USMLE Step 1

Sample

1. A drug is administered intravenously and its plasma concentration declines by 50% every 4 hours regardless of the starting concentration. Which of the following best describes the elimination kinetics of this drug?

A constant fractional decline (constant half-life independent of concentration) is the hallmark of first-order kinetics, in which a fixed percentage of drug is eliminated per unit time. Zero-order elimination removes a constant amount per unit time and yields a linear concentration-time decline. Most drugs at therapeutic concentrations follow first-order kinetics.

Sample

2. A drug has a volume of distribution of 42 L in a 70-kg adult. This value most strongly suggests that the drug is distributed into which of the following compartments?

Total body water in a 70-kg adult is approximately 42 L (about 0.6 L/kg), so a volume of distribution near this value suggests distribution throughout total body water. A Vd near plasma volume (about 3-5 L) suggests plasma confinement, while extracellular fluid is roughly 14 L. Very large Vd values indicate extensive tissue binding.

Sample

3. A patient receives a continuous intravenous infusion of a drug that follows first-order kinetics. Approximately how many half-lives are required to reach 90% of the steady-state concentration?

Reaching steady state during constant infusion follows the same exponential pattern as elimination; approximately 3.3 half-lives are needed to reach about 90% of steady state, and 4-5 half-lives reach about 94-97%. A loading dose can achieve target concentrations faster. This is independent of infusion rate.

Sample

4. A loading dose is calculated to rapidly achieve a target plasma concentration. Which pharmacokinetic parameter is used directly in the loading dose calculation?

The loading dose equals the target plasma concentration multiplied by the volume of distribution (divided by bioavailability for non-IV routes). Clearance determines the maintenance dose rather than the loading dose. Volume of distribution relates the amount of drug in the body to its plasma concentration.

Sample

5. A drug undergoes extensive metabolism during its first pass through the liver after oral administration, reducing the amount reaching systemic circulation. This phenomenon primarily reduces which pharmacokinetic parameter?

First-pass metabolism reduces the fraction of orally administered drug reaching systemic circulation, thereby lowering oral bioavailability. Drugs with high first-pass extraction often require higher oral doses than intravenous doses. Routes bypassing the portal circulation, such as sublingual or intravenous, avoid this effect.

Sample

6. A weak acid drug with a pKa of 4.4 is present in gastric fluid at pH 1.4. In which form will the drug predominantly exist, and how does this affect absorption?

For a weak acid, the nonionized (protonated) form predominates when the pH is below the pKa. At pH 1.4 with a pKa of 4.4, the acid is largely nonionized and lipid-soluble, favoring passive diffusion across membranes. Nonionized species cross membranes more readily than ionized species.

Sample

7. Alkalinization of the urine with sodium bicarbonate is used to enhance the elimination of an overdose of a weak acid such as aspirin. What is the mechanism of this therapeutic maneuver?

Raising urine pH shifts a weak acid toward its ionized form in the tubular lumen; ionized drug cannot readily diffuse back across tubular cells and is trapped and excreted. This ion-trapping principle enhances renal elimination of weak acids. Conversely, urine acidification would trap weak bases.

Sample

8. A drug binds extensively to plasma albumin. When a second drug that competes for the same albumin binding sites is added, which change in the first drug is expected initially?

Displacement from albumin binding sites increases the free (pharmacologically active) fraction of the first drug, potentially enhancing its effect and elimination. Only unbound drug can diffuse to tissues, act on receptors, and be filtered or metabolized. This interaction is most clinically significant for highly protein-bound drugs with narrow therapeutic indices.

Sample

9. A competitive antagonist is added to a system with a full agonist. Which change is observed in the agonist dose-response curve?

A competitive antagonist shifts the agonist dose-response curve to the right (decreasing apparent potency) but does not reduce maximal efficacy, because increasing agonist concentration can overcome the antagonism. This surmountable inhibition is the defining feature of competitive antagonism. Noncompetitive antagonists reduce Emax.

Sample

10. A noncompetitive (irreversible) antagonist is added to a system with a full agonist. What effect is seen on the agonist dose-response curve?

A noncompetitive or irreversible antagonist reduces the maximal response (Emax) that the agonist can produce because affected receptors are effectively removed and additional agonist cannot overcome the blockade. This is nonsurmountable antagonism. In contrast, competitive antagonism is surmountable and lowers apparent potency without reducing Emax.