosyncratic reactions to the antiepileptic drugs to these strict criteria, however, the list of such reactions would contain very few members and would be of no practical value (Table 2). In addition, one of these depends in part on a drug-disease interaction and the other on a drug interaction. For the clinician, the major problem presented by the idiosyncratic reactions, since they are rare and unpredictable, is recognition that the symptom or condition is indeed a drug reaction. This is equally true, however, for idl rare or unusual drug reactions, regardless of the underlying mechanism. Thus, from a clinical point of view, there is

173

IDIOSYNCRATIC REACTIONS To ANTIEPILEPTIC DRUGS

TABLE 2 . Adverse reactions to the antiepileptic drugs due to a single, low-frequency gene Reactions Acute crisis in porphyria Phenytoin intoxication Phenytoin intoxication associated with INH

Mechanisms Stimulation of amino-levulinicacid synthatase via enzyme induction Deficiency of hydroxylation of phenytoin Inhibition of phenytoin metabolism by high levels of INH associated with deficient acetyl-transferase

justification to include in our discussion other reactions that pharmacologists would not consider true idiosyncrasies. Recognition of overdose and side effects usually occurs rapidly after a drug is introduced into clinical use, as it awaits only the administration of the drug to a large enough population or to a smaller population in higher doses. Indeed, generic adverse effects-can even be anticipated when the new drug is a member of an established class of drugs. On the other hand, recognition of reactions that occur infrequently or only after chronic use will depend upon administration of the drug to large populations for prolonged periods of time. The reaction must occur and be documented in several patients before it can reliably be attributed to the drug in question and the relative risk assessed. As an example, diphenylhydantoin was introduced into clinical use in 1938, yet it was 20 years later that Saltzstein and Ackerman (1959) focused attention upon the possible relationship of this drug to lymphoma. Even then, it was another 1 0 years until supporting statistical evidence of an increased risk of lymphoma related to administration of hydantoins was presented (Anthony, 1970). Thus it is unlikely that idiosyncratic reactions will be detected in preclinical testing and in initial clinical investigation. Therefore, the responsibility for their identification will fall primarily upon the clinician. The first problem is to establish that a given reaction is due to the drug in question. It is unrealistic to designate every symptom that develops while a patient is under treatment as an adverse drug effect. Many of the symptoms of adverse drug effects are nonspecific and ubiquitous (dizziness, headache, nausea, etc.) and have a high incidence in the population not

Transmission Autosomal Recessive Autosomal Autosomal Recessive

taking any medication. Thus they can be expected frequently in association with drug administration on the basis of chance. Also,the reaction may range from an asymptomatic abnormality revealed only on laboratory testing to a syndrome identical to or closely resembling a disease state. In the latter case the clinician may be led to diagnose a disease rather than a drug reaction. Not only does this not correct the problem, but frequently it leads to further drug reaction or interaction. Also, remission of a symptom or symptom complex after drug withdrawal, while suggestive, does not in itself prove that the symptom was due to an adverse drug effect. However, when a series of similar reports are accumulated for a given drug, a point will sooner or later be reached when it seems reasonable to assume that the burden of proof that it is safe to continue the drug in the presence of the symptom is upon the individual who chooses to continue the drug. In this regard, continued reporting of adverse reactions where the role of the drug is reasonably certain to central collection agencies, such as the AMA Registry of Adverse Reactions, would be important. Another problem is presented by the fact that drug reactions can occur some time after the drug is discontinued. A particularly dangerous example is given by the interaction of phenobarbital with coumarin-type anticoagulants (Prescott, 1969). Administration of phenobarbital increases the metabolism of these anticoagulants by way. of induction of the hepatic microsomal enzymes. During the period of treatment with both drugs, increased doses of anticoagulants are required to maintain therapeutically prolonged prothrombin times. If the dose of anticoagulant is not carefully readjusted when the phenobarbital is withdrawn, serious, even fatal hemorrhage may

