Valproic acid serum level

Besag FM, Berry DJ, Vasey M. Methsirximide reduces valproic acid serum levels. Ther Drug Monit 2001 23(6) 694-7. 

Hamilton, R.A., Garnett, W.R., and Kline, B.J., Determination of mean valproic acid serum level by assay of a single pooled sample, Clin. Pharmacol. Ther., 29(3), 408, 1981. 

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... 

Assess the AED serum concentration and adjust therapy as needed for agents with a defined therapeutic range (e.g., phenytoin, carbamazepine, valproic acid, and phenobarbital). Drug levels can also be used to determine adherence to medication regimens for agents that do not have defined ranges. 

Carbamazepine is believed to be effective in BPD, though the data is far less robust than with valproic acid. It is prescribed at doses up to 1200mg/day. Like valproic acid, it can also canse birth defects and requires laboratory monitoring including serum levels. For more information on the use of carbamazepine, please refer to the discussion of bipolar disorder treatment in Chapter 3. 

Drugs that can decrease carbamazepine serum levels include charcoal, cisplatin, doxorubicin, felbamate, hydantoins, rifampin, phenobarbital, primidone, theophylline. The serum levels of oral contraceptives, haloperidol, bupropion, anticoagulants, felbamate, valproic acid, felodipine, tricyclic antidepressants, acetaminophen, ziprasidone, voriconazole, topiramate, tiagabine, olanzapine, and lamotrigine can be lowered by carbamazepine. 

Several controlled trials have shown that lithium is efficacious in the maintenance treatment of bipolar disorder, with higher serum levels (0.8 1 mol/1) being more indicative of successful prophylaxis (Keck and McElroy. 2002). Valproic acid also appears to have efficacy in maintenance therapy, specifically in bipolar patients with mixed mania and rapid cycling (Bowden et al., 1995). The results concerning carbamazepine s efficacy as a maintenance medication are controversial (Stuppaeck et al., 1994). Other potential agents with some evidence of good maintenance value include clozapine and olanzapine. A combination of lithium and carbamazepine or other anticonvulsants is recommended under certain conditions if an adequate preventive effect cannot be obtained with the substances individually (Bauer et al., 2002). 

Tipranavir both inhibits and induces the CYP3A4 system. When used in combination with ritonavir, its net effect is inhibition. Tipranavir also induces P-glycoprotein transporter and thus may alter the disposition of many other drugs (Table 49-4). Concurrent administration of tipranavir with fosamprenavir or saquinavir should be avoided owing to decreased blood levels of the latter drugs. Tipranavir/ritonavir may also decrease serum levels of valproic acid and omeprazole. Levels of lovastatin, simvastatin, atorvastatin, and rosuvastatin may be increased, increasing the risk for rhabdomyolysis and myopathy. 

When a specific antidote or other treatment is under consideration, quantitative laboratory testing may be indicated. For example, determination of the acetaminophen serum level is useful in assessing the need for antidotal therapy with acetylcysteine. Serum levels of salicylate (aspirin), ethylene glycol, methanol, theophylline, carbamazepine, lithium, valproic acid, and other drugs and poisons may indicate the need for hemodialysis (Table 58-3). 

May Increase or Decrease Phenytoin Serum Levels Phenobarbital, sodium valproate, valproic acid... 

It is difficult to establish a relation between valproate encephalopathy and increased serum ammonium concentrations. Valproate-induced hyperammonemic encephalopathy has been reported in several single case reports, but still it is difficult to ascertain whether hyperammonemia or valproic acid is the cause of the encephalopathy. In one case valproate was used in combination with lithium, which in itself could have caused encephalopathy by displacement of protein binding or other mechanisms, regardless of hyperammonemia (1181). In a second case it was also impossible to evaluate the effect of hyperammonemia on the level of consciousness, since it involved a woman who took valproic acid (30 g) in addition to... 

