Phenytoin epilepsy

Other drugs are also used for the treatment of epilepsy, phenytoin, 59, carbomazepine, 60, and valproic acid, 61 are well-known anticonvulsants. 

Epilepsy Phenytoin is effective against partial and tonic-clonic but not absence seizures. Phenytoin preparations differ significantly in bioavailabdity and rate of absorption. In general, patients should consistently be treated with the same drug from a single manufacturer. However, if it becomes necessary to temporarily switch between products, care should be taken to select a therapeutically equivalent product and patients should be monitored for loss of seizure control or onset of new toxicides. 

Cj jH,2N202. Used as its sodium salt, which is a white hygroscopic powder. Unstable, readily absorbing carbon dioxide and liberating phenytoin. Made by treating a-bromodi-phenylacetylurea with alcoholic ammonia. It has a mild hypnotic and strong anticonvulsant action, and is used in the treatment of grand-mal and focal epilepsy. 

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...

Introduced initially for absence seizures, this drug is now known to be effective in and used to treat tonic lonic seizures and most types of epilepsy. It was found to inhibit GABA transaminase and so elevate GABA concentrations and inhibition. This is achieved, however, over a slower time-course than its anti-seizure effect, especially experimentally, which is now thought to be due to its phenytoin-like, use-dependent block of sodium channels. Since, unlike phenytoin, the full effect of valproate takes some weeks to develop, its slower effect on GABA metabolism and activity should not be ignored. 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

This is not really a treatment but there is a view that glial cells can protect against seizures since the enzyme systems they possess (e.g. Na-K+ATPase and carbonic anhydrase) facilitate the regulation of ion movements and reduce the spread of seizures. Certainly ageing, a fatty diet, and phenytoin itself increase glial cell count while decreasing seizure susceptibility. In fact inhibition of carbonic anhydrase and the production of bicarbonate was one of the first treatments for epilepsy and a recent discovery that under certain circumstances intracellular bicarbonate can depolarise neurons has created a fresh interest in it. 

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Depression is a common problem in patients with epilepsy, with approximately 30% having symptoms of major depression at some point.34 Patients with epilepsy should be routinely assessed for signs of depression, and treatment should be initiated if necessary. Certain AEDs may exacerbate depression, for example levetirac-etam and phenytoin. Other AEDs (e.g., lamotrigine, carba-mazepine, and oxcarbazepine) maybe useful in treating depression. Changes in mood can be precipitated by addition or discontinuation of an AED. If treatment for depression is necessary, caution should be exercised in choosing an agent that does not increase seizure frequency and does not interact with AEDs. 

CH, a 42-year-old man, comes into the emergency department after his sister discovered him seizing at home. He has a history of hypertension, diabetes, epilepsy, and rheumatoid arthritis. His medications include hydrochlorothiazide, gly-buride, phenytoin, and aspirin. He smokes one pack per day, drinks heavily on the weekends, and has a history of cocaine use. Upon further discussion with his sister, you discover that he stopped taking his phenytoin 4 days ago due to failure to obtain a refill from his doctor. He is currently unarousable since his last seizure 10 minutes ago. 

A 27-year-o d woman with epilepsy has been taking phenytoin to control her seizures. She is now pregnant, and her physician is considering changing her medication to prevent potential bleeding episodes in the in nt. What biochemical activity might be deficient in the infant if her medication is continued ... 

Seizure control is improved in many patients when the dose of phenytoin, and blood concentration, is increased, although the occurrence of toxic symptoms may limit this process. Baylis (B7) and co-workers examined the monthly fit frequency in 47 children with severe epilepsy in whom the only change in medication was in the dose of phenytoin, which in each case was sufficient to produce a rise in blood phenytoin... 

Regular monitoring of blood phenytoin levels provides a valuable contribution to the management of patients with epilepsy. The value of determining the blood level of other anticonvulsant drugs is unconfirmed. At present such work should be undertaken only as prospective research procedures combining clinical and biochemical methods of assessment and patient-management. 

L19. Lund, L., Effects of phenytoin in patients with epilepsy in relation to plasma concentrations. Symp. Biol. Eff. Drugs Relat. Plasma Concentration, London (1972). 

Epilepsy, monotherapy Indicated for conversion to monotherapy in adults with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED). 

Mamiya K, leiri I, Shimamoto J, Yukawa E, Imai J, Ni-nomiya H et al. The effects of genetic polymorphims of CYP2C9 and CYP2C19 on phenytoin metabohsm in Japanese adult patients with epilepsy studies in stereoselective hydroxylation and population pharmacokinetics. Epilepsia 1998 29(12) 1317-23. 

A reduced response to simvastatin was noted after phenytoin was added for epilepsy the cholesterol level increased from 9.4 mmol/1 to 15.99 mmol/1. The level decreased again when phenytoin was discontinued. Phenytoin induces the CYP3A4 isoform which is involved in simvastatin metabolism. Some other examples of this type of interaction are shown in Table 5. 

Carbamazepine is a tricyclic iminostilbene derivative and structurally related to the tricyclic antidepressants. It is used as a first-line agent for the management of generalized tonic-clonic epilepsy. It is also highly effective for partial seizures but has no efficacy in patients with absence seizures or atonic seizures. In epilepsy it supposedly has the same mechanism of action as phenytoin. An other well... 

At present, phenobarbital and primidone are considered as alternative drugs for the treatment of partial seizures and for generalized tonic-clonic epilepsy. They are judged to be less effective than carbamazepine and phenytoin. 

Convulsions associated with fever often occur in children 3 months to 5 years of age. Epilepsy later develops in approximately 2 to 3% of children who exhibit one or more such febrile seizures. Most authorities now recommend prophylactic treatment with anticonvulsant drugs only to patients at highest risk for development of epilepsy and for those who have multiple recurrent febrile seizures. Phenobarbital is the usual drug, although diazepam is also effective. Phenytoin and carba-mazepine are ineffective, and valproic acid may cause hepatotoxicity in very young patients. 

One of the authors recently encountered a 21-year-old male presenting to the emergency room in status epilepticus (prolonged, uncontrolled seizures). This patient had a seven-year history of epilepsy, well controlled with the drug phenytoin at a dose of 300 mg/day. Indeed, he had not experienced a seizure in more than a year. In the emergency... 

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