174

H.E. BOOKER

occur. Due to the prolonged serum half-life of phenobarbital and the time required for the enzyme induction to reverse, the hemorrhage may not occur until 2 weeks or more after the phenobarbital was stopped. In such circumstances, it would not be surprising if the causative role of the drug discontinued 2 weeks prior to the reaction would be overlooked. Many reports of adverse drug effects are based upon single cases. To be convincing, such reports need to show that the reaction cleared upon withdrawal and reappeared on subsequent challenge. An excellent example is given in the case reported by Brittingham et al. (1964).In their patient, erythroid aplasia cleared when diphenylhydantoin was withdrawn, and reappeared on two subsequent occasions when the drug was readministered. Such an approach, while documenting the reaction, obviously carries a high risk, particularly when the reaction is potentially serious. The safety of the patient will obviously limit the general use of this method. A safer approach would be to develop a model for the reaction in experimental animals. This is often unsatisfactory, as many drug effects are species-specific. Also, it seems unlikely that appropriate models for such adverse effects as headache or delusional thinking, for example, will be easily developed in experimental animals. An alternate, more suitable, but perhaps more difficult approach would be to demonstrate the mechanism underlying the reaction. That such an approach can be successful in individual cases is illustrated by the case of erythroid aplasia described above. This case was further studied by Yunis et al. (1967). These workers were able to demonstrate that diphenylhydantoin, when added to cultures of the patient’s bone marrow, caused an inhibition of nucleic acid synthesis. The defect apparently occurred at a level dependent upon riboflavin, as addition of riboflavin to culture prevented the effect. When the patient was treated with riboflavin and rechallenged with diphenylhydantoin, no reoccurrence of the reaction occurred. These workers are to be congratulated for giving us a model of what can be done, even in individual cases. In many cases, when the mechanism is known, biochemical markers or traits can be identified which can safely be studied in humans. A good example is the sensitivity to

succinylcholine described above. Abnormal sensitivity to this drug can be measured by the capacity of dibucaine (a local anesthetic) to inhibit plasma pseudocholinesterase activity in vitro. The percent inhibition is known as the dibucaine number. As the affinity of dibucaine for the normal enzyme is over 1,000 times greater than its affinity for the abnormal enzyme, low dibucaine numbers indicate the homozygous state for the two abnormal genes, intermediate numbers the heterozygous state, and high numbers the normal condition. By this means, large populations have been screened and the prevalence and pattern of genetic transmission of this defect have been established. Further, the test can be used as a screening procedure prior to the administration of succinylcholine. Currently techniques are available for determination of the concentration of most antiepileptic drugs and many of their metabolites in biological fluids and tissues. Much information about the metabolism and pharmacokinetics of these drugs in humans has already been obtained by the simple procedure of venipuncture and urine collection. Not only have many normal dose-response relationships been established, but the use of these techniques has led to the discovery of patients or families with abnormal metabolism of antiepileptic drugs. More general use of these techniques, particularly in patients experiencing adverse effects, undoubtedly will contribute a great deal more to our knowledge in the future. MECHANISMS OF TIONS

INDIVIDUAL REAC-

Individual adverse drug effects can be produced by two general mechanisms (Table 3). In one, the individual is rendered more or less sensitive or susceptible to the usual or generic drug effects, while in the other, a new or novel drug effect emerges. Unusual sensitivity to the anticonvulsant properties of the antiepileptic drugs is not well documented, and indeed, ordinarily would not be considered an adverse effect. Unusual sensitivity to the side effects of the drugs is known, however, at least in the case of primidone. Sedation, dizziness, and nausea are common side effects of this drug, particularly when high doses are given. However, there are

IDIOSYNCRATIC REACTIONS TO ANTIEPILEPTIC DRUGS TABLE 3. Mechanisms of indiuidwl reactions Altered sensitivity to usual effects primary

Secondary to abnormal pharmacokinetics Potentiation due to preexisting disease Emergence of new or novel effects primary

Abnormal metabolites Immunologic responses Antigenic stimrilation Indirect

individuals who show a prolonged reaction with lethargy and even stupor associated with nausea and vomiting in response to single, small doses of primidone (Booker, 1972). It is not known whether this sensitivity is genetically determined, or whether it is a primary phenomenon or is secondary to unusual metabolism or distribution of primidone. However, as techniques for determining the concentration of primidone and its metabolites, phenylethylmalondimide and phenobarbital, are available, study of individuals undergoing the reaction should disclose abnormal kinetics if they are present. Reduced sensitivity to the usual therapeutic effects is well known and all too frequent. However, in such cases, seizures are usually intractable to treatment with several drugs, and thii is usually related to acquired factors such as age of onset, type of seizures, and degree of associated encephalopathy. In other cases, it can be related to abnormalities of drug kinetics discussed below. While there are marked individual differences in the rates of absorption, metabolism, and excretion of most drugs, including the antiepileptic drugs, such variance is usually continuous and determined by multiple factors. Therefore such variance by itself should not be considered idiosyncratic. Regardless of the mechanism, however, extreme degrees of unusual kinetics can be the cause of clinically significant adverse effects. For example, Kutt et al. (1966) have reported a patient in whom inability to absorb diphenylhydantoin was almost complete, while other drugs were absorbed normally. We have recently seen a patient in whom therapeutic failure of diphenylhydantoin was related to the presence of undigested capsules of this drug in the stool. This patient did well when placed on a

