Management of Seizure Disorders with Anticonvulsant Drugs: Current Concepts

Symposium on Pediatric Neurology

Management of Seizure Disorders with Anticonvulsant Drugs: Current Concepts Peter H. Berman, MD.*

The successful treatment of seizures with anticonvulsant drugs began in 1857 when, during the discussion of a paper read before the Royal Medical and Chirurgical Society of London by Sieverking, Locock remarked that potassium bromide had been successful in controlling seizures in a small number of his patients. 72 Fifty-five years later, Hauptman presented an anecdotal account of his experience with phenobarbital as an anticonvulsant drug. 59 No significant investigation preceded the introduction of either of these drugs into clinical practice. The introduction of diphenylhydantoin in 1938, however, occurred only after extensive preclinical testing had established its efficacy in suppressing seizures in experimental animals. 82 ,83 Subsequently all anticonvulsant drugs have been subjected to extensive experimental investigation to assess their effectiveness and safety prior to their introduction into clinical practice. The clinical management of seizures with anticonvulsant drugs, however, has remained quite empiric. Recommended "standard" doses are based predominantly on rough estimates which attempt to bridge the gap between clinical effectiveness and toxicity. Such "standard" doses fail to recognize the wide variation in drug metabolism among patients. Therapeutic failure can result when the "standard" dose proves ineffective in a particular patient who metabolizes a drug more rapidly. Conversely toxic symptoms can result from the "standard dose" of a potentially beneficial drug because of excessively slow detoxification and excretion. Recent technologic advances have led to the availability of laboratory procedures which allow for the rapid, reliable, and specific measurement of the concentration of most anticonvulsant drugs and their metabolites in small samples of tissues and body fluids,38, 79, 99 With these methods it has become more practical to study drug metabolism and pharmacokinetics. s2 , 68, 69, 80 The information gained from studies utilizing these techniques is beginning to have important implications for the clinical management of patients with seizures. 2,39,65-67,111 "Associate Professor of Neurology and Pediatrics, School of Medicine, University of Pennsylvania; Director, Division of Neurology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Pediatric Clinics of North America- Vol. 23, No.3, August 1976

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BARBITURATES

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PHENOBARBITAL

p-HYDROXY PHENOBARBITAL

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Figure 1. The chemical structures of phenobarbital and its major metabolite p-hydroxy phenobarbital, and of primidone and. its metabolites phenobarbital and phenylethyl malonamide (PEMA) are demonstrated.

PHENOBARBITAL

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PRIMIDONE PHENYLETHYL MALONAMIDE

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From these studies it is becoming increasingly apparent that factors affecting the absorption, distribution, metabolism, and excretion of drugs play a vital role in determining the success or failure of treatment. Furthermore, although it is possible to make some generalizations about these parameters, it is becoming increasingly evident that individual metabolic differences, which affect the outcome of treatment, frequently occur. The purpose of this article is to summarize the present knowledge of pharmacology and metabolism of the more commonly used anticonvulsant drugs, emphasizing those features which will allow for the more rational use of these drugs in clinical practice. Although the literature on this subject is growing rapidly, the reader is cautioned that some current concepts are based on studies involving relatively small human populations, and that in many instances data derived from patients in the pediatric age groups are especially meager.

BARBITURATES Phenobarbital and primidone (Mysoline) are the two barbiturates most commonly used as anticonvulsants. The structure of primidone is the same as that of phenobarbital except that the barbiturate ring is reduced at the 2 carbon position to form a desoxybarbiturate (Fig. 1).

PHENOBARBIT AL

First introduced as an antiepileptic agent in 1912,59 phenobarbital remains the most commonly used anticonvulsant in children because of its broad spectrum, low toxicity, and low cost. It raises the threshold for seizures in a wide variety of experimental epileptic models and inhibits

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the spread of discharges from an epileptic focus. 68 Clinically it is most effective in the treatment of generalized tonic-clonic (grand mal) convulsions, but it is also helpful in controlling focal and psychomotor seizures.

