Pharmacology_Katzung

Pharmacology_Katzung. The collecting tubule system that connects the DCT to the renal pelvis and the ureter consists of several sequential tubular segments: the connecting tubule, the collecting tubule, and the collecting duct (formed by the connection of two or more collecting tubules). Although these tubule segments may be anatomically distinct, the physiologic gradations are more gradual, and in terms of diuretic activity it is easier to think of this complex as a single segment of the nephron containing several distinct cell types. The collecting tubule system is responsible for only 2–5% of NaCl reabsorption by the kidney. Despite this small contribution, it plays an important role in renal physiology and in diuretic action. As the final site of NaCl reabsorption, the collecting system is responsible for tight regulation of body fluid volume and for determining the final Na+ concentration of the urine. Furthermore, the collecting system is the site at which mineralocorticoids exert a significant


Pharmacology_Katzung

Pharmacology_Katzung. for tight regulation of body fluid volume and for determining the final Na+ concentration of the urine. Furthermore, the collecting system is the site at which mineralocorticoids exert a significant influence.


Pharmacology_Katzung

Pharmacology_Katzung. R Cl – Lumen-urine Collecting tubule Interstitium-blood Na+ K+ Cl – Na+ K+ Aldosterone Principal cell Intercalated cell H+ HCO3 – ENaC ++ATP ATP FIGURE 15–5 Ion transport pathways across the luminal and basolateral membranes of collecting tubule and collecting duct cells. Inward diffusion of Na+ via the epithelial sodium channel (ENaC) leaves a lumen-negative potential, which drives reabsorption of Cl− and efflux of K+. R, aldosterone receptor. Lastly, this is the most important site of K+ secretion by the kidney and the site at which virtually all diuretic-induced changes in K+ balance occur.


Pharmacology_Katzung

Pharmacology_Katzung. The mechanism of NaCl reabsorption in the collecting tubule system is distinct from the mechanisms found in other tubule segments. The principal cells are the major sites of Na+, K+, and water transport (Figures 15–5 and 15–6), and the intercalated cells (α, β) are the primary sites of H+ (α cells) or bicarbonate (β cells) secretion. The α and β intercalated cells are very similar, except that the membrane locations of the H+-ATPase and Cl−/ HCO3− exchanger are reversed. Principal cells do not contain apical cotransport systems for Na+ and other ions, unlike cells in other nephron segments. Principal cell membranes exhibit separate ion channels for Na+ and K+. Since these channels exclude anions, transport of Na+ or K+ leads to a net movement of charge across the membrane. Because Na+ entry into the principal cell predominates over K+ secretion into the lumen, a 10–50 mV lumen-negative electrical potential develops. Sodium that enters the principal cell from the tubular fluid is then


Pharmacology_Katzung

Pharmacology_Katzung. into the principal cell predominates over K+ secretion into the lumen, a 10–50 mV lumen-negative electrical potential develops. Sodium that enters the principal cell from the tubular fluid is then transported back to the blood via the basolateral Na+/K+-ATPase (Figure 15–5). The 10–50 mV lumen-negative electrical potential drives the transport of Cl− back to the blood via the paracellular pathway and draws K+ out of cells through the apical membrane K+ channel. Thus, there is an important relationship between Na+ delivery to the collecting tubule system and the resulting secretion of K+. Upstream diuretics increase Na+ delivery to this site and enhance K+ secretion. If Na+ is delivered to the collecting system with an anion that cannot be reabsorbed as readily as Cl− (eg, HCO3−), the lumen-negative


Pharmacology_Katzung

Pharmacology_Katzung. AQP3,4 H2O FIGURE 15–6 Water transport across the luminal and basolateral membranes of collecting duct cells. Above, low water permeability exists in the absence of antidiuretic hormone (ADH). Below, in the presence of ADH, aquaporins are inserted into the apical membrane, greatly increasing water permeability. AQP2, apical aquaporin water channels; AQP3,4, basolateral aquaporin water channels; V2, vasopressin V2 receptor.


Pharmacology_Katzung

Pharmacology_Katzung. potential is increased, and K+ secretion is enhanced. This mechanism, combined with enhanced aldosterone secretion due to volume depletion, is the basis for most diuretic-induced K+ wasting. Reabsorption of Na+ via the epithelial Na channel (ENaC) and its coupled secretion of K+ are regulated by aldosterone. This steroid hormone, through its actions on gene transcription, increases the activity of both the apical membrane channels and the basolateral Na+/K+-ATPase. This leads to an increase in the transepithelial electrical potential and a dramatic increase in both Na+ reabsorption and K+ secretion.


Pharmacology_Katzung

Pharmacology_Katzung. The collecting tubule system is also the site at which the final urine concentration is determined. In addition to their role in control of Na+ absorption and K+ secretion (Figure 15–5), principal cells also contain a regulated system of water channels (Figure 15–6). Antidiuretic hormone (ADH, also called arginine vasopressin, AVP) controls the permeability of these cells to water by regulating the insertion of pre-formed water channels (aquaporin-2, AQP2) into the apical membrane. Vasopressin receptors in the vasculature and central nervous system (CNS) are V1 receptors, and those in the kidney are V2 receptors. V2 receptors act via a Gs protein-coupled, cAMP-mediated process. In the absence of ADH, the collecting tubule (and duct) is impermeable to water, and dilute urine is produced. ADH markedly increases water permeability, and this leads to the formation of a more concentrated urine. ADH also stimulates the insertion of urea transporter UT1 (UT-A, UTA-1) molecules into the


Pharmacology_Katzung

Pharmacology_Katzung. ADH markedly increases water permeability, and this leads to the formation of a more concentrated urine. ADH also stimulates the insertion of urea transporter UT1 (UT-A, UTA-1) molecules into the apical membranes of collecting duct cells in the medulla.


Pharmacology_Katzung

Pharmacology_Katzung. Urea concentration in the medulla plays an important role maintaining the high osmolarity of the medulla and in the concentration of urine. ADH secretion is regulated by serum osmolality and by volume status. A new class of drugs, the vaptans (see Agents That Alter Water Excretion), are ADH antagonists. A number of locally produced compounds exhibit physiologic effects within the kidney and are therefore referred to as autacoids, or paracrine factors. Several of these autacoids (adenosine, the prostaglandins, and urodilatin) appear to have important effects on the pharmacology of diuretics. Since these effects are complex, they will be treated independently of the individual tubule segments discussed above.


