PharmacologyTier 1Medical Sciences concept

Zero-order (saturable) vs first-order pharmacokinetics (phenytoin); enzyme autoinduction (carbamazepine)

Core concept

First-order kinetics: constant fraction of drug eliminated per unit time -- rate proportional to concentration; most drugs at normal doses
Zero-order (saturable) kinetics: constant amount eliminated per unit time -- rate is fixed once metabolising enzymes are saturated, independent of concentration
Phenytoin is the classic example: first-order at low/therapeutic doses, switches to zero-order once hepatic metabolism saturates near the therapeutic range

Zero-order kinetics -> small dose increases cause disproportionately large rises in concentration -- half-life is not constant, becomes progressively longer as dose rises
- Trap: increasing phenytoin dose by a "small" increment near/above therapeutic range can produce toxic levels -- titrate in small increments once near target
Enzyme autoinduction: a drug induces its own metabolising enzyme (CYP) over time -> clearance increases with continued use -> falling levels despite unchanged dose
- Carbamazepine is the classic example -- autoinduces CYP3A4 over ~2-4 weeks, often requiring dose increase after initiation to maintain therapeutic levels

Phenytoin levels must be checked with attention to where on the dose-concentration curve the patient sits -- linear at low doses, steep/unpredictable near saturation
Carbamazepine: a level checked in the first 1-2 weeks may look adequate then fall as autoinduction proceeds -- recheck after ~1 month at a stable dose
Common trap: attributing a falling carbamazepine level to non-adherence when autoinduction is the cause

Zero-order kinetics also seen with ethanol (fixed amount metabolised per hour) and high-dose aspirin/salicylates
Autoinduction is the mirror image of enzyme inhibition interactions (e.g. valproate inhibiting lamotrigine metabolism) -- both alter clearance over time but in opposite directions
Relates to half-life/clearance calculation note: in zero-order kinetics, the standard t1/2 = 0.693 x Vd/CL formula does not apply (CL is not constant)

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