Katzung Questions

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PART I Basic Principles

B. Other Distribution Models A few drugs behave as if they are distributed to only 1 compartment (eg, if they are restricted to the vascular compartment). Others have more complex distributions that require more than 2 compartments for construction of accurate mathematical models.

QUESTIONS 1. A 3-year-old is brought to the emergency department having just ingested a large overdose of diphenhydramine, an antihistaminic drug. Diphenhydramine is a weak base with a p.K. of 8.8. 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 diphenhydramine overdose is most correct? (A) Urinary excretion would be accelerated by administration of NH 4Cl, an acidifying agent (B) Urinary excretion would be accele rated by giving NaHC0 3, an alkalinizing agent (C) More of the drug would be ionized at blood pH than at stomach pH (D) Absorption of the drug would be faster from the stomach than from the small intestine (E) H emodialys is is the only effective therapy 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) Aqueous hydrolysis (C) Endocytosis (D) Lipid diffusion (E) Special carrier transport 3. Which of the following terms describes the process by which the amount of active drug in the body is reduced after administration but before entering the systemic circulation? (A) Excretion (B) First-order elimination (C) First-pass effect (D) Metabolism (E) Pharmacokinetics 4. Ampicillin is a weak organic acid with a p.K. 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%

5. Which of the following statements best describes the process by which the plasma concentration of a drug declines with first-order kinetics? (A) There is only 1 metabolic path for drug elimination (B) The half-life is the same regardless of the plasma concentration (C) The drug is largely metabolized in the liver after oral administration and has low bioavailability (D) The rate of elimination is proportional to the rate of administration at all times (E) The drug is distributed to only I compartment outside the vascular system 6. Which of the following statements is true regarding the termination of drug action? (A) Drugs must be excreted from the body to terminate their action (B) Metabolism of drugs always increases their water solubility (C) Metabolism of drugs _always abolishes their pharmacologic activity (D) Hepatic metabolism and renal excretion are the 2 most important mechanisms involved (E) Distribution of a drug out of the bloodstream terminates the drug's effects 7. Which statement about the distribution of drugs to specific tissues is most correct? (A) Distribution to an organ is independent of blood flow (B) Distribution is independent of the solubility of the drug in that tissue (C) Distribution depends on the unbound drug concentration gradient between blood and the tissue (D) Distribution is increased for drugs that are strongly bound to plasma proteins (E) Distribution has no effect on the half-life of the drug 8. Timolol is being considered for the treatment of glaucoma in a 58-year-old patient. Except for previously reported elevated intraocular pressure, the patient's history is unremarkable. Vital signs include blood pressure 140/88 mm Hg; heart rate 76/bpm; respiratory rate 12/min. Body temperature (sublingual) is 37.5°C. On examination, breath sounds are clear, no murmurs are heard, and there is no abdominal tenderness. Timolol is a weak base of p.K. 9.2. Which of the following statements is most correct? (A) If given by the intravenous route, the concentration of timolol in the aqueous humor (pH 7.8) will be lower than the concentration in the duodenum (pH 5.5) (B) When administered as eyedrops, the rate of absorption into the eye will be slower if the drops are alkaline (pH 8.0) than if they are acidic (pH 5.0) (C) Excretion in the urine will be slower if urine pH is alkaline (pH 8.0) than if the urine pH is acidic (pH 5.8) (D) The proportion of timolol in the protonated form will be approximately 10% at pH 8.2 (E) The proportion of timolol in the more lipid-soluble form will be approximately 10% at pH 10.2

CHAPTER 1 In troduction

9. T he pharmacokineri c principl e rhar is characteristic of the eliminatio n o f ethano l and hi gh d oses of phenyroin and as pirin is called (A) Disrribu rion (B) Excretion (C) Fi rst-pass effect (D) First-order elimination (E) Zero-order elimination 10. T he set of p ropenies that characterize the effects of a drug on rhe body is called (A) Disrribu rion (B) Permeation (C) Pharm acodynamics (D ) Pharm aco kinetics (E) Proro nario n 11. A new drug was administered inrrave nously, and irs plasma levels were measured for several hours. A graph was prepared as shown below, with the plasma levels plon ed on a logarithmic ordinate and rime on a linear abscissa. Ir was concluded that the drug has first-order kinetics. From rhis graph, what is the best estimate of the half-life?

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(A) 0.5 h (B) 1 h (C) 3 h

(D) 4 h (E) 7 h

ANSWERS 1. Questions that deal with acid-base (H enderson-Hasselbalch) manipulations are common on examinations. Since absorption involves permeation across lipid membranes, we can (a t least in theory) treat an overdose by decreasing absorption fro m the gut and reabsorption from the tubular urine by making the drug less lipid-soluble. Ionization attracts water molecules and decreases lipid solubi lity. Diphenhydramine is a weak base, which means that it is mo re ionized (protonared) at acid pH than at basic pH. C hoice C suggests that the drug wo uld be mo re ionized at pH 7.4 than at pH 2.0, which is

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clearly wrong. C hoice D says (in effect) that the more ionized fo rm is absorbed fas ter, which is inco rrect. A and B are opposites because N H 4Cl is an acidifying salt and sodium bicarbonate an alkali nizing one. From the poinr of view of res t strategy, opposites always deserve careful attenrion and, in this case, encourage us to excl ude E, a distracter. Because an acid environmenr favors ionizatio n of a weak base, we should give NH 4C l. T he answer is A. Similar questions may be designed aro und other comparrments, eg, prostatic and vaginal fluids, and breast milk (more acidic than blood) and cerebrospinal flui d and aqueous humor (mo re alkali ne) . Note that clinical managemenr of overdose involves many other considerations in addition to trapping the drug in urine; manipulation of urine pH may be contraindicated for other reasons. 2. Endocytosis is an imporranr mechanism fo r transporr of ve ry large molecules across membranes. Aqueo us diffusion is rarely used for transporr across cell mem branes. Li pid diffus ion and special carrier transporr are common for smaller molecules. H yd rolysis has nothing to do with the mechanisms of permeation; rather, hydrolysis is one mechanism of drug metabolism. T he answer is C. 3. "Firs t-pass effect" is the term given to elimination of a drug before it enters the systemic circulatio n (ie, on irs fi rs t pass th ro ugh the porral circulation and liver) . T he fi rst-pass effect is usually, but nor always, due to metabolism in the porral blood or the liver. T he answer is C. 4. Ampicillin is an acid, so it is more ionized at alkaline pH and less ionized at acidic pH. T he Henderson-Hasselbalch equatio n p redicts that the ratio changes fro m 50/50 at the pH equal to the pi