175

suspension of the drug. Kutt et al. (1966)have also reported several patients in whom the rate of metabolism of diphenylhydantoin was markedly increased. The effect was pronounced enough that therapeutic failure related to low serum concentration on usual doses was the result. The same workers have also reported a patient with inability to metabolize diphenylhydantoin, although metabolism of phenobarbital and other drugs was normal (Kutt et al., 1964). A similar trait was seen in other family members, so that this abnormality may represent the result of a single-factor genetic abnormality. A more common but more complicated example of inhibition of diphenylhydantoin metabolism involves acetylation of isoniazid. Slow acetylators run higher serum levels than fast acetylators on equivalent doses, and thus have an increased potential for peripheral neuropathy. Isoniazid inhibits the metabolism of diphenylhydantoin, and the degree of inhibition is related to the concentration of isoniazid. When the two drugs are given simultaneously to slow acetylators, the higher serum concentrations of isoniazid result in greater depression of diphenylhydantoin metabolism. The accumulation of diphenylhydantoin in serum can be clinically significant in producing intoxication (Brennan et al., 1970). While this is an example of a drug interaction, slow acetylation of isoniazid itself is considered an idiosyncrasy. Many of the antiepileptic drugs are highly bound to serum protein. As only the free or unbound drug is active and available for diffusion, the degree of protein binding in serum determines in part the distribution of the drug. In a recent study of protein binding of diphenylhydantoin, we found the usual signs of clinical intoxication better correlated with the free or unbound concentration than with the total serum level (Booker and Darcey, 1973). Wile there was considerable variance in binding between individuals, binding has been reasonably constant for a given individual over time in our experience. Several different types of serum albumin have been related to single-factor, low-frequency genotypes (Beam and Cleve, 1972). It is not known whether these are associated with abnormal drug-binding ratios, but this is theoretically possible. If so, unusual binding ratios could be present on a

176

H.E. BOOKER

genetic basis, and might accaunt for a variety of unusual patterns of drug distribution in addition to tolerance or intolerance to the side effects of diphenylhydantoin. While not true idiosyncratic reactions, several drug-disease interactions involve the antiepileptic drugs. The ability of diphenylhydantoin to inhibit insulin release has been demonstrated in animals and man (Malherbe et al., 1972), and probably should be considered generic. It is usually mild and of no clinical significance in the majority of patients. However, as will be discussed later by Dr. Reynolds in more detail, the effect may be . significant in diabetic patients. Another important interaction involves myasthenia gravis and the antiepileptic drugs. Hoefer et al. (1958) found that epilepsy and myasthenia gravis coexisted in greater than chance association. Noms et al. (1964) demonstrated a mild curare-like effect of diphenylhydantoin in experimental animals. While not a problem in the great majority of patients, the effect may become clinically significant in patients with myasthenia gravis or in massive overdoses of diphenylhydantoin. In two cases, a myasthenic state was attributed to an autoimmune reaction related to trimethadione (Booker et al., 1970). Thus the antiepileptic drugs may induce or aggravate myasthenia gravis by a direct toxic or an indirect autoimmune mechanism. While pregnancy is not ordinarily considered a disease, it does render the mother, and more importantly the fetus, sensitive to the ability of diphenylhydantoin, phenobarbital, and primidone to interfere with the metabolism of vitamin K-dependent clotting factors. Even though several cases have been reported (Monnet et al., 1968, Evans et al., 1970), the problem is not generally recognized. Emergence of new or novel drug effects is the category usually considered by clinicians at least to be the main type of idiosyncratic mechanism. One of the more common and best understood examples is that of phenobarbital and acute intermittent porphyria. The immediate action is probably induction of amino-levulinic acid synthetase, with increased production of heme and porphobilinogen (Marver and Schmid, 1972). This effect itself may be secondary to induction of the heme containing enzyme cytochrome-P450 reductase, which would necessitate an increase in heme synthesis.

