Valproic acid toxicity

Decreased level of valproic acid enzyme induction Increased free level of valproic acid—risk of valproic acid toxicity... 

Monitor valproic acid toxicity over time—if toxicity continues, consider decreasing dose... 

Shill HA, Fife TD. Valproic acid toxicity mimicking multiple system atrophy. Neurology 2000 55(12) 1936-7. 

Sztajnkrycer MD (2002) Valproic acid toxicity Overview and Management. Journal of Toxicology. Clinical Toxicology 40(6) 789-801. (Erratum in (2003) Journal of Toxicology. Clinical Toxicology 41(4) 215.)... 

Dockweiler U. Isoniazid-induced valproic-acid toxicity, or vice versa. Lancet ( 9Z1) ii, 152. 

Jones GL, Popli GS, Silvia MT. Lacosamide-induced valproic acid toxicity. Pediatr Neurol April 2013 48(4) 308-10. 

When carbamazepine is administered with primidone, decreased primidone levels and higher carbamazepine serum levels may result. Cimetidine administered with carbamazepine may result in an increase in plasma levels of carbamazepine that can lead to toxicity. Blood levels of lamotrigine increase when the agent is administered with valproic acid, requiring a lower dosage of lamotrigine... 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

The answer is b. (Katzung, p 41L) Severe hep at o toxicity of an idiosyncratic nature is associated with valproic acid The risk is very high in the pediatric population, particularly in patients below the age of two. Fatalities generally occur within four months of treatment Hepatotoxicity may be reversed in some individuals. 

Tang, W. and Abbott, F.S. 1996. Characterization of thiol-conjugated metabolites of 2-propylpent-4-enoic acid (4-ene VPA), a toxic metabolite of valproic acid, by electrospray tandem mass spectrometry. J. Mass Spectrom. 31 926. 

Dawson, D.A., Schultz, T.W., Wilke, T.S., and Bryant, S. Developmental toxicity of valproic acid stndies with Xenopus, Teratology, 45(5) 493, 1992. 

Anticonvulsants. Scattered case reports suggest that carbamazepine (Tegretol) and valproic acid (Depakote, Depakene) may be helpful in the treatment of panic disorder. This has yet to be verified in systematic studies. Furthermore, because these anticonvulsants are hindered by toxicity and side effect concerns (cf. Chapter 3), they should only be considered if other better studied and more tolerable treatment options have failed. 

Valproic acid (VPA) is gaining increasing acceptance as a first-line drug it is less sedating than other anticonvulsants. Tremor, gastrointestinal upset, and weight gain are frequently observed reversible hair loss is a rarer occurrence. Hepatotoxicity may be due to a toxic catabolite (4-en VPA). 

Sodium valproate is converted to valproic acid in the intestine and the acid is absorbed. Absorption may be delayed by food or by enteric-coated tablets. Valproic acid has a low volume of distribution and high plasma protein binding. In the elderly there is a risk for increased free valproic acid concentrations requiring lower doses and plasma concentrations at the lower therapeutic range. However it should be realized that these plasma concentrations do not correlate very well with the therapeutic or toxic effects and careful observation for symptoms is mandatory. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Steatosis, commonly known as fatty liver, is a condition in which lipids accumulate in the liver in excess of about 5%. It may result from toxicants that cause an increase in lipid synthesis, a decrease in lipid metabolism, or a decrease in the secretion of lipids as lipoproteins. An example of a substance that causes steatosis is valproic acid, once used as an anticonvulsant ... 

The two most serious toxic effects of valproic acid are hepatocellular injury (96) and teratogenesis (97). Since CYP2A6 and CYP2C9 are known to oxidize valproic acid to a 4-ene metabolite that is hepatotoxic, inducers of these isoforms, including other antiepileptic agents, are likely to increase the risk of hepatotoxicity (98). However, valproic acid also is metabolized by several other pathways that may be involved in causing its toxicities (99). 

Porubek DJ, Grillo MP, Olsen RK, et al. Toxic metabolites of valproic acid inhibition of rat liver acetoacetyl-CoA thiolase by 2-n-propyl-4-pentenoic acid (A4-VP A) and related branched chain carboxylic acids. In Levy RH, Penry JK, eds. Idiosyncratic Reactions to Valproate Clinical Risk Patterns and Mechanisms of Toxicity. New York Raven Press, 1991 53-58. 

The antipsychotic chlorpromazine is a prototype heptotoxicant for production of cholestasis. Pleiotropic effects of chlorpromazine on membrane permeability and associated ion gradients and microfilament-mediated canalicular contraction have been attributed to detergent effects. Valproic acid, an anticonvulsant, is associated with microvesicular steatosis. Inhibition of mitochondial fatty acid (S-oxidation is an important component of this toxic effect and is apparently related to carnitine availability as evidenced by the protection afforded by L-carnitine supplements. The hypolipidemic drugs clofibrate, fenofibrate, and gemfibrozil are peroxisome prolif-erators in rodent liver, but not in humans. Isoniazid, an antibiotic used to treat tuberculosis, exhibits an approximately 1 % incidence of hepatotoxicity. Although toxicity is known to be metabolism-dependent and protein adduction has been well-... 

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