Clinical Psychopharmacology · Paper A
Zero-order kinetics
Most drugs work like a wide-open drain: the fuller the tub, the faster it drains, so a fixed PERCENTAGE disappears every hour and the half-life never changes. A tiny handful of drugs — phenytoin, alcohol, and aspirin in overdose — work like a drain capped by a narrow grate: the same fixed AMOUNT leaves every hour no matter how full the tub is, so a small extra dose near that cap can push the level up far more than expected. The exam's real question is never 'define zero-order kinetics' — it is whether you can spot the moment a drug has quietly crossed from the wide-open drain into the capped one.
A man on phenytoin for epilepsy has done well for years. His doctor raises his daily dose by a single small step, 300mg to 350mg, less than a fifth more, because of one breakthrough seizure. Ten days later he is unsteady, seeing double, and his blood level of the drug has more than doubled — nowhere near the modest increase that was reasoned would follow. Most drugs do not do this: a similar step increase raises the level by more or less the identical proportion. Phenytoin is not broken, but something changes once the numbers reach a certain point, and building that change from scratch is what this page does.
Most drugs are cleared by first-order kinetics: the amount removed per unit time is proportional to how much of the drug is around, so doubling the dose roughly doubles the level, and the level halves in a fixed period called the half-life (the time taken for a level to fall by half) regardless of the starting dose. Zero-order kinetics describes something else: the body clears a fixed AMOUNT of drug per unit time no matter the level, because the enzyme (a protein that carries out one specific chemical job, here breaking the drug down) or transporter responsible is already saturated (working flat out, with no spare left). Push the dose up when a drug is already in that saturated zone, and the level does not rise proportionally — it rises far more.
Here is the trap: assuming any drug with a scary reputation, or any drug whose level has moved unexpectedly, must be zero-order. It does not. Lithium and digoxin are genuinely dangerous at only slightly elevated levels, but both are cleared by completely ordinary first-order kinetics — their danger comes from a narrow gap between a helpful level and a harmful one, not from any saturation. A first-order drug's level can also rise sharply for entirely different reasons: a new drug slowing down (inhibiting) the enzyme that clears it, an infection or dehydration reducing kidney function, or simply someone's own genetics giving them a naturally slower version of the clearing enzyme. None of that changes the ORDER of the kinetics — the drug is still first-order, just moving at a different, slower rate.
Imagine a bathtub draining through a wide-open plughole. The fuller the tub, the more water presses down, so the more water rushes out each minute — flow tracks pressure, which is level. That is first-order elimination: the rate of rises and falls with the concentration, and because of that proportional relationship a constant fraction, not a fixed amount, leaves every minute, giving a fixed whatever the starting level.
Now cap that same plughole with a narrow metal grate that can only pass one cupful per minute, no matter how much water presses on it from above. A full tub and a half-full tub both lose exactly one cup a minute — the level falls by a constant AMOUNT, not a constant fraction. That is zero-order elimination, and the grate is the saturated enzyme: it is already working as fast as it physically can, so extra drug arriving above it simply queues up rather than being cleared any faster. This is why a zero-order drug's apparent is not one fixed number — a fuller tub loses the same cupful proportionally faster than a nearly-empty one loses its own, so the half-life stretches out as the level climbs.
Phenytoin's single metabolising enzyme has a limited , and ordinary therapeutic doses sit right at the edge of that capacity, so phenytoin behaves like a first-order drug at low doses, where there is plenty of spare capacity, and slides into zero-order behaviour as the dose approaches and enters the therapeutic range. For example, moving from a low dose to a moderate one might raise the level in roughly the proportion you would expect. But once a patient is already in that saturated corner, the same size of dose increase — 300mg to 350mg, the example that opened this page — pushes the level up disproportionately, because the enzyme has no spare capacity left to absorb the extra load. This is precisely why phenytoin doses are raised in small steps, commonly 25 to 50mg at a time, with a level checked after each change, rather than by simple proportional scaling.
Ethanol shows an even more complete version of the same idea: alcohol dehydrogenase, the enzyme that clears it, is already saturated even at the modest concentrations reached after ordinary drinking, so blood alcohol falls by roughly the same fixed amount, often quoted as around 15 to 20 mg/dL, every hour, across essentially the whole range a drinker experiences. That straight-line fall, rather than the curve of a first-order drug, is what lets a single blood alcohol reading, plus the known elimination rate, be used to estimate how many hours have passed since drinking stopped.
Aspirin sits between the two: at ordinary painkilling or antiplatelet doses it is a perfectly ordinary first-order drug, and only in a large overdose does the hepatic conjugation (attaching a small chemical group to a drug so the body can excrete it) pathway that clears it become saturated. The clinical sting is that a salicylate level can keep climbing for several hours after a large overdose even once no more aspirin is being absorbed, which is why management leans on repeated levels rather than a single number.
Several situations produce a level that rises unexpectedly, and only one of them is genuinely zero-order kinetics.
| Looks like zero-order saturation | How to tell it apart |
|---|---|
| (a new drug speeding up over days to weeks) | Levels usually FALL, not rise, as the enzyme works harder, and the drug stays first-order throughout |
| (a new drug slowing clearance) | The level rises in proportion to how much the enzyme is inhibited, not because the drug itself has saturated |
| Reduced renal clearance (dehydration, an NSAID, worsening kidney function) | Explains a rise in a renally-cleared drug like lithium without any change to the drug's own kinetics |
| Genetic slow metabolism | Produces a higher-than-expected level from the very FIRST dose, not a disproportionate rise after a dose CHANGE |
For phenytoin, the practical rule is to raise the dose in small steps once a patient is near the therapeutic range, with a level checked after each change rather than assuming the next step will behave like the last one did at a lower dose. For a salicylate overdose, repeat levels rather than a single reading are used to judge whether the level is still climbing, since zero-order elimination in overdose means an early level can understate how high things will go. For ethanol, the practical use of its zero-order elimination is mostly toxicological, estimating an earlier blood alcohol concentration from a later measured one, rather than a treatment decision, since there is no dose to titrate for a drug someone has already drunk.
Whenever a vignette hands you a small dose change and a disproportionately large change in level, resist naming zero-order kinetics before checking two things: is the named drug actually one of the handful that saturate (phenytoin, ethanol, high-dose aspirin), and is the level described actually in the range where that drug is known to saturate? A rising level with NO dose change at all is almost never zero-order kinetics; it is someone else's changing underneath an ordinary first-order drug. Before you move on, see if you can explain to a friend why halving a phenytoin dose right at the saturated point does not simply halve the level.
Zero-order kinetics is what happens when a drug's system is already working flat out: a fixed amount, not a fixed fraction, leaves per unit time, so a small increase near that ceiling, as with phenytoin, ethanol, and high-dose aspirin, can push the level up far more than expected.