USMLE PRACTICE QUESTION #129
TOPIC: Principles of Pharmacology
USMLE practice question #129 will test your knowledge about a foundational concept in pharmacology.
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A 52-year-old man with a history of epilepsy is brought to the emergency department due to altered mental status and ataxia. He has been taking phenytoin for seizure control but reports doubling his dose over the past week due to an increase in seizure frequency. Laboratory studies reveal a significantly elevated phenytoin level. Which of the following best explains the pharmacokinetic behavior of phenytoin that led to this outcome?
A) Constant percentage of the drug is eliminated per unit time, leading to predictable accumulation
B) Dose-dependent transition from first-order to zero-order kinetics at higher concentrations
C) Non-saturable metabolism of the drug leading to increased toxicity with overdose
D) Dependence on renal clearance, leading to reduced elimination in renal impairment
E) Competitive inhibition of hepatic enzymes causing impaired drug metabolism
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the pharmacokinetic behavior of phenytoin that led to this outcome?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Identify how phenytoin is metabolized; 2nd: Select the answer choice that reflects your knowledge of phenytoin’s metabolism
Step 3: Read the vignette carefully and ask yourself: “Based on my knowledge of phenytoin’s metabolic properties, the most likely cause of his side effects is X.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 52-year-old man with epilepsy presents with altered mental status and ataxia after doubling his dose of phenytoin, leading to significantly elevated phenytoin levels.
ANSWER CHOICES:
CHOICE A: Constant percentage of the drug is eliminated per unit time, leading to predictable accumulation
Explanation: This describes first-order kinetics, where a constant percentage of the drug is eliminated per unit time. Drugs following first-order kinetics have predictable accumulation and clearance. Phenytoin does not follow first-order kinetics at therapeutic or toxic concentrations.
CHOICE B: Dose-dependent transition from first-order to zero-order kinetics at higher concentrations
Explanation: Phenytoin metabolism transitions from first-order to zero-order kinetics as plasma concentrations increase and hepatic enzymes become saturated. Once saturation occurs, a constant amount of drug is eliminated per unit time (zero-order kinetics), regardless of plasma concentration. This leads to a disproportionate rise in drug levels with small dose increases, resulting in toxicity.
CHOICE C: Non-saturable metabolism of the drug leading to increased toxicity with overdose
Explanation: Non-saturable metabolism implies that the rate of drug elimination remains proportional to its concentration (first-order kinetics) even at high doses. Phenytoin metabolism is saturable due to enzyme capacity limits, leading to zero-order kinetics at higher concentrations. Non-saturable metabolism does not explain phenytoin toxicity.
CHOICE D: Dependence on renal clearance, leading to reduced elimination in renal impairment
Explanation: Drugs dependent on renal clearance are eliminated primarily through the kidneys, and their clearance decreases in renal impairment. Phenytoin is primarily metabolized by hepatic enzymes (CYP2C9 and CYP2C19), not by renal clearance. Renal impairment affects protein binding but does not significantly alter its metabolism.
CHOICE E: Competitive inhibition of hepatic enzymes causing impaired drug metabolism
Explanation: Competitive inhibition occurs when another substance competes for the same metabolic pathway, reducing drug clearance. Phenytoin toxicity here is due to enzyme saturation from excessive dosing rather than competitive inhibition by another substance.
FINAL VERDICT…
CORRECT ANSWER: B) Dose-dependent transition from first-order to zero-order kinetics at higher concentrations
Phenytoin is metabolized by the liver via the cytochrome P450 system, and its elimination follows dose-dependent pharmacokinetics. At low plasma concentrations, phenytoin metabolism follows first-order kinetics, where the rate of elimination is proportional to the drug concentration. However, as plasma concentrations increase, the metabolizing enzymes (primarily CYP2C9 and CYP2C19) become saturated, and phenytoin elimination switches to zero-order kinetics, where a constant amount of drug is eliminated per unit time regardless of concentration. This transition results in a disproportionate increase in plasma drug levels with small dose increases, leading to toxicity.
KEY CONCEPTS:
Pharmacokinetics of Phenytoin:
At low plasma concentrations (<10 mg/L), phenytoin follows first-order kinetics.
At higher plasma concentrations (>10–15 mg/L), hepatic enzymes become saturated, and elimination shifts to zero-order kinetics (capacity-limited metabolism).
Small increases in dose can result in large increases in plasma levels once saturation occurs.
Mechanism of Toxicity:
Zero-order kinetics leads to disproportionate accumulation of phenytoin when doses exceed metabolic capacity.
Toxicity manifests as central nervous system symptoms such as ataxia, altered mental status, nystagmus, and seizures.
Clinical Implications:
Phenytoin has a narrow therapeutic index (10–20 mg/L), requiring careful dosing and therapeutic drug monitoring.
Toxicity risk increases with dose adjustments >10%, especially near saturation levels.
Management includes discontinuing or reducing phenytoin dosage and monitoring serum levels.
Other Examples of Drugs with Saturable Kinetics:
Aspirin
Ethanol
Theophylline
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