Pharmacology_Katzung

Pharmacology_Katzung. Adenosine is an unphosphorylated ribonucleoside whose actions in the kidney have been intensively studied. As in all tissues, renal adenosine concentrations rise in response to hypoxia and ATP consumption. In most tissues, hypoxia results in compensatory vasodilation and, if cardiac output is sufficient, increased blood flow. The kidney has different requirements because increased blood flow leads to an increase in glomerular filtration rate (GFR) and greater solute delivery to the tubules. This increased delivery would increase tubule work and ATP consumption. In contrast, in the hypoxic kidney, adenosine actually decreases blood flow and GFR. Because the medulla is always more hypoxic than the cortex, adenosine increases Na+ reabsorption from the reduced flow in the cortex, so that delivery to medullary segments will be even further reduced.


Pharmacology_Katzung

Pharmacology_Katzung. There are four distinct adenosine receptors (A1, A2a, A2b, and A3), all of which have been found in the kidney. However, probably only one of these (A1) is of importance. The adenosine A1 receptor is found on the pre-glomerular afferent arteriole, as well as the PCT and most other tubule segments. Adenosine is known to affect ion transport in the PCT, the medullary TAL, and collecting tubules. In addition, adenosine (via A1 receptors on the afferent arteriole) reduces blood flow to the glomerulus (and GFR) and is also the key signaling molecule in the process of tubuloglomerular feedback. Adenosine receptor antagonists have generally been found to block the enhancement of NHE3 activity and thus exhibit diuretic activity (see below). It is particularly interesting that unlike other diuretics that act upstream of the collecting tubules, adenosine antagonists do not cause wasting of K+.


Pharmacology_Katzung

Pharmacology_Katzung. Prostaglandins contribute importantly to renal physiology and to the function of many other organs (see Chapter 18). Five prostaglandin subtypes (PGE2, PGI2, PGD2, PGF2α, and thromboxane [TXA2]) are synthesized in the kidney and have receptors in this organ. The role of some of these receptors in renal physiology is not yet completely understood. However, PGE2 (acting on EP1, EP3, and possibly EP2 receptors) has been shown to play a role in the activity of certain diuretics. Among its many actions, PGE2 blunts Na+ reabsorption in the TAL of Henle’s loop and ADH-mediated water transport in collecting tubules. These actions of PGE2 contribute significantly to the diuretic efficacy of loop diuretics. Blockade of prostaglandin synthesis with NSAIDs can therefore interfere with loop diuretic activity.


Pharmacology_Katzung

Pharmacology_Katzung. The natriuretic peptides (ANP, BNP, and CNP, see Chapter 17) induce natriuresis through several different mechanisms. ANP and BNP are synthesized in the heart, while CNP comes primarily from the CNS. Some of these peptides exert both vascular effects (see Chapter 17) and sodium transport effects in the kidney, which participate in causing natriuresis. A fourth natriuretic peptide, urodilatin, is structurally very similar to ANP but is synthesized and functions only in the kidney. Urodilatin is made in distal tubule epithelial cells and blunts Na+ reabsorption through effects on Na+ uptake channels and Na+/K+-ATPase at the downstream collecting tubule system. In addition, through effects on vascular smooth muscle, it reduces glomerular afferent and increases glomerular efferent vasomotor tone. These effects cause an increase in GFR, which adds to the natriuretic activity. Ularitide is a recombinant peptide that mimics the activity of urodilatin.


Pharmacology_Katzung

Pharmacology_Katzung. The cardiac peptides ANP and BNP increase GFR through effects on glomerular arteriolar vasomotor tone and also exhibit diuretic activity. CNP has very little diuretic activity. Three agents in this group are in clinical use or under investigation: nesiritide (BNP), carperitide (ANP, available only in Japan), and ularitide (urodilatin, under investigation). Intravenous ularitide has been studied extensively for use in acute heart failure. Experimentally, it can improve cardiovascular function and promote diuresis without reducing creatinine clearance, but it has not yet proved to be clinically useful. There is also evidence that nesiritide (simulating BNP) may enhance the activity of other diuretics while helping to maintain stable renal function. However, the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study did not show an improvement in outcomes with nesiritide compared with regular care in patients with heart failure.


Pharmacology_Katzung

Pharmacology_Katzung. Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the epithelial cells of the PCT (Figure 15–2), where it catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane and rehydration of CO2 to TABLE 15–3 Carbonic anhydrase inhibitors used H2CO3 in the cytoplasm as previously described. By blocking orally in the treatment of glaucoma. carbonic anhydrase, inhibitors blunt NaHCO3 reabsorption and cause diuresis. Carbonic anhydrase inhibitors were the forerunners of mod-Dichlorphenamide 50 mg 1–3 times daily ern diuretics. They were discovered in 1937 when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used at sites other than the kidney. The ciliary body of the eye secretes as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic


Pharmacology_Katzung

Pharmacology_Katzung. rarely used at sites other than the kidney. The ciliary body of the eye secretes as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is HCO3− from the blood into the aqueous humor. Likewise, formation of cerebrospinal fluid (CSF) by the choroid plexus involves acetazolamide. HCO3− secretion. Although these processes remove HCO3− from the blood (the direction opposite of that in the proximal tubule), they are similarly inhibited by carbonic anhydrase inhibitors. The carbonic anhydrase inhibitors are well absorbed after oral administration. An increase in urine pH from the HCO3− diuresis is apparent within 30 minutes, is maximal at 2 hours, and persists


Pharmacology_Katzung

Pharmacology_Katzung. A. Glaucoma for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule S2 segment. Therefore, dosing must be The reduction of aqueous humor formation by carbonic anhyreduced in renal insufficiency. drase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma in some patients, making it the most common indication for use of carbonic anhydrase inhibitors (see Table 10–3). Topically active agents, Inhibition of carbonic anhydrase activity profoundly depresses which reduce intraocular pressure without producing renal or HCO3− reabsorption in the PCT. At maximal safe inhibitor dos-systemic effects, are available (dorzolamide, brinzolamide). age, 85% of the HCO3− reabsorptive capacity of the superficial PCT is inhibited. Some HCO3− can still be absorbed at other


