The quizzes about Renal System and Diuretic Pharmacology

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Renal System and Diuretic Pharmacology

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Question 1

After a few weeks on a drug that was prescribed by another physician, a patient reports fine tremors of his fingers, headache and fatigue, and transient GI More worrisome to him i s that he i s constantly thirsty and urinates copiously and frequently throughout the day and night. A 24-hour urine collection produces nearly 5 L of hypotonic urine. Blood tests show that levels of the causative drug are within i ts therapeutic range. Nonetheless, the cl inical picture leads you to hypothesize that the offending drug i s causing renal responses quite s imilar to a syndrome characterized by reduced production or renal response to ADH. Which drug most l ikely caused or contributed to these s igns and symptoms?

A	Diazepam
B	Fluoxetine
C	Haloperidol
D	Li thium
E	Phenytoin

Question 1 Explanation: 

Lithium treatment (for bipolar illness) frequently causes polyuria and (as a consequence of excessive renal fluid loss) polydipsia (increased thirst leading to increased fluid intake). The collecting ducts of the kidney lose the capacity to conserve water via the expected actions antidiuretic hormone (arginine vasopressin). This amounts to drug-induced nephrogenic diabetes insipidus, dilutional hyponatremia, and SIADH: a syndrome of inappropriate ADH secretion that tries, unsuccessfully, to limit or reduce free water loss from the kidneys. Such findings are not associated with diazepam (a; prototype benzodiazepine anxiolytic); fluoxetine (b; the prototypic SSRI antidepressant); haloperidol (c; butyrophenone antipsychotic); or phenytoin (e; hydantoin anticonvulsant).

Question 2

A patient taking an oral diuretic for about 6 months presents with elevated fasting and postprandial blood glucose You check the patient’s HbA₁c and find i t i s elevated compared with normal baseline values obtained 6 months ago. You suspect the glycemic problems are diuretic-induced. What was the most l ikely cause?

A	Acetazolamide
B	Amiloride
C	Chlorothiazide
D	Spironolactone
E	Triamterene

Question 2 Explanation: 

Thiazides and thiazide-like diuretics (eg, chlorthalidone, metolazone) tend to elevate blood glucose levels, impair glucose tolerance, and cause frank hyperglycemia. Several mechanisms have been proposed to explain the effect: decreased release of insulin from the pancreas; increased glycogenolysis and decreased glycogen synthesis; a reduction in the conversion of proinsulin to insulin; and reduced responsiveness of adipocyte and skeletal myocyte insulin receptor response to the hormone (insulin resistance—the most likely mechanism). (You might recall that diazoxide [mainly used as a parenteral drug for prompt lowering of blood pressure] can be used in its oral dosage form to raise blood glucose levels in some hypoglycemic states. It is, chemically, a thiazide, but is not used as a diuretic.) Elevations of blood glucose levels, or other manifestations of glycemic control, are rarely associated with treatment with acetazolamide (a), amiloride (b), spironolactone (d), or triamterene (e)

Question 3

A patient with severe heart failure i s in the ICU. His urine output i s dangerously You begin an intravenous infusion of dopamine at a usual therapeutic dose and urine output ri ses quickly and dramatically. What i s the most l ikely mechanism by which the dopamine caused this effect?

A	Blocked β-adrenergic receptors in the juxtaglomerular apparatus, thereby inhibiting renin release and susequent angiotensin-mediated aldosterone release from the adrenal cortex.
B	Directly inhibited a renal Na+, K+, 2Cl- cotransporter in the Loop of Henle.
C	Improved renal blood flow and glomerular fi l tration
D	Lowered the medullary-to-cortical osmotic gradient, such that normal urine concentrating mechanisms were impaired
E	Reduced the permeability of the ascending l imb, Loop of Henle, and of the collecting ducts, to water

Question 3 Explanation: 

The often dramatic increases in urine output caused by therapeutic doses of dopamine (so-called “renal doses”) is mainly due to improved hemodynamics. The drug, under these conditions, not only improves cardiac contractility and cardiac output (which, in turn, improves renal perfusion), but also dilates the renal arterioles; these effects lead to improved glomerular filtration, and the increased urine volume. Improved hemodynamics will suppress the renin-angiotensin-aldosterone system, which was activated in response to poor renal perfusion. Weak β1 receptor activation also contributes to this effect (particularly with such drugs as dobutamine). However, dopamine does not block (a) any of the adrenergic receptors. Dopamine also has renal tubular effects, much like traditional diuretics do, although we often overlook them (perhaps because they are less important than the effects described above. The drug, via its D1-receptor agonist actions, increases c-AMP formation in the proximal tubules and also in the thick ascending limb of the Loop of Henle. At the latter site, the result is inhibition of both the Na+-H+ exchange mechanism and the Na+, K+-ATPase, but not of water (e; recall that the thick ascending limb of the Loop of Henle is impermeable to water.) Taken together, the renal hemodynamic and tubular actions of dopamine make it particularly useful for managing heart failure that is accompanied by reduced renal function. Higher doses cause positive inotropy via β1-receptor activation, and causes neuronal NE release. High doses activate α1 receptors in various vascular beds, including the renal, leading to vasoconstriction that can raise blood pressure and total peripheral resistance, and can reduce renal blood flow, thereby reducing renal excretory function.

Question 4

Usual doses of a thiazide diuretic (eg, hydrochlorothiazide) produce a urine that i s relatively ri ch in sodium and potassium, but contains relatively l i ttle increase in urine volume (ie, comparatively l i ttle free water loss compared with the relative loss of ions). An action at what s i te in the nephron mainly accounts for the ability of the thiazides to cause these responses?

A	Ascending l imb of the loop of Henle
B	Cortical diluting segment of the proximal nephron
C	Cortical-to-medullary “countercurrent multiplier”
D	Descending l imb of the loop of Henle
E	Principal cells of the nephron

Question 4 Explanation: 

Thiazides typically produce a urine that is concentrated (hyper-osmolal, more concentrated than normal) because the urine contains a relative excess of sodium and potassium (and such anions as chloride and, to a lesser extent, bicarbonate), and little in the way of extra free water loss. The main site at which thiazides and thiazide-like diuretics (eg, chlorthalidone, metolazone) act to cause this effect is in the cortical diluting segment. Contrast this with the loop diuretics (furosemide, torsemide, bumetanide, and ethacrynic acid), which cause the formation of a dilute urine because they inhibit reabsorption of sodium in the descending limb of the Loop of Henle (a), thereby inhibiting the formation of the medullary-to-cortical osmotic gradient (c, d) necessary for the formation of a normally concentrated urine. None of the common diuretic drugs act on the ascending limb of the Loop of Henle (a). All the potassium-wasting diuretics, that is, the thiazides, thiazide-like agents, and loop agents, such as furosemide, indirectly act on the principal cells of the nephron (e). By inhibiting a portion of sodium reabsorption more proximally they deliver extra sodium distally to the principal cells. There, the principal cells take up (reabsorb) an additional fraction of sodium in exchange for potassium, which is lost into the urine. This accounts for the potassium-wasting effects of these diuretics, but does not account for whether they produce a concentrated or a dilute urine.

Question 5

A patient with essential hypertension i s being treated with hydro-chlorothiazide and a calcium channel blocker, and i s doing He also takes atorvastatin for hypercholesterolemia, and aspirin to reduce his ri sk of an acute coronary syndrome. He i s now diagnosed with a seizure disorder. We begin therapy with one of the suitable anticonvulsants that, fortunately, does not alter the metabolism of any of the medications prescribed for his cardiovascular problems. We’ve also read that systemic administration of acetazolamide may prove to be a useful adjunct to the anticonvulsant therapy: the metabolic acidosis i t causes may help suppress seizure development or spread. So, we start acetazolamide therapy too. What i s the most l ikely outcome of adding the acetazolamide?

A	Excessive ri ses of plasma sodium concentration
B	Hypertensive cris i s (antagonism of both antihypertensive drugs)
C	Hypokalemia via synergistic actions with the thiazide
D	Spontaneous bleeding (potentiation of aspirin’s actions)
E	Sudden ci rculating volume expansion, onset of heart failure

Question 5 Explanation: 

We seldom administer acetazolamide as a diuretic, because its effects are “mild”; associated with significant changes of both urine pH (up) and blood pH (down; metabolic acidosis); and self-limiting (once sufficient bicarbonate has been lost from the blood, into the urine, refractoriness to further diuresis occurs). More often we administer acetazolamide and other carbonic anhydrase inhibitors for nonrenal/noncardiovascular problems, such as to lower intraocular pressure in some cases of glaucoma (carbonic anhydrase inhibitors inhibit aqueous humor formation) or as an adjunct to anticonvulsant therapy as described here. As a result, we may forget that these systemically administered drugs are diuretics, one common property of all the diuretics being increased renal sodium loss (a natriuretic effect; thus, answer a is not correct). We may even forget that carbonic anhydrase inhibitors, given systemically, are potassium-wasting diuretics: they act proximally and deliver extra sodium distally where, at the principal cells of the nephron, some extra Na+ is taken up in exchange for additional K+ that gets eliminated in the urine. In this scenario the patient is taking a thiazide, which is obviously potassium-wasting and has the potential in its own right to cause hypokalemia. Add a carbonic anhydrase to the regimen and the risks of hypokalemia increase. Acetazolamide does not antagonize the antihypertensive effects of thiazides or calcium channel blockers, nor provoke hypertension or a hypertensive crisis (b). If there were any interactions between the acetazolamide and the aspirin, it would be antagonism, not potentiation (d) of aspirin’s antiplatelet effects. Aspirin undergoes renal tubular reabsorption, and that is a pH-dependent effect. Aspirin’s reabsorption is reduced (that is, its excretion increases) in an alkaline urine, which is precisely what occurs with acetazolamide. (You should recall that alkalinizing the urine is an important adjunctive measure in treating severe salicylate poisoning, in part because it reduces tubular reabsorption of salicylate.) There is no reason to suspect sudden rises of blood volume, with or without concomitant heart failure from that (e). Indeed, the added diuresis from the acetazol-amide may, at least transiently, potentiate the effects of the thiazide on urine volume, blood pressure, or both

Question 6

A patient has very high plasma uric acid levels, has had two acute gout attacks in the last 8 months, and i s at imminent ri sk of developing acute uric acid We will treat the patient with proper anti-inflammatory drugs and other agents, but feel that reducing solubility of uric acid in the urine might help ward-off the development of renal problems. What drug i s best able to produce this desired renal effect vis-á-vis urate solubility without appreciably increasing systemic ri sks of the hyperuricemia?

