Phenytoin concentrations

Due to the Michaelis-Menten metabolism of phenytoin, alterations in its protein binding will result in increased severity of dose-related adverse effects. In patients with suspected changes in protein binding, it is useful to measure unbound phenytoin concentrations. 

Qi, X. 1., Huang, Y., Wang, Y. Q. et al. (2004). Association of plasma sodium phenytoin concentration with CYP2C19 gene polymorphism. Chinese Journal of New Drugs, 13( 10), 922-5. 

Absorption may be saturable. Absorption is affected by particle size, and the brand should not be changed without careful monitoring. Food may slow absorption. The intramuscular route is best avoided, as absorption is erratic. Fosphenytoin can safely be administered IV and intramuscularly. Equations are available to normalize the phenytoin concentration in patients with hypoalbuminemia or renal failure. 

Phenytoin is prone to many drug interactions (see Table 52-5). If proteinbinding interactions are suspected, free rather than total phenytoin concentrations are a better therapeutic guide. 

If the patient has been on phenytoin prior to admission and the phenytoin concentration is known, this should be considered in determining a loading dose. 

Continuous ECG, blood pressure, and respiratory status monitoring is recommended for all loading doses of fosphenytoin. Serum phenytoin concentrations should not be obtained for at least 2 hours after IV and 4 hours after intramuscular administration of fosphenytoin. 

Once seizures are terminated, dosages can be decreased by 1 mcg/kg/min every 2 hours. Successful discontinuation is enhanced by maintaining serum phenytoin concentrations above 20 mg/L and phenobarbital concentrations above 40 mg/L. 

Continuously monitor the electrocardiogram, blood pressure, and respiratory function and observe the patient throughout the period of maximal serum phenytoin concentrations, approximately 10 to 20 minutes after the end of the infusion. 

Renal/Hepatic function impairment- Because of an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, interpret total phenytoin plasma concentrations with caution. Unbound phenytoin concentrations may be more useful in these patients. After IV administration, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance. This has the potential to increase the frequency and severity of adverse events. 

Drug/Food interactions Several case reports and single-dose studies suggest that enteral nutritional therapy may decrease phenytoin concentrations however, this has not been substantiated. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Theoretical depiction of phenytoin concentrations achieved following various doses of the antiepileptic phenytoin. Shaded area indicates the therapeutic range of phenytoin concentrations below 10 (xg/mL, results in subtherapeutic effect above 20 (xg/mL, results in toxicity. Within the therapeutic range, a relatively small increase in dose results in a greater than proportional increase in concentration, suggesting nonlinear pharmacokinetics. 

Plasma phenytoin concentrations are increased in the presence of chloramphenicol, disulfiram, and isoniazid, since the latter drugs inhibit the hepatic metabolism of phenytoin. A reduction in phenytoin dose can alleviate the consequences of these drug-drug interactions. 

An 8-year-old child with grand mal seizures experiences nystagmus while on 200 mg/day of long-term phenytoin treatment, given in three divided doses. A steady-state phenytoin concentration of 5.0 mg/L is measured (therapeutic range, 8-20 mg/L). Beside normal laboratory results, it was noted that the child had profound hypoalbuminemia. Free (unbound) phenytoin concentration was 2.4 mg/L (therapeutic range 0.2-2 mg/L). 

In this example, the increased unbound phenytoin concentration resulted in a larger volume of distribution (more free drug distributed to the tissues), increased clearance (more free drug available for metabolism), but no change in the drug s half-life. The paradox in this case is that the increased clearance caused the total phenytoin blood concentration to go down, while the free concentration was elevated and led to clinical toxicity. Moreover, the unchanged half-life would not have clarified the cause of the subther-apeutic phenytoin level. 

Two patients stabilized on a phenytoin regimen suffered a loss of seizure control after taking shankhapushpi, an Ayurvedic antiepileptic medicine, three times a day. There was also a significant decrease in serum phenytoin concentration from 9.6 to 5.1mg/L. To investigate the possible mechanisms, multiple doses of shankhapushpi were administered to rats and resulted in decreased plasma phenytoin concentrations, whereas single-dose administration was reported to interfere with the antiplatelet effect of phenytoin, thereby implying both a pharmacokinetic and pharmacodynamic basis for the interaction (73). 