Pharmacology_Katzung

Pharmacology_Katzung. age, 85% of the HCO3− reabsorptive capacity of the superficial PCT is inhibited. Some HCO3− can still be absorbed at other B. Urinary Alkalinization nephron sites by carbonic anhydrase–independent mechanisms, Uric acid and cystine are relatively insoluble and may form stones so the overall effect of maximal acetazolamide dosage is only about in acidic urine. Therefore, in cystinuria, a disorder of cystine reab45% inhibition of whole kidney HCO3− reabsorption. Neverthesorption, solubility of cystine can be enhanced by increasing urinary less, carbonic anhydrase inhibition causes significant HCO3− losses pH to 7–7.5 with carbonic anhydrase inhibitors. In the case of uric and hyperchloremic metabolic acidosis (Table 15–2). Because − − acid, pH needs to be raised only to 6–6.5. In the absence of HCO3 of reduced HCO3 in the glomerular filtrate and the fact that − administration, these effects of acetazolamide last only 2–3 days,


Pharmacology_Katzung

Pharmacology_Katzung. HCO3 depletion leads to enhanced NaCl reabsorption by the so prolonged therapy requires oral HCO3−. As a result, these agents remainder of the nephron, the diuretic efficacy of acetazolamide have proved to be of limited utility for this indication. decreases significantly with use over several days. At present, the major clinical applications of acetazolamide


Pharmacology_Katzung

Pharmacology_Katzung. decreases significantly with use over several days. At present, the major clinical applications of acetazolamide C. Metabolic Alkalosis involve carbonic anhydrase–dependent HCO3− and fluid transport Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid TABLE 15–2 Changes in urinary electrolyte patterns levels. However, when the alkalosis is due to excessive use of diuretand body pH in response to diuretic ics in patients with severe heart failure, replacement of intravascular drugs. volume may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may appear following the correction of respiratory acidosis. D. Acute Mountain Sickness


Pharmacology_Katzung

Pharmacology_Katzung. D. Acute Mountain Sickness Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. The symptoms are usually mild and last for a few days. In more seri ous cases, rapidly progressing pulmonary or cerebral edema can be life-threatening. By decreasing CSF formation and by decreas+, increase; −, decrease; 0, no change; ↓, acidosis; ↑, alkalosis. ing the pH of the CSF and brain, acetazolamide can increase ventilation and diminish symptoms of mountain sickness. This mild metabolic central and CSF acidosis is also useful in the treatment of sleep apnea. E. Other Uses


Pharmacology_Katzung

Pharmacology_Katzung. E. Other Uses Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of epilepsy and in some forms of hypokalemic periodic paralysis. They are also useful in treating patients with CSF leakage (usually caused by tumor or head trauma, but often idiopathic). By reducing the rate of CSF formation and intracranial pressure, carbonic anhydrase inhibitors can significantly slow the rate of CSF leakage. They also increase urinary phosphate excretion during severe hyperphosphatemia. Finally, acetazolamide may have a role in the treatment of Meniere’s disease, nephrogenic diabetes insipidus, idiopathic intracranial hypertension, and Kleine-Levin syndrome (episodes of hypersomnia and cognitive and behavioral abnormalities). A. Hyperchloremic Metabolic Acidosis


Pharmacology_Katzung

Pharmacology_Katzung. A. Hyperchloremic Metabolic Acidosis Acidosis predictably results from chronic reduction of body HCO3− stores by carbonic anhydrase inhibitors (Table 15–2) and limits the diuretic efficacy of these drugs to 2 or 3 days. Unlike the diuretic effect, acidosis persists as long as the drug is continued. B. Renal Stones Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use. Calcium phosphate salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced. C. Renal Potassium Wasting


Pharmacology_Katzung

Pharmacology_Katzung. C. Renal Potassium Wasting Potassium wasting can occur because the increased Na+ presented to the collecting tubule (with HCO3−) is partially reabsorbed, increasing the lumen-negative electrical potential in that segment and enhancing K+ secretion. This effect can be counteracted by simultaneous administration of potassium chloride or a K+-sparing diuretic. Potassium wasting is theoretically a problem with any diuretic that increases Na+ delivery to the collecting tubule. In addition to potassium wasting, carbonic anhydrase inhibitors can lead to phosphorus wasting, and even symptomatic hypophosphatemia has been reported with these agents. Therefore, both serum potassium and serum phosphorus should be monitored in patients who are being treated chronically with these agents. D. Other Toxicities


Pharmacology_Katzung

Pharmacology_Katzung. D. Other Toxicities Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity. Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur. Carbonic anhydrase inhibitor–induced alkalinization of the urine decreases urinary excretion of NH4+ (by converting it to rapidly reabsorbed NH3) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis.


Pharmacology_Katzung

Pharmacology_Katzung. In the normal individual, the proximal convoluted tubule reabsorbs almost all of the glucose filtered by the glomeruli. Ninety percent of the glucose reabsorption occurs through SGLT2 (Figure 15–2), but inhibiting this transporter using the currently available drugs will result in glucose excretion of only 30–50% of the amount filtered. Although we have known about the proximal tubule sodium/glucose cotransporter for many years, the inhibitors of this transport channel were developed only recently. Four SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin, and ipragliflozin [available in Japan]) are currently available. Angiotensin II has been shown to induce SGLT2 production via the AT1 receptor. Thus, blockade of the renin-angiotensinaldosterone axis may result in lower SGLT2 availability.


Pharmacology_Katzung

Pharmacology_Katzung. The SGLT2 inhibitors are rapidly absorbed by the gastrointestinal (GI) tract. The elimination half-life of dapagliflozin is 10–12 hours, and up to 70% of the given dose is excreted in the urine in the form of 3-O-glucuronide (only around 2% of the drug is excreted unchanged in the urine). Although the drug levels are higher with more severe renal failure, urinary glucose excretion would also decline as chronic kidney disease worsens. The dose of canagliflozin is recommended not to exceed 100 mg/d with an estimated GFR of 45–59. The drugs are not recommended in patients with more severe renal failure or advanced liver disease. Drug-drug interactions are a consideration with these drugs. For example, concomitant rifampin administration reduces the total exposure to dapagliflozin by 22%.