Absorption, Distribution, Metabolism, and Excretion Phenobarbital is readily and almost completely absorbed after oral, rectal, or intramuscular administration. In one series involving infants and children, 90 per cent of the maximal plasma concentration was reached within four hours after the administration of a single oral or intramuscular dose in the therapeutic range. 6l Following absorption, there is a fairly rapid distribution into most body tissues, but equilibration between plasma and brain may lag several hours.36 After chronic administration, the concentration in brain approximates plasma levels. 96 Approximately 50 per cent of the drug is bound to plasma or tissue proteins. 53. 106 Cerebrospinal fluid concentrations reflect unbound phenobarbital and are approximately 50 per cent of the brain and plasma levels. lo6 Phenobarbital is partially excreted in the urine and partially metabolized, predominantly by hepatic microsomal enzymes, to p-hydroxyphenylbarbital. 77 P-hydroxyphenylbarbital has no known anticonvulsive properties and is rapidly excreted in the urine. Both the hydroxylation and the renal clearance of phenobarbital, however, proceed relatively slowly, 11 to 27 per cent of the available drug being eliminated in the first 24 hours following discontinuation of a chronic dose.22.102 Following the discontinuation of a chronic dose, the serum phenobarbital concentration will fall with a mean half life of 96 hoursP

Clinical Applications The effective serum concentration of phenobarbital is said to range between 10 and 25 f-Lg per mlP In children, however, the relationship between serum concentration and seizure control has not been extensively studied. Buchtal and coworkers significantly reduced the amount of electroencephalographic abnormality and stopped the occurrence of grand mal seizures in 11 adults by raising the serum concentration of phenobarbital above 10 f-Lg per ml, but in 9 of the 11 patients seizures were controlled during the duration of the study with serum levels above 4 f-Lg permU 9 In another study, 7 of 33 children with a history of febrile convulsions had recurrent convulsions associated with a serum level below 15 f-Lg per ml, whereas further seizures occurred in only 1 of 27 infants whose serum level was maintained at a concentration greater than 15 f-Lg per m1. 42 Although large differences occur among patients, the correlation between the dose administered and the resulting serum concentration approaches linearity in a particular individual. In children, 3 to 6 mg per kg per day of phenobarbital must usually be administered to maintain a serum concentration between 10 to 25 f-Lg per ml, and in adolescents serum levels in the therapeutic range can be maintained with a dose of 1 to 2 mg per kg per day.l03 Higher doses are presumably necessary in the younger age group because phenobarbital is metabolized and/or excreted more rapidly.

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With such daily maintenance doses, it will take 2 to 3 weeks to reach therapeutic levels. 102 A loading dose of approximately twice the maintenance dose (6 to 10 mg per kg per day in children and 2 to 4 mg per kg per day in adolescents) for 2 to 3 days will bring the serum concentration to the therapeutic ranges within 48 to 72 hours. 17 Transient drowsiness will, however, occur with these doses in some patients. Because of phenobarbital's relatively slow metabolism and excretion, hourly variations in serum concentration are sufficiently small to permit the administration of a single daily dose at bedtime in most adolescents and adultsP' I\!2 Since the rate of elimination is more rapid in children, hm',ver, two doses per day should be administeredP Drowsiness is the most frequent dose-related side effect of phenobarbital. Although this symptom may occur at low serum levels with the initiation of therapy, tolerance occurs rapidly.22, 101 With chronic therapy, dose-related side effects rarely occur with serum levels below 30 ILg per mlY Severe lethargy, stupor, and coma are usually associated with serum concentrations above 60 ILg per m1P,101 The occurrence of paradoxical hyperactivity, a much more frequent side effect in children than drowsiness, has not been related to dose or plasma concentration.

PRIMIDONE

Primidone was introduced into clinical practice in 1952 by Handley and Stewart after experimental data demonstrated that it protected animals from electrically and chemically induced seizures.57 Clinically it has proved most effective in the treatment of psychomotor and generalized tonic-clonic (grand mal) seizures. Absorption, Distribution, Biotransformation, and Excretion Primidone is fairly rapidly absorbed from the gastrointestinal tract, peak serum levels occurring within a few hours after the ingestion of an initial single dose in adults. 9, 47 We could find no information concerning the rate of absorption in children. Following the administration of a single dose in the therapeutic range, peak primidone concentrations usually occur within 2 to 3 hours and then decline with a half life of approximately 3 to 7 hours. 5,47 With chronic administration, there may be some slowing of both the rate of absorption (5 to 7 hours) and the rate of decline (11 to 25 hours) in some patients. 47 Primidone is converted into two major metabolites: phenylethylmalonamide (PEMA) and phenobarbitalY PEMA also has anticonvulsant properties. 47 PEMA can be detected within two hours after the ingestion of a single oral dose of primidone, reaches a peak in 7 to 8 hours, and declines with a half life of 29 to 36 hours.5 The relatively slow excretion of PEMA and phenobarbital leads to significant accumulation of both compounds with chronic primidone treatment,S although phenobarbital levels usually do not appear for 5 to 7 days.9 Little is known about the distribution of primidone or PEMA. Unlike phenobarbital, they are not bound to serum or tissue proteins.5,53 Animal experiments indicate that

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both unmetabolized primidone and PEMA are excreted in the urine. 46 The ultimate disposition of phenobarbital has already been discussed.

