Anticonvulsant agents phenobarbital

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]. 

Major events preceding this work are the fortuitous discovery of phenobarbital as an anticonvulsant agent, stmcture/hypnotic activity studies with barbiturates and hydantoins in the early 1920s by A.W. Dox in the Parke Davis laboratories, and the development of anticonvulsi-vant assay techniques in animals, by a number of laboratories. Phenytoin was the first item on the list of compounds sent to Putnam by Dox and W.G. Bywater in April 1936. It was found to have anticonvulsivants properties in animals late in 1936, but no public reports were issued until the following year. Clinical efficacy was established in 1937, but again no public reports were issued until 1938. Dilantin sodium capsules were prepared by Parke, Davis Co. and were ready for marketing the same year. ... 

Convulsive disorders are still a serious therapeutic problem and new agents are being actively sought. Classical therapy was based upon the barbiturates that are no longer in favor because of their many side effects and their suicide potential. Interestingly, a seemingly minor structural variation of phenobarbital (152, shown as its sodium salt) leads to an anticonvulsant of increased potency and which has less hypnotic activity. In this case, sodium phenobarbital serves as its own base (so the yield is limited to 50%) and reacts readily with... 

Pharmacology These agents depress the sensory cortex, decrease motor activity, alter cerebellar function, and produce drowsiness, sedation, and hypnosis. Barbiturates have little analgesic action at subanesthetic doses and may increase the reaction to painful stimuli. All barbiturates exhibit anticonvulsant activity in anesthetic doses. However, only phenobarbital and mephobarbital are effective as oral anticonvulsants in subhypnotic doses. 

True hypersensitivity reactions to phenytoin are related to the "aromatic" anticonvulsants. Thus, in patients in whom a reaction is suspected, other arene anticonvulsants such as carbamazepine, oxcarbazepine, phenobarbital, or primidone should be avoided, as there is a high rate of cross-reactivity (estimated as high as 80%). Valproic acid is an agent that can be safely used as an alternative anticonvulsant in such patients. 

Remacemide, which chemically is ( )-2-aini-no-iV-( 1-methyl- l,2-diphenylethyl)acetamide (58), and its principal active desglycinyl metabolite (58a), are low-affinity, noncompetitive NMDA receptor blockers and Na+ fast-channel blockers (242). Remacemide is rapidly absorbed on oral administration and achieves a peak plasma level in 1 h, whereas the active metabolite (58a) takes 2-3 h. The parent has a half-life of 3-4 h, compared to 12-15 h for the active metabolite (243). Comedication with enzyme-inducing anticonvulsants (i.e., phe-nytoin, carbamazepine, and phenobarbital) induces the metabolism of both remacemide and (68a), thus reducing their plasma concentration. The agent has been studied for its anticonvulsant effect, and because of its neuro-... 

Phenobarbital is indicated as a hypnotic agent for the shortterm treatment of insomnia, as an anticonvulsant in the treatment of partial and generalized tonic-clonic and cortical focal seizures and in emergency control of certain acute convulsive episodes (e.g., those associated with status epi-lepticus, eclampsia, tetanus, and toxic reactions to strychnine or local anesthetics). 

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)]... 

Sedatives or anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, and pheny-toin, but not valproate) that induce CYPs (see Chapter S) can enhance the metabolism of antipsychotic and many other agents (including anticoagulants and oral contraceptives), sometimes with significant clinical consequences. Conversely, selective serotonin (5-HT) reuptake inhibitors including fluvoxamine, fluoxetine, paroxetine, venlafaxine, sertraline, and nefazodone (see Chapter 17) compete for these enzymes and can elevate circulating levels of neuroleptics. 

In addition to the classical environmental or nutritional cause of these diseases, both osteomalacia and rickets can have a pharmacological origin via chronic treatment with anticonvulsants (phenobarbital and phenytoin) or glucocorticoids. These agents interfere with intestinal absorption of calcium and, thereby, cause pseudohyperparathyroidism. As a result, an increase in bone turnover and a decrease in the formation of appropriately mineralized bone is observed. In these patients, treatment with vitamin D improves calcium absorption, ultimately enhancing mineralization of the bone. 

I. Pharmacology. Phenobarbital Is a barbiturate commonly used as an anticonvulsant. Because of the delay In onset of the therapeutic effect of phenobarbital, diazepam (see p 415) Is usually the Initial agent for parenteral anticonvulsant therapy. After an oral dose of phenobarbital, peak brain concentrations are achieved within 10-15 hours. Onset of effect after intravenous administration is usually within 5 minutes, although peak effects may take up to 30 minutes. Therapeutic plasma levels are 15-35 mg/L. The dmg is eliminated by metabolism and renal excretion, and the elimination half-life is 48-100 hours. 

Pseudoallergic reactions resemble allergic reactions clinically but are not immunologically mediated. Examples include asthma and rashes caused by aspirin and maculopapular erythematous rashes due to ampicillin or amoxicillin in the absence of penicillin hypersensitivity. Few other entities that can initiate this reaction are sulfonamides, anticonvulsants (phenytoin, carbamazepine and phenobarbital), NSAIDs (aspirin, naproxen, nabumetone and keto-profen), antiretroviral agents and cephalosporins [1 ]. 

---