Clinical Pharmacology

"Adverse Drug Event of the month"

Case details:

A 10 year old male child had his first epileptic seizure when he was two years old. He had partial seizures with jerks in the left leg , mostly at night and occasionally secondary generalized tonic clonic seizures. His interictal EEG findings showed abnormal neuronal hyperexicitability. He was diagnosed as case of simple partial epilepsy with secondary generalization. Sodium Valproate therapy was started at 20 mg/kg at the age of 2 years. In the view of the fact that his seizures were not adequately controlled, therapy with sodium valproate was gradually increased to 40 mg/kg after 2 years and continued thereafter upto the age of 10 years. His body weight recorded at the age of 10 years was 35 kg and serum valproate level was 94 ug/ml (N 50 - 100ug/ml) . Because of recurrence of 1-2 episodes of seizure, his therapy was further increased to 60 mg/kg at the age of 10 years. Four months later he complained of increased sleep and appetite after increasing the dose of valproate to 60 mg/kg and was free from any seizure episode. However his body weight had increased to 42 kg and his serum valproate level was 133.5 ug/ml. A diagnosis of Valproate induced weight gain was made A causality analysis using the Naranjo's algorithm was done and the adverse event was scored at 7 out of a possible total of 13 (score for a probable adverse event being 5-8) (1). He was advised to decrease the dose of valproate to 40 mg/kg. One month later his follow up visit showed body weight of 42 kg and serum level was 84 ug/ml and was seizure free

Discussion:

Drug induced weight gain is a side effect of many commonly used antiepileptic drugs (2). Although Sodium valproate which is a widely used epileptic drug in the pediatric population is regarded as safe, it can cause considerable increase in body weight in 8 -59% patients (3). The direction and extent of weight gain are gradual and varies from 8- 14 kg. Potential deleterious effects of weight gain include non compliance with medication, risk factors for diabetes and coronary artery disease. Although mechanism of valproate induced weight gain remains unclear, it is postulated that valproate increases the appetite by acting on the hypothalamus and decreases the energy expenditure, thermogenesis and ghrelin concentration leading to insulin resistance (3,4) . However recent evidence also suggests that it increases leptin concentration in epileptic patient which results in increased production of adipose tissue (4). Since drug associated weight gain does not regress easily and there is no established treatment for drug induced weight gain, rigorous diet and exercise should alleviate weight gain(2) . Hence it is recommended that the clinicians consider switching patients to medications that are less likely to cause weight gain before clinically significantly gain occurs. The below table summaries the drugs that cause weight gain and possible alternatives. When an effective agent has caused major fluctuations in weight and no appropriate alternative treatment is available, an informed patient and physician should discuss the risks and benefits of maintaining, discontinuing or changing the dosage or medications and decision should be based on severity of weight problem.

Table Drugs that causes weight gain and possible alternatives (2)

References:

1. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA , Janecek E, Domecq C, Greenblatt DJ A method for estimating the probability of Adverse drug reaction Clin Pharmacol Ther 1981; 8:239 - 44
2. Vanina Y , Podolskaya A, Sedky K, Shahab H, Siddiqui A, Munshi F, Lippmann S Body weight changes Associated with Psychopharmacology Top Med Cardiovasc Dis 2005; 28 : 9-31
3. Greco R, Latini G, Chiarelli F, Iannetti P and Verotti A Leptin, ghrelin and adiponectin in epileptic patients treated with Valproic acid . Neurology 2005; 65 :1808 - 09
4. Ness - Abramof R, Apovian CM Drug induced weight gain. Drugs Today 2005; 41:547-55

Dept. of Clinical Pharmacology,
1st Floor, MS Building,
Seth GS Medical College and KEM Hospital,
Parel, Mumbai. 400012.
Ph. 91-22-24174420, 91-22-24133767
Fax 91-22-24143435
dcpkem@vsnl.com