Phenytoin saturation

Phenytoin is metabolized in the fiver by parahydroxylation. The major isoforms responsible for the metabolism of phenytoin are CYP2C9 and CYP2C19. Phenytoin displays Michaelis-Menton pharmacokinetics, which means that the metabolism of phenytoin saturates at doses used clinically. The clinical importance of this is that a small change in dose can result in a very disproportionally large increase in serum concentrations leading to potential toxicity. The metabolism of phenytoin may saturate even at low serum... 

I With zero-order kinetics (see Fig. 2.1) a fixed amount of drag is absorbed or ehminated for each unit of time independent of drag concentrations, because of some other rate-limiting factor. Examples are the metabolism of alcohol and phenytoin (saturation of metabolic enzymes) and absorption of controlled-release drags and depot antipsychotics. 

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. 

It has been forty-five minutes since CH s arrival, and he has been given lorazepam 4 mg twice and loaded with 1500 mg of phenytoin. He received another 400 mg dose of phenytoin 15 minutes ago, but is still unarousable. His jerking movements have slowed down, but his temperature is now 39.9°C (103.8°F), and his blood pressure has dropped to 124/62 mm Hg. His oxygen saturation is 91% on 4 L oxygen via nasal cannula. Bilateral crackles are heard upon auscultation of his lungs. A CT scan of his head is obtained which shows no evidence of hemorrhage, tumor, or mass effect. 

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. 

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 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. 

In clinical practice we increase the dose of phenytoin cautiously when we think we are approaching the saturation point and the manufacturers have recognized this problem by providing not only a standard 100 mg capsule but also a 30 mg capsule so that we can approach the saturation point gently. 

B. Phenytoin is one of a handful of drugs that demonstrates zero-order (or saturation) kinetics. If a patient is showing signs of toxicity to phenytoin, it is important to measure blood levels, since the likelihood that phenytoin is demonstrating zero-order kinetics is very high. 

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. 

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. 

This is known as Michaelis-Menten or saturation kinetics. The processes that involve specific interactions between chemicals and proteins such as plasma protein binding, active excretion from the kidney or liver via transporters, and metabolism catalyzed by enzymes can be saturated. This is because there are a specific number of binding sites that can be fully occupied at higher doses. In some cases, cofactors are required, and their concentration may be limiting (see chap. 7 for salicylate, paracetamol toxicity). These all lead to an increase in the free concentration of the chemical. Some drugs, such as phenytoin, exhibit saturation of metabolism and therefore nonlinear kinetics at therapeutic doses. Alcohol metabolism is also saturated at even normal levels of intake. Under these circumstances, the rate of... 

Weigh accurately about 500 mg of phenytoin and transfer to a 125-ml conical flask. Dissolve in 50 ml of dimethylformamide, add 3 drops of a saturated solution of azoviolet in benzene, and titrate with 0.1N sodium methoxide to a blue end-point. Perform a blank determination, and make any necessary correction. Each ml of 0.1 N sodium methoxide is equivalent to 25.23 mg of C- 5H-]2N202-4°... 

When hepatic hydroxylation system becomes saturated, small increases in dose of phenytoin cause a large... 

Correct choice = D. Less than 5% of phenytoin is excreted unchanged in the urine it is metabolized by the hepatic hydroxylation system. Saturation of hepatic metabolizing enzymes at high doses of phenytoin leads to an increase in the half-life of the drug. 

Several drugs, including salicylate (in overdose), alcohol, and possibly some hydrazines and other drugs which are metabolised by acetylation, have saturable elimination kinetics, but the only significant clinical example is phenytoin. With this drug, capacity-limited elimination is complicated further by its low therapeutic index. A 50% increase in the dose of phenytoin can result in a 600% increase in the steady-state blood concentration, and thus expose the patient to potential toxicity. Capacity-limited pathways of elimination lead to plasma concentrations of drugs which can be described by a form of the Michaelis-Menten equation. In such cases, the plasma concentration at steady state is given by... 

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... 

FIGURE 2.8 Metabolism of phenytoin to form p-HPPH and p-HPPH glucuronide. The first step in this enzymatic reaction sequence is rate limiting and follows Michaelis-Menten kinetics, showing progressive saturation as plasma concentrations rise within the range that is required for anticonvulsant therapy to be effective. 

Some fractional transfer functions of compartmental models may actually be functions, (i.e., the model may actually be nonlinear). The most common example is when a transfer or loss is saturable. Here a Michaelis-Menten type of transfer function can be defined, as was shown in Chapter 2 for the elimination of phenytoin. In this case, loss from compartment 1 is concentration dependent and saturable, and one can write... 

Drugs that are exhibit saturable metabolism (zero-order kinetics), when small interference with kinetics may lead to large alteration of plasma concentration, e.g. phenytoin, theophylline... 

Saturation kinetics. Phenytoin is extensively hyd-roxylated in the liver and this process becomes saturated at about the doses needed for therapeutic effect. Thus phenytoin at low doses exhibits first-order kinetics but saturation or zero-order kinetics develop as the therapeutic plasma concentration range (10-20 mg/1) is approached, i.e. the dose increments of equal size produce disproportional rise in steady-state plasma concentration. 

Drugs that show saturable metabolism within the therapeutic range include phenytoin and salicylate. Because of the serious side effects encountered with... 

Small amounts of phenytoin are excreted unchanged in the urine (2-4%) and feces (5%). Most is eliminated renally as inactive conjugated metabolites. The elimination half-life at linear doses averages 20-30 h (12-20 h in children) but may be as long as 60 h, and as high as 200 h after overdose, due to saturation of hydroxylation pathways. The maximum rate of metabolism is estimated at 6mgkg day. ... 

Ethotoin. Chemically, 3-ethyl-5-phenylhy-dantoin, ethotoin (Ic) undergoes two biotransformation pathways leading to inactive products p-hydroxylation [pathway (1)] and deethylation [pathway (2)]. This product has relatively low potency compared to that of phenytoin. Like phenytoin, ethotoin displays saturable metabolism with respect to the formation of the two metabolites (18). 

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