A	Acetazolamide
B	Antidiuretic hormone (ADH) (vasopressin [VP])
C	Ethacrynic acid
D	Furosemide
E	Hydrochlorothiazide

Question 6 Explanation: 

Here I asked about reducing the risk of urate nephropathy acutely by increasing uric acid solubility, through urinary alkalinization. One key to answering this question correctly is to realize that uric acid becomes more soluble (lesslikely to precipitate or crystallize) as local pH rises. Recall that normal urine is acidic. We want to alkalinize the urine, and that is precisely what acetazolamide does, by inhibiting carbonic anhydrase in the proximal nephron. Note that acetazolamide is only an adjunct, and in addition to (or instead of) using it, we might also administer sodium bicarbonate, which will alkalinize the urine; and keep the patient well hydrated to help form large amounts of a dilute urine. Acetazolamide does cause a metabolic acidosis, which would seemingly favor reductions of uric acid solubility in the blood. However, we are keeping our patient well hydrated (helps reduce precipitation); and the volume of blood is far greater than urine volume at any given time, and given the great size of the “blood pool” we have little to worry about in terms of urate precipitation systemically. Antidiuretic hormone (b) would be illogical. It would reduce urine volume and concentrate solutes (such as uric acid) in it. Ethacrynic acid (c) and furosemide (d) lead to the formation of copious volumes of dilute urine. In terms of renal problems, that may be beneficial. However, the loop diuretics tend to cause such large amounts of fluid loss via the urine that the concentration of solutes (including uric acid) in the blood may go up. Hydrochlorothiazide (e) and related drugs tend to form a very concentrated urine by interfering with normal urine-diluting mechanisms in the kidneys. While some of these drugs have carbonic anhydrase activity, and alkalinize the urine, these effects are weak in comparison with acetazolamide. The most likely predominant renal effect is the unwanted one: increased risk of urate nephropathy. In addition, thiazides tend to elevate urate levels (by interfering with tubular secretion of urate), and so these drugs are likely to pose additional systemic problems.

Question 7

A patient with heart failure has been managed with digoxin and furosemide and i s doing well by all measures, for 3 He develops acute rheumatoid arthritis and i s placed on rather large doses of a very efficacious  nonsteroidal anti-inflammatory drug—one  that inhibits both the  COX- 1 and -2 cyclooxygenase pathways. What i s the most l ikely outcome of adding the NSAID?

A	Hyperchloremic acidosis indicative of acute diuretic toxicity
B	Dramatic increase of furosemide’s potassium-sparing effects
C	Edema, weight gain, and other s igns/symptoms indicative of reduced diuresis
D	Increased digoxin excretion
E	Reduced digoxin effects because the NSAID competes with digoxin for myocyte receptor-binding s i tes

Question 7 Explanation: 

An important element in the renal responses to furosemide is maintenance of adequate renal blood flow. That is, to a degree, prostaglandin-mediated. Prostaglandins dilate the afferent arteriole (to the glomeruli) and increase GFR and urine production. The NSAIDs, such as the hypothetical one described here, inhibit prostaglandin synthesis. That, in turn, antagonizes the desired effects of the loop diuretic, leading to less fluid and salt elimination: edema, weight gain, and other markers of heart failure are likely to develop as a result. Hyperchloremic alkalosis (a) is incorrect: chronic or acute excessive effects of loop diuretics are characterized by hypochloremic metabolic alkalosis. Regardless, NSAIDs are not likely to potentiate the effects of these diuretics. “Dramatic increases of furosemide’s potassium-sparing effects (b)” is incorrect. Recall that loop diuretics are potassium-wasting. Digoxin is eliminated by renal excretion. If we accept the notion that loop diuretics may increase excretion of digoxin, then we should accept the likely possibility that NSAID-induced reductions of diuretic action should reduce the glycoside’s renal loss, not increase it (d). The NSAIDs do not bind to and inhibit the myocyte Na+, K+-ATPase, which is digoxin’s cellular receptor (e). Do remember that furosemide (and thiazides) are apt to increase the risk or severity of digoxin toxicity. The mechanism mainly involves diuretic-induced hypokalemia, not changes in circulating fluid volume or urine volume per se.

Question 8

A patient was in a recumbent position for a 45-minute oral surgery procedure. When the surgery was completed the patient stood up quickly and promptly got l ight-headed and fainted. The cause was hypotension due to hypovolemia from excessive diuresis, attributed to a drug prescribed by her physician and taken for several What drug was the most l ikely cause?

A	Acetazolamide
B	Furosemide
C	Hydrochlorothiazide
D	Spironolactone
E	Triamterene

Question 8 Explanation: 

One way to simplify answering this question is merely to ask “which diuretic has the greatest ability to cause hypovolemia?” That narrows the choice to furosemide or the other loop diuretics (bumetanide, torsemide, ethacrynic acid). In terms of extra free water loss (and the concomitant risk of hypovolemia) the maximal efficacy of acetazolamide (carbonic anhydrase inhibitor; a) is modest at best, and self-limiting to boot. Hydrochlorothiazide (c) and the two potassium-sparing diuretics listed (spironolactone and triamterene; d, e) also have modest efficacy in terms of the peak diuretic effect, even if unusually large doses were to be given. Note: Hyponatremia reduces the responsiveness of the peripheral vasculature to vasoconstrictors (eg, EPI, NE, and angiotensin II). If I stated that the patient’s hypotension were due to diuretic-induced hyponatremia, then the most likely correct answer would be hydrochlorothiazide or another thiazide or thiazide-like diuretic (eg, metolazone); of all the diuretics classes (and most other classes of drugs), they are the most common cause of hyponatremia.

Question 9

One of your cl inic patients i s being treated with spironolactone. Which statement correctly describes a property of this drug?

A	Contraindicated in heart failure, especially i f severe
B	Inhibits Na+ reabsorption in the proximal renal tubule of the nephron
C	Interferes with aldosterone synthesis
D	Is a rational choice for a patient with an adrenal cortical tumor
E	Is generally preferred to a thiazide in most patients with essential hypertension

Question 9 Explanation: 

Spironolactone is a potassium-sparing diuretic. Its active metabolite blocks aldosterone receptors in the distal nephron (thus answer b is incorrect). Neither spironolactone nor its active metabolite alter aldosterone synthesis (c). The drug is ineffective in the absence of aldosterone. Recall that aldosterone normally causes renal Na+ retention and K+ loss. The effects of aldosterone are qualitatively the opposite: Na+ loss, K+ retention. Owing to the ability of spironolactone to counteract the effects of aldosterone, it is particularly suited for patients with primary or secondary hyperaldosteronism (eg, adrenal cortical tumor or hepatic dysfunction, as might occur with long-term/high-dose alcohol consumption, respectively). There is growing evidence that the drug is beneficial in heart failure and probably reduces morbidity in severe heart failure (and so a is incorrect). Although spironolactone has antihypertensive effects, it is not considered to be a first-line choice (e) for most patients with essential hypertension. For those patients a thiazide (most often), an ACE inhibitor, a β-blocker, or a calcium channel blocker is usually chosen first. In addition to the potential for causing hyperkalemia (especially if combined with oral potassium supplements, which should not be done) and hyponatremia (overall risk is low if spironolactone is the only diuretic used), spironolactone may cause several other side effects. CNS side effects include lethargy, headache, drowsiness, and mental confusion. Other side effects that are fairly common arise from the drug’s androgen receptorblocking actions: gynecomastia (in men and women) and erectile dysfunction. It may also cause seborrhea, acne, and coarsening of body hair. (Paradoxically, the drug can cause hirsutism in some patients, but it is also used to manage hirsutism in others.)

Question 10

Chlorthalidone and torsemide are members of different diuretic classes, in terms of mechanisms of action and chemical structure, but they share the ability to cause Which statement best describes the general and common mechanism by which these drugs cause their effects that lead to net renal potassium loss?