If SO, the underlying action would occur in most individuals and experimental animals, and could not be considered idiosyncratic. However, the secondary effect on amino-levulinic acid synthetase would seem to be of clinical importance only in the unfortunate individual who carries the single autosomal gene for acute intermittent porphyria and already has excessive activity of this enzyme. In addition to phenobarbital, we have seen individuals in whom hydantoins and succinimides apparently acted as inducers. Although not as well documented, the mechanism is probably the same. Blood dyscrasias constitute some of the more frequent serious reactions to the antiepileptic drugs. When damage is limited to the more mature elements, the reaction is usually limited to a single cell line, as in thrombocytopenia or hemolytic anemia. "he latter can occur in patients with a deficiency of erythrocytic glucose-6-phosphate dehydrogenase deficiency in response to any drug that has oxidizing properties and stimulates the hexosemonophosphate shunt (Beutler, 1972), although the antiepileptic drugs have not been involved. When more primitive, blast cells are damaged, pancytopenia or aplastic anemia can occur. The mechanism can be allergic, as in the leukopenia induced by amidopyrine and related sulfa drugs, or it can be due to direct toxicity as in the case of phenothiazines or chloromycetin (Pisciokta, 1971). Direct toxicity is probably involved in the antiepileptic drugs, as many cases occur after prolonged exposure or in response to excessive doses. In any event, an individual susceptibility seems to be involved, as the reactions are rare. Both acute sensitivity reactions associated with circulating antibodies and delayed or tissue-mediated immune reactions have been caused by the antiepileptic drugs, although they are not ordinarily considered idiosyncratic. Nevertheless, they are based upon an individual sensitivity or capacity of the immune system to respond adversely in the presence of drug. As a significant portion of an individual's capacity to respond to various immunologic challenges are genetically determined, allergic and idiosyncratic reactions may share the common substrait of rare or unusual genotypes. Allergic reactions often present the same problems to the clinician as do idiosyncratic reactions. That

IDIOSYNCRAnC REACTIONS TO ANTIEPILEPTIC DRUGS is, they can be rare and unpredictable, and particularly in the case of the delayed-type reactions, can mimic a disease syndrome. The lupus erythematosis4ike reaction associated with a variety of the antiepileptic drugs, for example, is ordinarily indistinguishable from the spontaneously occumng disease, except perhaps in retrospect upon complete disappearance of the reaction following withdrawal of the offending drug. Therefore there is justification for including a brief discussion of these reactions here, particularly with regard to possible mechanisms. Satisfactory evidence that drugs could induce the presence of circulating antibodies has been accomplished for several reactions, with leukopenia induced by amidopyrine and related drugs as the best-known example (Rsciotta, 1971). With regard to antiepileptic drugs,,the picture is less clear. Robinson et al. (1965) reported positive basophil cfegranulation, indicating antibodies against diphenylhydantoin, in one patient with a lymphoma4ike reaction, and Holland and Mauer (1965) reported positive blast transformation of cultured lymphocytes in response to diphenylhydantoin in another patient with serum sickness. However, such attempts have not always been successful. In our own studies (MacKinney and Booker, 1972) we have been unable to confirm the general usefulness of lymphocyte transformation in reactions of the allergic type to diphenylhydantoin. Of 8 patients studied, only 1 showed a positive response on a culture obtained 10 months after a Stevens-Johnson reaction. However, negative results were obtained in two other cultures taken at 9 and 11 months, so that the significance of the one positive response is not clear. Failure to demonstrate antibodies against drug does not prove that they are not present, as such determinations can be extremely difficult. However, there are other possible mechanisms besides drug-hapten as antigen by which a drug might adversely influence the immune systems. Considering the essential role of lymphocytes in immunological reactivity, and the ability of antiepileptic drugs to produce autoimmune disorders and to stimulate benignand malignant-appearinglymphocytic reactions, we investigated the possible effects of diphenylhydantoin on cultured human lymphocytes

177

(MacKinney and Booker, 1972;MacKinney and Vyas, 1972). Addition of diphenylhydantoin in therapeutic concentrations to cultures of lymphocytes from normal controls and patients with and without allergic reactions to diphenylhydantoin was associated with a reversible, time- and dose-dependent inhibition of growth and DNA synthesis. The effect did not seem to be related to interference with folate metabolism. In vivo we found a negative correlation between DPH serum concentration and the number of circulating lymphocytes in 65 patients taking diphenylhydantoin chronically. We have hypothesized that the antilymphocytic effect of chronic administration of diphenylhydantoin was associated with an immunosuppressant effect, and found decreased immunoglobulin levels in patients taking diphenylhydantoin. At about the same time, Sorrell et al. (1971) independently presented more direct evidence of depression of the capacity of patients treated with diphenylhydantoin to respond to a variety of immunologic challenges. Similar results have subsequently been reported by Grob and Herold (1972). In our studies, the inhibition of DNA synthesis was greater in cultures from patients with reactions to diphenylhydantoin than in normal controls or patients taking diphenylhydantoin without a history of adverse reactions. The difference could be a result of the reaction itself, but it also suggests the possibility of preexisting sensitivity to the effect. Currently our hypothesis is that the mild antilymphocytic, immunosuppressant effect of diphenylhydantoin is of no consequence in the majority of individuals. However, in predisposed individuals, the effects sets in motion the mechanism underlying the interrelationship between immunosuppression, autoimmune disease, and neoplasia, particularly lymphoma. The mechanism could possibly involve a break in surveillance, and/or the appearance of abnormal, even malignant clones as a result of the organism's attempt to overcome the chronic lymphocytic inhibition. It would not be surprising to find that the predisposition was geneticply determined. A great deal of work remains to be done before this can be advanced as anything more than interesting speculation. Nevertheless, the hypothesis has the advantage of proposing a single underlying mechanism for both autoimmune reactions and lymphoma