Clinical Applications There is thus far no data relating the serum levels of primidone or its major metabolit" PEMA to seizure control in children, and there has been some speculation that primidone's anticonvulsant effect is primarily due to the derived phenobarbital.2 3 • 48. 88 In adults, 15 to 25 per cent of the administered primidone is eventually metabolized to phenobarbital, and the administration of standard doses of 1.0 to 2.0 gm of primidone per day led to serum phenobarbital concentrations of 16 and 30 p.,g per ml after six days of therapy.23, 88 The substitution of phenobarbital to provide serum concentrations equivalent to those produced by administration of phenobarbital worsened seizure control in only 4 of 19 adult epileptics. s8 The prevailing clinical opinion, however, is that primidone and PEMA have significant anticonvulsant properties of their own, and the recent demonstration that PEMA in low doses potentiates the anticonvulsant properties of phenobarbital in rats supports this view. 5 Further clinical studies must be performed before serum levels of primidone and PEMA can be used to assess the effectiveness of a given dose. Dose-related side effects of primidone include sedation, vertigo and dizziness, nausea and vomiting, ataxia, diplopia, and nystagmus. 6 Ataxia and/or somnolence has occurred in adult patients with serum primidone levels above 10 p.,g per ml when phenobarbital concentrations were not excessive. 6 The pronounced sedation occasionally seen within hours after the initiation of primidone therapy is presumably related to an excessive primidone concentration since appreciable amounts of phenobarbital are not formed in so short a time.

HYDANTOINS The hydantoin derivative most frequently used in anticonvulsant therapy is 5,5-diphenylhydantoin (Dilantin~ (Fig. 2). Mephenytoin, 5ethyl-3-methyl-phenylhydantoin (Mesantoin) and ethotoin, 3-ethyl-5phenylhydantoin (Peganone), offer no practical advantage over diphenylhydantoin and their use is limited to those patients who prove refractory to other medications.

DIPHENYLHYDANTOIN

Diphenylhydantoin, first introduced as an antiepileptic drug by Putnam and MeITit in 1938, has had more extensive investigation than any other anticonvulsant. In experimental animals it is most effective in inhibiting the spread of electrical discharges from an epileptic focus. 68 Clinically, it is as effective in the treatment of generalized tonic-clonic (grand mal), focal, and psychomotor seizures as phenobarbitaU 6 It is not effective in the treatment of simple febrile seizures or petit maU6,81

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HYDANTOINS

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DIPHENYLHYDANTOIN

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Figure 2. The chemical structures of diphenylhydantoin and its major metabolite 5-(p-hydroxyphenyl)-5phenylhydantoin, and the chemical structures of me phenytoin and ethotoin are demonstrated.

ETHOTOIN

Following oral administration, diphenylhydantoin is absorbed in the duodenum. 34 Peak levels are usually obtained within 4 to 8 hours after the ingestion of a single dose. 34,91 Absorption after intramuscular administration may be quite erratic, and this route of administration is not recommended. 32 , 110 Following intravenous administration, a peak serum concentration is reached within 15 minutes, but this is followed by a rapid fall as the drug is distributed to other tissues. l04 On entering the circulation, diphenylhydantoin is rapidly bound to proteins. Experimental data suggests that the anticonvulsant effect correlates best with the concentration of unbound diphenylhydantoin. 99 In man, between 70 and 95 per cent of the drug may be protein bound. 7 , 75, 106 Since protein binding is significantly lower in premature and newborn infants, infants in these age groups may respond to lower doses than older children.91 Diphenylhydantoin distributes rapidly throughout the body tissues, binding to subcellular fractions, and is deposited in fat. 86 After intravenous injection, it rapidly enters the brain, peak levels occurring in 15 minutes. ll2 With repeated administration, the concentration in the brain is 1.5 to 3 times that of the serum.35 ,96 Spinal fluid concentrations reflect nonprotein bound serum levels and are approximately 10 per cent of the total serum concentration. l06 Diphenylhydantoin is metabolized by hepatic microsomal enzymes to form inactive metabolites which, after conjugation with glucoronate, are ultimately excreted in the urine. 29 Approximately 70 per cent of the drug appears in the urine as 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) in the urine and approximately 5 per cent is excreted unchanged. 21

