Valproic acid metabolic effects

Bismuth Subsalicylate (Pepto-Bismol) [Antidiarrheal/ Adsorbent] [OTC] Uses Indigestion, N, D combo for Rx of H. pylori Infxn Action Antisecretory anti-inflammatory Dose Adults. 2 tabs or 30 mL PO PRN (max 8 doses/24 h) Peds. 3-6 y 1/3 tab or 5 mL PO PRN (max 8 doses/24 h) 6-9 y 2/3 tab or 10 mL PO PRN (max 8 doses/24 h) 9-12 y 1 tab or 15 mL PO PRN (max 8 doses/24 h) Caution [C, D (3rd tri), -] Avoid w/ renal failure Hx severe GI bleed Contra Influenza or chickenpox (T risk of Reye synd), ASA allergy (see Aspirin) Disp Chew tabs, caplets, Liq, susp SE May turn tongue stools black Interactions T Effects OF ASA, MTX, valproic acid 4 effects OF tetracyclines 4 effects W/ corticosteroids, probenecid EMS Monitor for hypovolemia and electrolyte disturbances d/t D may darken tongue stool OD Similar to ASA OD V, tinnitus, metabolic acidosis activated charcoal may be effective... 

Abbott FS, Kassam J, Orr JM, Farrell K. The effect of aspirin on valproic acid metabolism. Clin Pharmacol Ther 9%6) 40, 94-100. 

The most frequent side effects are diplopia, drowsiness, ataxia, and headache. Rashes are usually mild to moderate, but Stevens-Johnson reaction has also occurred. The incidence of the more serious rashes appears to be increased in patients who are also receiving valproic acid and who have rapid dosage titration. Valproic acid substantially inhibits the metabolism of lamotrigine. 

The enteric-coated tablet divalproex sodium causes fewer GI side effects. It is metabolized in the gut to valproic acid. When switching from Depakote to Depakote-ER, the dose should be increased by 14% to 20%. Depakote ER may be given once daily. 

Of the many drugs that have been developed which modulate GABA function, the inhibitors of GABA transaminase have been shown to be effective anticonvulsants. These are derivatives of valproic acid that not only inhibit the metabolism of GABA but may also act as antagonists of the GABA autoreceptor and thereby enhance the release of the neurotransmitter. GABA-uptake inhibitors have also been developed (for example, derivatives... 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Valproic acid causes hair loss in about 5% of patients, but this effect is reversible. Transient gastrointestinal effects are common, and some mild behavioral effects have been reported. Metabolic effects, including hyperglycemia, hyperglycinuria, and hyperammonemia, have been reported. An increase in body weight also has been noted. Valproic acid is not a CNS depressant, but its administration may lead to increased depression if it is used in combination with phenobarbital, primidone, benzodiazepines, or other CNS depressant agents. 

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). 

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-... 

Clozapine inhibits the metabolism of valproate (277). Valproic acid has been reported to increase the sedative effects of clozapine (SEDA-20, 50) and alter serum concentrations of clozapine. 

After the addition of stiripentol (50 mg/kg) in 20 children treated with clobazam, mean serum clobazam concentrations increased about twofold and norclobazam concentrations increased about threefold a mean 25% reduction in clobazam dose was required because of adverse effects (15). Serum concentrations of concomitantly administered valproic acid rose by about 20%. These findings are in agreement with evidence that stiripentol is a potent metabolic inhibitor. 

The effects of concomitant carbamazepine, phenytoin, sodium valproate, and zonisamide on the steady-state serum concentrations of clonazepam have been investigated in 51 epileptic in-patients under 20 years of age (14). Serum concentrations of clonazepam correlated positively with the dose of clonazepam and negatively with the doses of carbamazepine and valproic acid, but not with phenytoin or zonisamide. These results confirm that as the oral doses of carbamazepine and sodium valproate increase, the serum concentration of clonazepam falls, but there is no interaction with either phenytoin or zonisamide. In the case of carbamazepine the mechanism of action is thought to be enzyme induction, increasing the metabolism of clonazepam. It is not known what the mechanism is with sodium valproate. In patients with epilepsy, the co-administration of either sodium valproate or carbamazepine will reduce the serum concentration of clonazepam and increase the risk of a seizure. When... 

UGTs are responsible for the metabolism of many anxiolytics, antidepressants, mood stabilizers and antipsychotics. Inhibition of the metabolism of carbamazepine by valproic acid in part results from an effect on UGTs. Amitriptyline and clomipramine decrease the metabolism of morphine by affecting UGTs. 

Thurston JH and Hauhart RE (1992) Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice possible clinical significance. Pediatric Research 31, 419-23. 

Orr JM, Abbott FS, Farrell K, Ferguson S, Sheppard I, Godolphin W. Interaction between valproic acid and aspirin in epileptic children serum protein binding and metabolic effects. Clin Pharmacol Ther 1982 31(5) 642-9. 

Perucca E, Hebdige S, Frigo GM, Gatti G, Lecchini S, Crema A. Interaction between phenytoin and valproic acid plasma protein binding and metabolic effects. Chn Pharmacol Ther 1980 28(6) 779-89. 

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