A	Act as aldosterone receptor agonists, thereby favoring K+ loss
B	Block proximal tubular ATP-dependent secretory pumps for K+
C	Increase delivery of Na+ to principal cells in the distal nephron, where tubular Na+ i s transported into the cells via a sodium channel in exchange for K+, which gets eliminated in the urine
D	Stimulate a proximal tubular Na, K-ATPase such that K+ i s actively pumped into the urine
E	Lower distal tubular urine osmolality, thereby favoring passive diffusion of K+ into the urine

Question 10 Explanation: 

Thiazides (and thiazide-like agents such as chlorthalidone and metolazone) and loop diuretics (furosemide, bumetanide, torsemide, and ethacrynic acid) increase delivery of Na+ to the distal nephron because they inhibit reabsorption of Na+ at more proximal sites. This extra Na+ reaches the principal cells in the distal nephron, and some of it is taken from the tubular fluid via sodium channels. This reclamation of Na+ leads to exchange of K+, which is lost into the urine (ie, potassium “wasting”). In essence, the more Na+ delivered (and recovered) distally, the more K+ that is eliminated in exchange. The processes by which these potassium-sparing drugs work do not involve proximal tubular ATP-dependent potassium secretion (b), nor does it involve any direct effect on proximal tubular ATPase (d). In addition, there are no agonist effects on aldosterone receptors (a)—an action that would cause an antidiuretic effect and renal potassium loss. Indeed, no diuretic acts as an aldosterone receptor agonist; spironolactone and eplere-none (not listed here) exert their natriuretic and potassium-sparing effects by blocking aldosterone receptors. Finally, lowering distal tubular osmolality (e) does not occur, nor would such an effect (if it occurred) favor passive diffusion of K+ into the urine.

Question 11

A 52-year-old man presents to your cl inic for his fi rst vis i t with you, after moving from a distant His only medications are a  statin, aspirin, (81 mg/day) and metolazone. The pharmacist who fi l led his prescriptions explained to the gentleman why he was taking the  aspirin and the statin, but merely referred to the metolazone as a “water pill.” Thus, you’re asked about i t. What i s the most l ikely reason why the metolazone was prescribed?

A	Adjunctive management of an adrenal cortical tumor
B	Adjunctive management of hepatic ci rrhosis from years of excessive alcohol consumption
C	Hypertension accompanied by a history of gout and diabetes
D	Treatment of essential hypertension
E	Treatment of edema and ascites from heart failure

Question 11 Explanation: 

Metolazone, although not a thiazide (benzothiadiazide) in the chemical sense, is largely (hydrochloro)thiazide-like in terms of its pharmacologic properties and uses, although it has a much longer duration of action than the prototype, hydrochlorothiazide. As far as the “main use” of thiazides goes, that would be essential hypertension (assuming no contraindications), with lesser uses being “mild” and especially transient edema, management of idiopathic hypercalciuria, adjunctive management of nephrogenic diabetes insipidus, and perhaps management of Meniere disease. Thiazides (or such thiazide-like drugs as metolazone) would not be rational, nor very efficacious, for drug therapy of an adrenal cortical tumor (a). In that instance, if we are considering only diuretics, the proper drug would be spironolactone, the aldosterone receptor blocker. Likewise, since thiazides can raise circulating urate andglucose levels, they would not be good choices for the patient with hepatic cirrhosis or other diseases characterized by poor liver function (b; here too spironolactone would be the best choice) or gout or diabetes (e). If our goal were to manage severe edema (e) with or without ascites (as in a patient with heart failure), our best choice would be a loop diuretic.

Question 12

Urinary potassium concentrations are measured before and after several weeks of administering a loop diuretic (eg, furosemide, at typical daily dosages). We find that post-treatment urine K+ concentrations are substantially lower than those measured at What i s  the  most l ikely explanation for this observation?

A	An expected response to the drug
B	Loop diuretics cause potassium-wasting only in in vi tro experimental models
C	Measurements of post-treatment urine K+ concentrations were erroneous
D	The patient has hypoaldosteronism from bilateral adrenalectomy
E	Potassium secretion by principal cells of the nephron are inhibited by loop diuretics

Question 12 Explanation: 

One expected response to therapeutic doses of loop diuretics, which are clearly and correctly classified as potassium-wasting, is a reduction of urinary potassium concentrations. How can this be? Note that the term concentration reflects the amount of a substance (here, potassium) per unit volume; it is not equivalent to “amount” per se. The loop diuretics do increase K+ excretion: because they work more proximally, they provide an added load of Na+ delivered to the distal nephron, where sodium channels in the principal cells take up the Na+ in exchange for K+. Potassium secretion by the principal cells is not inhibited (e). Loop diuretics also impair the ability of the kidneys to form a concentrated urine and so promote formation of a large volume of more dilute (= less concentrated) urine. The net loss of K+ (say, on a 24-h basis) is increased, but it’s accompanied by a disproportionate increase in free water loss such that urine K+ concentration (but not total amount lost) is decreased.

Question 13

You have just completed your third-year medicine clerkship, having spent some time in general internal medicine, cardiology, nephrology, and endocrine-metabolism cl In each of those venues you have reviewed charts of patients taking eplerenone. What phrase best describes a characteristic or other property of this drug?

A	Facilitates renal sodium water loss and potassium retention
B	Inhibits steroidogenesis (steroid hormone production)
C	Mimics antidiuretic hormone (vasopressin)
D	Specifically inhibits aldosterone synthesis
E	Used to counteract glycosuria in patients with type 1 or 2 diabetes mellitus

Question 13 Explanation: 

Eplerenone is a relatively new spironolactone-like drug. As such, its main mechanism of action involves blockade of aldosterone receptors (eg, in the nephron). Its main uses are also largely identical to those of spironolactone: heart failure, hypertension (mainly as a potassium-sparing adjunct, and especially when plasma renin levels are elevated, as that leads to increased angiotensin II synthesis which, in turn, increases aldosterone release from the adrenal cortex); and in patients in whom aldosterone levels are high from other causes (eg, adrenal cortical tumor, Cushing disease). The drug has no effect on the synthesis of aldosterone (d) or other steroid hormones (b); its ultimate renal effects are the opposite of those of ADH (at least in terms of free water loss or conservation), so c. is incorrect. Finally, the drug has no direct or clinically useful effects on glucose metabolism or levels, nor on glycosuria (e) and other consequences of hyperglycemia.

Question 14

A 58-year-old man with a history of hypertension and hypercholesterolemia i s diagnosed with heart We start therapy with furosemide as one of several medications. Which of the following would you expect to occur along with the increased urine volume caused by this diuretic?

A	Dilute (hypotonic) urine because normal urine concentrating mechanisms are impaired
B	Hypercalcemia due to impaired renal Ca 2+ excretion
C	Reduced net excretion of Cl -
D	Metabolic acidosis due to increased renal bicarbonate excretion
E	Reduced plasma uric acid (urate) concentrations because of increased urate excretion

Question 14 Explanation: 

Recall one of the main mechanisms by which a concentrated urine is formed: a hypertonic milieu in the renal medulla—and a medullary-to-cortical osmotic gradient—osmotically withdraws water (but not solute) from the tubular fluid as it passes through the collecting ducts. What creates that hypertonic medullary-to-cortical gradient? Reabsorption of Na+ and Cl- as tubular fluid ascends the loop of Henle, which ultimately increases interstitial osmolality. However, that process of ion resorption is impaired by loop diuretics. That reduces osmolality in the medullary interstitium, thereby dramatically reducing the osmotic gradient that enables the tubular fluid to become hypertonic as water is lost in the distal nephron. Thus, in the presence of a loop diuretic the urine remains dilute and hypotonic. Hypercalcemia (b) is not an expected accompaniment. Loop diuretics (in contrast with thiazides) increase renal Ca2+ elimination. Recall that the main anion excreted (along with Na+, K+, etc) in response to a loop diuretic is chloride, and so net Cl- excretion goes up (not down; c). Metabolic acidosis from increased bicarbonate excretion (d) doesn’t occur. Bicarbonate tends to be reabsorbed, therefore. You should recall that hypochloremic alkalosis (also called contraction alkalosis, because blood volume contracts as the result of excessive fluid loss in the urine) is one potential and quite dangerous adverse responses caused by loop diuretics. Loop diuretics do not lower urate concentrations (e). Rather, urate levels tend to rise, in part, because of reduced urate excretion combined with a “concentration” of urate in the blood owing to increased free water loss via the urine. Blood uric acid concentration tends to rise. The loop diuretics reduce urate excretion through a direct renal tubular action. More important, perhaps, the proportionally large extra free water loss shrinks blood volume and tends to increase solute concentration, independent of any renal tubular effects on urate elimination.

Question 15

A patient post-head trauma i s in the neurosurgery unit at your He has become hypervolemic and hyponatremic from two  main causes: (1) trauma probably increased vasopressin release from his posterior pituitary gland; and (2) the staff was not sufficiently careful when administering IV fluids, which further increased blood volume and lowered blood sodium concentrations. This patient also has symptomatic heart failure that would be further compromised by additional ri ses of blood volume, even i f s l ight or short-lived. He had been on a  number of drugs prior to admission. One was oral potassium-supplements to counteract diuretic-induced hypokalemia. Unfortunately, the supplement dose was excessive, and the  patient was borderline-hyperkalemic too. What drug would be the  most rational to  administer, with the  goal of normalizing or at least improving blood volume and electrolyte composition and without further compromising the patient’s hemodynamic status?