Pharmacology_Katzung

Pharmacology_Katzung. Currently, the only indication for the use of these drugs is as third-line therapy for diabetes mellitus (see Chapter 41). SGLT2 inhibitors will reduce the hemoglobin A1c by 0.5–1.0%, similar to other oral hypoglycemic agents. Even though SGLT2 inhibitors are not indicated for other diagnoses, they do have other minor effects. SGLT2 inhibitors will result in an average weight loss of 3.2 kg versus a weight gain of 1.2 kg with glipizide. It is not clearly established how much of this is due to the diuretic effect, but it is notable that SGLT2 inhibitors also induce a drop in systolic blood pressure by an average of 5.1 mm Hg, compared with an increase in systolic blood pressure of approximately 1 mm Hg after starting sitagliptin. In one study, ipragliflozin resulted in an increase in urine volume from day 1 to day 3. There was a 0.7-kg decrease in body weight by day 3 compared to day 1. Both urine sodium and urine potassium excretion increased with the use of ipragliflozin, but the


Pharmacology_Katzung

Pharmacology_Katzung. volume from day 1 to day 3. There was a 0.7-kg decrease in body weight by day 3 compared to day 1. Both urine sodium and urine potassium excretion increased with the use of ipragliflozin, but the serum concentrations of both electrolytes remained stable. Thus, it is likely that at least part of the weight loss is due to the diuretic effect of the drugs. Recently there have also been reports of acute kidney injury (AKI) with these drugs. At this point, it is unclear how much the diuretic and blood pressure-lowering effects of these drugs contribute to the reported AKI.


Pharmacology_Katzung

Pharmacology_Katzung. SGLT2 inhibitor therapy is associated with a low incidence of hypoglycemia (3.5% versus 40.8% with glipizide). There is a sixfold increased incidence of genital fungal infection in women and a slightly higher risk of urinary tract infections (8.8% versus 6.1%). All of these agents have been shown to have no or minimal effects on serum electrolyte concentrations. Loop diuretics selectively inhibit NaCl reabsorption in the TAL. Because of the large NaCl absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available. The two prototypical drugs of this group are furosemide and ethacrynic acid (Table 15–4). The structures of these diuretics are shown in Figure 15–7. In addition to furosemide, bumetanide and torsemide are sulfonamide-based loop diuretics.


Pharmacology_Katzung

Pharmacology_Katzung. Ethacrynic acid—not a sulfonamide derivative—is a phenoxyacetic acid derivative containing adjacent ketone and methylene groups (Figure 15–7). The methylene group (shaded in figure) forms an adduct with the free sulfhydryl group of cysteine. The cysteine adduct appears to be the active form of the drug. Organic mercurial diuretics also inhibit salt transport in the TAL but are no longer used because of their toxicity. The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion. Absorption TABLE 15–4 Typical dosages of loop diuretics. Bumetanide 0.5–2 mg 1As single dose or in two divided doses. FIGURE 15–7 Two loop diuretics. The shaded methylene group on ethacrynic acid is reactive and may combine with free sulfhydryl groups.


Pharmacology_Katzung

Pharmacology_Katzung. of oral torsemide is more rapid (1 hour) than that of furosemide (2–3 hours) and is nearly as complete as with intravenous administration. Bumetanide pharmacokinetics are similar to those of torsemide, but bumetanide is a much more potent loop diuretic. The duration of effect for furosemide is usually 2–3 hours. The effect of torsemide lasts 4–6 hours. Half-life depends on renal function. Since loop agents act on the luminal side of the tubule, their diuretic activity correlates with their secretion by the proximal tubule. Reduction in the secretion of loop diuretics may result from simultaneous administration of agents such as NSAIDs or probenecid, which compete for weak acid secretion in the proximal tubule. Metabolites of ethacrynic acid and furosemide have been identified, but it is not known whether they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. Because of the variable


Pharmacology_Katzung

Pharmacology_Katzung. it is not known whether they have any diuretic activity. Torsemide has at least one active metabolite with a half-life considerably longer than that of the parent compound. Because of the variable bioavailability of furosemide and the more consistent bioavailability of torsemide and bumetanide, the equivalent dosages of these agents are unpredictable, but estimates are presented in Table 15–5.


Pharmacology_Katzung

Pharmacology_Katzung. Loop diuretics inhibit NKCC2, the luminal Na+/K+/2Cl− transporter in the TAL of Henle’s loop. By inhibiting this transporter, TABLE 15–5 Relative potency of loop diuretics. Bumetanide 0.5 mg Ethacrynic acid ∼50 mg 1Doses are approximate as bioavailability of furosemide is variable.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 15–5 Relative potency of loop diuretics. Bumetanide 0.5 mg Ethacrynic acid ∼50 mg 1Doses are approximate as bioavailability of furosemide is variable. the loop diuretics reduce the reabsorption of NaCl and also diminish the lumen-positive potential that comes from K+ recycling (Figure 15–3). This positive potential normally drives divalent cation reabsorption in the TAL (Figure 15–3), and by reducing this potential, loop diuretics cause an increase in Mg2+ and Ca2+ excretion. Prolonged use can cause significant hypomagnesemia in some patients. Since vitamin D–induced intestinal absorption and parathyroid hormone–induced renal reabsorption of Ca2+ can be increased, loop diuretics do not generally cause hypocalcemia. However, in disorders that cause hypercalcemia, Ca2+ excretion can be enhanced by treatment with loop diuretics combined with saline infusion.


Pharmacology_Katzung

Pharmacology_Katzung. Loop diuretics have also been shown to induce expression of the cyclooxygenase COX-2, which participates in the synthesis of prostaglandins from arachidonic acid. At least one of these prostaglandins, PGE2, inhibits salt transport in the TAL and thus participates in the renal actions of loop diuretics. NSAIDs (eg, indomethacin), which blunt cyclooxygenase activity, can interfere with the actions of loop diuretics by reducing prostaglandin synthesis in the kidney. This interference is minimal in otherwise normal subjects but may be significant in patients with nephrotic syndrome or hepatic cirrhosis.


Pharmacology_Katzung

Pharmacology_Katzung. Loop agents have direct effects on blood flow through several vascular beds. Furosemide increases renal blood flow via prostaglandin actions on kidney vasculature. Both furosemide and ethacrynic acid have also been shown to reduce pulmonary congestion and left ventricular filling pressures in heart failure before a measurable increase in urinary output occurs. These effects on peripheral vascular tone are also due to release of renal prostaglandins that are induced by the diuretics. The most important indications for the use of the loop diuretics include acute pulmonary edema and other edematous conditions. Many times the treatment of the fluid overload will also serve as an effective anti-hypertensive agent, especially in the presence of renal insufficiency. The use of loop diuretics in these conditions is discussed below in Clinical Pharmacology of Diuretic Agents. Other indications for loop diuretics include hypercalcemia, hyperkalemia, acute renal failure, and anion overdose.