178

H.E. BOOKER

in response to the antiepileptic drugs and is an the relative safety must consider the effectiveness of the drugs in controlling seizures. For alternative to the drug as antigen model. these reasons, we shall not attempt to present a comprehensive list, but rather will confine our discussion to either the more frequently occurring individual reactions or those which, THE CLINICAL PROBLEM although extremely rare, are potentially fatal The clinical problem can be rather simply (Table 4). Overdose and side effects have not defined as first recognition or correct diagnosis been considered, as these will be discussed by that indeed a drug reaction is taking place, and others. However, some potentially dangerous secondarily treatment or prevention. Correct drug interactions and drug-disease interactions diagnosis will depend upon a general awareness have been included. The list does not contain of the potential for adverse drug effects, plus a all reported reactions or implicated drugs. thorough knowledge of the potential hazards of Therefore, it is not intended as a complete any particular treatment the clinician pre- source or reference, but more as a guide to the scribes. In general, the risk of an adverse more likely reactions and involved drugs. More reaction is greater in females than in males, complete sources are available, and the reader is increases with age and number of drugs encouraged to consult the selected sources administered and with increased dose and included in the references (Martin, 1971; duration of treatment. There is greater Meyler, 1957-1966;Moser, 1969; Rous and potential for problems in patients with more Verdilla, 1971; Stansbury et al., 1972; Woodthan one disease. Certainly a history of an bury et al., 1972). unusual or adverse reaction in any patient in While most of the antiepileptic drugs have the past would call for careful consideration of been reported to cause or aggravate a variety of the need for or choice of therapy in the future, benign skin reactions (acne, hirsutism, alopecia, not only in the patient but also in his close morbiliform rashes, fixed drug erruptions, urticaria, etc.), of more concern here are the relatives. Within the general epidemiology of adverse dangerous, potentially fatal reactions (erythema drug effects, the type of reaction will vary with multiforme, exfoliative dermatitis, Stevensthe tirug or class of drugs employed. Unfortun- Johnson syndrome, and epidermal necrolysis). ately, the constantly increasing number of Most occur on an allergic basis, and have been known or suspected drug reactions is probably reported for almost all of the antiepileptic already too large to realistically expect the F g s . Their occurrence calls for withdrawal of clinician to keep in his working memory. all medications whenever possible, as unforTherefore, there would seem to be a real need tunately there is no easy or reliable way to for readily available reference sources that identify the offending drug when the patient is catalogue the available information. For reasons taking more than one medication. In many cases, bone marrow suppression can discussed above, the list of reactions to the antiepileptic drugs definitely established as and should be detected in the early, asymptomidiosyncratic is very short and would not be of atic stage by means of periodic’blood counts. much practical value. On the other hand, a When detected in this stage, the reaction is comprete list of all the adverse effects of these usually reversible with drug withdrawal. Leukodrugs would be beyond the scope of this penia progressing to aplastic anemia is more presentation. In attempting to compile such a often seen in patients taking trimethadione, list, it became apparent that, by and large, ethosuximide, methsuximide, mephenytoin, drugs with few entries were either the less carbamazepine, and phenacemide. Diphenylhyeffective and less frequently used drugs, or the dantoin, phenobarbital, and primidone, hownewer drugs with which we have notshad as ever, seem to be relatively safe, and it has not much experience. Such lists therefore do not been our policy to require routine periodic define the relative safety of these drugs, as this blood counts with these drugs. One possibility will depend upon the true incidence of adverse to keep in mind, although it has not yet been reactions in the total at-risk population, and reported for the antiepileptic drugs, is the these data are not available. Also, definition of occurrence of leukemia as a late sequel of