A	Conivaptan
B	Mannitol
C	Metolazone
D	Sodium chloride 0.9% (normal saline)
E	Spironolactone

Question 15 Explanation: 

This patient probably has SIADH—a syndrome of inappropriate vasopressin (antidiuretic hormone; ADH) secretion—and the scenario described above (hypervolemia, dilutional hyponatremia) is a fairly common cause or accompaniment of it. Conivaptan, a relatively new drug, is indicated for managing SIADH. It is a nonpeptide and competitive antagonist of ADH’s water-sparing effects in the nephron’s collecting duct. Why not mannitol (b)? Its anatomic site of renal action is the same as conivaptan’s, but it increases free water loss through an osmotic, ADHindependent, mechanism. (In fact, a compensatory response to counteract mannitol’s effects and conserve water is increased ADH release, but mannitol’s effects typically “win out” and diuresis indeed occurs.) Recall that the osmotic mechanism by which mannitol causes diuresis also contributes to increased plasma osmolality and blood volume—at least initially and until sufficient mannitol has been excreted. Heart failure (which this patient had) is a contraindication, or at least an important precaution, to mannitol’s use because even a transient increase of circulating fluid volume, which transiently increases blood pressure, can provide a significant added hemodynamic load on the failing heart. (The risk would be even greater if the patient had poor renal blood flow or function that would slow mannitol’s elimination and keep blood osmolality high longer.) Metolazone (c) is a thiazide-like diuretic. Recall that, as a class, thiazides or related agents have only a modest (actually slight) ability to reduce circulating fluid volume (which would be desirable in SIADH). More importantly, thiazides and thiazide-like agents tend to cause hyponatremia; that’s something we don’t want to cause or, in this case, worsen. Infusing 0.9% NaCl (d) will not correct sodium concentrations and if too much is infused too quickly may put additional fluid-overload-related hemodynamic stresses on the failing heart. Spironolactone (e) is irrational. First, it will not correct the excessive free water loss. More important, by antagonizing the renal tubular effects of aldosterone it will increase sodium loss and increase renal potassium retention—precisely the opposite of what we want to do with this patient.

Question 16

A 60-year-old man has multiple medical problems, including severe hepatic ci rrhosis from hepatitis at age 40, and over 30 years of excessive alcohol intake. Three days after a vis i t to a physician, who prescribed a drug for a condition unrelated to the l iver dysfunction, the man i s found He i s transported to the emergency department. What drug, prescribed 3 days before, most l ikely induced or contributed to the onset coma in this man?

A	Acetazolamide
B	Eplerenone
C	Furosemide
D	Hydrochlorothiazide
E	Triamterene

Question 16 Explanation: 

Acetazolamide, the prototypic carbonic anhydrase inhibitor, causes metabolic acidosis as it increases renal bicarbonate excretion, which in turn alkalinizes the urine. Although acetazolamide is infrequently used as a diuretic, it is used more for other conditions including altitude sickness, an adjunct to certain antiepileptic drugs, and (perhaps in this case) for management of glaucoma. Patients with severe liver dysfunction cannot synthesize urea adequately. As a result, elimination of a variety of endogenous nitrogen-based metabolic waste products becomes dependent on renal excretion of ammonium ion. In normally acidic urine the ammonium ions are eliminated rather efficiently. However, and due to the acetazolamide’s urinary-alkalinizing effects, ammonia gas forms in the urine. It then readily diffuses from the urine to the circulation. This causes hyperammonemia, which is the most likely cause of the coma. Eplerenone (b) and the older related drug, spironolactone, tend not to alter blood or urine pH. Indeed, since patients with severe liver dysfunction (such as this patient, with hepatitis- and alcohol-induced hepatic cirrhosis) tend to have high circulating aldosterone levels, the blockade of aldosterone receptors by eplerenone would probably be beneficial for this patient, and not at all likely to account for the coma and related neurologic abnormalities. Furosemide (c) also is an unlikely explanation. It is likely to facilitate ammonium excretion, and pH-related changes (eg, urinary alkalinization) are not apt to occur. Recall that one manifestation of loop diuretic excess is hypochloremic metabolic alkalosis (also called contraction alkalosisbecause circulating fluid volume shrinks—contracts) in response to the very efficacious loop agents. Because the kidneys tend to lose large amounts of chloride, and tend to retain bicarbonate, urinary alkalinization that leads to ammonia production in the urine is not likely. Some of the thiazides (eg, hydrochlorothiazide, d) and thiazide-like agents (eg, chlorthalidone, metolazone) have carbonic anhydrase activity that could lead to alkalinization of the urine. However, this property is generally weak in comparison with acetazolamide or related agents that are more appropriately classified as carbonic anhydrase inhibitors. Triamterene (e, or the related drug amiloride), a potassium-sparing diuretic with actions that are aldosterone-independent (contrast with eplerenone, spironolac-tone), is not likely to alter urine pH or cause other effects that might precipitate coma in this patient.

Question 17

Your patient, who l ives in Death Valley, California (240 feet below sea level) i s planning a vacation that includes a short hike to the top of Mount Everest (approx. 29,000 feet above sea level). You’re concerned about “altitude s i ” He has no other s ignificant medical conditions, and takes no other drugs that would interact with the drug you will prescribe for his trip. Which drug would you recommend that this adventurer start taking before his trek, and continue until he returns to an altitude much closer to sea level?

A	Acetazolamide
B	Amiloride
C	Bumetanide
D	Furosemide
E	Sprionolactone
F	Triamterene

Question 17 Explanation: 

The signs and symptoms of altitude sickness are related to the development of respiratory alkalosis: At high altitudes the partial pressure of O2 in the inspired air is low. The hypoxia triggers hyperventilation, which increases net ventilatory loss of CO2. Blood pH rises. Acetazolamide effectively inhibits carbonic anhydrase and so increases bicarbonate loss. This, in turn, causes a metabolic acidosis that counteracts the ventilatory-induced rise of blood pH. It is the drug of choice for prophylaxis or management of altitude sickness. It is true that some of the thiazide or thiazide-like diuretics inhibit carbonic anhydrase, but the effect is very weak in comparison to that of acetazolamide. None of the other drugs listed would be suitable for this patient and the altitude sickness he is likely to exp

Question 18

A patient presents with chronic open angle What “renal” drug, or a drug in the same chemical and pharmacologic class, might be prescribed as an adjunct to lower intraocular pressure and help manage this condition?

A	Acetazolamide
B	Amiloride
C	Furosemide
D	Sprionolactone
E	Triamterene

Question 18 Explanation: 

Aqueous humor formation (as well as that of cerebrospinal fluid) involves carbonic anhydrase activity. Reduce aqueous humor synthesis and, all other factors being equal, intraocular pressure goes down. Acetazolamide is, of course, “the” carbonic anhydrase-inhibiting diuretic. Note that when a carbonic anhydrase inhibitor is used to manage glaucoma, the drug’s renal/diuretic effects, which certainly occur if the drug is given systemically, have nothing to do with the beneficial effects that are due to an ocular (ciliary body) site of action. If fact, those extraocular effects aren’t needed for glaucoma control. That is why, when we prescribe a carbonic anhydrase inhibitor for glaucoma, we usually choose a topical ophthalmic carbonic anhydrase inhibitor (eg, dorzolamide or methazolamide).

Question 19

A patient has unacceptably low cardiac output and intense reflexmediated sympathetic activation of the peripheral vasculature that i s attempting, unsuccessfully, to keep vi tal organ perfusion pressure sufficiently The patient i s edematous because of the poor cardiac function and renal compensations for i t. Which one of the following drugs should be avoided in this patient because i t i s  most l ikely to  compromise function of the already-failing heart and the ci rculatory system overall?

A	Amiloride
B	Ethacrynic acid
C	Hydrochlorothiazide
D	Mannitol
E	Spironolactone

Question 19 Explanation: 

Mannitol is an osmotic diuretic, the prototype of that small class of drugs (glycerin/glycerol is another somewhat noteworthy member of the group) with indications and potential side effects that are quite different from those of “typical” diuretics like the thiazides or loop agents. What happens when you inject (intravenously) this nonmetabolizable sugar, which has a structure similar to that of glucose and the same molecular weight? Initially, and until it is excreted by glomerular filtration, mannitol increases plasma osmolality. That, in turn, osmotically withdraws water from the extracellular space and, ultimately, from the parenchymal cells, and into the blood. If the patient has good renal function, renal blood flow and GFR rise, and the drug is eventually excreted. If he or she has adequate cardiac function, circulating that extra volume (up to a limit) is not a problem. However, if the patient has a sufficiently contractility or cardiac output to begin with, or renal perfusion is compromised, the increased blood volume and pressure may be such that the heart simply cannot handle the added workload. Indeed, in a futile attempt to circulate that additional volume and eject it against a higher afterload, the heart may fail acutely. Amiloride (a), a potassium-wasting diuretic with relatively low efficacy in terms of its ability to increase urine volume, should have no adverse effects in this patient. The same applies to hydrochlorothiazide (c), which is potassium-wasting. Ethacrynic acid (b) is a loop diuretic. It is one of several loop agents we might choose to help “unload” this patient’s ventricles, provided the patient isn’t hypovolemic already. Spironolactone (e), a potassium-sparing aldosterone antagonist, might ultimately be prescribed for this patient, particularly if his heart failure worsens. Nonetheless, at this time it is not a drug we should avoid.

