zero-order kinetics

**Definition:** In zero-order (saturation) kinetics, the rate of elimination is constant and independent of drug concentration (rate = k; dC/dt = -k). Metabolic enzymes or transporters are saturated (operating at Vmax), so increasing the concentration cannot increase the elimination rate.

**Key features:** - Constant AMOUNT (e.g., mg/hr) eliminated per unit time. - Plasma concentration vs. time is LINEAR (on a standard linear plot). - Half-life is NOT constant: it decreases as concentration falls (t1/2 is proportional to concentration). Therefore the concept of a fixed half-life does not apply. - Clearance is not constant: it decreases as concentration increases. - Often described by Michaelis-Menten kinetics at concentrations well above Km.

**Contrast with first-order kinetics:** - First-order: constant FRACTION eliminated per unit time; rate is proportional to concentration; constant half-life; log concentration vs. time is linear; most drugs at therapeutic doses. - Zero-order: constant AMOUNT eliminated; rate independent of concentration; variable half-life; linear concentration vs. time.

**Clinical significance:** - Small dose increases can cause disproportionately large rises in plasma levels (nonlinear kinetics), raising the risk of toxicity. Steady state is not reached predictably and takes longer. - Drugs can shift from first-order to zero-order kinetics when elimination pathways saturate (overdose).

**High-yield examples (mnemonic "PEA" – think "zero-order PEA"):** - Phenytoin: saturable CYP2C9/2C19 metabolism at therapeutic range; small dose changes cause large level changes and toxicity (nystagmus, ataxia, diplopia). Requires careful level monitoring. - Ethanol: alcohol dehydrogenase saturated; about 1 drink/hr (roughly 10–15 mg/dL/hr) elimination in typical adults. - Aspirin: first-order at low (analgesic) doses, zero-order at high/toxic doses (salicylate toxicity). - Others sometimes cited: theophylline, heparin (at high doses, saturable binding to endothelium/macrophages), and Warfarin (listed in some mnemonics, e.g., "PEA-W"), though warfarin is in most texts first-order.

**Related concepts:** Michaelis-Menten kinetics (zero-order when [S] >> Km), nonlinear pharmacokinetics, therapeutic drug monitoring, loading vs. maintenance dose considerations, and dose-dependent half-life (e.g., aspirin half-life increases from ~3–5 hr at low doses to 15–30 hr in overdose).

**Exam pearl:** If a question describes a drug where a small dose increase causes a disproportionate rise in plasma level, or elimination at a constant mg/hr, think zero-order kinetics (phenytoin, ethanol, high-dose aspirin).