IDIOSYNCRATIC REACTIONS TO ANTIEPILEPTIC DRUGS

179

TABLE 4. Serious individual reaction@ ~

Skin (exfoliative dermatitis, etc.)-potentially all drugs Liver-phenacemide, trimethadione; phenytoin, mephenytoin, methsuximide, carbamazepine,acetazolamide, sulthiame Renal-phenacemide, trimethadione, methsuximide; acetazolamide, phensuximide Bone marrow-trimethadione, ethosuximide, mephenytoin, carbamcrzepine; methosuximide, phenacemide Lupus erythematosis-phenytoin; mephenytoin, trimethadione, primidone, ethosuximide Thyroiditis-phenytoin, trimethadione Myasthenia gravis-phenytoin, mephenytoin, trimethadione Lymphoma-phenytoin, mephenytoin; trimethadione, primidone Hemorrhage in newborn-phenytoin, primidone, Phenobarbital Porphyria-pheno barbital; hydantoins, succinimides Hyperglycemia-phenytoin Increased steroid metaboliim-phenytoin, phenobarbital Coumarin anticoagulants-phenytoin, phenobarbital aThe table does not include common overdose, side effects, or drug interactions. .Drugs more frequently reported in any reaction appear in italics. Absence of any drug under any reaction should not be taken to imply that the drug has never been implicated.

drug-induced bone marrow damage (Pisciotta, 1971). Liver damage due to both cholestasis and hepato-cellular damage has been reported but is not common. The mechanism may be direct toxicity, as in the case of phenacemide, or it may occur in association with other symptoms suggesting an autoimmune reaction. While most dru~ have been implicated, phenacemide and trimethadione seem implicated more often. Similarly, renal damage is not common, but phenacemide, trimethadione, and methsuximide seem most likely to be responsible when it occurs. With the exception of these three drugs, hepatic and renal damage occurs so seldom that it has not been our policy to perform routine laboratory screening of liver and renal function in patients taking the other antiepileptic drugs. A variety of autoimmune reactions are &ported, with a lupus erythematosis-like syndrome being most frequent. Drugs implicated include phenobarbital, primidone, diphenylhydantoin, mephenytoin, trimethadione, and ethosuximide. Thyroiditis is less common, usually related to diphenylhydantoin or trimethadione. Myasthenia gravis may be aggravated by many drugs, including hydantoins. The de nouo appearance of a myasthenic state has also been related to mephenytoin and trimethadione. In two cases, trimethadione seemed to initiate an autoimmune reaction responsible for the myasthenic reaction. Thus antiepileptic drugs, as well as many other drugs, should be given with caution to patients with

myasthenia. Appearance of myasthenic symptoms in epileptics should alert the clinician to the possibility that the antiepileptic drugs are responsible. The occurrence of malignant-appearing lymphocytic reactions identical to or closely mimicking Hodgkin's disease, lymphosarcoma, and reticulum cell sarcoma has been reported for diphenylhydantoin, primidone, mephenytoin, and trimethadione. Of these, the hydantoins seem to be the most frequently involved. The reaction often remits when these drugs are withdrawn, so that initial treatment should not involve irradiation or cytotoxic agents, unless the tumor is progressing rapidly. Unfortunately, the tumor does not always remit, and these cases must then be treated fully. In addition to tissue reactions, a variety of serious, potentially fatal metabolic abnormalities are encountered. Precipitation of crisis in patients with acute intermittent pokphyria has been seen with barbiturates, hydhtoins, and succinimides. If the porphyria is complicated by seizures, the choice of antiepileptic drugs is thus severely limited. Carbamazepine and benzodiazepines seem to be relatively safe, however. There is not as yet general awareness of the potential for hemorrhagic disease of the newborn in response to maternal ingestion of phenobarbital, diphenylhydantoin, and primidone. Prophylactic administration of vitamin K to mothers near term and to the newborn should be a simple and efficient preventive. The ability of diphenylhydantoin to inhibit insulin

180

H.E. BOOKER

release is usually mild and of no consequence, but may be of clinical significance in patients with diabetes or in overdoses. Also, the ability of diphenylhydantoin and phenobarbital to interfere with steroid metabolism is usually of no consequence, but may be in patients with preexisting endocrine disease or those taking exogenous steroids (Brooks et al., 1972; Buchanan and Sholiton, 1972). Particularly important drug interactions involve diphenylhydantoin and phenobarbital and the coumarin-type anticoagulants. Increased metabolism of the anticoagulants due to enzyme induction with the attendant potential for hemorrhage on phenobarbital withdrawal has been discussed above. Diphenylhydantoin increases the anticoagulant effect by displacing the coumarin-type anticoagulants from binding sites on serum albumin. Thus when diphenylhydantoin is added or withdrawn in anticoagulated patients, careful regulation of the anticoagulant does is required. Conversely, the anticoagulants inhibit the metabolism of diphenylhydantoin, and clinical intoxication may appear. The possibility exists that phenobarbital and other enzyme-inducing agents may inhibit the effectiveness of oral contraceptives (Fahin et al., 1968;Levin et al.,