Question 20

A patient i s recently diagnosed with adrenal cortical Among the pertinent Cushingoid s igns and symptoms are hypertension and weight gain from fluid retention; and hypernatremia and hypokalemia. Which drug would be the most rational to prescribe, alone or adjunctively, to specifically antagonize both the renal and the systemic effects of the hormone excess?

A	Acetazolamide
B	Amiloride
C	Furosemide
D	Metolazone
E	Spironolactone

Question 20 Explanation: 

The most rational choice for specifically antagonizing the consequences of hormone excess—aldosterone being the hormone of most importance in terms of the renal, hemodynamic, and electrolyte problems here—is spironolactone (or eplerenone). Its primary mechanism of action is blockade of aldosterone receptors. Remember that the main renal effects of aldosterone are sodium (and water) retention, and increased renal loss of potassium. Acetazolamide (a), the carbonic anhydrase inhibitor, exerts weak and self-limiting diuretic and natriuretic effects. It is also potassium-wasting, and increased excretion of potassium is what we do not want to do in situations of preexisting hypokalemia. Amiloride (b) would help increase sodium excretion and help normalize potassium levels too. However, it does not provide the “rational” approach to hyperaldosteronism because it does not block aldosterone receptors. Furosemide (c) or another loop diuretic might prove effective in terms of increasing excretion of sodium and reducing that of potassium. Indeed, if the hyperaldosteronism is sufficiently great to cause dangerous degrees of fluid retention (hypervolemia) and heart failure we may need to administer it. Nonetheless, spironolac-tone would be a reasonable, rational, and probably necessary element of management. Metolazone (d), a thiazide-like diuretic, would desirably help increase renal sodium excretion and lower blood pressure. Having relatively low efficacy in terms of increased urine production, it may not do much to manage the hypervolemia and the resulting weight gain. More important, metolazone is likely to aggravate the preexisting hypokalemia because it is, of course, a potassiumwasting diuretic.

Question 21

A patient has been referred to your academic medical center because of recent-onset ventricular ectopy, second-degree AV nodal block, chromatopsia, and other extracardiac s igns and symptoms of digoxin intoxication. His family doctor, who has been treating him for a host of common medical problems over the last 30 years, had prescribed furosemide and digoxin for this gentleman’s heart Blood tests show that digoxin levels are well within a normal range. We believe the problems are  diuretic-induced. What did the  diuretic most l ikely do to  precipitate the digoxin toxicity?

A	Caused hypercalcemia
B	Caused hypokalemia
C	Caused hyponatremia
D	Displaced digoxin from ti ssue binding s i tes
E	Inhibited digoxin’s metabolic elimination

Question 21 Explanation: 

While many ionic and other factors can predispose a patient to digoxin toxicity, hypokalemia, as can be caused by a loop diuretic (usually used for edema and/or ascites, including that associated with heart failure) or thiazide diuretic (mainly used for treating essential hypertension), is arguably the most important, if not the most common. There is a competition between extracellular K+ and digoxin for binding to digoxin’s cellular receptor, the Na+, K+-ATPase on the sarcolemma. When circulating (extracellular) K+ concentration is reduced (ie, when hypokalemia develops), the binding of digoxin is enhanced and so its effects are increased, even without a rise of digoxin concentrations, and usually those increased effects are deleterious, as described here. Hypercalcemia can increase the risk or severity of digoxin toxicity. However, loop diuretics increase renal Ca2+ loss, and so hyperkalemia (a) is not a likely explanation. Hyponatremia (c) is not at all likely to have occurred with a loop diuretic, which tends to increase both renal Na+ and H2O loss, with the loss of free water being much greater than the loss of Na+. Loop diuretics do not displace digoxin from tissue binding sites (d) or inhibit digoxin’s elimination (which involves renal excretion, not metabolism). Note that in the scenario I described the patient as having been treated by “his family doctor who has been treating him for the last 30 years.” This is not at all meant to impugn family doctors or general practitioners. The point is that nowadays, and for a variety of reasons (toxicity being one), digoxin is no longer considered an appropriate drug for managing heart failure, with or without signs or symptoms of congestive failure, until all other reasonable and more suitable options have been tried and the patient’s condition has deteriorated to the point that inotropes (digoxin or parenteral agents) are warranted. Recall that our preferred approach for initial therapy of failure involves ACE inhibitors, a β-blocker, and perhaps a loop diuretic. Nonetheless, and unfortunately, some physicians still use the “old way,” involving digoxin. It is these patients who are likely to be seen in the hospital when the almost inevitable problems due to digoxin develop

Question 22

A 48-year-old man with bilateral diabetic nephropathy develops acute heart failure and additional, and s ignificant, declines of renal function (eg, declines of GFR) as two of several consequences  of You will administer appropriate antibiotics, vasodilators, and cardiac inotropes, but also need to administer a diuretic to promptly reduce ci rculating fluid volume and “unload” the failing heart. What drug would be most appropriate in terms of managing the hemodynamic problems for this patient?

A	Acetazolamide
B	Hydrochlorothiazide
C	Mannitol
D	Torsemide
E	Metolazone (or chlorthalidone)

Question 22 Explanation: 

This patient needs a diuretic that has a fast onset of action the ability to rather significantly increase renal excretion of free water to “unload” the heart. Torsemide is very similar in terms of actions and uses to the prototype loop or “high ceiling” diuretic, furosemide, which inhibits a Na+/K+/2Cl- transporter in the ascending limb of the Loop of Henle. (Note that both furosemide and torsemide end in “-Semite”—a tip for name recognition.) Acetazolamide (a), the prototype carbonic anhydrase inhibitor, would be unsuitable. Its onset of action is slow; its peak effects in terms of increasing free water elimination are low; and its ability to cause metabolic acidosis (secondary to increased renal bicarbonate loss) would not only compromise the patient described in the scenario but also cause loss of the drug’s diuretic effects. Hydrochlorothiazide (b) and thiazide-like diuretics (eg, metolazone and chlorthalidone, e) would not be suitable; their efficacies are low in terms of managing edema; their effects are slow to develop; and only one thiazide, chlorothiazide, can be given parenterally (a point I do not think you need to commit to memory). Mannitol (c), the prototype osmotic diuretic, is given parenterally; it has a relatively prompt onset of action; and it can significantly increase fluid elimination via the kidneys. Mannitol’s intensity and duration of effects, however, depend on many variables, including baseline renal function. Nonetheless, mannitol initially raises circulating fluid volume—increasing the hemodynamic load on the heart and being particularly problematic in the face of heart failure—and its adverse volume-related effects will be prolonged if GFR is reduced in patients such as the one described in the question.

Question 23

A patient with severe infectious disease i s being treated with an aminoglycoside Which diuretic should be avoided, i f possible, for this patient, because of the ri sk of a serious adverse effect shared by both drugs?

A	Acetazolamide
B	Furosemide
C	Metolazone
D	Spironolactone
E	Triamterene

Question 23 Explanation: 

Both the loop diuretics and the aminoglycosides (tobramycin, streptomycin, gentamicin, others) are ototoxic—capable of causing vestibular damage (eg, balance problems), cochlear damage (tinnitus or sensorineural hearing loss), or both. The ototoxic effects of each drug is enhanced (often significantly) by the other’s, and so it is best to avoid use of both these drugs (or other ototoxins) unless the benefits clearly outweigh the risk of perhaps permanent and total hearing loss. (Of course, there are instances in which such combinations are necessary.) There’s strong evidence that of all the loop diuretics, the risk of ototoxicity is highest with ethacrynic acid (and its parenteral formulation, sodium ethacrynate). Nonetheless, all the other loop diuretics—bumetanide, furosemide, and torsemide—are definitely on the short list of ototoxic drugs. Acetazolamide (a), metolazone (c) or other thiazide or thiazide-like diuretics, spironolactone (d), and triamterene (e) are not ototoxic, nor do they potentiate the adverse auditory effects of other ototoxic drugs.

Question 24

Amiloride i s a useful drug for managing hypokalemia caused by other drugs. Which phrase best describes the  mechanism by which i t causes i ts potassium-sparing effects?

A	Blocks the agonist effects of aldosterone with i ts renal tubular receptors
B	Blocks distal tubular sodium channels and, ultimately, Na+-K+ exchange
C	Hastens metabolic inactivation of aldosterone
D	Stimulates a proximal tubular Na, K-ATPase
E	Suppresses cortisol and aldosterone synthesis and release in the adrenal cortex

Question 24 Explanation: 

Amiloride and triamterene block distal tubular Na+ channels that provide for Na+ reabsorption in exchange for K+, which is lost into the urine. This sodium channel, which is the main site of action of amiloride, is on the luminal side of the principal cell membranes. (Principal cells in the nephron are located in the late distal tubule and collecting ducts.) There is an ATPase on the interstitial face of the principal cells (again, these are in the distal nephron, not proximal; d). The ATPase is responsible for the extrusion of potassium into the urine in exchange for extra sodium taken up by the luminal sodium channels, and so it is essential in the overall actions of potassium-sparing diuretics. Nonetheless, the ATPase is not inhibited (or stimulated; d) directly by amiloride. Amiloride has no direct effects on aldosterone synthesis or metabolism (c), or on aldosterone receptors (a; those receptors are blocked by spironolactone).

