Anticonvulsants phenytoin

If the therapeutic range of a drug is broad then many substitutions can probably be made. This occurs, for example, with the penicillins. However, if there is a narrow therapeutic range then bioavailability must be carefully considered. Examples of this situation are the use of digoxin (cardiac stimulant) and phenytoin (anticonvulsive). 

CAUTION. Phenytoin. (anticonvulsant) and phenobarbital (long-acting barbiturate) can induce hepatic microsomal enzymes and thereby retard the half-life significantly and, therefore, ultimately interfering with the prevalent efficacy of the drug . 

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. 

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trimethadione [127-48-0] C H NO (50), at one time the dmg of choice for the treatment of absence sei2ures, has been replaced by ethosuximide (41) and valproate (49).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. 

Phenytoin. Phenytoin sodium is sodium diphenylhydantoin [630-93-3] which is stmcturally related to the barbiturates. It was originally introduced as an anticonvulsant (18) (see Hypnotics, sedatives, and anticonvulsants) and later found to have antiarrhythmic properties (19), although not approved by the PDA for any arrhythmic indications. Phenytoin is effective in the treatment of ventricular arrhythmias associated with acute MI and with digitalis toxicity (20). It is not very effective in treatment of supraventricular arrhythmias (20). 

Na+ channels at clinically relevant concentrations (carbamazepine, phenytoin, lamotrigine). Most of these anticonvulsant dtugs display three distinct effects on Na+ channels ... 

Occasionally, status epilepticus (an emergency situation characterized by continual seizure activity with no interruptions) can occur. Diazepam (Valium) is most often the initial drug prescribed for this condition. However, because the effects of diazepam last less than 1 hour, a longer-lasting anticonvulsant, such as phenytoin or phenobarbital, also must be given to control the seizure activity. 

HYDANTOINS Fhenytoin is the most commonly prescribed anticonvulsant because of its effectiveness and relatively low toxicity. However, a genetically linked inability to metabolize phenytoin has been identified. For this reason, it is important to monitor serum concentrations of the drug on a regular basis to detect signs of toxicity Fhenytoin is administered orally and parenterally. If the drug is administered parenterally, the IV route is preferred over the intramuscular route because erratic absorption of phenytoin causes pain and muscle damage at the injection site... 

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. 

The interaction of ketamine with each of the three anticonvulsant compounds was also tested. Ketamine, 15 mg/kg, a dose showing no anti-PTZ effect and causing no overt behavioral changes, potentiated the effect of phenobarbital (20 mg/kg) in delaying the clonic and tonic convulsive responses and lethality (figure 3). Ketamine also potentiated the ability of phenytoin (20 mg/kg) to delay... 

I with seizures and require anticonvulsant therapy. Phenytoin is the most frequently used agent, with a loading dose of 15 mg/kg followed by 300 mg by mouth daily (titrated to therapeutic levels between 10 and 20 mcg/mL). Diazepam 5 mg intravenously may be used for rapid control of persistent seizures. Prophylactic anticonvulsants have been used frequently, but a recent meta-analysis did not support their use.23 Thus, because adverse effects and drug interactions are common, the routine use of prophylactic anticonvulsants is not recommended. 

In some cases, use of intravenous phenytoin or another anticonvulsant medication may be prudent. 

Ibeanu GC, Blaisdell ], Ferguson R], Ghanayem Bl, Brosen K, Benhamou S et al. A novel transversion in the intron 5 donor splice junction of CYP2C19 and a sequence polymorphism in exon 3 contribute to the poor metabolizer phenotype for the anticonvulsant drug S-me-phenytoin. J Pharmacol Exp Ther 1999 290[2] 635—640. 

Acute management of toxaphene-induced seizures in humans with anticonvulsants, especially diazepam, phenobarbital, and phenytoin (USPHS 1994). 

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

Phenobarbital, carbamazepine, and phenytoin potentially reduce efficacy of OCs, and many anticonvulsants are known teratogens. The use of condoms in conjunction with high-estrogen OCs or intrauterine devices (IUDs) may be considered for women taking these drugs. 

Diazepam is extremely lipophilic and quickly distributed into the brain, but redistributes rapidly into body fat, causing a very short duration of effect (0.25 to 0.5 hours). Therefore, a longer-acting anticonvulsant (e.g., phenytoin, phenobarbital) should be given immediately after the diazepam. The initial dose of diazepam can be repeated if the patient does not respond within 5 minutes. 

The Working Group on Status Epilepticus recommends that phenobar-bital be given after a BZ plus phenytoin has failed. Most practitioners agree that phenobarbital is the long-acting anticonvulsant of choice in patients with hypersensitivity to the hydantoins or in those with cardiac conduction abnormalities. 

An EEG is a key tool that allows practitioners to determine when abnormal electrical activity has been aborted and may assist in determining which anticonvulsant was effective. Vital signs must be monitored during the infusion. It may also be necessary to monitor the ECG in some patients. The infusion site must be assessed for any evidence of infiltration before and during administration of phenytoin. 

The anticonvulsant phenytoin, and to a lesser degree carbamazepine, can inhibit the synthesis of antibodies, and in some cases these drugs can result in lymphoproliferation [77-79]. These effects on the immune system could be viewed as a type of autoimmunity. The relationship between such effects and autoimmunity are still not clear, although the more recent observations that cytokines and anti-cytokines can cause autoimmunity support the existence of such a relationship. The previous edition of this book contained an extensive discussion of the possible relationship between immunosuppression and autoimmunity [80], Phenytoin and carbamazepine can also cause a lupus-like syndrome although the incidence is lower than with many other drugs. 

The anticonvulsant and antiepileptic phenytoin (211) has long been known to decompose in sunlight. It was photolysed in methanol with a high-pressure... 

A child weighing 28 lb is to receive 4 mg of phenytoin per kilogram of body weight daily as an anticonvulsant. How many milliliters of pediatric phenytoin suspension containing 30 mg per 5 mL should the child receive ... 

In 1968, fifty-one patients suffered from an epidemic of anticonvulsant intoxication in Brisbane. A thorough investigation revealed that the intoxication was caused by altering one of the excipients from calcium phosphate to lactose in the drug product Phenytoin Capsule without adequate pre-testing by the manufacturer. 

G. K. E. Scriba, D. M. Lambert, Bioavailability of Phenytoin and Anticonvulsant Activity after Oral Administration of Phenytoin-Ws-hydroxyisobutyrate to Rats , Pharm. Res. 1997, 14, 251-253. 

E. Shek, T. Murakami, C. Nath, E. Pop, N. S. Bodor, Improved Anticonvulsant Activity of Phenytoin by a Redox Brain Delivery System III Brain Uptake and Pharmacological Effects , J. Pharm. Sci. 1989, 78, 837-843. 

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