Hepatic effects valproate

The oxa2ohdinedione trimethadione [127-48-0] C H NO (50), at one time the dmg of choice for the treatment of absence sei2ures, has been replaced by ethosuximide (41) and valproate (49). (50) has a distinct profile from that of phenytoin but causes photophobia and night blindness in approximately 30% of the patients taking it and has the CNS and sedative properties seen for other anticonvulsants together with moderate neutropenia, hepatitis, and skin rashes (13). Trimethadione does not appear to produce its effects via modulation of GABA-mediated responses. 

When valproate protein binding is altered, the risk for severe dose-related adverse effects is much less compared to phenytoin. Michaelis-Menten metabolism is not a factor with valproate, so hepatic enzymes are able to efficiently metabolize the additional unbound portion. 

As noted above, many of the AEDs induce hepatic microsomal enzyme systems and thus reduce the effectiveness of hormonal contraceptives. Women taking AEDs that may reduce the effectiveness of hormonal contraceptives should be encouraged to also use other forms of birth control. Due to induction or inhibition of sex hormone metabolism and changes in binding of hormones to sex hormone binding globulin, some AEDs may reduce fertility. For example, valproate has been associated with a drug-induced polycystic ovarian syndrome. Women who experience difficulties with fertility should seek the advice of health care professionals with expertise in fertility. 

As with carbamazepine, the historical use of valproate for anxiety is not supported by robust clinical trials. A randomised study showed efficacy in panic disorder (Lum et al. 1991) and benefit has been reported in open studies in OCD and PTSD. The major side-effects are tremor, nausea, ataxia and weight gain and there is the potential for drug interactions via inhibition of hepatic enzymes. 

Although it is estimated that 1 in 118,000 patients dies from non-dose-related hepatic failure, no cases have occurred in patients older than 10 years who were receiving valproate monotherapy. Nonetheless, baseline liver function tests are indicated. If baseline test results are normal, monitoring for clinical signs of hepatotoxic-ity is more important than routine monitoring of liver enzyme levels, which has little predictive value and may be less effective than clinical monitoring (Pellock and WiUmore 1991). 

Carbamazepine is a hepatic microsomal enzyme inducer and therefore will lower the serum concentration of a wide variety of drugs given concurrently. These include the antiepileptic drugs phenytoin, primidone, valproate, ethosuximide and clonazepam. In addition, carbamazepine can compromise the therapeutic effects of oral contraceptives, oral anticoagulants, beta-blockers, haloperidol and theophylline. 

Pharmacokinetics. Carbamazepine is extensively metabolised one of the main products, an epoxide (a chemically reactive form), has anticonvulsant activity similar to that of the parent drug but may also cause some of its adverse effects. The t) of carbamazepine falls from 35 h to 20 h over the first few weeks of therapy due to induction of hepatic enzymes that metabolise it as well as other drugs, including corticosteroids (adrenal and contraceptive), theophylline and warfarin. Cimetidine and valproate inhibit its metabolism. There are complex interactions with other antiepilepsy drugs, which constitute a reason for monodrug therapy. 

Lott RS, Helmboldt KM, Madaras-Kelly KJ. Retrospective evaluation of the effect of valproate therapy on transaminase elevations in patients with hepatitis C. Pharmacotherapy 2001 21 (11 ) 1345-51. 

Sodium vaipro-ate 7.5 to 15 mg/kg/day adjust for side effect and TDM 1% 100% 100% 100% Plasma concentration 50-150 mcg/ml side effects include weight gain, hepatitis check free valproate level NC NC NC... 

A rare complication is fulminant hepatitis. Children <2 years of age with other medical conditions who were given multiple antiseizure agents were especially likely to suffer fatal hepatic injury there were no deaths reported for patients >10 years old who received only valproate. Acute pancreatitis and hyperammonemia have been associated with the use of valproic acid. Valproic acid can produce teratogenic effects such as neural tube defects. 

Anticonvulsants Carbamazepine decreases the plasma concentration of bupropion to about 90% even after a single dose of 150 mg of carbamazepine. Long-term administration of valproate (a weak inhibitor of hepatic metabolism) has no effect on bupropion plasma concentration. It has been shown that bupropion does not cause clinically relevant changes in the pharmacokinetics of a single dose of 100 mg of lamotrigine. 

Valproate has some inhibitory effects on hepatic metabolism, and when co-administered with carbamazepine it can increase the serum levels and effects of the latter. Carbamazepine has been reported to reduce valproate serum levels by about 60%. 

Carbamazepine induces hepatic catabolic enzymes, with a consequent reduction in serum levels of antidepressants (mainly described with amitriptyline, desipramine, doxepin, imipramine, mianserin, and nortriptyline). A decrease in bupropion serum levels was also reported with carbamazepine. These effects were not observed with clomipramine. Fluoxetine and fluvoxamine inhibit the metabolism of carbamazepine and valproate (up to 30% and 50% increases in serum levels, respectively). No significant interaction has yet been found between paroxetine and carbamazepine or valproate. 

Ethosuximide is associated with a very low incidence of serious adverse effects. However, gastric irritation, lethargy, fatigue, and annoying CNS effects are quite common. In contrast, valproate carries with it a low but significant risk of serious hepatic injury liver function... 

Because of its inducing effect on hepatic enzymes, phenobarbitai has many drug interactions, decreasing plasma levels of CBZ, valproate, lamotrigine, tiagabine, zonisamide, warfarin, theophylline, cimetidine, and those of other CYP3A4 substrates. Serum concentrations of phenobarbitai are increased by valproate. 

Valproiife. The advantages of valproate are its relative lack of sedative effects, its wide spectrum of activity and the mild nature of most of its adverse effects (nausea, weight gain, bleeding tendencies and transient hair loss). The main disadvantage is that occasional idiosyncratic responses cause severe or fatal hepatic to.xicity. 

Age-dependent differences in the incidence or severity of adverse effects, such as the increased hepatic toxicity of valproate in infants, may also be due to pharmacodynamic determinants. 

Aspirin displaces valproate from its protein binding sites and also alters its metabolism by the liver so that the levels of free (and pharmacologically active) valproate rise. This could temporarily increase both the therapeutic and toxic effects of the valproate. However, there is evidence that increased hepatic elimination of valproate counterbalances this effect. 

Another child who had been treated with valproate for several years was prescribed isoniazid for the treatment of tuberculosis. At the same time, seizures recurred, and the valproate was stopped and primidone 750 mg daily started. Seven months later seizures persisted, and she was admitted to hospital. Liver enzyme values were normal. Valproate 300 mg daily increased to 600 mg daily was added, and within 2 days she was vomiting and drowsy. After 5 days she had increased liver enzymes and her prothrombin time had fallen, so the valproate was stopped. Valproate levels were 81 micrograms/mL. It was speculated that the CNS effects and hepatic impairment were due to an interaction between the valproate and isoniazid. ... 

---