The elimination of phenytoin is dose-dependent. At very low blood levels, phenytoin metabolism follows first-order kinetics. However, as blood levels rise within the therapeutic range, the maximum capacity of the liver to metabolize phenytoin is approached. Further increases in dosage, though relatively small, may produce very large changes in phenytoin concentrations (Figure 24-5). In such cases, the half-life of the drug increases markedly, steady state is not achieved in routine fashion (since the plasma level continues to rise), and patients quickly develop symptoms of toxicity. 

Phenytoin Decreased phenytoin concentrations, loss Multiple coadministered doses (but not single... 

A 45-year-old woman taking phenytoin 300 mg/day had a plasma phenytoin concentration of 66 pmol/1 (29). When she became depressed fluvoxamine 50 mg/day was added. A month later her depressive symptoms had improved, but she was ataxic and the plasma phenytoin concentration was 196 pmol/1. The fluvoxamine was withdrawn and the phenytoin dose reduced to 150 mg/day. Her plasma phenytoin concentration fell to 99 pmol/1, with resolution of the ataxia. 

Chlorpromazine, and in some cases other phenothiazines, has been reported to increase plasma phenytoin concentrations (656-659), to reduce plasma phenytoin concentrations (657-661), or to have no effect (658). In one case co-administration of thioridazine caused phenytoin toxicity (662). 

A reduction in albumin binding would lead to a fall in the bound and hence the total concentrations of drug in the plasma, but the unbound concentration would usually be unchanged. For example, a total phenytoin concentration of 15 mg/L in a patient with an albumin concentration of 30 g/L would be equivalent to a total concentration of 21 mg/L if the albumin concentration had been normal. This can be seen by applying a commonly used equation for correcting phenytoin concentrations in hypoalbuminaemia [7], i.e. 

Adverse reactions include nystagmus, dizziness, and ataxia. Paresthesias and pruritus typically disappear within 5 to 10 minutes after the infusion. In adults, the rate of administration should be 100 to 150 mg PE/min. Pediatric patients should receive fosphenytoin at a rate of 1 to 3 mg PE/kg/min. Continuous ECG, blood pressure, and respiratory status monitoring is recommended for aU loading doses of fosphenytoin. Seram phenytoin concentrations should not be obtained for at least 2 hours after IV and 4 hours after intramuscular administration of fosphenytoin. 

FIGURE 2.9 The lines show the relationsliip betw een dose and steady-state plasma phenytoin concentrations predicted for tw o patients who became toxic after initial treatment with 300 mg/day. Measured steady-state plasma concentrations are shown by the circles and triangles. The shaded area shows the usual range of therapeutically effective phenytoin plasma concentrations. (Reproduced with permission from Atkinson AJ Jr. Med Clin North Am 1974 58 1037-49.)... 

A major problem arises in clinical practice when only total (protein bound + free) phenytoin concentrations are measured and used to guide therapy of patients with severely impaired renal function. The decreases in phenytoin binding that occur in these patients result in commensurate decreases in total plasma levels (Figure 5.2). Even though therapeutic and toxic pharmacologic effects are correlated with unbound rather than total phenytoin concentrations in plasma, the decrease in total concentrations can mislead physicians to increase phenytoin doses inappropriately. Fortunately, rapid ultrafiltration procedures are available that make it possible to measure free phenytoin concentrations in these patients on a routine basis. 

Valproate Phenytoin Total serum phenytoin concentration underestimates the unbound phenytoin concentration toxicity can occur in some patients Displacement of phenytoin from plasma proteins, sometimes associated with inhibition of phenytoin metabolism... 

Azapropazone Phenytoin Risk of phenytoin toxicity altered relation between total phenytoin concentration and effect Displacement from plasma proteins and inhibition of phenytoin metabolism... 

Ethanol Clobazam Diazepam Phenytoin Risk of toxicity of the object drugs chronic ethanol can reduce serum phenytoin concentrations Inhibition of metabolism induction of phenytoin metabolism by chronic ethanol... 

Inconclusive evidence suggests that salicylic acid can potentiate valproate toxicity (mechanism unclear). Sulfafurazole, sulfamethoxypyridazine, possibly other sulfonamides, and sulfinpyrazone displace phenytoin from plasma protein binding sites with different affinities total phenytoin concentrations may underestimate the concentration of unbound (pharmacologically active) drug. 

Similarly, drugs given for the treatment of associated disorders may inhibit the metabolism of anticonvulsants and precipitate signs of intoxication (Table 3). Examples include the increase in serum phenytoin concentrations by isoniazid and the increase in serum carbamazepine concentrations by verapamil, diltiazem, and most macrolide antibiotics (175-179). 

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