Phenytoin elimination

Unfortunately, the elimination of some drugs does not follow first-order kinetics. For example, the primary pathway of phenytoin elimination entails initial metabolism to form 5-(parahydroxyphenyl)-5-phenylhydantoin (p-HPPH), followed by glucuronide conjugation (Figure 2.8). The metabolism of this drug is not first order but follows Michaelis-Menten kinetics because the microsomal enzyme system that forms p-HPPH is partially saturated at phenytoin... 

Lau AH, Kronfol NO. Effect of continuous hemofiltration on phenytoin elimination. Ther Drug Monitor 1994 16 53-7. 

Mauro LS, Mauro VE, Brown DL, et al. (1987) Enhancement of phenytoin elimination by multiple-dose activated charcoal. Annals of Emergency Medicine 16 1132-1135. 

A) At high doses, phenytoin elimination follows first-order kinetics... 

D. Enhanced elimination. Repeat-dose activated charcoal (see p 57) may enhance phenytoin elimination, but is not necessary and may increase the risk of aspiration pneumonitis in drowsy patients. There is no role for diuresis, dialysis, or hemoperfusion. 

The reason for this reaction is not known. An animal study confirmed that 50 mg/kg, but not 20 mg/kg, of allopurinol reduced phenytoin elimination, but was unable to work out the mechanism. ... 

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... 

Zero-order kinetics describe the time course of disappearance of drugs from the plasma, which do not follow an exponential pattern, but are initially linear (i.e. the drug is removed at a constant rate that is independent of its concentration in the plasma). This rare time course of elimination is most often caused by saturation of the elimination processes (e.g. a metabolizing enzyme), which occurs even at low drug concentrations. Ethanol or phenytoin are examples of drugs, which are eliminated in a time-dependent manner which follows a zero-order kinetic. 

In nonacute situations, phenytoin may be initiated in adults at oral doses of 5 mg/kg/day and titrated upward. Subsequent dosage adjustments should be done cautiously because of nonlinearity in elimination. Most adult patients can be maintained on a single daily dose, but children often require more frequent administration. Only extended-release preparations should be used for single daily dosing. 

When a preparation of phenytoin was administered to a patient, the volume of distribution was found to be 70 liters, and the half-life of elimination was 1.5 hours. What is the total clearance of phenytoin ... 

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. 

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. 

The apparent clearance of lamotrigine is affected by the coadministration of AEDs. Lamotrigine is eliminated more rapidly in patients who have been taking hepatic enzyme inducing antiepileptic drugs (ElAEDs), including carbamazepine, phenytoin, phenobarbital, and primidone. 

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. 

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. 

Amiodarone increases the hypoprothrombinemic response to warfarin (an oral anticoagulant) by reducing its metabolism. Patients receiving digoxin may undergo an increase in serum digoxin concentrations when amiodarone is added to the treatment regimen. Amiodarone interferes with hepatic and renal elimination of flecainide, phenytoin, and quinidine. 

Induction of drug metabolism can occur in older persons. The rate of elimination of theophylline is increased by smoking and by phenytoin in both young and older persons alike. Thus, this adaptive response is preserved with age. Not all metabolizing isoenzymes are induced equally in the young and the old. For example, an-tipyrine elimination is increased after pretreatment with dichlorolphenazone in younger patients but not in older patients. 

Repeated dose of activated charcoal administered by oral route have been shown to enhance the non-renal elimination of carbamazepine, salicylates, phenobarbitone, phenytoin, digoxin, theophylline and meprobamate. In severe cases activated charcoal is to be administered via a nasogastric tube. 

Non-linear pharmacokinetics are much less common than linear kinetics. They occur when drug concentrations are sufficiently high to saturate the ability of the liver enzymes to metabolise the drug. This occurs with ethanol, therapeutic concentrations of phenytoin and salicylates, or when high doses of barbiturates are used for cerebral protection. The kinetics of conventional doses of thiopentone are linear. With non-linear pharmacokinetics, the amount of drug eliminated per unit time is constant rather than a constant fraction of the amount in the body, as is the case for the linear situation. Non-linear kinetics are also referred to as zero order or saturation kinetics. The rate of drug decline is governed by the Michaelis-Menton equation ... 

For drugs that exhibit capacity-limited elimination (eg, phenytoin, ethanol), clearance will vary depending on the concentration of drug that is achieved (Table 3-1). Capacity-limited elimination is also known as saturable, dose- or concentration-dependent, nonlinear, and Michaelis-Menten elimination. 

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