Answers to the Given Questions

• A constant amount (not a constant fraction/percentage) of drug is eliminated per unit time, regardless of plasma concentration.
• This happens when the elimination pathway (usually an enzyme system or active transport carrier) becomes saturated — it is working at its maximum capacity (Vmax), so the rate no longer depends on concentration ([C] >> Km).
• Because the process is saturable, elimination is capacity-limited / dose-dependent (nonlinear) kinetics:
  • Half-life is not constant — it lengthens as the dose/concentration increases.
  • A small increase in dose can cause a disproportionately large rise in plasma concentration, raising the risk of toxicity.
  • On a normal (non-log) concentration-vs-time plot, zero-order elimination gives a straight line reaching zero; it is only curved when plotted on a log scale (as in the given graph), because the log function compresses high values and stretches low ones as concentration approaches zero.

• Phenytoin (at usual/therapeutic-to-toxic doses, once CYP2C9/2C19 are saturated)
• Ethanol (alcohol)
• Aspirin/salicylates (at high or toxic doses)
• Heparin (at high doses)

• Zero-order kinetics defined as "a constant amount of drug is metabolized per unit time... rate of elimination is constant and does not depend on the drug concentration" - Lippincott Illustrated Reviews: Pharmacology
• "For some drugs, such as ethanol and phenytoin, metabolic capacity is saturated... drug metabolism becomes zero order" - Goodman & Gilman's The Pharmacological Basis of Therapeutics
• "At supratherapeutic concentrations, CYPs 2C9 and 2C19 become saturated and phenytoin elimination becomes zero order" - Goodman & Gilman's The Pharmacological Basis of Therapeutics

Additional Practice Questions (Same Exam Pattern)

Set 2 — Graph: Log Concentration vs Time is a straight, downward-sloping line

1. First-order kinetics (a straight line on a semi-log plot is diagnostic of first order).
2. Implies a constant fraction/percentage of drug (not a fixed amount) is eliminated per unit time; rate of elimination is directly proportional to plasma concentration (Rate = k × C). Half-life is constant and independent of dose/concentration; the elimination rate constant (k) is fixed; plasma concentration falls exponentially on a normal plot. Most drugs at therapeutic doses follow this pattern.
3. Examples: Digoxin, gentamicin, theophylline (at therapeutic doses) — in fact most drugs in clinical use.

Set 3 — Graph: Plasma Concentration (linear/arithmetic scale, not log) vs Time is a straight line declining to zero

1. Zero-order kinetics (on a normal arithmetic scale, zero order gives a straight line; first order would give a curved/exponential decline here instead).
2. Implies constant amount eliminated per unit time; saturable elimination pathway; dose-dependent half-life; risk of accumulation and toxicity with dose increases.
3. Examples: Ethanol, phenytoin (high dose), aspirin (toxic dose).

Set 4 — Concept question: Half-life

1. Plasma half-life is the time required for the plasma concentration of a drug (or the amount of drug in the body) to fall by 50%.
2. A constant half-life (same at all doses/concentrations) implies first-order elimination, since t½ = 0.693 × Vd / Clearance is independent of concentration only when clearance is constant.
3. Phenytoin — its half-life lengthens as dose increases because it shifts to zero-order kinetics once metabolizing enzymes are saturated.

Set 5 — Concept question: Renal drug excretion

1. Glomerular filtration, active tubular secretion, and tubular reabsorption (passive/active).
2. Increased active tubular secretion increases total renal clearance of the drug, since secretion adds to filtration in removing drug from plasma (Rate of excretion = Rate of filtration + Rate of secretion − Rate of reabsorption); it implies the drug is actively transported by carrier proteins (e.g., organic anion/cation transporters) and its excretion can be competitively inhibited by other drugs sharing the same transporter (e.g., probenecid blocking penicillin secretion).
3. Example: Penicillin (secreted by the organic anion transporter; probenecid prolongs its action by competing for secretion).

Set 6 — Concept question: Clearance

1. Clearance is the volume of plasma from which a drug is completely removed per unit time (i.e., the volume of blood/plasma cleared of drug per unit time by all eliminating organs combined).
2. Low clearance implies slow elimination and a long half-life, so the drug needs a longer dosing interval (or lower maintenance dose) to avoid accumulation and toxicity.
3. Example: Propranolol or lidocaine — drugs with high hepatic extraction ratio, whose clearance approaches hepatic blood flow (first-pass metabolism is extensive).

Answers

• A constant fraction (percentage) of the drug is eliminated per unit time, not a constant amount — the rate of elimination is directly proportional to the plasma drug concentration (Rate = k × Cp).
• As shown in the graph, when Cp is high the absolute amount eliminated per hour is large (5 units/h); as Cp falls, the absolute elimination rate falls too (2.5, then 1.25 units/h), even though the fraction eliminated per unit time stays the same.
• This produces an exponential decline in plasma concentration over time (the curved line seen in the graph on a normal/arithmetic scale).
• The elimination rate constant (k) and half-life (t½) remain constant and are independent of the dose or plasma concentration — each half-life, the concentration drops by 50%.
• Clearance is constant, and steady-state concentration is directly (linearly) proportional to the maintenance dose — this is why first-order kinetics is also called linear kinetics.
• Most drugs at their usual therapeutic doses are eliminated this way because the metabolizing enzymes/transporters are not saturated.

• "A first-order kinetic process is one in which a constant fraction of the drug is removed during a finite period of time, regardless of the drug amount or concentration" - Barash, Cullen, and Stoelting's Clinical Anesthesia
• "A constant fraction of drug is metabolized per unit of time (that is, with each half-life, the concentration decreases by 50%). First-order kinetics is also referred to as linear kinetics" - Lippincott Illustrated Reviews: Pharmacology
• "In usual doses (4-5 mg/kg), thiopental exhibits first-order kinetics (i.e., a constant fraction of drug is cleared from the body per unit time)" - Miller's Anesthesia

• First-order = curved/hyperbolic (exponential decay)
• Zero-order = straight line

• First-order = straight line (log converts the exponential decay into a line)
• Zero-order = curved (hyperbolic-looking) line