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Chapter 1: Introduction

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A 3-year-old is brought to the emergency department having just ingested a large overdose of tolbutamide, an oral antidiabetic drug. Tolbutamide is a weak acid with a pKa of 5.3. It is capable of entering most tissues, including the brain. On physical examination, the heart rate is 100/min, blood pressure 90/50 mm Hg, and respiratory rate 20/min. Which of the following statements about this case of tolbutamide overdose is most correct?

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(A) Urinary excretion would be accelerated by administration of NH4Cl, an acidifying agent

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(B) Urinary excretion would be accelerated by giving NaHCO3, an alkalinizing agent

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(C) Less of the drug would be ionized at blood pH than at stomach pH

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(D) Absorption of the drug would be slower from the stomach than from the small intestine

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(E) Hemodialysis is the only effective therapy

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Questions that deal with acid-base (Henderson-Hasselbalch) manipulations are common on examinations. Since absorption involves permeation across lipid membranes, we can in theory treat an overdose by decreasing absorption from the gut and reabsorption from the tubular urine by making the drug less lipid-soluble. Ionization attracts water molecules and decreases lipid solubility. Tolbutamide is a weak acid, which means that it is less ionized when protonated, ie, at acid pH. Choice C suggests that the drug would be less ionized at pH 7.4 than at pH 2.0, which is clearly wrong for weak acids. Choice D says (in effect) that the more ionized form is absorbed faster, which is incorrect. A and B are opposites because NH4Cl is an acidifying salt and sodium bicarbonate an alkalinizing one. (From the point of view of test strategy, opposites in a list of answers always deserve careful attention.) E is a distracter. Because an alkaline environment favors ionization of a weak acid, we should give bicarbonate. The answer is B. Note that clinical management of overdose involves many other considerations in addition to trapping the drug in urine; manipulation of urine pH may be contraindicated for other reasons.

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Botulinum toxin is a large protein molecule. Its action on cholinergic transmission depends on an intracellular action within nerve endings. Which one of the following processes is best suited for permeation of very large protein molecules into cells?

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(A) Aqueous diffusion

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(B) Endocytosis

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(C) First-pass effect

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(D) Lipid diffusion

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(E) Special carrier transport

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Endocytosis is an important mechanism for transport of very large molecules ...

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