Phenobarbitones

C12H12N2O3. White crystals, m.p. 174°C. Prepared by condensing the ethyl ester of phenylethylmalonic acid with urea. It is a more active hypnotic than barbitone. It and its sodium salt - soluble phenobarbitone - are used as sedatives and in treating epilepsy. 

Phenylethylbarbituric acid (also termed luminal and phenobarbitone) may be prepared by condensing ethyl phenyletUylmalonate with urea in the presence of sodium methoxide ... 

Pellotine is a convulsant in the frog and cat. Clerc, Janot and Paris, state that the intravenous lethal dose in dogs is 10 mgm./kilo. In chloralosed dogs 5 mgm./kilo slowed the heart and caused a fall in blood pressure the effects lasted for a few minutes and resembled those due to acetylcholine they were inhibited by atropine and increased by yohimbine and ergotamine. A few injections of this dose at short intervals produced convulsions and this effect was inhibited by phenobarbitone. 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

As outlined above (see also Chapter 9), these drugs have been found to influence the Cl channel of the GABAa receptor. Phenobarbitone acts directly to prolong its... 

Figure 16.7 The structure of some established antiepileptic drugs (AEDs) and some newer ones. Note that while the structures of phenytoin and ethosuximide are similar and also close to that of phenobarbitone, they are effective in different forms of epilepsy. Vigabatrin, progabide and gabapentin are clearly related to GABA. Muscimol is a GABAa agonist but is not an effective antiepileptic drug...

Phenobarbitone GM/FE 2 Sedative. Withdrawal fits. Little used (50-100)... 

Primidone GM/PE Works partly by conversion to phenobarbitone in body... 

Phenobarbitone may be as effective as phenytoin and carbamazepine in partial and generalised tonic-clonic seizures but its other central effects such as sedation, depression, listlessness and cognitive impairment mar its usefulness. 

Clonazepam, a typical 1 4 benzodiazepine, is effective in absence seizures, myoclonic jerks and tonic-clonic seizures and given intravenously it attenuates status epilepticus. It is less sedative than phenobarbitone but tolerance develops and its withdrawal, as... 

Newer AEDs do have some advantages in that they tend to have fewer effects on the metabolism of each other or other drugs. By contrast, phenobarbitone is one of the most potent inducers of the microsomal enzyme system (cytochrone T 450) responsible for the metabolism of drugs. Phenytoin and carbamazepine have a similar but less marked effect while valproate inhibits the system. 

If excessive noradrenergic transmission is a causal factor in anxiety, then it would be predicted that a lesion of central noradrenergic neurons would have an anti-anxiety effect in behavioural models of this condition. Unfortunately, the behavioural effects of such lesions are notoriously inconsistent and there are many reports of negative findings (e.g. Salmon, Tsaltas and Gray 1989). One study has even shown that a lesion of central noradrenergic neurons, induced by the selective neurotoxin, DSP-4, abolishes the anti-anxiety effects of tricyclic antidepressants and MAO inhibitors, but not those of the benzodiazepine, alprazolam, or the barbiturate, phenobarbitone (Fontana,... 

Jalsenjak, I., Nicolaidou, C.F. and Nixon, J.R. (1976) The in vitro dissolution of phenobarbitone sodium from ethylcellulose microcapsules. Journal of Pharmacy and Pharmacology, 28, 912-914. 

Phenobarbitone A barbiturate sedative-hypnotic used to treat epilepsy. It is a potent inducer (stimulator) of cytochrome P-450 activity. 

MNaH2P04-Na2HP04 with 40% vol methanol flowrate, 2 ml/min temp., ambient detector, UV, 220 nm samples, 1-10 pg. (1) Salicylic acid (2) phenobarbitone ... 

Patriarca, C. et al., Popliteal lymph node response to procainamide and isoniazid. Role of beta-naphthoflavone, phenobarbitone and S9-mix pretreatment. Toxicol. Lett., 66, 21, 1993... 

From investigations of the effect of emorfazone on liver drug-metabolizing enzymes, (3) has been classified as a phenobarbitone (phenobarbital)-type inducer of enzymes [65]. For results of clinical evaluations of emorfazone, see [66, 67],... 

From the examination of structure-activity relationships, it has been concluded that a phenyl moiety at C-6 as well as a 4-hydroxypiperidine side-chain attached to C-3 of the pyridazine system is essential for anticonvulsant activity in this class of compounds [184], Compounds (54) and (55) have been found to have similar anticonvulsant profiles in animals (mice, rats and baboons) [165, and literature cited therein] and to represent potent broad-spectrum antiepileptic drugs. Their potency with regard to antagonizing seizures (induced by electro-shock or various chemicals) has been compared with standard anticonvulsants like carbamazepine and phenobarbitone [185, 186], A quantitative electroencephalographic analysis of (55) has been published [187]. From in vitro studies it has been concluded that the anticonvulsant activities of these compounds are not mediated by an enhancement of GABAergic transmission or by an interaction with benzodiazepine receptor sites [ 165,186,187], On the other hand, in vivo experiments showed that (54), at anticonvulsant doses, increases the affinity of flunitrazepam for its central receptor site [ 186], Investigations of (54) and (55) in a behavioural test predictive of antianxiety activity revealed a marked difference in the pharmacological profiles of these structurally closely related compounds the dichloro compound SR 41378 (55) has also been found to possess anxiolytic (anticonflict) properties [165],... 

Standard Method of S9 Fraction Preparation. The following describes the production of hepatic S9 mix from rats induced with a combination of phenobarbitone and jS-naphthoflavone, and is an adaptation of the method described by Gatehouse and Delow (1979). 

---