Primidone and carbamazepine

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. 

While regular monitoring of plasma phenytoin levels can result in improved seizure control, the benefit derived from measuring other commonly prescribed anticonvulsant drugs is difficult to assess. Phenobarbitone, primidone, and carbamazepine will be discussed briefly. 

Exchange the phenytoin for another antiepileptic barbiturates (including primidone ) and carbamazepine, are also enzyme-inducers, but valproate is a possible non-interacting alternative where clinically appropriate. However, remember that corticosteroids should only be given to epileptics with care and good monitoring because of the risk that they will exacerbate the disease condition. 

The anticonvulsants primidone and carbamazepine inhibit biotin uptake into brush-border membrane vesicles from human intestine (Zempleni et al. 2009). Long-term therapy with anticonvulsants increases both biotin catabolism and urinary excretion of 3-hydroxyisovaleric acid. These eifects might be due to displacement of biotin from biotinidase by anticonvulsants, thereby aifecting plasma transport, renal handling or cellular uptake of biotin. 

Fig. 1 Reflectance scan of a blank (A) and of a mixture of antiepileptics with 500 ng substance per chromatogram zone (B). Start (1), primidone (2), carbamazepine (3), phenytoin (4), phenobarbital (5), ethosuximide (6), hexobarbital (7) and solvent front (8).

From the clinical point of view, antiepileptic drugs are primarily divided into two categories those effective in treating major attacks (phenytoin, carbamazepine, mephobarbi-tal, and also primidone), and those effective in treating minor attacks (ethosuximide, acetazolamide, clonazepam, trimethadione, and valproic acid). 

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

RPC has found use in the analysis of barbiturates including the determination of drugs taken in an overdose (332). Thiopental was determined using a mobile phase comprised of methanol-0.1% sodium citrate buffer, pH 6.5 (45 55) (333). Hydantoins, along with other species which have anticonvulsant activity, have been determined with barbiturates. These include phenytoin in the presence of phenobarbital and primidone (334,335) and the related anticonvulsants ethosuximide and carbamazepine (336). 

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. 

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. 

OPIOIDS ANTIEPILEPTICS 1. Barbiturates T sedative effects of opioids 2.1 efficacy of fentanyl and methadone with carbamazepine, phenobarbital, phenytoin or primidone 3. Carbamazepine l tramadol levels 4. Risk of pethidine toxicity 1. Additive sedative effect 2. t hepatic metabolism of fentanyl and methadone, and possibly an effect at the opioid receptor 3. Carbamazepine T metabolism of tramadol 4. Phenytoin induces metabolism of pethidine, which causes T level of a neurotoxic metabolite 1. Monitor respiratoiy rate and conscious levels 2. Be aware that the dose of fentanyl and methadone may need to be t 3. Watch for poor effect of tramadol. Consider using an alternative opioid 4. Co administer with caution the effect may be i by administering pethidine intravenously... 

Clearance of tiagabine is increased if taken with an enzyme-inducing antiepileptic drug (e.g., carbamazepine, phenobarbital, phenytoin, primidone) and thus plasma levels are reduced however, no dose adjustments are necessary for treatment ot epilepsy as the dosing recommendations for epilepsy are based on adjunctive treatment with an enzyme-inducing antiepileptic drug... 

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... 

A 72-year-old woman developed somnolence and continuous sharp waves over the left hemisphere when carbamazepine was added to primidone and a diuretic. Her serum sodium concentration was initially 130 mmol/1 and fell further to 100 mmol/1. 

Failure of contraceptive therapy and breakthrough bleeding have been noted repeatedly in patients concurrently taking various enzyme-inducing anticonvulsant drugs (305,314). These include phenytoin, primidone, ethosux-imide, phenobarbital, and carbamazepine. The specific isozyme responsible for metabolic 2-hydroxylation of ethinylestradiol is CYP3A4, which is induced by... 

Levonorgestrel is metabolised in the liver and drugs, including primidone, phenytoin, carbamazepine, St John s wort, griseofulvin, rifampicin, rifabutin and ritonavir, that induce liver enzymes will increase its metabolism and may... 

Drugs induce osteomalacia through various mechanisms. Phenyt-oin, primidone, phenobarbital, carbamazepine, rifampin, and some hypnotic medications may cause osteomalacia, potentially through... 

Transient elevations of the serum transaminases occur in 12% to 15% of patients receiving isoniazid and usually occur within the first 8 to 12 weeks of therapy. Overt hep ato toxicity, however, occurs in only 1% of cases. Risk factors for hepatotoxicity include patient age, preexisting liver disease, excessive alcohol intake, pregnancy, and the postpartum state. Isoniazid also may result in neurotoxicity, most frequently presenting as peripheral neuropathy or, in overdose, as seizures and coma. Patients with pyridox-ine deficiency, such as pregnant women, alcoholics, children, and the malnourished, are at increased risk. Isoniazid may inhibit the metabolism of phenytoin, carbamazepine, primidone, and warfarin." Patients who are being treated with these agents should be monitored closely, and appropriate dose adjustments should be made when necessary. 

Anticonvulsants Phenobarbitone, phenytoin primidone, ethosuximide and carbamazepine in serum Partition ODS-SIL-X-I Water/acetonitrile (83 17)... 

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... 

Gerson, B. Bell, F. Chan, S. Antiepileptic agents—primidone, phenobarbital, phenytoin, and carbamazepine by reversed-phase liquid chromatography. Clin.Chem., 1984, 30, 105-108 Kapetanovic, I.M. Kupferberg, H.J. Nafimidone, an imidazole anticonvulsant, and its metabolite eis potent inhibitors of microsomal metabolism of phenytoin and carbamazepine. Drug Metab.Dispos., 1984, 12, 560-564 [microsomal incubations rat liver column temp 50 extracted metabolites 2-methylcarbamazepine (IS)]... 

Kabra, P.M. Nelson, M.A. Marton, L.J. Simultaneous very fast liquid-chromatographic analysis of ethosuximide, primidone, phenobarbital, phenytoin, and carbamazepine in serum. Clin.Chem., 1983,29, 473-476... 

Neels, H.M. Totte, J.A. Verkerk, R.M. Vlietinck, A.J. Scharpe, S.L. Simultaneous high performance liquid-chromatographic determination of carbamazepine, carbamazepine-10,ll-epoxide, ethosuximide, phenobarbital, phenytoin, primidone and phenylethylmalonamide in plasma. J.Clin. Chem.Clin.Biochem., 1983, 21, 295-299... 

Simple partial seizures can have the characteristics described in this patient. The Jacksonian march is due to progression of epileptiform discharges in the contralateral motor cortex. Phenytoin, carbamazepine, primidone, and lamotrigine are effective in partial seizures. The succinimides (ethosuximide, phensuximide) are not effective in partial seizures or in generalized tonic-clonic seizure states. The answer is (B). 

Nicotinamide 41 to 178 mg/kg daily increased the levels of primidone and deereased the levels of primidone-derived phenobarbital in 3 ehil-dren. Although two of the children had refractory seizures, seizure frequency decreased while on nicotinamide. Two of the ehildren on carbamazepine had increases in their carbamazepine levels. ... 

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