Pharmacology_Katzung

Pharmacology_Katzung. A. Hyperkalemia In mild hyperkalemia—or after acute management of severe hyperkalemia by other measures—loop diuretics can significantly enhance urinary excretion of K+. This response is enhanced by simultaneous NaCl and water administration. B. Acute Renal Failure Loop agents can increase the rate of urine flow and enhance K+ excretion in acute renal failure. However, they cannot prevent or shorten the duration of renal failure. Loop agents can actually worsen cast formation in myeloma and light-chain nephropathy because increased distal Cl− concentration enhances secretion of Tamm-Horsfall protein, which then aggregates with myeloma Bence Jones proteins. C. Anion Overdose Loop diuretics are useful in treating toxic ingestions of bromide, fluoride, and iodide, which are reabsorbed in the TAL. Saline solution must be administered to replace urinary losses of Na+ and to provide Cl−, so as to avoid extracellular fluid volume depletion. A. Hypokalemic Metabolic Alkalosis


Pharmacology_Katzung

Pharmacology_Katzung. A. Hypokalemic Metabolic Alkalosis By inhibiting salt reabsorption in the TAL, loop diuretics increase Na+ delivery to the collecting duct. Increased Na+ delivery leads to increased secretion of K+ and H+ by the duct, causing hypokalemic metabolic alkalosis (Table 15–2). This toxicity is very common and is a function of the magnitude of the diuresis and can be reversed by K+ replacement and correction of hypovolemia. At least one study has found that potassium supplementation upon initiation of loop diuretics, irrespective of the serum potassium concentration, will improve survival. B. Ototoxicity Loop diuretics occasionally cause dose-related hearing loss that is usually reversible. It is most common in patients who have diminished renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics. C. Hyperuricemia


Pharmacology_Katzung

Pharmacology_Katzung. C. Hyperuricemia Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. It may be prevented by using lower doses to avoid development of hypovolemia. D. Hypomagnesemia Magnesium depletion is a predictable consequence of the chronic use of loop agents and occurs most often in patients with dietary magnesium deficiency. It can be reversed by administration of oral magnesium preparations. E. Allergic and Other Reactions All loop diuretics, with the exception of ethacrynic acid, are sulfonamides. Therefore, skin rash, eosinophilia, and less often, interstitial nephritis are occasional adverse effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal. Allergic reactions are much less common with ethacrynic acid.


Pharmacology_Katzung

Pharmacology_Katzung. Because Henle’s loop is indirectly responsible for water reabsorption by the downstream collecting duct, loop diuretics can cause severe dehydration. Hyponatremia is less common than with the thiazides (see below), but patients who increase water intake in response to hypovolemia-induced thirst can become hyponatremic with loop agents. Loop agents can cause hypercalciuria, which can lead to mild hypocalcemia and secondary hyperparathyroidism. On the other hand, loop agents can have the opposite effect (hypercalcemia) in volume-depleted patients who have another—previously occult—cause for hypercalcemia, such as metastatic breast or squamous cell lung carcinoma. Long-term loop diuretic therapy may worsen thiamine deficiency in patients with heart failure. Intravenous bumetanide administration has rarely caused injection site superficial tenderness of the skin, an effect not seen with other loop diuretics.


Pharmacology_Katzung

Pharmacology_Katzung. Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides, but this appears to be very rare. Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure. The thiazide diuretics were discovered in 1957, as a result of efforts to synthesize more potent carbonic anhydrase inhibitors. It subsequently became clear that the thiazides inhibit NaCl, rather than NaHCO3− transport and that their action is predominantly in the DCT, rather than the PCT. Some members of this group retain significant carbonic anhydrase inhibitory activity (eg, chlorthalidone). The prototypical thiazide is hydrochlorothiazide (HCTZ). Like carbonic anhydrase inhibitors and three loop diuretics, all of the thiazides have an unsubstituted sulfonamide group (Figure 15–8). FIGURE 15–8 Hydrochlorothiazide and related agents. TABLE 15–6 Thiazides and related diuretics.


Pharmacology_Katzung

Pharmacology_Katzung. FIGURE 15–8 Hydrochlorothiazide and related agents. TABLE 15–6 Thiazides and related diuretics. 1Not a thiazide but a sulfonamide qualitatively similar to the thiazides. All thiazides can be administered orally, but there are differences in their metabolism. Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration. HCTZ is considerably more potent and should be used in much lower doses (Table 15–6). Chlorthalidone is slowly absorbed and has a longer duration of action. Although indapamide is excreted primarily by the biliary system, enough of the active form is cleared by the kidney to exert its diuretic effect in the DCT. All thiazides are secreted by the organic acid secretory system in the proximal tubule and compete with the secretion of uric acid by that system. As a result, thiazide use may blunt uric acid secretion and elevate serum uric acid level.


Pharmacology_Katzung

Pharmacology_Katzung. Thiazides inhibit NaCl reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Cl− transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15–4) and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as a result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, primary hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are sometimes useful in the prevention of calcium-containing kidney stones caused by hypercalciuria.


Pharmacology_Katzung

Pharmacology_Katzung. due to other causes (eg, primary hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are sometimes useful in the prevention of calcium-containing kidney stones caused by hypercalciuria. They may also modestly reduce the risk of osteoporotic fractures.


Pharmacology_Katzung

Pharmacology_Katzung. The action of thiazides depends in part on renal prostaglandin production. As described for loop diuretics, the actions of thiazides can also be inhibited by NSAIDs under certain conditions. The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes insipidus. Use of the thiazides in each of these conditions is described below in Clinical Pharmacology of Diuretic Agents. A. Hypokalemic Metabolic Alkalosis These toxicities are similar to those observed with loop diuretics (see previous text and Table 15–2). B. Impaired Carbohydrate Tolerance


Pharmacology_Katzung

Pharmacology_Katzung. A. Hypokalemic Metabolic Alkalosis These toxicities are similar to those observed with loop diuretics (see previous text and Table 15–2). B. Impaired Carbohydrate Tolerance Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. It occurs at higher doses of HCTZ (>50 mg/d) and has not been seen with doses of 12.5 mg/d or less. The effect is due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Thiazides have a weak, dose-dependent, off-target effect to stimulate ATP-sensitive K+ channels and cause hyperpolarization of beta cells, thereby inhibiting insulin release. This effect is exacerbated by hypokalemia, and thus thiazide-induced hyperglycemia may be partially reversed with correction of hypokalemia. C. Hyperlipidemia


Pharmacology_Katzung

Pharmacology_Katzung. C. Hyperlipidemia Thiazides cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs). These levels may return toward baseline after prolonged use. D. Hyponatremia Hyponatremia is an important adverse effect of thiazide diuretics. It is caused by a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake. Genetic studies have shown a link between KCNJ1 polymorphism and thiazide-induced hyponatremia. E. Impaired Uric Acid Metabolism and Gout Thiazides are the diuretics most associated with development of gout. One large study found that thiazide diuretics only increase the risk of gout in men younger than age 60 years and not in women or older men. The increased risk in this group of patients was found to be only about 1%. F. Allergic Reactions


Pharmacology_Katzung

Pharmacology_Katzung. F. Allergic Reactions The thiazides are sulfonamides and share cross-reactivity with other members of this chemical group. Photosensitivity or generalized dermatitis occurs rarely. Serious allergic reactions are extremely rare but do include hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis. G. Other Toxicities Weakness, fatigability, and paresthesias similar to those of carbonic anhydrase inhibitors may occur. Impotence has been reported but is probably related to volume depletion. Cases of acute angle-closure glaucoma from hyponatremia caused by thiazide diuretics have been reported. Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure (see text that follows).