Question 25

A patient who admits to drinking many l i ters of water each day has had recurrent episodes of symptomatic hyponatremia, and i s at great ri sk of recurrences. Because of another medical problem he now requires administration of a Which drug i s most l ikely to precipitate another recurrence of the hyponatremia, whether or not the patient’s daily water intake i s reduced to a more acceptable level?

A	Bumetanide
B	Ethacrynic acid
C	Furosemide
D	Hydrochlorothiazide
E	Torsemide

Question 25 Explanation: 

Thiazide and thiazide-like diuretics should be high (highest!) on your list of drugs that are likely to cause hyponatremia. Was it easy to select hydrochlorothiazide as the correct answer because it was the only drug listed that was not a loop diuretic? Were you puzzled because you knew that furosemide is the prototype loop agent, and weren’t sure about the classification bumetanide, ethacrynic acid, or torsemide. Or did you not select the thiazide because you considered its diuretic effects to be mild, or modest, and therefore least likely to cause hyponatremia? In absolute or relative terms the natriuretic (sodium-wasting) effects can be considered weak (especially in comparison with loop diuretics). They cause relatively slight increases in free water loss in the urine (compared with normal), interfere with normal urine-diluting mechanisms, and lead to the formation of a concentrated (in terms of such solutes as sodium) urine. That is, the amount of extra sodium lost is, in a relative sense, much greater than the extra volume lost. This is reflected, in the blood, as not much extra volume loss coupled with proportionally greater declines in the amount of sodium. Remember that hyponatremia means excessively reduced sodium concentration, and concentration is a function of amount per unit volume. The thiazides have caused “dilutional hyponatremia.

Question 26

A hypertensive patient has been on long-term therapy with l i s inopril, a long-acting ACE inhibitor, for The drug i sn’t controlling pressure as well as wanted, so the physician decides to add amiloride. What i s a potential, i f not l ikely, outcome of adding this diuretic to the ACE inhibitor regimen?

A	Blood pressure would ri se abruptly
B	Blood pressure would fall again once amiloride was added (better BP control), but there’s a l ikelihood that the patient would become hyperkalemic
C	Cardiac depression, because both drugs directly depress heart rate and left ventricular contractility
D	Diabetes insipidus-like syndrome with production of large volumes of dilute urine, plus dilutional hyponatremia
E	Hypokalemia because of the two drugs’ additive or synergestic effects on renal potassium handling

Question 26 Explanation: 

Lisinoprol (a “-pril,” and therefore an angiotensin-converting enzyme inhibitor) indirectly reduces aldosterone release from the adrenal cortex by inhibiting angiotensin II synthesis. (Remember: A-II is the major physiologic stimulus for aldosterone release.) Normally aldosterone causes renal Na+ retention and K+ loss. When there is less aldosterone, the kidneys will now tend to lose Na+ and retain K+. Amiloride (like triamterene) blocks sodium channels on the luminal face of the principal cells of the nephron. Those sodium channels normally are responsible for Na+ and K+ exchange (some extra Na+ reclaimed, extra K+ lost into the urine). In the presence of amiloride the ion exchange is inhibited and this constitutes the potassium-sparing effects that we use to classify these diuretics. Although aldosterone plays a role in renal handling of Na+ and K+, amiloride (like triamterene) will work in the absence of aldosterone—unlike the potassium-sparing effects of spironolactone or eplerenone, which only work in the presence of aldosterone because their mechanism involves blockade of aldosterone receptors, with no direct effects on principal cell ion channels. There is no logical mechanism with which to envisage an ACE inhibitor/potassium-sparing diuretic causing hypertension (a). Neither an ACE inhibitor nor a K+-sparing diuretic, alone or together, has direct cardiac-depressant effects (c; unless the drugs were administered at such toxic doses that electrolyte levels changed so much that they affected the heart). Polyuria, a diabetes insipidus-like state (d) and a syndrome of inappropriate ADH secretion do not occur with either of these drugs or with the two combined. As noted above, both drugs exert potassium-sparing effects, and so hypokalemia (e) will not occur.

Question 27

Consider again the patient described in the previous He now presents with diuretic-induced hyponatremia. The condition is symptomatic and severe enough that the excessively low Na+ concentration needs to be corrected promptly. In addition to cautious intravenous administration of Na Cl , adjunctive drug therapy i s indicated. Which drug or drug class would be the most rational to use adjunctively, in addition to IV Na Cl and stopping the causative diuretic at least temporarily, to help correct sodium concentration?

A	Captopril
B	Furosemide
C	Spironolactone
D	Thiazide-like diuretic (eg, metolazone)
E	Triamterene

Question 27 Explanation: 

That a loop diuretic (furosemide, bumetanide, torsemide, or perhaps even ethacrynic acid) would be a rational choice for helping to manage diuretic-induced hyponatremia seems irrational, if not plain wrong. After all, these drugs are considered to be the “big guns” of all diuretics, capable of causing almost limitless dose-dependent diuresis—large increases of renal loss of water, sodium, potassium, and other ions. So, what is the explanation? When I described the actions of a thiazide or thiazide-like diuretic I said that they impair the kidney’s ability to form a normally dilute urine: in a relative sense they cause the loss of more Na+ than of free water, and so Na+ concentration in the blood falls (dilutional hyponatremia). The situation is essentially the opposite with loop diuretics. By reducing the medullary-to-cortical interstitial osmotic gradient (the countercurrent multiplier phenomenon), secondary to reduced Na+ transport out of the urine in the ascending limb of the Loop of Henle, they impair the ability of the kidneys to form a normally concentrated urine. In a relative sense, the urine formed in the presence of a loop agent therefore contains more water than sodium, and so the concentration of Na+ in the blood rises. This tends to correct the hyponatremia. Captopril (a), the prototype ACE inhibitor, tends to lower or not change blood Na+ concentrations, but it does not raise them. ACE inhibitorsreduce the formation of A-II, which normally stimulates aldosterone release from the adrenal cortex. Aldosterone causes the renal tubules to retain Na+ and lose K+. So when aldosterone release is reduced (due to less A-II available), the opposite occurs: Na+ (and water) elimination rises (but Na+ concentration tends not to change), and additional K+ is lost. Spironolactone (c) tends to do many of the same things that an ACE inhibitor does to the kidneys, but it works by blocking renal aldosterone receptors (leading to increased Na+ loss and K+ retention) and has no effects on AII’s synthesis or direct effects. Thiazides or related agents (d) are clearly the wrong choice: to reiterate an important point, of all the diuretics the thiazides and related agents are the most common cause of hyponatremia. Triamterene (and the related drug amiloride) are K+-sparing diuretics that act by blocking Na+ channels on the luminal face of the principal cells, thereby inhibiting Na+ for K+ exchange, in a manner that is not dependent on aldosterone. They do not raise plasma Na+ concentrations and are not effective or used for dilutional hyponatremia.

Question 28

The table below shows the urinary electrolyte excretion patterns typical of various  prototype  These are qualitative changes, and do not reflect the magnitude of the changes. They show whether excretion of an electrolyte (net amount) is increased or decreased; they do not reflect changes in urine concentrations of these substances. Which drug causes effects most s imilar, i f not identical, to unknown drug 2, above? Your answer choices are:  

A	Acetazolamide
B	Amiloride
C	Chlorthalidone
D	Furosemide
E	Hydrochlorothiazide

Question 28 Explanation: 