Unterberger I, Bauer G, Lechleitner M. Increase in postprandial serum insulin levels in epileptic patients with valproic acid therapy. Metabolism 2002 51(10) 1274—8. 

Nagai K, Shimizu T, Togo A, Takeya M, Yokomizo Y, Sakata Y, Matsuishi T, Kato H. Decrease in serum levels of valproic acid during treatment with a new carbapenem, panipenem/betamipron. J Antimicrob Chemother 1997 39(2) 295-6. 

Valproic acid Fluoxetine may increase serum levels of valproic acid. 

Kinze S, Clauss M, Reuter U, et al. Valproic acid is effective in migraine prophylaxis at low serum levels A prospective open-label study. Headache 2001 41 774-778. 

Valproate is usually uot recorumeuded duriug the first trimester of preguaucy due to a 1% to 5% risk of ueural tube birth defects, primarily spiua bifida. Adruiuistratiou of folate may reduce the risk of neural mbe defects therefore the risks versus beuefits of us-iug valproate duriug preguaucy must be discussed with the patient. Valproic acid is excreted into human breast milk in low concentrations (less than 1% to 10% of the mother s serum level), so is considered to be compatible with breast-feeding." One case report of... 

Recommended baseline and routine laboratory tests for valproate are listed in Table 68-12. Data from clinical trials in acutely manic patients indicated that there was an earlier response when trough serum levels were greater than 45 mcg/mL during the Hrst week of treatment. Although therapeutic serum concentrations of valproic acid have not been established in bipolar disorder, most clinicians use the anticonvulsant therapeutic range of 50 to 125 mcg/mL taken 12 hours after the last dose. Patients with cyclothymia or mild bipolar II disorder may have a therapeutic response to lower doses and blood levels, whereas some patients with a more severe form of bipolar disorder may require up to 150 mcg/mL. Serum valproic acid levels are usually determined every 1 to 2 weeks during the first 2 months, and then every 3 to 6 months during maintenance therapy. ... 

Valproic Acid (Depakote) A fatty acid which inhibits GABA-transaminase and succinic semialdehyde dehydrogenase, the enzymes which degrade GABA. Preferred drug for seizure disorders which have components of more than one seizure type. Therapeutic serum levels are 50-100 jg/ml. Toxicity Tremor and sedation. Metab 90% protein bound. Metabolites inactive. 

A. Specific levels. Obtain a stat serum valproic acid level. Serial valproic acid level determinations should be obtained, particularly after ingestion of divalproex-containing preparations (Depakote), owing to the potential for delayed absorption. Peak levels have been reported up to 18 hours after Depakote overdose, and could be even later after ingestion of the new formulation Depakote ER. 

B. Other useful laboratory studies include electrolytes, glucose, BUN, creatinine, calcium, ammonia, liver transaminases, bilirubin, prothrombin time (PT), amylase, serum osmolality and osmolar gap (see p 32 serum levels > 1500 mg/L may increase the osmolar gap by 10 mOsm/L or more), arterial blood gases or oximetry, and EGG monitoring. Valproic acid may cause a falsepositive urine ketone determination. 

B. Specific drugs and antidotes. There is no specific antidote. Naloxone (see p 469) has been reported to increase arousal, but inconsistently, with greatest success in patients with serum valproic acid levels of 185-190 mg/L. L-Camitine (p 426) has been used to treat valproic acid-induced hyperammonemia. 

D. Enhanced elimination (see p 54). Although valproic acid is highly protein bound at therapeutic serum levels, saturation of protein binding in overdose (binding decreases to 35% at 300 mg/L) makes valproic acid favorably disposed to enhanced removal methods. 

Spiller HA et al Multicenter case series of valproic acid ingestion serum concentrations and toxicity. J Toxicol Clin Toxicol 2000 38(7) 755-760. Erratum In J Toxicol Clin Toxicol 2001 39(1) 115. [PMID 11192462] (Peak VPA levels of >450 mg/L were associated with significant clinical effects and >850 mg/L were associated with coma and respiratory depression.)... 

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