Pharmacology_Katzung

Pharmacology_Katzung. Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure (see text that follows). Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone in collecting tubules. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na+ influx through ion channels in the luminal membrane (amiloride, triamterene). Finally, ularitide (recombinant urodilatin), which is currently still under investigation, blunts Na+ uptake and Na+/K+-ATPase in collecting tubules and increases GFR through its vascular effects. Nesiritide, which is available for intravenous use only, increases GFR and blunts Na+ reabsorption in both proximal and collecting tubules. The structures of spironolactone and amiloride are shown in Figure 15–9.


Pharmacology_Katzung

Pharmacology_Katzung. The structures of spironolactone and amiloride are shown in Figure 15–9. Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Onset and duration of its action are determined substantially by the active metabolites canrenone and 7-α-spirolactone, which are produced in the liver and have FIGURE 15–9 Potassium-sparing diuretics.


Pharmacology_Katzung

Pharmacology_Katzung. long half-lives (12–20 and approximately 14 hours, respectively). Spironolactone binds with high affinity and potently inhibits the androgen receptor, which is an important source of side effects in males (notably, gynecomastia and decreased libido). Eplerenone is a spironolactone analog with much greater selectivity for the mineralocorticoid receptor. It is several hundredfold less active on androgen and progesterone receptors than spironolactone, and therefore, eplerenone has considerably fewer adverse effects (eg, gynecomastia). Finerenone is a new investigational agent in this class. It is a nonsteroidal mineralocorticoid antagonist that reduces nuclear accumulation of mineralocorticoid receptors more efficiently than spironolactone. Like eplerenone, it binds less avidly to the androgen and progesterone receptors. Finerenone accumulates similarly in the heart and the kidneys, whereas eplerenone has three times higher drug concentration in the kidney than the heart and


Pharmacology_Katzung

Pharmacology_Katzung. the androgen and progesterone receptors. Finerenone accumulates similarly in the heart and the kidneys, whereas eplerenone has three times higher drug concentration in the kidney than the heart and spironolactone is even more preferentially concentrated in the kidneys. Because of this effect, finerenone may prove to be useful for cardioprotection. Finerenone results in less hyperkalemia than spironolactone or eplerenone for poorly understood reasons but possibly from its decreased tendency to accumulate in the kidneys. It also does not have as great a blood pressure-lowering effect as spironolactone or eplerenone. DSR-71167 is an investigational agent in this class that is believed to have carbonic anhydrase inhibitory activity in addition to antimineralocorticoid activity and is thus less likely to cause hyperkalemia.


Pharmacology_Katzung

Pharmacology_Katzung. Amiloride and triamterene are direct inhibitors of Na+ influx in the CCT. Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for the active form and the metabolites. Because triamterene is extensively metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized). Potassium-sparing diuretics reduce Na+ absorption in the collecting tubules and ducts (Figure 15-5). Potassium absorption (and K+ secretion) at this site is regulated by aldosterone, as described above. Aldosterone antagonists interfere with this process. Similar effects are observed with respect to H+ handling by the intercalated cells of the collecting tubule, in part explaining the metabolic acidosis seen with aldosterone antagonists (Table 15–2).


Pharmacology_Katzung

Pharmacology_Katzung. Spironolactone and eplerenone bind to mineralocorticoid receptors and blunt aldosterone activity. Amiloride and triamterene do not block aldosterone but instead directly interfere with Na+ entry through the epithelial Na+ channels (ENaC; Figure 15–5) in the apical membrane of the collecting tubule. Since K+ secretion is coupled with Na+ entry in this segment, these agents are also effective K+-sparing diuretics. The actions of the aldosterone antagonists depend on renal prostaglandin production. The actions of K+-sparing diuretics can be inhibited by NSAIDs under certain conditions. Potassium-sparing diuretics are most useful in states of mineralocorticoid excess or hyperaldosteronism (also called aldosteronism), due either to primary hypersecretion (Conn’s syndrome, ectopic TABLE 15–7 Potassium-sparing diuretics and combination preparations. 1Eplerenone is currently approved for use only in hypertension.


Pharmacology_Katzung

Pharmacology_Katzung. TABLE 15–7 Potassium-sparing diuretics and combination preparations. 1Eplerenone is currently approved for use only in hypertension. adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephrotic syndrome, or other conditions associated with diminished effective intravascular volume). Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism. In the setting of enhanced mineralocorticoid secretion and excessive delivery of Na+ to distal nephron sites, renal K+ wasting occurs. Potassium-sparing diuretics of either type may be used in this setting to blunt the K+ secretory response.


Pharmacology_Katzung

Pharmacology_Katzung. It has also been found that low doses of eplerenone (25–50 mg/d) may interfere with some of the fibrotic and inflammatory effects of aldosterone. By doing so, it can slow the progression of albuminuria in diabetic patients. It is notable that eplerenone has been found to reduce myocardial perfusion defects after myocardial infarction. In one clinical study, eplerenone reduced mortality rate by 15% (compared with placebo) in patients with mild to moderate heart failure after myocardial infarction. Liddle’s syndrome is a rare autosomal dominant disorder that results in activation of sodium channels in the cortical collecting ducts, causing increased sodium reabsorption and potassium secretion by the kidneys. Amiloride has been shown to be of benefit in this condition, while spironolactone lacks efficacy. Amiloride is also useful for treatment of nephrogenic diabetes insipidus although only studied in patients with lithium-induced diabetes insipidus. A. Hyperkalemia


