Elimination zero-order

Saturation of the processes involved in the elimination of a foreign compound from the plasma, such as metabolism and excretion, may also have toxicological consequences. Thus, ethanol exhibits zero-order elimination kinetics at readily attainable plasma concentrations, because the metabolism is readily saturated. Therefore, once these plasma concentrations have been attained, the rate of elimination from the plasma is constant. Increasing the dosage of ethanol leads to accumulation and the well-known toxic effects. 

Zero-order elimination kinetics are described by the following equation 1... 

A plot of this equation is linear with a slope, -k, and a 37-intercept, C0. The elimination half-life may be calculated from this equation for a drug that exhibits zero-order elimination. When t = tm, then C = 1/2 C0, the initial or peak concentration. This results in the following equation ... 

When a drug is subject to first-order kinetics and by definition the rate of elimination is proportional to plasma concentration, then the t) is a constant characteristic, i.e. a constant value can be quoted throughout the plasma concentration range (accepting that there will be variation in t) between individuals), and this is convenient. If the rate of a process, e.g. removal from the plasma by metabolism, is not directly proportional to plasma concentration, then the t) cannot be constant. Consequently, when a drug exhibits zero-order elimination kinetics no single value for its t] can be quoted for, in fact, t) decreases as plasma concentration falls and the calculations on elimination and dosing that are so easy with first-order elimination (see below) become too complicated to be of much practical use. 

In contrast, zero-order elimination processes are occasionally encountered. These usually represent saturation by the drug of the elimination mechan-ism(s). These drug disappearance curves are straight and thus described simply by ... 

Drugs with zero-order elimination have no fixed half-life (tl/2 is a variable). Graphically, zero-order elimination follows a straight-line decay versus time. 

Drugs with zero-order elimination include ethanol (except low blood levels), phenytoin (high therapeutic doses), and salicylates (toxic doses). 

No specific antidote. Management includes gastric lavage (+/- activated charcoal) plus ventilatory support and symptomatic management of acid-base and electrolyte imbalance, and the hyperthermia and resulting dehydration. Increased urine volume and its alkalinization facilitate salicylate renal elimination. Note ASA follows zero-order elimination kinetics at toxic doses. 

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. 

Zero order—elimination rate is constant t,y2 is a variable. 

Draw graphs of the blood level versus time for drugs subject to zero-order elimination and for drugs subject to first-order elimination. 

Figure 1-2. Comparison of first-order and zero-order elimination. For drugs with first-order kinetics (left panel), rate of elimination is proportionate to concentration in the case of zero-order elimination (right panel), the rate is constant and independent of concentration.

Skill Keeper Zero-Order Elimination (see Chapter 1)... 

The following is the derivation of the equation for a zero-order elimination process ... 

For example, substitution of X (mass of drug in the body at time t) for Y in Eq. 1.8 yields the zero-order elimination rate equation ... 

Unit of the rate constant (Kb) for zero-order elimination of drug... 

Km the first-order rate constant for metabolism of dmg or [in context] the Michaelis constant in non-linear pharmacokinetics Ko the zero-order elimination rate constant Mother the first-order rate constant for elimination of dmg by a process other than metabolism or renal excretion Kio for a two-compartment dmg, the first-order rate constant for elimination of dmg from the central compartment Ki2 for a two-compartment drug, the first-order rate constant for transfer from the central to the peripheral compartment K21 for a two-compartment drug, the first-order rate constant for transfer from the peripheral to the central compartment MAT mean absorption time mean residence time in the gastrointestinal tract synonymous with MRTgit... 

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