SN4 SHORT NOTE 5M ★ High-yield

Differentiate zero-order from first-order kinetics with examples and clinical significance.

Pharmacology · 2nd Professional — Para-Clinical

Definitions

Order	Definition	Equation
First-order kinetics	The rate of elimination is directly proportional to the plasma concentration; a constant fraction of the drug present is eliminated per unit time	Rate = k × C
Zero-order (saturation, Michaelis–Menten) kinetics	A constant amount of drug is eliminated per unit time, independent of the plasma concentration, because the eliminating enzymes or carriers are saturated	Rate = k (a constant)

Comparison

Feature	First-order	Zero-order
Enzyme saturation	Not saturated	Saturated
Amount eliminated per unit time	Varies with concentration	Constant
Fraction eliminated per unit time	Constant	Varies
Half-life	Constant and meaningful	Not constant — rises with dose; the term does not properly apply
Semilogarithmic plot	Straight line	Curved
Linear plot	Curved (exponential decay)	Straight line
Clearance	Constant	Falls as concentration rises
Doubling the dose	Doubles the steady-state concentration — predictable	Causes a much greater than twofold rise — may precipitate toxicity
Time to steady state	4 to 5 half-lives	Prolonged and unpredictable
Applies to	The great majority of drugs at therapeutic doses	Phenytoin, ethanol, aspirin in high dose, theophylline, tolbutamide, heparin, warfarin at high dose, dicoumarol

CLINICAL PEARL

Zero-order kinetics is dangerous because the margin between an effective and a toxic dose disappears. With phenytoin, an increase from 300 to 400 mg a day may raise the plasma level not by a third but three- or fourfold, tipping a controlled patient into nystagmus, ataxia and confusion. This is why phenytoin doses are increased in 25 to 50 mg increments once the level approaches the therapeutic range.

Drugs Showing a Change of Order

Some drugs follow first-order kinetics at therapeutic doses and switch to zero-order once the enzymes saturate — and it is exactly this transition that makes them hazardous
Aspirin — first-order at analgesic doses, zero-order at anti-inflammatory and toxic doses; hence the danger of salicylate poisoning
Phenytoin — saturation occurs within the therapeutic range itself
Ethanol is zero-order at almost all concentrations, eliminated at about 10–15 mL an hour whatever the amount consumed — which is why time is the only remedy for intoxication
Theophylline and tolbutamide at higher doses

Applied Aspects

Increase phenytoin in small increments and monitor levels — the single most important practical consequence of zero-order kinetics
In salicylate poisoning, elimination is slow and unpredictable, so levels must be repeated; urinary alkalinisation and, in severe cases, haemodialysis are used
There is no way to accelerate ethanol elimination — coffee, exercise and cold showers do nothing; only time works
Drug levels rise disproportionately in a saturated system, so a patient who has been stable for months may become toxic after a small dose increase or after starting an enzyme inhibitor
Steady state cannot be predicted from half-life in zero-order kinetics, so the usual rule of four to five half-lives does not apply

All questions in General Pharmacology: Pharmacokinetics

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