Pharmacology_Katzung

Pharmacology_Katzung. Unlike most other diuretics, K+-sparing diuretics reduce urinary excretion of K+ (Table 15–2) and can cause mild, moderate, or even life-threatening hyperkalemia. The risk of this complication is greatly increased by renal disease (in which maximal K+ excretion may be reduced) or by the use of other drugs that reduce or inhibit renin (β blockers, NSAIDs, aliskiren) or angiotensin II activity (angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor inhibitors). Since most other diuretic agents lead to K+ losses, hyperkalemia is more common when K+-sparing diuretics are used as the sole diuretic agent, especially in patients with renal insufficiency. With fixed-dosage combinations of K+-sparing and thiazide diuretics, the thiazide-induced hypokalemia and metabolic alkalosis are ameliorated. However, because of variations in the bioavailability of the components of fixed-dosage forms, the thiazide-associated adverse effects often predominate. Therefore, it is generally


Pharmacology_Katzung

Pharmacology_Katzung. are ameliorated. However, because of variations in the bioavailability of the components of fixed-dosage forms, the thiazide-associated adverse effects often predominate. Therefore, it is generally preferable to adjust the doses of the two drugs separately.


Pharmacology_Katzung

Pharmacology_Katzung. B. Hyperchloremic Metabolic Acidosis By inhibiting H+ secretion in parallel with K+ secretion, the K+sparing diuretics can cause acidosis similar to that seen with type IV renal tubular acidosis. C. Gynecomastia Synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors. Gynecomastia, impotence, and benign prostatic hyperplasia (very rare) have been reported with spironolactone. Such effects have not been reported with eplerenone, presumably because it is much more selective than spironolactone for the mineralocorticoid receptor and virtually inactive on androgen or progesterone receptors. D. Acute Renal Failure The combination of triamterene with indomethacin has been reported to cause acute renal failure. This has not been reported with other K+-sparing diuretics. E. Kidney Stones Triamterene is only slightly soluble and may precipitate in the urine, causing kidney stones.


Pharmacology_Katzung

Pharmacology_Katzung. E. Kidney Stones Triamterene is only slightly soluble and may precipitate in the urine, causing kidney stones. Potassium-sparing agents can cause severe, even fatal, hyperkalemia in susceptible patients. Patients with chronic renal insufficiency are especially vulnerable and should rarely be treated with these diuretics. Oral K+ administration should be discontinued if K+-sparing diuretics are administered. Concomitant use of other agents that blunt the renin-angiotensin system (β blockers, ACE inhibitors, angiotensin receptor blockers) increases the likelihood of hyperkalemia. Patients with liver disease may have impaired metabolism of triamterene and spironolactone, so dosing must be carefully adjusted. Strong CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, and grapefruit juice) can markedly increase blood levels of eplerenone, but not spironolactone.


Pharmacology_Katzung

Pharmacology_Katzung. The proximal tubule and descending limb of Henle’s loop are freely permeable to water (Table 15–1). Any osmotically active agent that is filtered by the glomerulus but not reabsorbed causes water to be retained in these segments and promotes a water diuresis. Such agents can be used to reduce intracranial pressure and to promote prompt removal of renal toxins. The prototypic osmotic diuretic is mannitol. Glucose is not used clinically as a diuretic but frequently causes osmotic diuresis (glycosuria) in patients with hyperglycemia. Mannitol is poorly absorbed by the GI tract, and when administered orally, it causes osmotic diarrhea rather than diuresis. For systemic effect, mannitol must be given intravenously. Mannitol is not metabolized and is excreted by glomerular filtration within 30–60 minutes, without any important tubular reabsorption or secretion. It must be used cautiously in patients with even mild renal insufficiency (see below).


Pharmacology_Katzung

Pharmacology_Katzung. Osmotic diuretics have their major effect in the proximal tubule and the descending limb of Henle’s loop. Through osmotic effects, they also oppose the action of ADH in the collecting tubule. The presence of a nonreabsorbable solute such as mannitol prevents the normal absorption of water by interposing a countervailing osmotic force. As a result, urine volume increases. The increase in urine flow decreases the contact time between fluid and the tubular epithelium, thus reducing Na+ as well as water reabsorption. The resulting natriuresis is of lesser magnitude than the water diuresis, leading eventually to excessive water loss and hypernatremia. Reduction of Intracranial and Intraocular Pressure


Pharmacology_Katzung

Pharmacology_Katzung. Reduction of Intracranial and Intraocular Pressure Osmotic diuretics alter Starling forces so that water leaves cells and reduces intracellular volume. This effect is used to reduce intracranial pressure in neurologic conditions and to reduce intraocular pressure before ophthalmologic procedures. A dose of 1–2 g/kg mannitol is administered intravenously. Intracranial pressure, which must be monitored, should fall in 60–90 minutes. At times the rapid lowering of serum osmolality at initiation of dialysis (from removal of uremic toxins) results in symptoms. Many nephrologists also use mannitol to prevent adverse reactions when first starting patients on hemodialysis. The evidence for efficacy in this setting is limited. A. Extracellular Volume Expansion


Pharmacology_Katzung

Pharmacology_Katzung. A. Extracellular Volume Expansion Mannitol is rapidly distributed in the extracellular compartment and extracts water from cells. Prior to the diuresis, this leads to expansion of the extracellular volume and hyponatremia. This effect can complicate heart failure and may produce florid pulmonary edema. Headache, nausea, and vomiting are commonly observed in patients treated with osmotic diuretics. B. Dehydration, Hyperkalemia, and Hypernatremia Excessive use of mannitol without adequate water replacement can ultimately lead to severe dehydration, free water losses, and hypernatremia. As water is extracted from cells, intracellular K+ concentration rises, leading to cellular losses and hyperkalemia. These complications can be avoided by careful attention to serum ion composition and fluid balance. C. Hyponatremia


Pharmacology_Katzung

Pharmacology_Katzung. C. Hyponatremia When used in patients with severe renal impairment, parenterally administered mannitol cannot be excreted and is retained in the blood. This causes osmotic extraction of water from cells, leading to hyponatremia without a decrease in serum osmolality. D. Acute Renal Failure Acute renal failure has been well described with use of mannitol. The effect is thought to be mediated by the increase in osmolality. The incidence of acute kidney injury with mannitol use has been estimated to be 6–7% of patients who receive the drug. ANTIDIURETIC HORMONE (ADH, VASOPRESSIN) AGONISTS Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. They are discussed in Chapter 37. Their renal action appears to be mediated primarily via V2 ADH receptors, although V1a receptors may also be involved.