Clinical Applications The effective serum concentration in most patients ranges between 10 and 20 JLg per ml. Several clinical studies have demonstrated a sig-

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nificant improvement in seizure control and/or a reduction in associated electroencephalographic abnormalities in patients when the serum concentration is greater than 10 to 12 f.Lg per mUs, 74, S7 Although there is considerable variation between the dose administered and the resulting serum concentration, some generalizations can be made. 16 Because the biotransformation and excretion of diphenylhydantoin increases with age, younger children require a relatively higher dose per weight. To achieve a serum concentration between above 10 f.Lg per ml, children under 20 kg usually require a dose of 10 mg per kg per day; children between 20 and 40 kg usually require a dose of 5 to 7 mg per kg per day, and children over 40 kg, a dose of 4 to 6 mg per kg per day.I03 In one study involving children with seizure disorders, Borofosky and coworkers found that with a dose less than 5 mg per kg, serum diphenylhydantoin concentrations ranged between 5 and 8 f.Lg per ml, and with a dose between 5 and 8 mg per kg, the serum concentrations ranged between 10 and 24 f.L g per ml.lO However, in 26 per cent of the 53 children in this study, the resulting serum concentrations differed from these ranges; higher levels were most common in obese patients and lower levels in younger patients. Because of this marked variation among individual patients, serum diphenylhydantoin levels should be performed after initiation of therapy especially when the drug seems to be ineffective. After oral administration, the serum half life of diphenylhydantoin varies from 7 to 42 hours (mean 22 hours) in adults. 1 Because of this relatively long half life, there is little fluctuation in the plasma concentration over a 24 hour period after the administration of a single daily dose. 56 , 100 In children, two doses per day are usually recommended/ 6. 103 although recent data suggests that even in this age group one daily dose will usually suffice and not lead to an increase in toxic symptoms. 15 Following the initiation of diphenylhydantoin therapy, it may take from one to two weeks to reach a plateau in the plasma concentration. A loading dose of four times the daily dose (up to 20 mg per kg per day) for the first day and twice the daily dose for the next two days will bring the plasma concentration to and maintain it at therapeutic levels within 24 hours.16 Gingival hyperplasia, a common side effect, occurs with serum diphenylhydantoin concentrations in the therapeutic range. 64 Nystagmus, a common side effect in adults, occurs infrequently in children but may also be seen when serum levels are in the therapeutic range. 70 More serious dose-related side effects rarely occur with serum concentrations below 30 f.Lg per m1. 64

SUCCINIMIDES Three substituted succinimides, ethosuximide (Zarontin), methuximide (Celontin), and phensuximide (Milontin) are available for use in the treatment of epilepsy (Fig. 3). Because the use of methsuximide and phensuximide is quite limited, only ethosuximide will be reviewed.

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SUCCINIMIDES

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ETHOSUXIMIDE

METHSUXIMIDE

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Figure 3. illustrated are the chemical structures of the succinimides: ethosuximide, methsuximide, and phensuximide.

