Phenytoin plasma concentrations

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. 

DIGITOXIN ANTIEPILEPTICS-BARBITURATES, CARBAMAZEPINE, PHENYTOIN Plasma concentrations of digitoxin may be 1 by up to half by barbiturates Possibly T hepatic metabolism Watch for poor response to digitoxin... 

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.)... 

Topiramate is routinely administered orally, absorbed rapidly, and metabolized minimally, but its disposition is affected by CyP 2C19. Serum concentrations of other anticonvulsant drugs are not significantly affected by the concurrent administration of topiramate, with the exception in individual patients on phenytoin who exhibit increased phenytoin plasma concentrations after addition of topiramate. Co-administration of phenytoin or carbamazepine decreases topiramate serum concentrations. Changes in cotherapy with phenytoin or carbamazepine (e.g., addition or withdrawal) for patients stabilized on topiramate therapy may require topiramate dose adjustment. As with other... 

Protein binding 90% protein bound to albumin, = 0.1 Unbound phenytoin plasma concentrations correlate with effect and toxicity. A decrease in protein binding occurs due to hypoalbuminemia or protein binding displacement interactions. 

Phenytoin s absorption is slow and variable yet almost complete absorption eventually occurs after po dosing. More than 90% of the dmg is bound to plasma protein. Peak plasma concentrations are achieved in 1.5—3 h. Therapeutic plasma concentrations are 10—20 lg/mL but using fixed po doses, steady-state levels are achieved in 7—10 days. Phenytoin is metabolized in the fiver to inactive metabolites. The plasma half-life is approximately 22 h. Phenytoin is excreted primarily in the urine as inactive metabolites and <5% as unchanged dmg. It is also eliminated in the feces and in breast milk (1,2). Prolonged po use of phenytoin may result in hirsutism, gingival hyperplasia, and hypersensitivity reactions evidenced by skin rashes, blood dyscrasias, etc... 

Phenytoin Increased plasma concentrations of phenytoin symptoms of phenytoin toxicity... 

The clearance of a drug is usually defined as the rate of elimination of a compound in the urine relative to its concentration in the blood. In practice, the clearance value of a drug is usually determined for the kidney, liver, blood or any other tissue, and the total systemic clearance calculated from the sum of the clearance values for the individual tissues. For most drugs clearance is constant over the therapeutic range, so that the rate of drug elimination is directly proportional to the blood concentration. Some drugs, for example phenytoin, exhibit saturable or dose-dependent elimination so that the clearance will not be directly related to the plasma concentration in all cases. 

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

Absorption/Distrlbutlon - Phenytoin is slowly absorbed from the small intestine. Rate and extent of absorption varies and is dependent on the product formulation. Bioavailability may differ among products of different manufacturers. Administration IM results in precipitation of phenytoin at the injection site, resulting in slow and erratic absorption, which may continue for up to 5 days or more. Plasma protein binding is 87% to 93% and is lower in uremic patients and neonates. Volume of distribution averages 0.6 L/kg. Phenytoin s therapeutic plasma concentration is 10 to 20 mcg/mL, although many patients achieve complete seizure control at lower serum concentrations. 

Metabolism/Excretion - Phenytoin is metabolized in the liver and excreted in the urine. The metabolism of phenytoin is capacity-limited and shows saturability. Elimination is exponential (first-order) at plasma concentrations less than 10 mcg/mL, and plasma half-life ranges from 6 to 24 hours. 

Drugs that might decrease plasma concentrations of lopinavir/ritonavir include rifampin, phenobarbital, carbamazepine, phenytoin, azole antifungals, delavirdine, rifabutin, St. John s wort, efavirenz, nevirapine, and corticosteroids. 

In experiments done many years ago on epileptic patients who were undergoing brain surgery, small brain biopsies were taken at operation. The concentration of anti-convulsant drug was measured in both the brain tissue and in the plasma from simultaneously-withdrawn venous blood. For the drugs phenobarbitone and phenytoin, a linear correlation was observed between plasma and brain concentrations. This suggested that plasma concentrations of anti-convulsants could reflect brain concentrations, and therefore, presumably concentrations at the receptor sites within the brain substance. 

The second problem is that of drugs, which can saturate their elimination mechanisms at plasma concentrations, which are within the therapeutic range. Perhaps the most important example is that of the anti-convulsant, phenytoin. 

