Primidone anticonvulsant

Primidone, anticonvulsant. Rabbit. Oxidation and ring opening. Ethyl-phenylmalondiamide (48% of dose), UP (20% of dose), and phenobarbital (m), in urine. Accumulation of phenobarbital noted upon repeated administration. 

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. 

These have generally been replaced in veterinary medicine by inhalation anesthetics. Phenobarbital /T(9-(9G, phenytan [57-41-0], and primidone [125-33-7] are used as anticonvulsants. 

The anticonvulsant primidone (1035) resembles phenobarbital but lacks the 2-oxo substituent. It was introduced in 1952 and has remained a valuable drug for controlling grand mal and psychomotor epilepsy. As might be expected, primidone is metabolized to yield phenobarbital (1034 X = 0) and C-ethyl-C-phenylmalondiamide (1036), both of which have marked anticonvulsant properties however, primidone does have intrinsic activity and an appropriate mixture of its metabolites has only a fraction of its activity (73MI21303). Primidone may be made in several ways, of which desulfurization by Raney nickel of the 2-thiobarbiturate (1034 X = S) or treatment of the diamide (1036) with formic acid (at 190 °C) seem to be the most satisfactory (54JCS3263). 

Anticonvulsants (barbiturates, including phenobar-bital and primidone carbamazepine felbamate phenytoin topiramate vigabatrin)... 

Least, CJ. Jr., Johnson, G.F., and Solomon, H.M. 1975. Therapeutic monitoring of anticonvulsant drugs Gas chromatographic simultaneous determination of primidone, phenylethylmalonamide, car-bamazepine, and diphenylhydantoin. Clin Chem. 21 1658. 

The anticonvulsant agent primidone (4.246) is the 2-dihydro derivative of phenobarbital (4.247), which is one of its metabolites. The second major metabolite, 2-ethyl-2-phenylmalondiamide (4.248), is produced by a double C-N cleavage [160]. The profile of plasma levels in rats strongly suggests that 2-ethyl-2-phenylmalondiamide is not derived from the metabolite phenobarbital, but directly from primidone. Indeed, a C(2)-hydroxylated metabolite serves as an intermediate for both detected metabolites (see also Chapt. 6 in [21]). N-Alkyl derivatives of primidone yield a greater proportion of ring-opened metabolites, an observation explained by their higher susceptibility to oxidative metabolism at C(2) [161]. 

Primidone (Mysoline) Anticonvulsant Probenecid (Benemid) Anti-gout... 

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. 

The relation between the drug levels and seizure control is not clear, and opinion is divided whether primidone exerts anticonvulsant activity solely as the metabolite phenobarbitone (B15, 06) or as native primidone, as suggested by experimental (Gl) and clinical (B7, B17) studies. 

Primidone is chemically and structurally similar to phenobarbital with the exception that the carbonyl group on Cj is replaced by a methylene group. This modification leads to the production of a drug with strong anticonvulsant properties without expressed soporific effects. 

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. 

Patients already receiving other anticonvulsants Start primidone at 100 to 125 mg at bedtime gradually increase to maintenance level as the other drug is gradually decreased. When therapy with primidone alone is the objective, the transition should not be completed in less than 2 weeks. 

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

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). 

Drugs acting on GABA/glutamate - hypnotics/anxiolytics barbiturates, benzodiazepines, chlormethiazole, chloral derivatives, baclofen - anticonvulsants phenobarbitone, primidone, phe-nytoin, sodium, valproate, carbamazepine - alcohol, phencyclidine, ketamine... 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

Phenobarbital and primidone are quite similar both chemically and pharmacologically, and much of the anticonvulsant activity of primidone may be ascribed to its metabolic conversion to phenobarbital. As would be expected in such a case, the clinical indications for the two compounds are very similar. There is some indication that primidone may be more effective in the treatment of partial seizures with complex symptoms, but the evidence is not compelling. 

Phenobarbital is effective orally and is distributed widely throughout the body. It is metabolized by microsomal drug-metabolizing enzymes, but up to 50% of the parent drug is excreted unchanged by the kidneys. Primidone is metabolized to phenobarbital and phenyl-ethylmalonamide. The latter metabolite has anticonvulsant activity, but most of the anticonvulsant efficacy of primidone is due to the phenobarbital that is produced. 

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. 

Typical inducers include the older anticonvulsants, i.e., barbiturates, primidone, phenytoin, and carba-... 

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, or 2-desoxyphenobarbital (Figure 24-6), was first marketed in the early 1950s. It was later reported that primidone was metabolized to phenobarbital and phenylethylmalonamide ( ). All three compounds are active anticonvulsants. 

Primidone [125-33-7] -as antiepileptic agent [HYPNOTICS, SEDATIVES, ANTICONVULSANTS, AND ANXIOLYTICS] (Vol 13)... 

Primidone has a relatively short half-life (4-15 hours), but it is metabolized to phenobarbitone and phenylethylmalonamide, which prolongs the duration of the anticonvulsant effect. 

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