ETHOSUXIMIDE

Introduced into clinical practice in1958, ethosuximide is the drug of choice in the treatment of petit mal epilepsy.ll5 In experimental models, it is most effective in raising the threshold against pentylenetetrazol induced seizures. 3o Absorption, Distribution, Biotransformation, and Excretion Ethosuximide is well absorbed after oral administration, and the drug appears to be fairly uniformly distributed in body tissues. In children peak serum levels occur 3 to 7 hours after the ingestion of a single dose}3 The degree of protein binding is negligible. 4 Approximately 10 to 20 per cent of the administered drug is excreted unchanged in the urine. 14 Two metabolites have been identified in rat urine, but only one of these appears to form in man. 20 No information is available about the potential anticonvulsant properties of these metabolites. Clinical Applications For the control of petit mal, the serum concentration of ethosuximide is between 40 and 100 ILg per mlP Raising the serum concentration to 120 ILg per ml improves the seizure control of some patients not adequately controlled at lower concentrations. 97 There is a linear relationship between the dose administered and the resulting serum concentration, but individual differences are so great that it is impossible to predict a given patient's plasma concentration from the dose. 12 • 97 In a particular patient one can expect the serum concentration to increase by 3 ILg per ml for each mg per kg per day increase in dose. 12 Following discontinuation of the drug after chronic therapy, serum levels fall with a mean half life of 46.0 hours (range 22.8 to 68.0) in children and adolescentsP Such a long half life would seem to make it unnecessary to administer the drug in more than two divided doses daily. Dose-related toxic symptoms due to ethosuximide include nausea, drowsiness, anorexia, hiccough, abdominal pain, and irritability. Although these symptoms may improve by lowering the dose in a given patient, it has not been possible to relate the appearance of side effects to excessive plasma concentrations.97

-451

ANTICONVULSANT DRUGS IN SEIZURE DISORDERS

Figure 4. trated.

The chemical structure of carbamazepine is illus-

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C=O I

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CARBAMAZEPINE

IMINOSTILBENES Carbamazepine (Tegretol) is the only imino stilbene currently marketed for use as a antiepileptic agent (Fig. 4). Carbamazepine was shown to have marked anticonvulsive activity in several experimental models in the late 1960's,62 and since that that time it has received extensive clinical use. 49 • 50. 71 It seems to be particularly effective in the control of psychomotor seizures, but it is also beneficial in the treatment of generalized tonic-clonic (grand mal) convulsions. 5o ,71 In the United States, carbamazepine was initially marketed for use in the treatment of trigeminal neuralgia but was approved for distribution as an antiepileptic in 1974. Because sufficient data attesting to its efficacy and safety in children have not yet been presented to the Federal Drug Administration, this agency requires the manufacturer to note this limitation on its official labeling. Such a restriction, however, does not prohibit its use. 40

Absorption, Distribution, Biotransformation, and Excretion Data from human volunteers based on single dose experiments suggest that the absorption of carbamazepine from the gastrointestinal tract, though fairly complete, is quite variable and relatively slow; peak serum levels occurring between 2.5 and 24 hours after administration. 26 With repeated doses, serum concentrations reach maximal concentrations in 3 to 4 days.28 Little information is available about the tissue distribution of carbamazepine, but in rats approximately equal brain and plasma concentrations are found at equilibrium after both single and repeated doses.S 4 About 67 per cent of the total plasma concentration may be bound to plasma proteins. 53 Carbamazepine is almost completely metabolized; less than 1 per cent of the administered dose is excreted unchanged in the urine. S4 Two metabolic products have been established with certainty: carbamazepine-10, ll-epoxide, and 10, II-dehydroxy-carbamazepine.<5 Since these compounds also account for only a small fraction of the administered dose, other products and/or further transformation is probable. The epoxide has anticonvulsant properties which may contribute to the clinical effect of the parent compound .." The metabolism and excretion of carbamazepine proceed quite slowly. In adults following the administration of a single dose, plasma concentrations after reaching a peak decline with a half life ranging between 20 and 75 hours.26 With repeated doses, the rate of metabolism and excretion is more rapid; plasma half life ranging from 16.4 to 26.6 hours after cessation of therapy'"

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Clinical Applications We could find no reports relating dose to serum concentration or serum concentration to efficacy of seizure control in children. Cerighino and his collaborators found that carbamazepine in doses of 1200 mg per kg per day was as effective as 300 mg per day of diphenylhydantoin or 300 mg per day of phenobarbital in controlling seizures during a 21 days study period in a group of institutionalized adultsP Carbamazepine serum concentrations ranged up to 12.7 JLg per ml with 50 per cent of the values falling between 5.8 and 9.0 JLg per ml. Unpleasant side effects (fatigue, malaise, dizziness, and lethargy) occurred frequently during the first week of therapy but were transient. There was no apparent relationship between clinical efficacy or toxicity and the serum concentration in this range. Summarizing the current knowledge about the relationship of dose to serum concentration, Cerighino concluded that therapeutic doses of 800 to 1200 mg per day in adults can be expected to lead to serum concentrations between 2 and 12 JLg per mlP Gamstrop has recently reviewed the clinical experience with carbamazepine in children. 50 She recommends an ultimate dose of 20 mg per kg per day administered in two equal amounts for children up to 60 kg. To prevent the occurrence of the transient side effects after the initiation of therapy, only 5 to 7.5 mg per kg per day should be administered in the first week of therapy. The dose can then be gradually increased until the ultimate dose of 20 mg per kg per day is reached in the third or fourth week. No mention of serum concentration is made in this review. Further studies relating dose to plasma concentration and plasma concentration to efficacy and toxicity are necessary before a determination of the role of carbamazepine serum concentrations in clinical pediatric practice can be established.