Pharmacology_Katzung

Pharmacology_Katzung. A variety of medical conditions, including congestive heart failure (CHF) and the syndrome of inappropriate ADH secretion (SIADH), cause water retention as a result of excessive ADH secretion. Patients with CHF who are on diuretics frequently develop hyponatremia secondary to excessive ADH secretion. Until recently, two nonselective agents, lithium (see Chapter 29) and demeclocycline (a tetracycline antimicrobial drug discussed in Chapter 44), were used for their well-known interference with ADH activity. The mechanism for this interference has not been completely determined for either of these agents. Demeclocycline is used more often than lithium because of the many adverse effects of lithium administration. However, demeclocycline is now being rapidly replaced by several specific ADH receptor antagonists (vaptans), which have yielded encouraging clinical results.


Pharmacology_Katzung

Pharmacology_Katzung. There are three known vasopressin receptors, V1a, V1b, and V2. V1 receptors are expressed in the vasculature and CNS, while V2 receptors are expressed specifically in the kidney. Conivaptan (currently available only for intravenous use) exhibits activity against both V1a and V2 receptors (see below). The oral agents tolvaptan, lixivaptan, mozavaptan, and satavaptan are selectively active against the V2 receptor. Lixivaptan, mozavaptan, and satavaptan are still under clinical investigation, but tolvaptan, which is approved by the US Food and Drug Administration (FDA), is very effective in treatment of hyponatremia and as an adjunct to standard diuretic therapy in patients with CHF. The half-lives of conivaptan and demeclocycline are 5–10 hours, while that of tolvaptan is 12–24 hours.


Pharmacology_Katzung

Pharmacology_Katzung. The half-lives of conivaptan and demeclocycline are 5–10 hours, while that of tolvaptan is 12–24 hours. Antidiuretic hormone antagonists inhibit the effects of ADH in the collecting tubule. Conivaptan and tolvaptan are direct ADH receptor antagonists, while both lithium and demeclocycline reduce ADH-induced cAMP by unknown mechanisms. A. Syndrome of Inappropriate ADH Secretion


Pharmacology_Katzung

Pharmacology_Katzung. A. Syndrome of Inappropriate ADH Secretion Antidiuretic hormone antagonists are used to manage SIADH when water restriction has failed to correct the abnormality. This generally occurs in the outpatient setting, where water restriction cannot be enforced, but can occur in the hospital when large quantities of intravenous fluid are needed for other purposes. Demeclocycline (600–1200 mg/d) or tolvaptan (15–60 mg/d) can be used for SIADH. Appropriate plasma levels of demeclocycline (2 mcg/mL) should be maintained by monitoring, but tolvaptan levels are not routinely monitored. Unlike demeclocycline or tolvaptan, conivaptan is administered intravenously and is not suitable for chronic use in outpatients. B. Other Causes of Elevated Antidiuretic Hormone


Pharmacology_Katzung

Pharmacology_Katzung. B. Other Causes of Elevated Antidiuretic Hormone Antidiuretic hormone is also elevated in response to diminished effective circulating blood volume, as often occurs in heart failure. Due to the elevated ADH levels, hyponatremia may result. As in the management of SIADH, water restriction is frequently the treatment of choice. In patients with heart failure, this approach is often unsuccessful in view of increased thirst and the large number of oral medications being used. For patients with heart failure, intravenous conivaptan may be particularly useful because it has been found that the blockade of V1a receptors by this drug leads to decreased peripheral vascular resistance and increased cardiac output. C. Autosomal Dominant Polycystic Kidney Disease


Pharmacology_Katzung

Pharmacology_Katzung. C. Autosomal Dominant Polycystic Kidney Disease Cyst development in polycystic kidney disease is thought to be mediated through cAMP. Vasopressin is a major stimulus for cAMP production in the kidney. It is hypothesized that inhibition of V2 receptors in the kidney might delay the progression of polycystic kidney disease. In a large multicenter prospective trial, tolvaptan was able to reduce the increase in kidney size and slow progression of kidney failure over a 3-year follow-up period. In this trial, however, the tolvaptan group experienced a 9% incidence of abnormal liver function test results compared with 2% in the placebo group. This led to discontinuation of the drug in some patients. A. Nephrogenic Diabetes Insipidus If serum Na+ is not monitored closely, any ADH antagonist can cause severe hypernatremia and nephrogenic diabetes insipidus.


Pharmacology_Katzung

Pharmacology_Katzung. A. Nephrogenic Diabetes Insipidus If serum Na+ is not monitored closely, any ADH antagonist can cause severe hypernatremia and nephrogenic diabetes insipidus. If lithium is being used for a psychiatric disorder, nephrogenic diabetes insipidus can be treated with a thiazide diuretic or amiloride (see Diabetes Insipidus, below). B. Renal Failure Both lithium and demeclocycline have been reported to cause acute renal failure. Long-term lithium therapy may also cause chronic interstitial nephritis. C. Other Dry mouth and thirst are common with many of these drugs. Tolvaptan may cause hypotension. Multiple adverse effects associated with lithium therapy have been found and are discussed in Chapter 29. Demeclocycline should be avoided in patients with liver disease (see Chapter 44) and in children younger than 12 years. Tolvaptan may also cause an elevation in liver function tests and is relatively contraindicated in patients with liver disease.


Pharmacology_Katzung

Pharmacology_Katzung. Medullary urine concentration depends in large part on urea movement in the kidney. Two families of urea transporters have been described. UT-A is present in inner medullary collecting duct cells and the thin descending limb of Henle. UT-B is present in the descending vasa recta and several extrarenal tissues. Inhibitors of both UT-A and UT-B (eg, PU-14) have been developed and are currently in preclinical studies. These agents are aquaretics that increase urea and water excretion but not sodium excretion. Urea transport inhibitors have been shown to blunt the increase in urine osmolality seen after desmopressin administration. These agents may prove to be useful in edematous states and even in SIADH; however, their potential clinical role as compared to that of vaptans remains to be established.


Pharmacology_Katzung

Pharmacology_Katzung. Some patients are refractory to the usual dose of loop diuretics or become refractory after an initial response. Since these agents have a short half-life (2–6 hours), refractoriness may be due to an excessive interval between doses. Renal Na+ retention may be greatly increased during the time period when the drug is no longer active. It was hoped that continuous loop diuretic infusions would be useful in treating patients with heart failure and diuretic resistance, but one high-quality study did not show a benefit for continuous loop diuretic infusion as opposed to bolus doses. However, after the dosing interval for loop agents is minimized or the dose is maximized, the use of two drugs acting at different nephron sites may exhibit dramatic synergy. