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PH1.6 | PH1.6 | Pharmacokinetics Across ADME — SDL Guide — SDL Guide (Part 3)
Zero-Order vs First-Order Kinetics and Steady State
Most drugs, at therapeutic concentrations, follow first-order (linear) kinetics: the rate of elimination is directly proportional to the drug's plasma concentration. If the concentration doubles, the amount eliminated per unit time also doubles — a constant fraction of drug is eliminated per unit time. The mathematical consequence is an exponential decay curve on a concentration-time plot, and a constant half-life independent of dose. First-order kinetics apply to most drugs because their metabolic enzymes are not saturated at therapeutic concentrations.
A minority of drugs, including ethanol and phenytoin at high doses, follow zero-order (saturation) kinetics: the rate of elimination is constant regardless of concentration, because the enzymes responsible are saturated at or below therapeutic concentrations. A fixed amount of drug is eliminated per unit time. This has clinically critical consequences:
- Half-life is not constant — it increases as plasma concentration increases (because the same fixed amount is eliminated, but the percentage eliminated falls as concentration rises).
- Dose-proportionality is lost — a small dose increment can produce a disproportionately large increase in plasma concentration, driving the patient from the therapeutic window to toxicity.
- No true steady state in the standard sense — plasma concentrations keep rising until a new equilibrium is reached, often at toxic levels.
Phenytoin's dose-concentration relationship is the canonical clinical teaching example: at low doses, phenytoin follows near-first-order kinetics; as the dose rises toward the therapeutic range, CYP2C9 becomes saturated and the drug shifts toward zero-order behaviour. A 10% dose increase at this point can move phenytoin from 15 mg/L (therapeutic) to >25 mg/L (toxic — nystagmus, ataxia, cognitive impairment). This is why phenytoin dose adjustments are made in small increments and guided by plasma level monitoring.
Ethanol is the textbook zero-order drug: in adults, ethanol is eliminated at ~10 mL of pure ethanol per hour regardless of blood alcohol level (until concentrations fall below the saturation threshold). This is why drinking three standard drinks and then waiting 'two hours' is not a reliable sobriety strategy — the elimination rate is fixed, not proportional to how much was consumed.
| Parameter | First-order kinetics | Zero-order kinetics |
|---|---|---|
| What is constant | Fraction eliminated per unit time | Amount eliminated per unit time |
| Mathematical relationship | dC/dt = -k × C | dC/dt = -k (constant) |
| Half-life | Constant (dose-independent) | Increases with concentration (dose-dependent) |
| Plasma concentration curve | Exponential decay | Linear decay |
| Risk of toxicity with dose increase | Predictable, proportional | Disproportionate — small dose increase → large [C] rise |
| Clinical examples | Most drugs at therapeutic doses | Ethanol; phenytoin at high therapeutic doses; high-dose aspirin |
CLINICAL PEARL
The steady-state trap: Clinicians sometimes increase a drug dose and check a plasma level the next day, finding it 'subtherapeutic.' They increase again. The danger: if the drug has a long half-life (e.g., amiodarone t½ 40–55 days, digoxin t½ ~36–48 hr), the plasma level at 24 hours after the first increased dose represents only a tiny fraction of the eventual steady state. By the time 4–5 half-lives elapse and steady state is truly reached, the accumulated dose from repeated escalations has driven the patient to toxicity. The rule: wait 4–5 half-lives after any dose change before measuring a steady-state level and adjusting further. For amiodarone, this means weeks — not days.
SELF-CHECK
A drug has a half-life of 8 hours and is given every 8 hours (one half-life per dosing interval). Approximately when will steady-state plasma concentrations be reached?
A. After 1 dose (the first dose establishes steady state)
B. After 4–5 doses (4–5 half-lives = 32–40 hours)
C. After 10 half-lives to be clinically safe
D. Steady state is never reached with q8h dosing; a loading dose is always needed
Reveal Answer
Answer: B. After 4–5 doses (4–5 half-lives = 32–40 hours)
Steady state is reached after 4–5 half-lives of repeated dosing, regardless of the dosing interval. For a drug with t½ = 8 hours dosed every 8 hours, this is 4 × 8 = 32 hours to 5 × 8 = 40 hours (approximately 4–5 doses). At steady state, the rate of drug input equals the rate of elimination, and average plasma concentration remains constant between doses. Dose size affects the height of Css but not the time to reach it — only t½ determines time to steady state.