BENZODIAZEPINES Introduced into clinical practice in the late 1950's, the benzodiazepines are used most frequently for their antianxiety and muscle relaxant effects. Most, however, also have significant anticonvulsant properties, and two, diazepam (Valium) and clonazepam (Clonopin) are currently approved for use as anticonvulsants in this country (Fig. 5). Nitrazepam (Mogadon) has received extensive use as an anticonvulsant in foreign countries but is not marketed in the United States. BENZODIAZEPlNES

Figure 5. The chemical structures of the anticonvulsants diazepam and clonazepam are pictured.

DIAZEPAM

CLONAZEPAM

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Anticonvulsant Properties The pharmacology and physiology of the benzodiazepines have been extensively reviewed. 92 • 114 As a group they suppress a wide variety of experimentally produced abnormal cerebral discharges and abolish the clinical symptoms and electroencephalographic discharges of pentylenetetrazol induced seizures. 11 Although they suppress epileptiform activity in both primary and secondary foci, their effect seems to be more pronounced on generalized than on focal abnormalities. 54. 55 Recent studies suggest that their anticonvulsant properties may be the result of their ability to mimic the action of the inhibitory neurotransmitter glycine at its receptor sites.ll3

DIAZEPAM

First synthesized in 1961, diazepam proved to be more potent in both its muscle relaxant and anticonvulsant properties than its parent compound, chlordiazepoxide (Librium).105 Diazepam is especially beneficial in the treatment of status epilepticus, and the intravenous administration of diazepam is now considered to be the drug of choice in this condition. 3 , 73. 78. 90 Its efficacy in the treatment of a variety of chronic seizure problems has also been reported, but under such circumstances it is now predominantly used in combination with other anticonvulsants. Absorption, Distribution, Metabolism, and Excretion Following intravenous injection, there is a prompt physiologic effect on central nervous system function associated with an immediate peak in the plasma concentration.31 The plasma concentration subsequently falls rapidly with an immediate half life of only approximately 15 minutes as the drug is distributed to other tissues, bound to protein, and deposited in fat.8. 107 After oral administration, diazepam is almost completely absorbed from the gastrointestinal tract. Peak blood levels usually occur within one to two hours of ingestion. 33 Diazepam is almost completely metabolized by liver microsomal enzymes to three compounds: N-desmethyl-diazepam, 3-hydroxy-diazepam, and oxazepam. 76.94.95 All three have anticonvulsant properties, and oxazepam is marketed under the trade name of Serax. N-desmethyl-diazepam is the major metabolite in man, and as treatment with diazepam continues, it accumulates in tissues and ultimately reaches concentrations several times those of the parent compound. 33 The Ndesmethyl and 3-hydroxy derivatives are subsequently further metabolized to oxazepam which is excreted in the urine after conjugation with glucuronide. With discontinuation of diazepam after chronic administration, the plasma concentration falls in two phases. There is an initial, fairly short, rapid decline with a half life of 7 to 10 hours followed by a slower fall with a half life of 2 to 6 days.95 The decrease in desmethyl-diazepam occurs even more slowly. The accumulation and slow excretion of desmethyl-diazepam may be of some clinical significance since in mice

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the protection against pentylenetetrazol induced seizures correlated best with peak levels of this metabolite. 31 Clinical Applications Few studies concerning the relationship of serum concentration to clinical effectiveness have been reported. Ferngren, after obtaining serum levels in three patients whose status was effectively controlled by intravenous diazepam, suggested that for the treatment of status epilepticus an effective serum concentration ranged between 0.15 and 0.2 ILg per ml. 44 Booker and coworkers, however, showed that in adults paroxysmal discharges were suppressed with peak serum concentrations between 0.5 and 2.0 ILg per ml after an intravenous dose. 8 The discharges remained suppressed for a variable time (2.5 to 60 minutes) and seemed to return when serum concentrations had fallen to 0.1 to 0.7 ILg per ml level.