1968). Treatment involves withdrawal of the offending drug in all of these reactions, as they are serious and potentially fatal. Other specific and supportive therapy is determined by the particular type and intensity of the individual reaction. In general, one should be particularly cautious about attempts to control symptoms in these reactions by the use of other drugs. This frequently complicates the picture and offers the possibility of still further adverse drug reactions and interactions. If the most important caveat in therapeutics in general is primun non nocere, then the most important caveat in the treatment of adverse drug effects would be secundum nonplus nocere. SUMMARY Idiosyncratic drug reactions can be defined

as those adverse drug effects caused by genetically determined enzymatic abnormalities. For the clinician, however, this definition is too limited, and other rare and unusual

adverse reactions to the antiepileptic drugs are discussed, including drug interactions, drug disease interactions, drug allergies, and organ toxicities, as well as true idiosyncrasies. Responsibility for initial recognition and later diagnosis of these reactions falls heavily upon the clinician. In addition to discussing the more common or serious rare reactions, the epidemiology and general mechanisms underlying the reactions are discussed. Treatment involves drug withdrawal, plus general supportive and specific therapy determined by the type and severity of the individual reaction. If primum non nocere guides therapy in general, then secundum non plus nocere should guide the treatment of adverse drug reactions.

REFERENCES Anthony JJ. Malignant lymphoma associated with hydantoin drugs. Arch Neurol 22:450-454,1970. Bearn AG and Cleve H. Genetic variations of plasma proteins. In: JB Stansbury, JB Wyngaarden, and DS Frederickson (Eds.), The Metabolic Bask of Inherited Disease, 3rd ed. McGraw-Hill, New York, 1972, pp. 1629-1642. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. In: JB Stansbury, JB Wyngarrden, and DS Frederickson (Eds.), The Metabolic Basis of Inherited Disease, 3rd ed. McGraw-Hill, New York, 1972, pp. 1358-1388. Booker HE: Primidone: Int0,xication. In: DM Woodbury, JK Penry, and RP Schmidt (Eds.), Antiepileptic Drugs. Raven Press, New York, 1972, pp. 377-383. Booker. HE. Chun RWM. and Sanmino M. Myasthenia gravis syndrome associated with trimethadione. JAMA 21 :2262-2263, 1970. Booker HE and Darcey B. Serum concentrations of free diphenylhydantoin and their relationship to clinical intoxication. Epilepsia 14:177-184,1973. Brennan RW, Dehejia H, Kutt H, Verbeley K, and McDowell F. Diphenylhydantoin intoxication attendant to slow inactivation of isoniazid. Neurology (Minneap) 20 :687-693, 1970. Brittingham TE, Lutcher CI, and Murphy DL. Reversible erythroid aplasia induced by diphenylhydantoin. Arch Intern Med 113~764-768,1964. Brooks SM, Werk EE, Ackerman SJ, Sullivan I, and Thrasher K. Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma. New Engl J Med 286:1125-1128,1972.

