Phenobarbital and primidone

Fig. 2.4. Flowdiagram of the procedure for extraction of phenobarbital, primidone and diphenyl-hydantoin from serum.

Antiepilepsy drugs pass into breast milk (see p. 116), phenobarbital, primidone and ethosuximide in significant quantities, phenytoin and sodium valproate less so. There is a risk that the baby will become sedated or suckle poorly but, provided a watch is maintained for these effects, the balance of advantage favours breast feeding whilst taking antiepilepsy drugs. 

With phenytoin, carbamazepine, phenobarbital, primidone, and lamotrigine, hepatotoxicity usually occurs as part of a hypersensitivity reaction, with skin rashes and fever in the early weeks of treatment. More rarely, hepatic disease can develop after many years without signs of hypersensitivity. Once hepatotoxicity develops, mortality... 

Liu, H. Delgado, M. Forman, L.J. Eggers, C.M. Montoya, J.L. Simultaneous determination of carbamazepine, phenytoin, phenobarbital, primidone and their principal metabolites by high-performance liquid chromatography with photodiode-array detection. J.Chromatogr., 1993, 616, 105-115... 

Similar results, both of increased seizure activity and decreased serum folate levels, have been described in other studies and reports in patients taking phenytoin, phenobarbital, primidone and phenetnride. " Another report describes lack of phenytoin efficacy in a patient receiving UFT with folinic acid, which was attributed to the effect of the folinic acid on phenytoin levels. ... 

A very well documented and clinically important interaction, which has been the subject of review." Reductions in serum phenytoin levels of 16 to 50% have been described in patients taking 5 to 15 mg folic acid daily for 2 to 4 weeks. If folic acid supplements are given to folate-deficient epileptics taking phenytoin, phenobarbital, primidone and possibly pheneturide, their serum antiepileptic levels should be well monitored so that suitable dosage increases can be made. 

Improved Method for the Simultaneous Determination of Phenobarbital, Primidone, and Diphenylhydantoin in Patients Serum by Gas-Liquid Chromatography... 

Carbamazepine, Phenobarbital, Primidone and Diphenylhydantoin in Human Serum... 

Phenytoin, Phenobarbital, Primidone, and Ethosuximide Simultaneous Determination with On-Column Methylation (TMAH) Antiepileptic Drugs Quant. Anal. Interpret. 1978 338-342 CA 88 130642p... 

Primidone [125-33-7] C22H24N2O2 (39) is an analogue of phenobarbital that is used for the treatment of generalized tonic-clonic seizures. It is metabolized in humans to phenobarbital (6) and phenylethyLmalondiamide [7206-76-0J, C22H24N2O2 (40) and these metaboUtes are probably responsible for its anticonvulsant actions. Primidone has many of the side effect HabiUties seen with phenobarbital. 

Phenobarbital, phenytoin, primidone, and carbamazepine are potent inducers of cytochrome P450 (CYP450), epoxide hydrolase, and uridine diphosphate glucuronosyltransferase enzyme systems. Valproic acid inhibits many hepatic enzyme systems and displaces some drugs from plasma albumin. 

K20. Kupferberg, H. J., Quarrtitative estimation of diphenylhydantoin, primidone and phenobarbital in plasma by gas-liquid chromatography. Clin. Chim. Acta 29, 283-288 (1970). 

From the chemical point of view, formally, antiepileptic drugs could be classified as derivatives of hydantoins (phenytoin, mephenytoin, ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), succinimides (ethosuximide, methosuximide, phensux-imide), benzodiazepines (diazepam, chlorodiazepoxide, clonazepam, lorazepam), oxazo-lidines (trimethadione, paramethadione), and also valproic acid, carbamazepine, and acetazolamide. 

Drugs that may affect methylphenidate include MAOIs. Drugs that may be affected by methylphenidate hydrochloride include guanethidine, anticonvulsants (eg, phenytoin, phenobarbital, primidone), selective serotonin reuptake inhibitors, coumarin anticoagulants, and tricyclic antidepressants. 

Safety and efficacy have not been established as initial monotherapy, for conversion to monotherapy from AEDs other than carbamazepine, phenytoin, phenobarbital, primidone, or valproate or for simultaneous conversion to monotherapy from 2 or more concomitant AEDs. 

Pharmacology Primidone s mechanism of antiepileptic action is not known. Primidone and its 2 metabolites, phenobarbital and phenylethylmalonamide (PEMA) have anticonvulsant activity. 

Pharmacokinetics Primidone is readily absorbed from the Gl tract. Phenobarbital appears in plasma after several days of continuous therapy. Therapeutic plasma concentrations are 5 to 12 mcg/mL for primidone and 15 to 40 mcg/mL for phenobarbital. PEMA and phenobarbital have longer half-lives (10 to 18 hours and... 

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. 

Drugs that may affect tiagabine include carbamazepine, phenobarbital, phenytoin, primidone, and valproate. Valproate may be affected by tiagabine. 

Phenobarbital, primidone, phenytoin and also carbamazepine are inducers of cytochrome P450 enzymes and in combination the effects of substrates... 

Type II Multiple actions enhance GABAergic inhibition, reduce T-calcium currents, and possibly block SRF Valproic acid Benzodiazepines Phenobarbital Primidone... 

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. 

Lamotrigine is metabolized by glucuronidation, possibly by the UGT 1A4 system. As such, it is vulnerable to other UGT inducers—oral contraceptives, phenytoin, carbamazepine, phenobarbital and primidone, and to a UGT inhibitor, valproate (Hachad et ah, 2002). 

Herranz, J.L., Armijo, J.A., and Arteaga, R. (1988) Clinical side effects of phenobarbital, primidone, phenytoin, carbamazepine, and valproate during monotherapy in children. Epilepsia 29 794-804. 

Sullivan, F.M. and McElhatton, P.R. (1975) Teratogenic activity of the antiepileptic drugs phenobarbital, phenytoin, and primidone in mice. Toxicol Appl Pharmacol 24 271—282. 

Valproate metabolism may be induced by other anticonvulsants, including carbamazepine, phenytoin, primidone, and phenobarbital, resulting in an increased total clearance of valproate and perhaps decreased efficacy. 

Primidone is metabolized by oxidation to phenobarbital, which accumulates very slowly, and by scission of the heterocyclic ring to form (Figure 24-6). Both primidone and phenobarbital also undergo subsequent conjugation and excretion. 

Smith DB, Mattson RH, Cramer JA, Collins JF, Novelly RA, Craft B. Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone. Epilepsia 1987 28(Suppl 3) S50-8. 

ANTIPSYCHOTICS CARBAMAZEPINE, PHENYTOIN, PHENOBARBITAL, PRIMIDONE 1 levels of apiprazole (all), haloperidol (carbamazepine, phenobarbital), clozapine, quetiapine, sertindole (carbamazepine, phenytoin), risperidone and olanzapine (carbamazepine) Induction of metabolism Watch for poor response to these antipsychotics, and consider increasing the dose... 

Also, if concomitant enzyme-inducing antiepileptic drugs such as carbamazepine, phenobarbital, phenytoin, and primidone are discontinued after lamotrigine dose is stabilized, then the lamotrigine dose should be maintained for 1 week following discontinuation of the other drug and then reduced by half over 2 weeks in equal decrements each week... 

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