Drug 2 is furosemide, and there are several tip-offs to help you pick the right answer, some that are admittedly less helpful than the others. Not at all helpful in distinguishing between diuretics is the increased renal sodium loss. All the common diuretics do that. Next, note the increase in renal potassium loss. This is also not too helpful, since acetazolamide (a), the thiazide-like diuretic chlorthalidone (c), and hydrochlorothiazide (e) have a potassium-wasting effect similar to that of furosemide. How do you narrow things down from here, then? First, the data show that Drug 2 causes no increase in renal bicarbonate loss. From that you can infer no inhibition of carbonic anhydrase activity. That rules out, especially, acetazolamide (a; it is, after all, a strong carbonic anhydrase inhibitor). But the absence of any changes in bicarbonate loss should also lead you away from selecting a thiazide (e) or thiazide-like (c) agent, since most of them have at least some—but rather weak in comparison with acetazolamide—carbonic anhydrase inhibitory activity. Perhaps the best tip-off to help you distinguish between furosemide and a thiazide or thiazide-like drug? Loop diuretics increase renal calcium loss; thiazides and thiazide like agents do the opposite, causing a calcium-sparing effect. Changes in renal magnesium loss aren’t too helpful, since thiazides, thiazide-like agents, and loop diuretics all increase magnesium loss. So, here’s the full set of answers: Acetazolamide (a) has a profile that best matches drug 4 (note the markedly increased HCO3- loss and decreased Cl- loss). Be aware, too, that acetazolamide is also a potassium-wasting diuretic, a point that is often overlooked because we tend to talk about thiazides and loop diuretics as the “main” potassium-wasting agents. Amiloride’s (b) profile fits that of drug 3. More so than anything else, the give-away is the reduced renal K+ loss—not surprising since amiloride is classified as a potassium-sparing diuretic. Chlorthalidone (c) and hydrochlorothiazide (e), which are thiazide-like or true thiazide diuretics (respectively), would produce profiles like drug 1: K+ loss, a decrease of Ca2+ excretion, and variable effects on HCO3- loss due to variable effects (drug- and dose-dependent, but generally weak) on carbonic anhydrase. Rather than rehashing the sites and mechanisms by which the “main” diuretics cause their effects—that’s largely been addressed elsewhere above—what follows are some tips for arriving at a correct answer more easily. I’ll add some additional comments that may not have been emphasized before. Note that all the profiles show an increased (qualitative) renal excretion of Na+. The essence of this is that it reflects the fact that all the common diuretics do that. Indeed, this natriuretic effect (sodium-excreting effect) is part of the working definition of “diuretic.” The next step is to identify which agents increase renal potassium excretion and which do the opposite, because the main diuretics are either potassium-sparing or potassium-wasting. That will narrow your choices nicely. You should be able to place a drug in the proper potassium-related class instantaneously (with the possible exception of acetazolamide, a potassium-wasting drug, because we tend to emphasize its CA-inhibitory effects and overload other important properties; see the answer to Question 268 above). Finally, once you see that a drug’s profile involves increased K+ loss, you have narrowed your choices to a thiazide or thiazide-like agent (hydrochlorothiazide, chlorthalidone, metolazone, many others), a loop agent, or a CA inhibitor. Look now at what happens to urinary Ca2+ excretion. If it’s reduced, it’s a thiazide or a related agent (recall we can use these drugs for idiopathic hypercalciuria, an effect that capitalizes on reduced presence of Ca2+ in the urine due to reduced renal Ca2+ loss). If Ca2+ excretion is increased, it’s a loop diuretic. Now, how do you identify which agent is a CA inhibitor (ie, acetazol-amide)? In addition to looking at Na+ and K+, note especially what happens to HCO 3 - and Cl-. Acetazolamide causes profound urinary alkalinization from the HCO3- loss; so much so that the blood’s other major anion, Cl-, is retained. Just looking at the table you would probably rule out a thiazide (a) as being acetazolamide because I indicate that the effect on that anion is variable (+/-). How could you rule out triamterene, since we showed increased HCO3- loss with it? (It’s a slight effect, by the way, and CA inhibition is not its main nor an important mechanism or outcome, but you can’t tell from the table.) Look at the Cl- profile and you will see that acetazolamide is the only diuretic that lowers Cl- excretion. That’s because one of the blood’s major anions, HCO3-, is lost to such a great degree that the other main anion, Cl-, is conserved.

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II. Preview all questions below

1.After a few weeks on a drug that was prescribed by another physician, a patient reports fine tremors of his fingers, headache and fatigue, and transient GI More worrisome to him i s that he i s constantly thirsty and urinates copiously and frequently throughout the day and night. A 24-hour urine collection produces nearly 5 L of hypotonic urine. Blood tests show that levels of the causative drug are within i ts therapeutic range. Nonetheless, the cl inical picture leads you to hypothesize that the offending drug i s causing renal responses quite s imilar to a syndrome characterized by reduced production or renal response to ADH. Which drug most l ikely caused or contributed to these s igns and symptoms?

1. Diazepam
2. Fluoxetine
3. Haloperidol
4. Li thium
5. Phenytoin

2. A patient taking an oral diuretic for about 6 months presents with elevated fasting and postprandial blood glucose You check the patient’s HbA₁c and find i t i s elevated compared with normal baseline values obtained 6 months ago. You suspect the glycemic problems are diuretic-induced. What was the most l ikely cause?

1. Acetazolamide
2. Amiloride
3. Chlorothiazide
4. Spironolactone
5. Triamterene

3. A patient with severe heart failure i s in the ICU. His urine output i s dangerously You begin an intravenous infusion of dopamine at a usual therapeutic dose and urine output ri ses quickly and dramatically. What i s the most l ikely mechanism by which the dopamine caused this effect?

1. Blocked β-adrenergic receptors in the juxtaglomerular apparatus, thereby inhibiting renin release and susequent angiotensin-mediated aldosterone release from the adrenal cortex.
2. Directly inhibited a renal Na+, K+, 2Cl- cotransporter in the Loop of Henle.
3. Improved renal blood flow and glomerular fi l tration
4. Lowered the medullary-to-cortical osmotic gradient, such that normal urine concentrating mechanisms were impaired
5. Reduced the permeability of the ascending l imb, Loop of Henle, and of the collecting ducts, to water

4. Usual doses of a thiazide diuretic (eg, hydrochlorothiazide) produce a urine that i s relatively ri ch in sodium and potassium, but contains relatively l i ttle increase in urine volume (ie, comparatively l i ttle free water loss compared with the relative loss of ions). An action at what s i te in the nephron mainly accounts for the ability of the thiazides to cause these responses?

1. Ascending l imb of the loop of Henle
2. Cortical diluting segment of the proximal nephron
3. Cortical-to-medullary “countercurrent multiplier”
4. Descending l imb of the loop of Henle
5. Principal cells of the nephron

5. A patient with essential hypertension i s being treated with hydro-chlorothiazide and a calcium channel blocker, and i s doing He also takes atorvastatin for hypercholesterolemia, and aspirin to reduce his ri sk of an acute coronary syndrome. He i s now diagnosed with a seizure disorder. We begin therapy with one of the suitable anticonvulsants that, fortunately, does not alter the metabolism of any of the medications prescribed for his cardiovascular problems. We’ve also read that systemic administration of acetazolamide may prove to be a useful adjunct to the anticonvulsant therapy: the metabolic acidosis i t causes may help suppress seizure development or spread. So, we start acetazolamide therapy too. What i s the most l ikely outcome of adding the acetazolamide?

1. Excessive ri ses of plasma sodium concentration
2. Hypertensive cris i s (antagonism of both antihypertensive drugs)
3. Hypokalemia via synergistic actions with the thiazide
4. Spontaneous bleeding (potentiation of aspirin’s actions)
5. Sudden ci rculating volume expansion, onset of heart failure

6. A patient has very high plasma uric acid levels, has had two acute gout attacks in the last 8 months, and i s at imminent ri sk of developing acute uric acid We will treat the patient with proper anti-inflammatory drugs and other agents, but feel that reducing solubility of uric acid in the urine might help ward-off the development of renal problems. What drug i s best able to produce this desired renal effect vis-á-vis urate solubility without appreciably increasing systemic ri sks of the hyperuricemia?

1. Acetazolamide
2. Antidiuretic hormone (ADH) (vasopressin [VP])
3. Ethacrynic acid
4. Furosemide
5. Hydrochlorothiazide

7. A patient with heart failure has been managed with digoxin and furosemide and i s doing well by all measures, for 3 He develops acute rheumatoid arthritis and i s placed on rather large doses of a very efficacious  nonsteroidal anti-inflammatory drug—one  that inhibits both the  COX- 1 and -2 cyclooxygenase pathways. What i s the most l ikely outcome of adding the NSAID?

1. Hyperchloremic acidosis indicative of acute diuretic toxicity
2. Dramatic increase of furosemide’s potassium-sparing effects
3. Edema, weight gain, and other s igns/symptoms indicative of reduced diuresis
4. Increased digoxin excretion
5. Reduced digoxin effects because the NSAID competes with digoxin for myocyte receptor-binding s i tes

8. A patient was in a recumbent position for a 45-minute oral surgery procedure. When the surgery was completed the patient stood up quickly and promptly got l ight-headed and fainted. The cause was hypotension due to hypovolemia from excessive diuresis, attributed to a drug prescribed by her physician and taken for several What drug was the most l ikely cause?

1. Acetazolamide
2. Furosemide
3. Hydrochlorothiazide
4. Spironolactone
5. Triamterene

9. One of your cl inic patients i s being treated with Which statement correctly describes a property of this drug?

1. Contraindicated in heart failure, especially i f severe
2. Inhibits Na+ reabsorption in the proximal renal tubule of the nephron
3. Interferes with aldosterone synthesis
4. Is a rational choice for a patient with an adrenal cortical tumor
5. Is generally preferred to a thiazide in most patients with essential hypertension

10. Chlorthalidone and torsemide are members of different diuretic classes, in terms of mechanisms of action and chemical structure, but they share the ability to cause Which statement best describes the general and common mechanism by which these drugs cause their effects that lead to net renal potassium loss?

1. Act as  aldosterone receptor agonists, thereby favoring K+ loss
2. Block proximal tubular ATP-dependent secretory pumps  for K+
3. Increase delivery of Na+ to principal cells in the distal nephron, where tubular Na+ i s transported into the cells via a sodium channel in exchange for K+, which gets eliminated in the urine
4. Stimulate a proximal tubular Na, K-ATPase such that K+ i s actively pumped into the urine
5. Lower distal tubular urine osmolality, thereby favoring passive diffusion of K+ into the urine

11. A 52-year-old man presents to your cl inic for his fi rst vis i t with you, after moving from a distant His only medications are a  statin, aspirin, (81 mg/day) and metolazone. The pharmacist who fi l led his prescriptions explained to the gentleman why he was taking the  aspirin and the statin, but merely referred to the metolazone as a “water pill.” Thus, you’re asked about i t. What i s the most l ikely reason why the metolazone was prescribed?

