General pharmacology and pharmacokinetics: drug interaction torsades: 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 · General pharmacology and pharmacokinetics: drug interaction torsades

Sample item

A man taking an older non-sedating antihistamine for hay fever is started on ketoconazole for tinea corporis. A week later he has syncope, and the ECG shows a long QT interval with polymorphic ventricular tachycardia. Which mechanism best explains this?

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

The answer and the reasoning

A. Inhibition of CYP3A4 so the parent antihistamine accumulates and blocks cardiac potassium channels

Terfenadine and astemizole are cleared by CYP3A4 into a safe metabolite. An inhibitor such as ketoconazole raises the parent drug, which blocks the hERG potassium channel, prolongs the QT interval and causes torsades de pointes. These antihistamines were withdrawn for this reason, and the same class of interaction is seen with erythromycin and grapefruit juice.

Option by option

  • A. Inhibition of CYP3A4 so the parent antihistamine accumulates and blocks cardiac potassium channels (correct)

    Correct. Blocked metabolism lets the cardiotoxic parent drug build up and prolong repolarisation.

  • B. Displacement of the antihistamine from plasma proteins by the azole

    Protein displacement is a minor effect and cannot explain QT prolongation of this size.

  • C. Additive central H1 blockade that depresses brainstem cardiac centres

    Central H1 blockade causes sedation and has no direct effect on cardiac repolarisation.

  • D. Induction of CYP3A4 that lowers the level of the active metabolite

    Induction would lower, not raise, the parent drug level, and ketoconazole is an inhibitor.

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.

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Questions about this Pharmacology question

What is the answer to this Pharmacology question?

The best answer is A, Inhibition of CYP3A4 so the parent antihistamine accumulates and blocks cardiac potassium channels. Terfenadine and astemizole are cleared by CYP3A4 into a safe metabolite.

Why is "Displacement of the antihistamine from plasma proteins by the azole" not the answer?

Protein displacement is a minor effect and cannot explain QT prolongation of this size.

Why is "Additive central H1 blockade that depresses brainstem cardiac centres" not the answer?

Central H1 blockade causes sedation and has no direct effect on cardiac repolarisation.

Why is "Induction of CYP3A4 that lowers the level of the active metabolite" not the answer?

Induction would lower, not raise, the parent drug level, and ketoconazole is an inhibitor.

What concept does this question test?

It tests General pharmacology and pharmacokinetics: drug interaction torsades in Pharmacology. An inhibitor such as ketoconazole raises the parent drug, which blocks the hERG potassium channel, prolongs the QT interval and causes torsades de pointes. These antihistamines were withdrawn for this reason, and the same class of interaction is seen with erythromycin and grapefruit juice.

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 General pharmacology and pharmacokinetics: drug interaction torsades?

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.