CLONAZEPAM

Although not licensed for marketing and generalized distribution in the United States until the middle of 1975, clonazepam has received extensive use in clinical trials and in foreign countries since 1971.24.43.51. 58. 60. 89. 93. 108 Like other benzodiazepine derivatives, its action appears to be due to its ability to potentiate inhibitory mechanisms in the subcortical brain structures that act in the propagation of seizure discharges. 93 Clinically, it has proved effective in a wide variety of the generalized epilepsies including infantile spasms and other forms of myoclonic seizures, petit mal absence attacks, akinetic seizures, and generalized tonic-clonic (grand mal) convulsions. Absorption, Distribution, Metabolism, and Excretion Clonazepam is rapidly absorbed after oral administration, peak serum levels occurring within one to two hours after the ingestion of a single dose. 63 Metabolism occurs rather slowly, serum levels declining with a half life of 19 to 39 hours after reaching a peak from a single dose,63 and with a half life of 22 to 32 hours after the cessation of 8 weeks of therapyP Several metabolic products have been identified,l09 Whether or not these products have anticonvulsant properties has yet to be determined. Clinical Applications Dreifuss and his co-workers related the serum concentration of clonazepam to dose, efficacy, and toxicity in 10 children with absence attacks. 37 Therewas a linear relationship between the dose administered and the serum concentration after eight weeks of therapy; between a dose range of 0.03 to 0.12 mg per kg per day, serum concentrations tended to increase by 4 to 6 nanograms per ml with each 0.01 mg per kg per day increase in dose. Serum concentrations in this study varied from 13 to 72 nanograms per ml, and there was no significant relationship between efficacy or toxicity in this range.

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Most other studies have suggested the use of an initial dose of 0.05 to 0.1 mg per kg per day administered in 3 to 4 divided doses. 58 • 93, 108 The dose can then be gradually increased until seizures are controlled, toxic side effects (ataxia, drowsiness, irritability, excessive weight gain and, in young infants, excessive bronchial secretions) appear or a maximal dose of 0.25 to 0.3 mg per kg per day is reached. Toxic side effects are often transient any may disappear within two weeks even if the dose is not reduced. Serum concentrations were, however, not reported in these studies.

CONCLUSION The pharmacology and metabolism of phenobarbital, primidone (Mysoline), diphenylhydantoin (Dilantin), ethosuximide (Zarontin), carbamazepine (Tegretol), diazepam (Valium), and clonazepam (Clonopin) have been reviewed. Much has been learned about the rates of absorption, distribution, metabolism, and excretion of these major anticonvulsant drugs in recent years, and the application of this knowledge has enhanced their rational use in clinical practice. Practical methods for the assay of the serum concentration of these drugs and some of their important biologically active metabolites have also become available. The judicious use of blood level determinations as an adjunct to clinical judgment can significantly increase the efficacy and safety of anticonvulsant drug therapy. The measurement of serum concentrations of anticonvulsant drugs is useful in facilitating dosage regulation, individualizing drug dosage, and detecting causes of drug failure. Blood level determinations should be performed whenever a drug appears to be ineffective after sufficient time has elapsed for equilibrium to have been established. Unexpected low serum concentrations frequently indicate a failure in compliance but may also occur because of poor absorption or unusually rapid drug metabolism. Blood level determinations should also be performed whenever symptoms or signs of drug toxicity appear. They are particularly useful in identifying the responsible agent or agents when symptoms of toxicity occur in patients receiving multiple medications. Although there are many instances in which the determination of serum concentrations play an important role in anticonvulsant therapy, their use is limited in patients whose seizures are under excellent control since in many individuals seizures may be controlled with less than "therapeutic levels."

REFERENCES 1. Arnold, K., and Gerber, N.: The rate of decline of diphenylhydantoin in human plasma.

Clin. Pharmacol. Ther., 11 :121-134,1970. 2. Atkinson, A. J.: Individualization of anticonvulsant therapy. Med. Clin. North Am., 58:1037-1048,1974. 3. Bailey, D. W.: The treatment of prolonged seizure activity with intravenous diazepam. J. Pediat., 73:923-927,1968. 4. Barlow, C. F., Firemark, H., and Roty, L. J.: Drug-plasma binding measured by Sephadex. J. Pharm. Pharmacol., 14:550-555, 1962.

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