Ethosuximide Phenytoin

Mode of action. The specific site of action of felbamate is unknown. There is experimental evidence that felbamate blocks NMDA receptors, but less potently than carbamazepine, ethosuximide, phenytoin or valproate. It also modulates sodium channel conductance but does not enhance GABAergic function. In addition to its protective action against chemically induced seizures felbamate has also been shown to have a neuroprotective action in models of hypoxic ischaemia as induced by bilateral carotid ligation. 

ETHOSUXIMIDE PHENYTOIN Cases oft phenytoin levels Uncertain Watch for early features of phenytoin toxicity... 

Carbamazepine can decrease piasma ieveis of acetaminophen, ciozapine, benzodiazepines, dicumaroi, doxycyciine, theophyiiine, warfarin, and haioperidoi as weii as other anticonvuisants such as phensuximide, methsuximide, ethosuximide, phenytoin, tiagabine, topiramate, iamotrigine, and vaiproate... 

Noninterfering clobazam, clonazepam, diazepam, ethosuximide, phenytoin, valproic acid... 

A) Carbamazepine Clonazepam Ethosuximide Phenytoin Valproie acid... 

The oxa2ohdinedione trimethadione [127-48-0] C H NO (50), at one time the dmg of choice for the treatment of absence sei2ures, has been replaced by ethosuximide (41) and valproate (49). (50) has a distinct profile from that of phenytoin but causes photophobia and night blindness in approximately 30% of the patients taking it and has the CNS and sedative properties seen for other anticonvulsants together with moderate neutropenia, hepatitis, and skin rashes (13). Trimethadione does not appear to produce its effects via modulation of GABA-mediated responses. 

Detection and result The chromatogram was freed from mobile phase (first dried for 5 min in a stream of cold air, then heated for 10 min at 110°C and allowed to cool), immersed for 5 s in the reagent solution and finally heated for 2 min at 110°C. Grey to grey-blue zones were formed on a light background. The following hRf values were obtained primidone QiR( 10-15) carbamazepine hRf 40 — 45) phenytoin hR( 50 — 55) phenobarbital hRf 60) ethosuximide hRf 75) hexobarbital hRf 90 — 95). 

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).

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. 

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...

Atenolol, hydralazine, procainamide, quinidine, carbamazepine, chlorpromazine, ethosuximide, isoniazid, methyldopa, minocycline, penicillamine, phenylbutazone, phenytoin, thiazides, and valproic acid... 

Antiepileptics Phenytoin Carbamazepine Valproic acid Gabapentin Vigabatrin Ethosuximide Benzodiazepines... 

Valproic acid, phenytoin, carbamazine Ethosuximide, valproic acid Valproic acid Diazepam, lorazepam Grand mal seizures Absence seizures Myoclonus Status epileptic us... 

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). 

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 valproic acid include carbamazepine, charcoal, chlorpromazine, cholestyramine, cimetidine, erythromycin, ethosuximide, felbamate, lamotrigine, phenytoin, rifampin, and salicylates. Drugs that may be affected by valproic acid include carbamazepine, clonazepam, diazepam, ethosuximide, lamotrigine, phenobarbital, phenytoin, tolbutamide, tricyclic antidepressants, warfarin, and zidovudine. 

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). 

Ethosuximide and mesuximide are succinimides. Ethosuximide is the agent of first choice for the management of absence (petit mal) seizures. It inhibits low-threshold Ca" " currents in the thalamus. As it may precipitate grand mal seizures it is frequently given together with a barbiturate or with phenytoin to prevent that. Its plasma concentrations do not closely correlate with the therapeutic effects. 

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. 

Ethosuximide Reduces low threshold Ca2+ currents (T-type) Well absorbed orally, with peak levels in 3-7 h not protein-bound completely metabolized to inactive compounds tjy2 typically 40 h Absence seizures Toxicity Nausea, headache, dizziness, hyperactivity Interactions Valproate, phenobarbital, phenytoin, carbamazepine, rifampicin... 

Regarding the usefulness in measuring the serum concentrations of antiepileptic drugs, it is often of value to do so with those drugs that are liable to cause toxic side effects such as carbamazepine, ethosuximide, phenobarbitone and phenytoin. In general, there seems to be little advantage in determining the serum concentrations of the newer, and better tolerated, antiepileptics. 

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