Serum phenobarbital concentration

Serum phenobarbital concentration (therapeutic range for seizure disorders 20-40 mcg/ml)... 

Nervous system An infant with drug-resistant epilepsy associated with bilateral Sturge-Weber syndrome became comatose after taking high-dose phenobarbital for a few months and regained consciousness as the serum phenobarbital concentration fell to below 40 [ig/ml. The authors suggested that patients with severe cerebrovascular diseases are more susceptible to the sedative effects of phenobarbital [232 ]. 

This rare inherited disorder also results from mutations in the gene encoding bilirubin-UGT, but some activity of the enzyme is retained and the condition has a more benign course than type I. Serum bilirubin concentrations usually do not exceed 20 mg/dL. Patients with this condition can respond to treatment with large doses of phenobarbital. 

In mammals, phenobarbital and phenytoin increase serum ceruloplasmin concentrations (Aaseth and Norseth 1986). Chronic copper poisoning in sheep is exacerbated when diets contain heliotrope plants (Heliotropium sp., Echium spp., Senecio sp.). Aggravated effects of the heliotrope plants include reduced survival and a twofold to threefold increase in liver and kidney copper concentrations when compared to control animals fed copper without heliotropes (Howell et al. 1991). Rats given acutely toxic doses of 2,3,7,8-tetrachlorodibenzo-para-dioxin had elevated concentrations of copper in liver and kidney because of impaired biliary excretion of copper (Elsenhans et al. 1991). Morphine increases copper concentrations in the central nervous system of rats, and dithiocarbam-ates inhibit biliary excretion (Aaseth and Norseth 1986). In human patients, urinary excretion of copper is increased after treatment with D-penicillamine, calcium disodium EDTA, or calcium trisodium diethylenetriamine penta acetic acid (Flora 1991). 

Once seizures are terminated, dosages can be decreased by 1 mcg/kg/min every 2 hours. Successful discontinuation is enhanced by maintaining serum phenytoin concentrations above 20 mg/L and phenobarbital concentrations above 40 mg/L. 

Phenytoin increases high-density lipoprotein (HDL) cholesterol (118), and may also increase total cholesterol and serum triglyceride concentrations (SED-13,143) (119). In a 5-year prospective study with carbamazepine, there was a persistent rise in total cholesterol and HDL cholesterol, whereas triglycerides and low-density lipoprotein (LDL) cholesterol increased only transiently (120). In a more recent study, total cholesterol fell when 12 patients were switched from carbamazepine to oxcarbazepine, but HDL cholesterol and triglycerides were unchanged (121). In a comparison of 101 epileptic patients with matched controls, valproate was associated with lower total and LDL cholesterol, whereas carbamazepine was associated with higher HDL cholesterol and apolipoprotein A concentrations and phenobarbital with higher concentrations of total and HDL cholesterol and apolipoproteins A and B. The ratio of total to HDL cholesterol was reduced with valproate and carbamazepine but not with phenobarbital (122). 

Chronic treatment with phenobarbital, phenytoin, and carbamazepine is associated with reduced serum folate concentrations. Although megaloblastic anemia is rare, macrocytic changes in red cells are common in these patients. The fact that serum folate is not reduced by valproate and zonisamide, which do not induce liver enzymes, is consistent with the hypothesis that enzyme induction plays a role in the pathogenesis of folate deficiency (99). 

The metabolism of digitoxin can be increased, with resulting increasing dosage requirements, by enzyme-inducing drugs (200). For example, phenobarbital 100 mg daily reduces steady-state serum digitoxin concentrations by 50%. 

Phenobarbital can increase the rate of chloramphenicol metabolism and so lead to abnormally low serum chloramphenicol concentrations. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations were 25 and 13 pg/ml respectively. In six patients phenobarbital reduced these concentrations to 17 and 7.5 pg/ml respectively (76). 

Drugs that induce liver microsomal enzymes, such as phenobarbital, phenytoin, carbamazepine, rifampicin, and isoniazid, can make paracetamol poisoning more severe (104,105). In patients taking such drugs the serum paracetamol concentration should be doubled before consulting the usual treatment nomogram. 

The optimal therapeutic concentration of primidone has been established as 5 to 12 U,g/mL. Because phenobarbital is an active metabolite of primidone, concurrent analysis of phenobarbital is required for complete result interpretation. The previously defined therapeutic range for phenobarbital applies to adequate primidone therapy. The phenobarbital concentrations rise gradually over a period of 1 to 2 weeks after therapy is initiated. Toxicity due to accumulation of primidone occurs at serum concentrations in excess of 15 llg/mL and is usually associated with symptoms of sedation, nausea, vomiting, diplopia, dizziness, ataxia, and a phenobarbital concentration greater than dOpg/mL. Specimen collection is dictated by the same rules that apply to phenobarbital the trough concentration is most useful. 

