Introducción: la naturaleza de los fármacos y su desarrollo y regulación

Question 1

A 3-year-old is brought to the emergency department hav- ing just ingested a large overdose of chlorpropamide, an oral antidiabetic drug. Chlorpropamide is a weak acid with a pKa of 5.0. It is capable of entering most tissues. On physical examination, the heart rate is 110/min, blood pres- sure 90/50 mm Hg, and respiratory rate 30/min. Which of the following statements about this case of chlorpropamide overdose is most correct?
(A) Urinary excretion would be accelerated by administra- tion of NH4Cl, an acidifying agent
(B) Urinary excretion would be accelerated by giving NaHCO3, an alkalinizing agent
(C) Less of the drug would be ionized at blood pH than at stomach pH
(D) Absorption of the drug would be slower from the stom- ach than from the small intestine

Answer 1

Questions that deal with acid-base (Henderson-Hasselbalch) manipulations are common on examinations. Since absorp- tion 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. Chlorpropamide 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 ion- ized 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 oppo- sites because NH4Cl is an acidifying salt and sodium bicar- bonate an alkalinizing one. (From the point of view of test strategy, opposites in a list of answers always deserve careful attention.) Because an alkaline environment favors ioniza- tion 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.

Question 2

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?
(A) Aqueous diffusion
(B) Endocytosis
(C) First-pass effect
(D) Lipid diffusion
(E) Special carrier transport

Answer 2

Endocytosis is an important mechanism for transport of very large molecules across membranes. Aqueous diffusion is not involved in transport across the lipid barrier of cell membranes. Lipid diffusion and special carrier transport are common for smaller molecules. The first-pass effect has nothing to do with the mechanisms of permeation; rather, it denotes drug metabolism or excretion before absorption into the systemic circulation. The answer is B.

Question 3

A 12-year-old child has bacterial pharyngitis and is to receive an oral antibiotic. She complains of a sore throat and pain on swallowing. The tympanic membranes are slightly red- dened bilaterally, but she does not complain of earache. Blood pressure is 105/70 mm Hg, heart rate 100/min, temperature 37.8°C (100.1°F). Ampicillin is a weak organic acid with a pKa of 2.5. What percentage of a given dose will be in the lipid- soluble form in the duodenum at a pH of 4.5?
(A) About 1% (B) About 10% (C) About 50% (D) About 90% (E) About 99%

Answer 3

U.S. Medical Licensing Examination (USMLE)-type ques- tions often contain a lengthy clinical description in the stem. One can often determine the relevance of the clinical data by scanning the last sentence in the stem and the list of answers, see Appendix I. In this question, the emphasis is clearly on pharmacokinetic principles. Ampicillin is an acid, so it is more ionized at alkaline pH and less ionized at acidic pH. The Henderson-Hasselbalch equation predicts that the ratio changes from 50/50 at the pH equal to the pKa to 1/10 (protonated/unprotonated) at 1 pH unit more alkaline than the pKa and 1/100 at 2 pH units more alkaline. For acids, the protonated form is the nonionized, more lipid-soluble form. The answer is A.

Se debe de usar la formula de Henderson-Hasselbach

%= 1/1+10^(pH-pKa)