Chronic Valproic Acid Therapy and Incidence of Increases in Venous Plasma Ammonia

Haidukewych, Dan; John, Geetha; Zielinski, Janusz J.; Rodin, Ervin Y.

doi:10.1097/00007691-198507030-00009

Cited by 36 publications

(25 citation statements)

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“…The mechanism of this interaction remains uncertain. Although the hyperammonemia frequently observed with valproate therapy is more likely to occur during combination therapy (Haidukewych et al, 1985; Zaccara et al, 1985), the episodes of altered consciousness do not correlate with the degree of hyperammonemia (Warter et Antiepileptic polytherapy may sometimes be both necessary and beneficial, but monitoring patients is frequently more difficult. In general, the problems associated with multiple-drug therapy are not severe and can be corrected if recognized.…”

Section: Idiosyncratic Toxic Interactionsmentioning

confidence: 99%

Problems of Combination Drug Therapy in Children

Bourgeois

1988

Epilepsia

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Despite the current trend toward monotherapy, polytherapy in children with epilepsy is still common. A drug combination is advantageous only if it achieves a higher efficacy:toxicity ratio (therapeutic index) or if its antiepileptic spectrum is wider. Studies of brain concentrations of antiepileptic drugs have so far shown that a higher efficacy:toxicity ratio is not achieved by most combinations. Problems are associated with drug combinations. First, numerous pharmacokinetic interactions are documented. These interactions, which can be associated with significant changes in blood levels at a given dose, make frequent measurements and dosage readjustments necessary. They can also alter the concentration of active metabolites or the free fraction of a drug. Second, toxicity can be assumed to be at least partially cumulative, since reduction in polytherapy has been shown to be associated with a reduction in side effects. Third, the therapeutic range appears to depend on whether a drug is taken alone or in combination, so that polytherapy confuses the interpretation of serum drug measurements. Fourth, the presence of more than one drug will add to the difficulty in evaluating the efficacy or side effects of any single drug. Finally, a pharmacodynamic interaction between valproate and several other antiepileptics, particularly the barbiturates, can lead to a stuporous state. Transition from polytherapy to monotherapy is much more difficult to achieve than the opposite.

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Section: Idiosyncratic Toxic Interactionsmentioning

confidence: 99%

Problems of Combination Drug Therapy in Children

Bourgeois

1988

Epilepsia

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“…In addition, Haidukewych et al. () and Sharma et al. () reported that the blood concentration of VPA was correlated positively with the ammonia level, but other studies have not detected a significant association.…”

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confidence: 97%

“…Our previous study established that high‐dose VPA therapy, concomitant use of hepatic enzyme inducers, and concomitant use of topiramate (TPM) were risk factors for an increase of the blood ammonia level in adult patients with epilepsy who were treated with VPA (Yamamoto et al., ). There have also been some reports regarding the risk of hyperammonemia in pediatric patients with epilepsy (Coulter & Allen, ; Batshaw & Brusilow, ; Murphy & Marquardt, ; Ohtani et al., ; Haidukewych et al., ; Laub, ; Iinuma et al., ; Thom et al., ; Kondo et al., ; Altunbaşak et al., ; Sharma et al., ). Verrotti et al.…”

