Zero-order kinetics phenytoin

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. 

Phenytoin is metabolized in the liver mainly by CYP2C9, but CYP2C19 is also involved. Zero-order kinetics occurs within the usual therapeutic range, so any change in dose may produce disproportional changes in serum concentrations. 

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. 

Zero-order kinetics With a few drugs, such as aspirin (see p. 407), ethanol and phenytoin (see p. 146), the doses are very large, so the [C] is much greater than Km, and the velocity equation becomes ... 

Consider the difference in response to drugs between older and younger people. Treatment should reflect biological age (rather than chronological). Pharmacokinetics, pharmacodynamics, tolerability, adverse reactions, economy and patient choice will all influence therapy chosen. Most commonly, car-bamazepine or sodium valproate are chosen for older people as their effects in older people are well documented. Both show a favourable balance of safety, efficacy and economy. Phenytoin is less preferable because of drug interactions, adverse effects and potential for toxicity (zero order kinetics). 

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. 

Serum phenytoin concentrations in overdose have been studied in nine patients aged 20-66 years (67). The serum phenytoin concentrations were initially 136-230 pmol/1 and fell linearly (that is with zero-order kinetics) the elimination rate varied from 19 to 41 pmol/l/day. In those with the highest serum concentrations at presentation there was a delay before the fall in concentrations began. 

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. 

Answer E. Back to basic principles. Zero-order elimination means that plasma levels of a drug decrease linearly with time. This occurs with ASA at toxic doses, with phenytoin at high therapeutic doses, and with ethanol at all doses. Enzymes that metabolize ASA are saturated at high plasma levels —> constant rate of metabolism = zero-order kinetics. Remember that application of the Henderson-Hasselbalch principle can be important in drug overdose situations. In the case of aspirin, a weak acid, urinary alkalinization favors ionization of the drug —>4 tubular reabsorption —>T renal elimination. 

The excretion of most drugs is determined by first-order kinetics. However, ethanol—and, in higher doses, aspirin and phenytoin— follow zero-order kinetics, ie, their elimination rates are constant regardless of blood concentration. The answer is (L). 

Phenytoin 1.5-3 7-60 0.5-1 >90 MDAC, CHP S zero-order kinetics at high levels half-life is concentration dependent... 

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 ... 

The three important drugs that follow zero-order rather than first-order kinetics are ethanol, aspirin, and phenytoin. 

Phenytoin The oral bioavailability of phenytoin is variable because of differences in first-j>ass metabolism. Phenytoin metabolism is nonlinear elimination kinetics shift from first-order to zero-order at moderate to high dose levels. The drug binds extensively to plasma proteins (97-98%), and free (unbound) phenytoin levels in plasma are increased transiently by drugs that compete for binding (eg, sulfonamides, valproic acid). The metabolism of phen)Toin is enhanced in the presence of inducers of liver metabolism (eg, phenobarbital, rifampin) and inhibited by other drugs (eg, cimetidine, isoniazid). Fos-phenytoin is a water-soluble prodrug form of phen)Toin that is used parenterally. 

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