Pharmacogenetics: prodrug and enzyme inhibition: practice question

A Pharmacology question in the style of the NEET PG paper. Answer it first, then read why the right option is right and why each of the others is wrong.

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Pharmacology · Pharmacogenetics: prodrug and enzyme inhibition

Sample item

A 45-year-old woman on paroxetine for depression is prescribed codeine for post-operative pain and reports almost no analgesia, though she takes it as directed. What explains this?

AUrinary acidification by paroxetine accelerates codeine excretionBParoxetine competes with codeine at mu receptorsCParoxetine inhibits CYP2D6, so codeine is not converted to morphineDParoxetine induces CYP3A4, so codeine is cleared before it acts

Original practice item, not a recalled exam question. Nothing here is recorded.

The answer and the reasoning

C. Paroxetine inhibits CYP2D6, so codeine is not converted to morphine

Codeine is a prodrug whose analgesia depends largely on O-demethylation to morphine by CYP2D6. Strong CYP2D6 inhibitors such as paroxetine and fluoxetine, or genetic poor metabolism, give little analgesia. The opposite occurs in ultra-rapid metabolisers, who can develop morphine toxicity.

Option by option

A. Urinary acidification by paroxetine accelerates codeine excretion
Paroxetine does not acidify urine and codeine elimination is not pH dependent in this way.
B. Paroxetine competes with codeine at mu receptors
Paroxetine has no appreciable mu receptor affinity.
C. Paroxetine inhibits CYP2D6, so codeine is not converted to morphine (correct)
Correct. Without CYP2D6 activity the active metabolite is formed in only small amounts.
D. Paroxetine induces CYP3A4, so codeine is cleared before it acts
Paroxetine is an inhibitor rather than an inducer, and CYP3A4 yields inactive norcodeine.

Source note: Original NextPrep sample item — pending expert review. This item is original practice material awaiting independent expert review, so confirm important facts in a standard textbook.

Questions about this Pharmacology question

What is the answer to this Pharmacology question?

The best answer is C, Paroxetine inhibits CYP2D6, so codeine is not converted to morphine. Codeine is a prodrug whose analgesia depends largely on O-demethylation to morphine by CYP2D6.

Why is "Urinary acidification by paroxetine accelerates codeine excretion" not the answer?

Paroxetine does not acidify urine and codeine elimination is not pH dependent in this way.

Why is "Paroxetine competes with codeine at mu receptors" not the answer?

Paroxetine has no appreciable mu receptor affinity.

Why is "Paroxetine induces CYP3A4, so codeine is cleared before it acts" not the answer?

Paroxetine is an inhibitor rather than an inducer, and CYP3A4 yields inactive norcodeine.

What concept does this question test?

It tests Pharmacogenetics: prodrug and enzyme inhibition in Pharmacology. Strong CYP2D6 inhibitors such as paroxetine and fluoxetine, or genetic poor metabolism, give little analgesia. The opposite occurs in ultra-rapid metabolisers, who can develop morphine toxicity.

How hard is this question?

We tag it as a multi-step question: it asks you to combine more than one idea. The tag is our own editorial judgement, not an official difficulty rating, so read the reason for every option, not only the answer.

How should I study Pharmacogenetics: prodrug and enzyme inhibition?

Learn drugs as classes, then the exception in each class that an examiner would pick. Then use the flashcards and the other Pharmacology questions on this site to test what stuck.

Is this a real NEET PG question?

No. It is an original practice item (editorial status: sample, version 1). NextPrep does not publish recalled or leaked questions, and independent faculty review of this item has not been completed yet, so confirm important facts in a standard textbook.