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confidence: 99%

Risk factors for hyperammonemia in pediatric patients with epilepsy

et al. 2013

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SUMMARYPurpose: To identify risk factors for hyperammonemia in pediatric patients with epilepsy. Methods: A total of 2,944 pediatric patients (ages 0-15 years) were classified into the following three groups: a group without drug treatment (n = 445, group I), a group receiving antiepileptic drugs other than valproic acid (VPA) (n = 673, group II), and a VPA-treated group (n = 1,826, group III). Hyperammonemia was defined as a plasma ammonia level exceeding 100 lg/dl with reference to the standard range and previous reports. Key Findings: The mean ammonia level of groups I, II, and III was 36.0, 56.0, and 86.8 lg/dl, respectively, and the incidence of hyperammonemia was 1.6%, 7.7%, and 31.7%, respectively. In each group, the mean ammonia level of patients aged 3 years or younger was significantly higher than that of patients aged 4-15 years. In group II, concomitant use of topiramate and zonisamide were risk factors for hyperammonemia (adjusted odds ratio [OR] 3.9, 95% confidence interval [CI] 1.7-9.2, and OR 3.5, 95% CI 1.9-6.5, respectively). In group III, the ammonia level increased in a VPA dose-dependent manner. At a VPA dose of 30 mg/kg, there was 4.3-fold increase in the incidence of hyperammonemia. The other significant risk factors identified were female gender (OR 1.3, 95% CI 1.0-1.6), symptomatic generalized epilepsy (OR 1.4, 95% CI 1.1-1.8), and the concomitant use of phenytoin (OR 4.7, 95% CI 3.3-6.9), phenobarbital (OR 2.2. 95% CI 1.6-3.2), acetazolamide (OR 6.6, 95% CI 2.5-17.2), topiramate, or zonisamide. Significance: A young age and concomitant use of carbonic anhydrase inhibitors are associated with an increased risk of hyperammonemia regardless of whether the patient is taking VPA. In patients receiving VPA, concomitant use of phenytoin and/or phenobarbital enhances the risk of hyperammonemia. An increase in ammonia can be caused by multiple factors. Our results may help clinicians to avoid problems of hyperammonemia. KEY WORDS: Hyperammonemia, Epilepsy, Children, Risk factor, Valproic acid, Phenytoin.Hyperammonemia is a frequent problem associated with antiepileptic drugs (AEDs) that can lead to vomiting, aggression, ataxia, and exacerbation of seizures. Acute hyperammonemia can also cause cerebral edema and severe brain damage (encephalopathy), whereas chronic hyperammonemia due to metabolic disorders is associated with developmental delay and intellectual disability (Cagnon & Braissant, 2007;Lichter-Konecki, 2008). Among the AEDs, valproic acid (VPA) is recommended as a first-line treatment for generalized epilepsy. Although VPA can cause an increase of the blood ammonia level, VPA therapy is rarely associated with hyperammonemic encephalopathy.The exact relationship between symptoms and the ammonia level remains unclear. Murphy and Marquardt (1982) reported that patients with hyperammonemia not exceeding 240 lg/dl were asymptomatic. In contrast, Coulter and Allen (1981) recommended reducing the VPA dose when the ammonia level exceeded 100 lg/dl. Our data (see later) indicate that hyperammo...

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“…Liver function tests have been performed in a few studies describing ammonia levels on valproic acid therapy. 3,4,12,13,20 No significant abnormalities of liver function tests have been found in patients with hyperammonemia on valproic acid therapy.…”

Section: Discussionmentioning

confidence: 99%

Blood Ammonia Levels in Epileptic Children on 2 Dose Ranges of Valproic Acid Monotherapy: A Cross-Sectional Study

et al. 2010

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This cross-sectional study was planned to study the blood ammonia levels in epileptic children on 2 dose ranges of valproic acid monotherapy. A total of 60 epileptic children aged 3 months to 12 years, that were on valproic acid monotherapy for at least 3 months, were enrolled and divided into 2 groups, a low-dose group (dose, 20-39 mg/kg/d [n = 32]) and a high-dose group (dose, 40-60 mg/kg/d [n=31]). Measurements of blood ammonia, serum valproic acid levels, and liver and renal function tests were performed. Blood ammonia levels were significantly higher in the high-dose group (median, 79.2 µg/dL; range, 55.23-114.29 µg/dL) as compared with the low-dose group (median, 47.2 µg/dL; range, 20.62-73.25 µg/dL). Blood ammonia levels significantly correlated with both the dose (r = .77, P < .001) and serum levels (r = .88, P < .001) of valproic acid. All the children with hyperammonemia were asymptomatic. There were no significant differences in the other biochemical parameters between the 2 groups.

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Chronic Valproic Acid Therapy and Incidence of Increases in Venous Plasma Ammonia

Cited by 36 publications

References 0 publications

Problems of Combination Drug Therapy in Children

Problems of Combination Drug Therapy in Children

Risk factors for hyperammonemia in pediatric patients with epilepsy

Blood Ammonia Levels in Epileptic Children on 2 Dose Ranges of Valproic Acid Monotherapy: A Cross-Sectional Study

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