Anticonvulsant drugs

G.A.B. Davies-Jones

7

Anticonvulsant drugs

G E N E R A L TOPICS

Anticonvuisant osteopenia (SED-IO, 109; SEDA-8, 69; SEDA-9, 56; SEDA-IO, 53) This feature of anticonvulsant treatment has been discussed in previous volumes and, in the main, is thought to be secondary to alterations in vitamin D metabolism. However, mention was made in SEDA-10 (p. 53) of a study in which hypocalcemia and osteopenia occurred in spite of normal levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, suggesting that the hypocalcemia was independent of vitamin D metabolism. Immunoreactive parathyroid hormone levels were increased possibly in response to the hypocalcemia. Nishiyama et al (1 R) studied bone density and biochemical parameters in severely handicapped children and adults with reference to the influence of limited mobility and anticonvulsant medication. The patients were categorized into 3 groups according to the degree of limited mobility (Group 1, bedridden; Group 2, capable of crawling; Group 3, capable of walking) and according to whether or not they were receiving anticonvulsant treatment. As determined by microdensitometric analysis of radiograms of the second metacarpal bone, bone width, bone-pattern area and bone-salt density were decreased in the patients, the decreases being most prominent in Group 1, less in Group 2 and least in Group 3. Significant decreases in bone-pattern area and bone-salt density but not in bone width were found in patients on anticonvulsant treatment in comparison with patients without therapy. Serum alkaline phosphatase, parathormone, urinary calcium and cyclic AMP excretion were significantly increased in Group 1. In comparison with the patients without therapy, anticonvulsant-treated children showed significantly decreased levels of serum calcium, ionized calcium, 25-hydroxyvitamin D3 and urinary phosphate excretion, and elevated serum levels of alkaline phosphatase, parathyroid hormone Side Effects of DrugsAnnual11 M.N.G. Dukes, editor 9 ElsevierSciencePublishers B.V., 1987

and calcitonin. The authors concluded that limited physical activity leads to decreased bone density accompanied by increased urinary calcium excretion, as expected, and may result in secondary hyperparathyroidism which is aggravated by anticonvulsant treatment.

Antieonvulsants and cognitive function (SED-IO, 110; SEDA-8, 69; SEDA-IO, 53) All the major anticonvulsant drugs, especially in combination may result in subacute cognitive and behavioral syndromes (2R). In varying degrees, Reynolds and Trimble (2R) also found that the drugs impair attention, concentration, memory and mental speed or processing. They summarize the 'neuropsychiatric toxicity' of anticonvulsants as shown in Table 1.

Table 1. "Neuropsychiatric toxicity" of anticonvulsant drugs Toxicity

Drug

Peripheral neuropathy

Phenytoin Phenobarbital Primidone

Cerebellar ataxia

Phenytoin Barbiturates (?)

Involuntary movements Phenytoin Dystonia Carbamazepine Phenytoin Asterixis Carbamazepine Barbiturates Valproate Tremor Behavioral disorders

Impaired cognitive function

Barbiturates Phenytoin Benzodiazepines Ethosuximide Valproate Carbamazepine (?) Barbiturates Phenytoin Benzodiazepines (clobazam > clonazepam) Valproate

Anticonvulsant drugs Chapter 7

63

Cholesterol and lipoproteins (SED-IO, 110; SEDA-9, 56) Besides phenytoin and phenobarbital, carbamazepine and valproate have more recently been found to increase highdensity lipoprotein cholesterol (HDLC) blood levels. In a study of the effect of anticonvulsant drugs on total cholesterol, HDLC and apolipoproteins A and B in 82 epileptic children, Reddy (3a) did not confirm this effect with valproate. Phenytoin, carbamazepine, phenobarbital and primidone significantly increased total cholesterol and HDLC levels, but the effect was more pronounced with HDLC. Among the subfracti0ns of HDLC, almost all the increase was in HDLC-2 with no effect on HDLC-3. Except for valproate, all the drugs resulted in significantly higher levels of apolipoprotein A but no change was observed in apolipoprotein B.

Conran et al (8c) found that hypothalamic pituitary function in children and adolescents was not compromised by long-term monotherapy with carbamazepine or sodium valproate. Cortisol levels in matched plasma and saliva samples in epileptic patients did not differ significantly from those of healthy controls, but the half-life of cortisol in plasma and saliva of epileptics was reduced significantly compared with healthy controls. This reduction in half-life is probably due to microsomal enzyme induction produced by anticonvulsant treatment (9c).

Fetal hemorrhage Gimovsky and Petrie (4c) describe 2 cases of severe bleeding after fetal scalp blood sampling, which necessitated cesarian section in one patient. This was probably associated with deficiency of vitamin-K-dependent clotting factors due to maternal anticonvulsant treatment in relation to phenytoin in one and the combination of phenytoin +phenobarbital in the other.

