Phenytoin for

A patient is prescribed phenytoin for a recurrent convulsive disorder. The nurse informs the patient that the most common adverse reactions are. ... 

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. 

If the patient requires phenytoin for his seizures, how should this medication be administered ... 

General supportive care should be provided. Aggressive gut decontamination should be carried out using repeated doses of activated charcoal and whole bowel irrigation. Propranolol or other blockers (eg, esmolol) are useful antidotes for B-mediated hypotension and tachycardia. Phenobarbital is preferred over phenytoin for convulsions most anticonvulsants are ineffective. Hemodialysis is indicated for serum concentrations greater than 100 mg/L and for intractable seizures in patients with lower levels. 

Drugs may compete for binding sites on the plasma or tissue protein, or may displace previously bound drugs. For example, phenylbutazone may compete with phenytoin for binding to albumin. 

The therapeutic plasma level of phenytoin for most patients is between 10 and 20 g/mL. A loading dose can be given either orally or intravenously the latter, using fosphenytoin, is the method of choice for convulsive status epilepticus (discussed later). When oral therapy is started, it is common... 

Once the emergency is over, exploration of the reason for the episode and reinstitution of normal therapy are essential. Magnesium sulphate may be better than phenytoin for the treatment of the seizure disorder of eclampsia (see also p. 493). ... 

Fosphenytoin, a prodrug of phenytoin, is soluble in water, easier and safer to administer its conver-tion in the blood to phenytoin is rapid and it may be used as an alternative to phenytoin for status epilepticus (Table 20.1). 

The mean values of and within the population are 4mg/L and 7mg/kg/day, respectively. The variation within the population is also depicted in Fig. 6, where 50% of the population has K a and Em values within the innermost circle, 75% within the second circle, and so on. With the help of this graph, the suitable dosing rate of phenytoin for an individual patient can be determined. With two plasma concentrations at two different dosing rates of phenytoin in one patient, his/her individual and values can be obtained to further optimize the dosing schedule. 

Many epileptics receiving anticonvulsants excrete increased amounts of copper and zinc in their urine. Increased serum ceruloplasmin also increases the total serum copper concentration. In 20% to 30% of epileptic children receiving anticonvulsant therapy, erythrocyte aspartate aminotransferase activity is low, indicating a lowered pyridoxal (vitamin Bg) status. In as many as 50% of the adults receiving phenytoin for some time, there will be folate deficiency, manifested by reduced erythrocyte and serum folate concentrations. The mechanism for the deficiency has not yet been established conclusively. In about 10% of adults taking phenytoin, the serum vitamin is low. 

Valproic add modulates the action of various other common antiepileptic drugs. It inhibits the nonrenal clearance of phenobarbital, resulting in elevated phenobarbital levels. It competes -with phenytoin for protein-binding sites. The free phenytoin concentration remains approximately the same, but the total phenytoin in the plasma decreases. Because the free phenytoin concentration remains unchanged, the pharmacological effect is retained. Other common antiepileptic drugs that induce hepatic oxidative enzymes result in increased valproic acid clearance this increased clearance rate requires a higher dose to maintain effective therapeutic levels. 

In 1959, radiographic changes characteristic of diffuse pulmonary fibrosis were reported in 87% of 31 patients who had taken phenytoin for 2 years or more. Since then, studies have been conflicting. If phenytoin does produce chronic fibrosis, it would appear to be a relatively rare event. 

Use of phenytoin for the prophylaxis of posttraumatic seizures usually should be discontinued after 7 days if no seizures are observed. 

Temkin NR, Dikmen SS, Wilensky AJ, etal. A randomized, double-blind study of phenytoin for the prevention of post-traumatic seizures. N Engl J Med 1990 323 497-502. 

Haltiner AM, Newell DW, Temkin NR, et al. Side effects and mortality associated with use of phenytoin for early posttraumatic seizure prophylaxis. J Neurosurg 1999 91 588-592. 

Phenytoin is extensively (-90%) bound to serum proteins, mainly albumin. Small variations in the bound fraction dramatically affect the absolute amount of free (active) drug increased proportions of free drug are evident in the neonate, in patients with hypoalbuminemia, and in uremic patients. Some agents e.g., valproic acid) can compete with phenytoin for binding sites on plasma proteins when combined with valproate-mediated inhibition of phenytoin metabolism, marked increases in free phenytoin can result. 

Two phases can be distinguished in the pathways of biotransformation. Phase I involves addition of functionally reactive groups by oxidation, reduction or hydrolysis. Phase II consists of conjugation of reactive groups, present either in the parent molecule or after phase I transformation. Phenytoin, for example, is first hydroxylated by a phase I reaction and subsequently conjugated with glucuronic acid. The various phase I and phase II reactions are summarized in Tables 30.3 and 30.5. 

Phenytoin may be administered either orally or intravenously and is absorbed slowly after oral administration, with peak plasma levels achieved after 3 to 12 hours. It is extensively plasma protein bound ( 90%), and the elimination half-life is between 15 and 30 hours. These large ranges reflect the considerable variability observed from patient to patient. Parenteral administration of phenytoin is usually limited to the intravenous route. Phenytoin for injection is dissolved in a highly alkaline vehicle (pFI 12). This alkaline vehicle is required because phenytoin is weakly acidic and has very poor solubility in its un-ionized form. Reportedly, however, its phosphate ester fosphenytoin has water solubility advantages over phenytoin for injection. Intramuscular phenytoin generally is avoided, because it results in tissue necrosis at the site of injection and erratic absorption because of high alkalinity. In addition, intermittent intravenous infusion is required to reduce the incidence of severe phlebitis. 

I. Pharmacology. The neuronal membrane-stabilizing actions of phenytoin make this a popular drug for sustained control of aoute and ohronic seizure disorders and a useful drug for certain cardiac arrhythmias. Because of the relatively slow onset of anticonvulsant action, phenytoin is usually administered after diazepam. At serum concentrations considered therapeutic for seizure control, phenytoin acts similarly to lidocaine to reduce ventricular premature depolarization and suppress ventricular tachycardia. After intravenous administration, peak therapeutic effects are attained within 1 hour. The therapeutic serum concentration for seizure control is 10-20 mg/L. Elimination is nonlinear, with an apparent half-life averaging 22 hours. Fosphenytoin, a prodrug of phenytoin for intravenous use, is converted to phenytoin after injection, with a conversion half-life of 8-32 minutes. 

Fosphenytoin. Dosage is based on the phenytoin equivalent 750 mg of fosphenytoin is equivalent to 500 mg of phenytoin. (For example, a loading dose of 1 g phenytoin would require a dose of 1.5 g fosphenytoin.) Dilute twofold to tenfold in 5% dextrose or normal saline and administer no faster than 225 mg/min. 

It should be noted that, in practice, some of the assumptions may not be valid for some drugs (e.g. salicylate, ethanol, phenytoin), for which capacity- limited kinetics (i.e. non-linear kinetics) may apply. 

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