If we apply this concept of samration to drug elimination we get a similar picture. The anticonvulsant phenytoin depends critically for its elimination on one enzyme reaction (to produce the p-hydroxy-phenyl metabolite) and this, like the turnstile, can exceed its capacity to metabolize the drug. Phenytoin is then eliminated at a constant amount (not a constant proportion) per unit time. If input then exceeds this elimination capacity (and volume of distribution does not change), plasma concentration will rise rapidly into the toxic range. 

How do you decide how much to give In this instance, firstly, as with all prescribing decisions, you need to be sure what you are aiming to do. Your aim is to raise the plasma concentration of phenytoin from zero to somewhere in the therapeutic plasma concentration range. This range has been well established, and, when you look it up, you find it is between 10-20 mg/1 - let s say you set your target midway between these points, at 15 mg/1. 

You will need to check the plasma concentration you achieve because the patient s phenytoin kinetics may differ from the average, but you will not be out by much and will have the confidence of having derived the dose in a logical and defensible way. 

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. 

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. 

Drugs that have been associated with elevations in quinidine concentrations include acetazolamide, the antacids magnesium hydroxide and calcium carbonate, and the H2-receptor antagonist cimetidine. Cimetidine inhibits the hepatic metabolism of quinidine. Phenytoin, rifampin, and barbiturates increase the hepatic metabolism of quinidine and reduce its plasma concentrations. 

In the presence of phenytoin, the metabolism of disopyramide is increased (reducing its effective concentration) and the accumulation of its metabolites is also increased, thereby increasing the probability of anticholinergic adverse effects. Rifampin also stimulates the hepatic metaboUsm of disopyramide, reducing its plasma concentration. 

The concurrent administration of lidocaine with cimeti-dine but not ranitidine may cause an increase (15%) in the plasma concentration of lidocaine. This effect is a manifestation of cimetidine reducing the clearance and volume of distribution of lidocaine. The myocardial depressant effect of lidocaine is enhanced by phenytoin administration. 

An upward adjustment in dose may be required when mexiletine is administered with phenytoin or rifampin, since these drugs stimulate the hepatic metabolism of mexiletine, reducing its plasma concentration. 

Carbamazepine, phenytoin, rifampicin. Plasma concentration of theophylline... 

After oral administration peak plasma concentration of phenytoin usually takes 2 to 4 hours with a second peak at 10 to 12 hours. When administered intramuscularly, pheny-toin is eventually absorbed completely, the drug first crystallises out at the injection site and then slowly redissolves in tissue fluids before entering into the circulation. As a result absorption of phenytoin by IM route is too slow to produce a reliable effect. In contrast a phosphate prodrug, fosphenytoin, is more soluble and is well absorbed after IM administration. 

Cardiac depressant effects may occur when verapamil or diltiazem is combined with a (p-adrenoceptor antagonoist or a cardiac glycoside. Nifedipine and verapamil are metabolised by cytochrome P-450 3A4. Inhibitors of this enzyme, e.g. HIV-protease inhibitors, cimetidine, fluoxetine, ketoconazole, erythromycin, will increase plasma levels and the dose should be carefully monitored. Conversely, enzyme inducers, e.g. carbamazepine, rifampicin, phenytoin, will decrease their plasma concentrations. 

Nonlinear relationship of phenytoin dosage and plasma concentrations. Five patients (identified by different symbols) received increasing dosages of phenytoin by mouth, and the steady-state serum concentration was measured at each dosage. The curves are not linear, since, as the dosage increases, the metabolism is saturable. Note also the marked variation among patients in the serum levels achieved at any dosage. 

Praziquantel is a synthetic isoquinoline-pyrazine derivative. It is rapidly absorbed, with a bioavailability of about 80% after oral administration. Peak serum concentrations are reached 1-3 hours after a therapeutic dose. Cerebrospinal fluid concentrations of praziquantel reach 14-20% of the drug s plasma concentration. About 80% of the drug is bound to plasma proteins. Most of the drug is rapidly metabolized to inactive mono- and polyhydroxylated products after a first pass in the liver. The half-life is 0.8-1.5 hours. Excretion is mainly via the kidneys (60-80%) and bile (15-35%). Plasma concentrations of praziquantel increase when the drug is taken with a high-carbohydrate meal or with cimetidine bioavailability is markedly reduced with some antiepileptics (phenytoin, carbamazepine) or with corticosteroids. 

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