IDIOSYNCRATIC REACTIONS TO ANTIEPILEPTIC DRUGS Buchanan RA and Sholiton LJ. Diphenylhydantoin: Interactions with other drugs in man. In: D M W o o d b ~JK Penry, and RP Schmidt (Eds.), Antiepileptic Drugs. Raven Press, New York, 1972, pp. 181-191. Cluff LE, Thomton G, and Seidl L. Epidemiological study of adverse drug reactions. Trans Assoc Amer Physicians 78:255-268, 1965. Evans AR, Forrester RM, and Discombe C. Neonatal hemorrhage following maternal anticonvulsant therapy. Lancet 1:517-518, 1970. Fahin MS, King TM, and Hall DG. Induced alterations in biologic activity of estrogen. Amer J Obstet Gynecol100:171-175,1968. Grob PJ and Herold GE. Immunological abnormalities atid hydantoins. Brit Med J 1~561-563,1972. Hoefer PF, Arnaow H, and Rowland LP. Myasthenia gravis and epilepsy. Arch Neurol Psychiatr 80~10-17,1958. Holland P. and Mauer AM. Diphenylhydantoin induced hypersensitivity reaction. J Pediatr 66:322-332,1965. Kutt H; Haynes J, and McDowell F. Some causes of ineffectiveness of diphenylhydantoin. Arch Neurol14:489-492,1966. Kutt H, Wolk M, Scheman R, and McDowell F. Insufficient parahydroxylation as a cause of Neurology diphenylhydantoin toxicity. (Minneap) 1:542-548,1964. Levin W, Welch RM, and Conney AH. Effect of phenobarbital and other drugs on the metabolism and uterotropic action of estradiol-17B and estrone. J Pharmacol Exp Ther 159:362-371,1968. MacKinney AA and Booker HE. Diphenylhydantoin effects on human lymphocytes in vitro and in vivo. Arch Intern Med 129~988-992,1972. MacKinney AA and Vyas R. Diphenylhydantoin-induced inhibition of nucleic acid synthesis in cultured human lymphocytes. Proc Soc Exp Biol Med 141:89-92,1972. Malherhe MD, Burrill KC, Levin SR, Karman JH, and Forsham PH. Effect of diphenylhydantoin on insulin secretion in man. New Engl JMed 286:339-342,1972. Martin EW. Hazards o f Medication. Lippincott, Philadelphia, 1971. Marver HS and Schmid R. The prophyrias. In: JB Stanbury, JB Wyngaarden, and DS Frederickson (Eds.), The Metabolic Basis o f Inherited Disease, 3rd ed. McGraw-Hill, New York, 1972, pp. 1087-1140. Meleney HE and Fraser ML. A retrospective study of drug usage and adverse drug reactions in hospital outpatients. Drug Inform Bull 3:124-127,1969. Meyler L (Ed.). Side Effects of Drugs as Reported in the Medical Literature o f the World, Vols. I-VI. Excerpta Medica, Mouton, Netherlands, 1 957 -19 66.

181

Monnet P, Rosenberg D, nd Bovier-Lapierre M. Antiepileptic drugs in pregnancy and hemorrhagic disease of the newborn (in French). Rev Franc Gynec 63:695-702,1968. Moser RH (Ed.). Diseases o f Medical ProgressA Study o f Iatrogenic Disease: A Contemporary Analysis o f Illness Produced by Drugs and Other Therapeutic Procedures, 3 ~ ded. Charles C Thomas, Springfield, Ill., 1969. Norris FH, Colella J, and McFarlin D. Effect of diphenylhydantoin on neuromuscular synapse. Neurology (Minneap) 14:869-876, 1964. Pisciotta AV. Drug-induced leukopenia and aplastic anemia. Clin Pharm Ther 12:13-43, 1971. Prescott LF. Pharmacokinetic drug interactions. Lancet 2 :123 9-1243,1969. Prous JR and Verdilla D (Eds.). Annual Drug Report, Vol 1, Drugs o f Today. Barcelona, 1971. Robinson DS, MacDonald MG, and Hobin EP. Sodium diphenylhydantoin reaction with evidence of circulating antibodies. JAMA 192:171-172.1965. Saltzstein SL and Ackerman LV. Lymphadenopathy induced by anticonvulsant drugs and mimicking clinically and pathologically malignant lymphomas. Cancer 1 2 :164-182, 1959. Sorrell TC, Forbes IJ, Burness FR, and Rischbieth RHC. Depression of immunological function. in patients treated with phenytoin sodium (sodium diphenylhydantoin). Lancet 2:1233-1235,1971. Stansbury JB, Wyngaarden JB, and Frederickson DS (Eds.). The Metabolic Basis o f Inherited Disease, 3rd ed. McGraw-Hill, New York 1972. Vesell ES. Drug therapy: Pharmacogenetics. New Engl JMed 287:904-909,1972. Whittaker M: Genetic aspects of succinycholine sensitivity. Anesthesiology 32 :143-150, 1970. Woodbury DM, Penry JK, and Schmidt RP (Eds.). Antiepileptic Drugs. Raven Press, New York, 1972. Yunis AA, Arimora GK, Lutcher CL, Blasquez J , and Halloran M. Biochemical lesion in Dilantininduced erythroid aplasia. Blood 30~587-600,1967.

N.B.: This paper was presented at the Symposium on Antiepileptic Drugs, session on Iatrogenic Aspects o f Antiepileptic Drugs: Toxicity, held a t the XII International Congress of Epilepsy, organized by the International League Against Epilepsy, X International Congress of Neurology, Barcelona, September 8 and 9,1973.