Carbamazepine-induced myoclonic, atonic and absence seizures have been described previously (SEDA-9, 58). Snead and Hosey (10c) again emphasize this occurrence and note that the most common seizure type that was exacerbated was generalized atypical absence. A minority of their cases had more frequent and severe generalized convulsive seizures. They found that an EEG bilaterally synchronous spike and wave discharge of 2.5 and 3 cycles per second was predictive of increased atypical absence seizures with carbamazepine, whereas generalized bursts of spikes and slow waves of 1-2 cycles per second suggested an increased risk of generalized convulsive seizures. Finger and toe nail hypoplasia at birth was found in a child of an epileptic mother after carbamazepine monotherapy which was started at the 26th week of pregnancy. The mother had borne 2 healthy children previously, the epilepsy having begun during the 3rd pregnancy. By the time the infant was aged 3 months, the nails had returned to normal

Endocrine function and anliconvalsants ( S E D A- 9 , 55) Phenytoin has been reported to produce an increase in growth hormone and prolactin levels (SEDA-9, 55)._Elwes at al (5c) again confirm this and suggest that the abnormalities in growth hormone may explain the well recognized effects of phenytoin on connective tissue. Faber et al (6c) studied the extrathyroidal metabolism of thyroid hormones before and after treatment with 350 mg of phenytoin daily for 14 days in 6 hypothyroid patients receiving constant thyroxine replacement therapy. They suggested that the lowering effect of phenytoin on serum thyroid hormone levels was not due to displacement of hormones from the binding proteins in the serum or due to induction of hepatic thyroxine-5'-deiodinase as has been previously suggested. In these patients, the primary effect of phenytoin seemed to be decreased intestinal absorption of thyroxine and increased non-deiodinative metabolism of thyroxine possibly caused by increased fecal loss. Hegedus et al (7c) noted an increase in thyroid size in epileptic patients on long-term phenytoin or earbamazepine treatment. They attributed this to the reduction in free thyroid hormones caused by phenytoin and carbamazepine.

I N D I V I D U A L DRUGS

Carbamazepine (SED-IO, 113; SEDA-8, 72; SEDA-9, 58; SEDA-IO, 53)

01%

Neuvonen (12c) compared the bioavailability and side effects of different formulations of carbamazepine. The formulations differed in speed of absorption, but this did not affect total bioavailability of carbamazepine. As central side effects (dizziness, ataxia) were significantly more common when a brand of tablets with rapid absorption was used, formulations with slow absorption might be preferable. Additionally, serum concentrations are more constant with slow absorption.

Interactions Verapamil (13 c) and diltiazem (14c) have been reported to increase plasma

64 concentration of carbamazepine and to precipitate toxicity.

Denzimol Denzimol, an imidazole derivative, is a new anticonvulsant presently undergoing clinical evaluation. Patsalos et al (15 c) report an important interaction between it and carbamazepine and phenytoin. There was a striking elevation of serum carbamazepine, carbamazepine-10,11-epoxide and phenytoin concentrations in all patients on the addition of denzimol therapy. Carbamazepine-induced toxic effects were observed which resolved with reduction of the carbamazepine dosage. The magnitude of this interaction is such that it might limit the usefulness of denzimol as an anticonvulsant. No interaction between denzimol and valproate was observed. Ganuna-vinyI-GABA ( SEDA-9, 60) Pedersen et al (16c) found gamma-vinylGABA to be a valuable anticonvulsant, the majority of their patients having complex partial seizures; 56% of the patients experienced more than 50% reduction in seizure frequency. Nausea and vomiting occurred in 2 patients out of the 36. Gram et al (17c) from the same unit observed the following side effects with GVG: fatigue, ataxia, diplopia, headache, dizziness, impairment of memory and

irritability. Phenobarbital ( SED- I O, 116) Saccar et al (18c) studied the effect of phenobarbital on theophylline clearance in children. After 19 days of phenobarbital therapy there was a significant increase in theophylline clearance, producing a 30% decrease in the mean steady-state serum theophylline concentration. Phenytoin (SED-10, 111; SEDA-8, 58;

SEDA-9, 71; SEDA-IO, 55) Taliercio et al (19c) described a case of

hypersensitivity myocarditis which was probably initiated by phenytoin. Carbamazepine may also have been a contributing factor in this case. The mechanism of the reaction was postulated to be delayed hypersensitivity. Phenytoin encephalopathy is characterized by the insidious development of impaired memory and intellectual function, with or

