Your answer choices are:

a. Acetazolamide

b. Amiloride

c. Chlorthalidone

d. Furosemide

e. Hydrochlorothiazide

Which drug causes effects most similar, if not identical, to unknown drug 2, above?

Renal System and Diuretic Pharmacology

Answers

264. The answer is d. (Brunton, pp 448-450; Katzung, pp 513-517, 1158t.) 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).

265. The answer is c. (Brunton, pp 686-690; Katzung, pp 260-261.) 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).

266. The answer is c. (Brunton, pp 288, 351-359; Katzung, pp 84t, 136f, 138t, 141.) 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.

267. The answer is b. (Brunton, pp 686-690; Katzung, pp 251-255, 260-261.) 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.

268. The answer is c. (Brunton, pp 677-681; Katzung, pp 256-257, 261-262, 265.) 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.

269. The answer is a. (Brunton, pp 677-681; Katzung, pp 256-257.) 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 (less likely 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.

270. The answer is c. (Brunton, pp 682-684; Katzung, pp 258-260.) 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.

271. The answer is b. (Brunton, pp 682-686; Katzung, pp 258-260.) 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.

272. The answer is d. (Brunton, pp 690-693, 1841; Katzung, pp 261-263, 711, 739.) 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 receptor-blocking 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.)

273. The answer is c. (Brunton, pp 676-677, 682-686; Katzung, pp 251-256, 259-261.) 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.

274. The answer is d.

Stay updated, free articles. Join our Telegram channel

Join