Interpretation In normal subjects, serum cortisol concentration is suppressed to 2 pg/dL or less after administration of 1 mg of dexamethasone. Most patients with Cushing s syndrome do not show adequate suppression, and 0800 hours cortisol concentrations are usually >10pg/dL. Serum cortisol >2pg/dL may also be seen in cases of stress, obesity, infection, acute or chronic illness, alcohol abuse, severe depression, oral contraceptive use, pregnancy, estrogen therapy, failure to take the dexamethasone, or treatment with phenytoin or phenobarbital (enhancement of dexamethasone metabolism). 

An inspiring, and likely the first, example for the therapeutic application of enzyme induction to affect the metabolic fate of an endogenous substance has recently been reported by Yaffe and his associates (71) phenobarbital treatment has been used to prevent hyperbilirubinemia by inducing the glucuronyl transferase, enhanced glucuronide formation enabled increased bilirubin excretion and resulted in decreased serum bilirubin concentration. 

Oil of sassafras has been reported to interfere with serum phenytoin concentration determination. A 4-mo-old boy was admitted to the hospital for failure to thrive and possible child abuse after an outpatient visit revealed that he was below the third percentile for height and weight, and had scattered bruises, including one above the left eye. The child s mother had a seizure disorder and was taking phenytoin and phenobarbital. It was suspected that she may have... 

Phenobarbital has been shown to decrease serum carbamazepine half-life and plasma concentration levels when given in combination. Significant changes in carbamazepine serum concentrations were seen within 5 days after the addition of phenobarbital to the therapeutic regimen. Conversely, carbamazepine appears to have no effect on serum phenobarbital levels. It has been reported to lower serum concentrations of primidone, but the decrease does not appear to be clinically significant. Other barbiturates (e.g., amobarbital, butabarbital, secobarbital) may interact in a manner similar to phenobarbital because of pharmacologic similarity. 

Phenobarbital is thought to induce the metabolism of carbamazepine to its epoxide metabolite. Accordingly, after phenobarbital administration, decreased serum carbamazepine concentrations were accompanied by increased epoxide levels. 

The authors of a literature review have concluded that carbamazepine, phenobarbital, phenjdoin, and valproic acid can increase plasma homocysteine and serum lipoprotein concentrations [77 ]. 

Age The serum concentrations of phenobarbital were followed in 24 preterm infants weighing less than 1500 g after loading with the recommended dose of 15-20 mg/kg followed by a maintenance dose of 3-i mg/kg/day. The serum phenobarbital levels reached supratherapeutic concentrations by 96 h in 17 (70.8%) patients. Although no adverse clinical events were reported in this study, the authors suggested tiiat low birth weight preterm infants may be prone to higher phenobarbital concentrations with standard dosing and therefore, may be more susceptible to toxic effects [121 ]. 

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. 

Valproic acid is an enzyme inhibitor that increases serum concentrations of concurrently administered phenobarbital and may increase concentrations of carbamazepine 10,11-epoxide without affecting concentrations of the parent drug. It also inhibits the metabolism of lamotrigine. 

Rats pretreated with xylene or phenobarbital and then exposed to -hexane by inhalation exhibited a markedly increased peak serum concentration of 2,5-hexanedione (Toftgard et al. 1983). Peak serum concentrations were approximately 4 g/mL in control rats, 11 g/mL in xylene-induced rats, and 13 g/mL in phenobarbital-induced rats. Peaks were reached in 1-2 hours. The half-life for elimination from serum was approximately one hour for both pretreated and untreated rats. The high serum 2,5-hexanedione concentrations were correlated with an induction of liver microsomal P-450 content (0.56 nmol/mg protein in control rats, 1.03 nmol/mg in xylene-induced rats, and 1.7 nmol/mg protein in phenobarbital-induced rats, respectively). 

It has been observed that while normal, rabbit serum failed to bind labelled phenobarbital, the serum from immunized rabbits bound 75 to 80% of the added pentobarbital and there exists a linear relationship between 14C-phenobarbital and the concentration of added antibody. Besides, when variable quantities of 14C-pentobarbital are added to a constant quantity of antibody, there exists a linear relationship between added and bound 14C-phenobarbital as depicted in Figure 32.4. 

CYP 450 Drugs that induce liver enzymes (eg, phenytoin, carbamazepine, phenobarbital) increase the metabolism and clearance of zonisamide and decrease its half-life. Concurrent medication with drugs that induce or inhibit CYP3A4 would be expected to alter serum concentrations of zonisamide. Zonisamide is not expected to interfere with the metabolism of other drugs that are metabolized by cytochrome P450 isozymes. 

Phenobarbital is still used for the management of partial seizures, generalized tonic-clonic seizures and for the control of status epilepticus. However because of its low therapeutic index and the possibility of dependence, phenobarbital has largely been displaced by other anticonvulsants. For newborns phenobarbital is often the drug of first choice. If given together with sodium valproate the metabolism of phenobarbital may be inhibited while in combination with carbamazepine the serum concentrations of carbamazepine will be reduced due to enzyme induction by phenobarbital. 

The major untoward effect of phenobarbital and primidone, when used as anticonvulsants, is sedation. Another side effect of considerable importance, particularly in children, is a possible disturbance in cognitive function. Even when the serum concentration is within the therapeutic range, apparently the ability to concentrate and perform simple tasks is decreased. 

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