Chapter 7 G.A.B. Davies-Jones without focal deficits or dyskinesias, nystagmus and ataxia. Increase in seizure frequency is another feature and, as Zwarts and Sie note, this may be accompanied by an increase in EEG spike and wave activity (20c). Stilman and Masdeu (21 c) correlated the increase in seizure activity seen with phenytoin toxicity with a serum phenytoin level of over 30 pg/ml. Parkinsonism secondary to phenytoin was described for the first time by Goni et al (22c). This resolved when the phenytoin was replaced by carbamazepine. Involuntary-movement disorders produced by phenytoin (choreoathetosis, orofacial or orobuccal dyskinesias, bradykinesia, tremor or dystonia) are well recorded and, although they have usually been associated with phenytoin intoxication, they may occur at therapeutic plasma concentrations. Howrie and Crumrine (23 c) observed 2 children who developed transient dystonia, choreoathetoid and orobuccal dyskinesia secondary to intravenous phenytoin for status epilepticus. In one child these appeared within 15 minutes of drug administration. Ornstein et al (24c) described resistance to metocurine-induced neuromuscular blockade in patients on chronic phenytoin therapy. Phenytoin-induced red cell aplasia has been recorded on rare occasions (SED-10, 112) and Dessypris et al (25 c) now suggest that this is immunologically mediated through an IgG inhibitor which requires the presence of the drug to suppress erythroid colony formation in vitro. The pseudolymphoma syndrome due to phenytoin is characterized by the triad of fever, lymphadenopathy and an erythematous rash and, in some instances, eosinophilia, hepatitis, hepatosplenomegaly, pharyngitis or nephritis. Wolf et al (26c) describe a mycosis-fungoideslike skin reaction in addition to lymphadenopathy and hepatosplenomegaly appearing 11 months after starting treatment with phenytoin which resolved completely after stopping it. Toxic epidermal necrolysis due to phenytoin has been described by Muhar et al (27c). Analysis of sister chromatid exchanges (SCE) is a sensitive cytogenetic test for detecting mutagenic activity of environmental substances. This was studied in lymphocyte cultures of 12 adult epileptic male patients on long-term monotherapy with phenytoin and of matched controls. A significantly increased frequency of SCE was found in the epileptic patients as a group and was seen in almost all the individuals, indicating a detectable chromosome-damaging effect of phenytoin (28c).

Anticonvulsant drugs Chapter 7 Experimental evidence suggests that the teratogenic and mutagenic effects of phenytoin are mediated by its irene oxide metabolite and Strickler et al (29 *) recently reported that although many factors contribute to the outcome of pregnancies in epileptic women treated with phenytoin, a genetic defect in irene oxide detoxification seems to increase the risk of major birth defects. Phenytoin interacts with propranolol and procainamide (30c) accelerating their clearance and decreasing their half-life, bioavailability and blood serum concentrations.

Progabide (SEDA-9, 60; SEDA-IO, 55) The side effects encountered to date with progabide have been mentioned in SEDA-9 and SEDA-10. Schmidt and Utech (31 R) found similar side effects when progabide was added to existing anticonvulsant therapy, with in addition vertigo, diplopia and nystagmus. Although these symptoms might well be due to progabide itself, an increase in plasma concentrations of the basic anticonvulsants might also have been responsible. Bergmann (32 a) noted nausea, pruritus and urticaria, and darkening of urine. Transient increase in serum transaminase concentrations occurred in one case reported by Bovier et al (33c).

Valproate semisodium (semisodium valproate) (SED-IO, 114; SEDA-8, 70; SEDA-9, 59; SEDA-IO, 55) Hyperammonemia of renal origin occurs regularly as a result of treatment with valpro-

65 ate (34R). The intake of medium-length straight-chain fatty acids abolishes this valproate-induced hyperammonemia and fatty acids therefore may well be useful in preventing and treating the hyperammonemic stuporous states which are complications of valproate medication. Acute valproate intoxication with fatal outcome in a 20-month-old infant was recorded by Janssen et al (35~ Naloxone was not used and death resulted from severe bronchopneumonia. Hjelm et al (36 c) suggested that an inherited urea-cycle defect - ornithine carbamoyltransferase deficiency - might predispose to fatal valproate toxicity. Valproic acid displaces phenytoin from protein binding, increasing the free fraction of phenytoin (SED-10, 116). Since plasma valproate concentrations exhibit wide diurnal fluctuations, the above protein binding interaction might be expected to fluctuate during the day. Riva et al (37 c) now report that this does occur, increasing valproate serum concentration and increasing the free phenytoin fraction.

Zonisamide Zonisamide is a new anticonvulsant drug which may be effective in controlling simple partial and complex partial seizures (38c). Side effects seem to be most frequent during the initial stages of treatment and consist of ataxia, dizziness, nystagmus, dysarthria, dipiopia, asterixis, tremor, confusion, nausea, vomiting, anorexia and weight loss.

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