1. Adjunctive management of an adrenal cortical tumor
2. Adjunctive management of hepatic ci rrhosis from years of excessive alcohol consumption
3. Hypertension accompanied by a history of gout and diabetes
4. Treatment of essential hypertension
5. Treatment of edema and ascites from heart failure

12. Urinary potassium concentrations are measured before and after several weeks of administering a loop diuretic (eg, furosemide, at typical daily dosages). We find that post-treatment urine K+ concentrations are substantially lower than those measured at What i s  the  most l ikely explanation for this observation?

1. An expected response to the drug
2. Loop diuretics cause potassium-wasting only in in vi tro experimental models
3. Measurements of post-treatment urine K+ concentrations were erroneous
4. The patient has hypoaldosteronism from bilateral adrenalectomy
5. Potassium secretion by principal cells of the nephron are inhibited by loop diuretics

13. You have just completed your third-year medicine clerkship, having spent some time in general internal medicine, cardiology, nephrology, and endocrine-metabolism cl In each of those venues you have reviewed charts of patients taking eplerenone. What phrase best describes a characteristic or other property of this drug?

1. Facilitates renal sodium water loss and potassium retention
2. Inhibits steroidogenesis (steroid hormone production)
3. Mimics  antidiuretic hormone (vasopressin)
4. Specifically inhibits  aldosterone synthesis
5. Used to counteract glycosuria in patients with type 1 or 2 diabetes mellitus

14. A 58-year-old man with a history of hypertension and hypercholesterolemia i s diagnosed with heart We start therapy with furosemide as one of several medications. Which of the following would you expect to occur along with the increased urine volume caused by this diuretic?

1. Dilute (hypotonic) urine because normal urine concentrating mechanisms are impaired
2. Hypercalcemia due to impaired renal Ca 2+ excretion
3. Reduced net excretion of Cl –
4. Metabolic acidosis due to increased renal bicarbonate excretion
5. Reduced plasma uric acid (urate) concentrations because of increased urate excretion

15. A patient post-head trauma i s in the neurosurgery unit at your He has become hypervolemic and hyponatremic from two  main causes: (1) trauma probably increased vasopressin release from his posterior pituitary gland; and (2) the staff was not sufficiently careful when administering IV fluids, which further increased blood volume and lowered blood sodium concentrations. This patient also has symptomatic heart failure that would be further compromised by additional ri ses of blood volume, even i f s l ight or short-lived. He had been on a  number of drugs prior to admission. One was oral potassium-supplements to counteract diuretic-induced hypokalemia. Unfortunately, the supplement dose was excessive, and the  patient was borderline-hyperkalemic too. What drug would be the  most rational to  administer, with the  goal of normalizing or at least improving blood volume and electrolyte composition and without further compromising the patient’s hemodynamic status?

1. Conivaptan
2. Mannitol
3. Metolazone
4. Sodium chloride 0.9% (normal saline)
5. Spironolactone

16. A 60-year-old man has multiple medical problems, including severe hepatic ci rrhosis from hepatitis at age 40, and over 30 years of excessive alcohol intake. Three days after a vis i t to a physician, who prescribed a drug for a condition unrelated to the l iver dysfunction, the man i s found He i s transported to the emergency department. What drug, prescribed 3 days before, most l ikely induced or contributed to the onset coma in this man?

1. Acetazolamide
2. Eplerenone
3. Furosemide
4. Hydrochlorothiazide
5. Triamterene

17. Your patient, who l ives in Death Valley, California (240 feet below sea level) i s planning a vacation that includes a short hike to the top of Mount Everest (approx. 29,000 feet above sea level). You’re concerned about “altitude s i ” He has no other s ignificant medical conditions, and takes no other drugs that would interact with the drug you will prescribe for his trip. Which drug would you recommend that this adventurer start taking before his trek, and continue until he returns to an altitude much closer to sea level?

1. Acetazolamide
2. Amiloride
3. Bumetanide
4. Furosemide
5. Sprionolactone
6. Triamterene

18. A patient presents with chronic open angle What “renal” drug, or a drug in the same chemical and pharmacologic class, might be prescribed as an adjunct to lower intraocular pressure and help manage this condition?

1. Acetazolamide
2. Amiloride
3. Furosemide
4. Sprionolactone
5. Triamterene

19. A patient has unacceptably low cardiac output and intense reflexmediated sympathetic activation of the peripheral vasculature that i s attempting, unsuccessfully, to keep vi tal organ perfusion pressure sufficiently The patient i s edematous because of the poor cardiac function and renal compensations for i t. Which one of the following drugs should be avoided in this patient because i t i s  most l ikely to  compromise function of the already-failing heart and the ci rculatory system overall?

1. Amiloride
2. Ethacrynic acid
3. Hydrochlorothiazide
4. Mannitol
5. Spironolactone

20. A patient i s recently diagnosed with adrenal cortical Among the pertinent Cushingoid s igns and symptoms are hypertension and weight gain from fluid retention; and hypernatremia and hypokalemia. Which drug would be the most rational to prescribe, alone or adjunctively, to specifically antagonize both the renal and the systemic effects of the hormone excess?

1. Acetazolamide
2. Amiloride
3. Furosemide
4. Metolazone
5. Spironolactone

21. A patient has been referred to your academic medical center because of recent-onset ventricular ectopy, second-degree AV nodal block, chromatopsia, and other extracardiac s igns and symptoms of digoxin intoxication. His family doctor, who has been treating him for a host of common medical problems over the last 30 years, had prescribed furosemide and digoxin for this gentleman’s heart Blood tests show that digoxin levels are well within a normal range. We believe the problems are  diuretic-induced. What did the  diuretic most l ikely do to  precipitate the digoxin toxicity?

1. Caused hypercalcemia
2. Caused hypokalemia
3. Caused hyponatremia
4. Displaced digoxin from ti ssue binding s i tes
5. Inhibited digoxin’s metabolic elimination

22. A 48-year-old man with bilateral diabetic nephropathy develops acute heart failure and additional, and s ignificant, declines of renal function (eg, declines of GFR) as two of several consequences  of You will administer appropriate antibiotics, vasodilators, and cardiac inotropes, but also need to administer a diuretic to promptly reduce ci rculating fluid volume and “unload” the failing heart. What drug would be most appropriate in terms of managing the hemodynamic problems for this patient?

1. Acetazolamide
2. Hydrochlorothiazide
3. Mannitol
4. Torsemide
5. Metolazone (or chlorthalidone)

23. A patient with severe infectious disease i s being treated with an aminoglycoside Which diuretic should be avoided, i f possible, for this patient, because of the ri sk of a serious adverse effect shared by both drugs?

1. Acetazolamide
2. Furosemide
3. Metolazone
4. Spironolactone
5. Triamterene

24. Amiloride i s a useful drug for managing hypokalemia caused by other drugs. Which phrase best describes the  mechanism by which i t causes i ts potassium-sparing effects?

1. Blocks the agonist effects of aldosterone with i ts renal tubular receptors
2. Blocks distal tubular sodium channels and, ultimately, Na+-K+ exchange
3. Hastens metabolic inactivation of aldosterone
4. Stimulates a proximal tubular Na, K-ATPase
5. Suppresses cortisol and aldosterone synthesis and release in the adrenal cortex

25. A patient who admits to drinking many l i ters of water each day has had recurrent episodes of symptomatic hyponatremia, and i s at great ri sk of recurrences. Because of another medical problem he now requires administration of a Which drug i s most l ikely to precipitate another recurrence of the hyponatremia, whether or not the patient’s daily water intake i s reduced to a more acceptable level?

1. Bumetanide
2. Ethacrynic acid
3. Furosemide
4. Hydrochlorothiazide
5. Torsemide

26. A hypertensive patient has been on long-term therapy with l i s inopril, a long-acting ACE inhibitor, for The drug i sn’t controlling pressure as well as wanted, so the physician decides to add amiloride. What i s a potential, i f not l ikely, outcome of adding this diuretic to the ACE inhibitor regimen?

1. Blood pressure would ri se abruptly
2. Blood pressure would fall again once amiloride was added (better BP control), but there’s a l ikelihood that the patient would become hyperkalemic
3. Cardiac depression, because both drugs directly depress heart rate and left ventricular contractility
4. Diabetes insipidus-like syndrome with production of large volumes of dilute urine, plus  dilutional hyponatremia
5. Hypokalemia because of the two drugs’ additive or synergestic effects on renal potassium handling

27.Consider again the patient described in the previous He now presents with diuretic-induced hyponatremia. The condition is symptomatic and severe enough that the excessively low Na+ concentration needs to be corrected promptly. In addition to cautious intravenous administration of Na Cl , adjunctive drug therapy i s indicated. Which drug or drug class would be the most rational to use adjunctively, in addition to IV Na Cl and stopping the causative diuretic at least temporarily, to help correct sodium concentration?

1. Captopril
2. Furosemide
3. Spironolactone
4. Thiazide-like diuretic (eg, metolazone)
5. Triamterene

28. The table below shows the urinary electrolyte excretion patterns typical of various  prototype  These are qualitative changes, and do not reflect the magnitude of the changes. They show whether excretion of an electrolyte (net amount) is increased or decreased; they do not reflect changes in urine concentrations of these substances.

Which drug causes effects most s imilar, i f not identical, to unknown drug 2, above?

Your answer choices are:

1. Acetazolamide
2. Amiloride
3. Chlorthalidone
4. Furosemide
5. Hydrochlorothiazide