Lorazepam Valproate

Anderson GD, Gidal BE, Kantor ED, et al. Lorazepam-valproate interaction studies in normal subjects and isolated perfused rat liver. Epilepsia 1994 35(l) 221-225. 

Lee S-A, Lee JK, Heo K. Coma probably induced by lorazepam-valproate interaction. Sei-zure(2002) 11,124-5. 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

First, optimize current mood stabilizer or initiate mood-stabilizing medication lithium,0 valproate,0 or carba-mazepine0 Consider adding a benzodiazepine (lorazepam or clonazepam) for short-term adjunctive treatment of agitation or insomnia if needed Alternative medication treatment options carbam-azepine0 if patient does not respond or tolerate, consider atypical antipsychotic (e.g., olanzapine, quetiapine, risperidone) or oxcarbazepine. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

Valproate Versus Lithium. The previously discussed Bowden et al. (135) study found the DVPX formulation to be comparable with lithium, which was used as a positive comparator in this placebo-controlled study. Freeman et al. (99) conducted a 3-week, double-blind, parallel-group comparison of VPA and lithium for acute mania. Both drugs demonstrated clinically significant efficacy (i.e., 9 of 14 responded to DVPX and 12 of 13 to lithium), and there was no difference in the need for rescue medications (i.e., lorazepam or chloral hydrate) between the two treatment groups. Response to VPA was associated with high pretreatment depression scores. 

Other than slow taper, no consistently effective treatment to alleviate withdrawal symptoms has been reported. Although several compounds have been studied (e.g., b-blockers, clonidine, carbamazepine, abercamil, ondansetron), results have been contradictory ( 250). Carbamazepine, however, may be useful in seizure-prone patients (251). Valproate (VPA) has also been reported to benefit patients undergoing BZD discontinuation after long-term dependence ( 252), which may be related to VPA s potential anxiolytic properties, its ability to alleviate withdrawal phenomena, or both. The azaspirone anxiolytic buspirone has been reported ineffective in suppressing withdrawal symptoms, particularly in long-term BZD users (253, 254). Hydroxyzine has also been found beneficial in treating patients for lorazepam withdrawal (255). 

Valproate Lorazepam -fr 20% increase in lorazepam AUC, 31% decrease in formation CL of lorazepam glucuronide 40% decrease in lorazepam CL 148,149... 

Catatonia occurred in a 42-year-old woman taking valproic acid, sertraline, and risperidone (79). The catatonic features evolved for the first time after a single dose of valproate and were alleviated by lorazepam the same catatonic signs recurred after a second dose of valproate and again remitted after lorazepam. 

First two or three dmg combinations lithiurtf or valproate plus a benzodiazepine (lorazepam or clonazepam) for short-tenn adjunctive treatment of... 

Valproate and probenecid may reduce clearance and raise plasma concentrations of lorazepam... 

Valproate monitor for hypertension, tachycardia, peripheral edema Benzodiazepines (lorazepam) for acute treatment... 

After first trimester carbamazepine, lamotrigine, oxcarbazepine, or valproate Second choice benzodiazepine (lorazepam) Third choice calcium channel blocker With psychosis first choice adjunctive high-potency typical antipsychotic (haloperidol, perphenazine, thiothixene, or trifluoperazine)... 

There appears to be no pharmacokinetic interaction between pregabalin and carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, topiramate, valproate, alcohol, lorazepam, or oxycodone. However, the impairment of cognitive and gross motor function caused by oxycodone was additive with pregabalin, and pregabalin may potentiate the effects of alcohol and lorazepam. 

In healthy subjects, lorazepam 1 mg every 12 hours for 3 days had no effect on the pharmacokinetics of valproate semisodium 500 mg every 12 hours. However, valproate semisodium increased the AUC and maximum serum levels of lorazepam by 20% and 8%, respectively. Sedation scores were not affected by concurrent treatment, suggesting that the interaction is not clinically significant. ... 

A 40% decrease in the clearance of a 2-mg intravenous bolus dose of lorazepam was seen in 6 out of 8 healthy subjects while they were taking valproate 250 mg twice daily. A woman taking valproate, phenytoin, and carbamazepine went into a coma after she received a total of 6 mg of intravenous lorazepam. She promptly recovered on stopping the valproate. ... 

It seems that valproate reduces the glucuronidation of lorazepam, and therefore benzodiazepines that are mainly metabolised by glucuronide conjugation, such as oxazepam and temazepam are also likely to be affected. It is also thought that valproate may displace midazolam from its... 

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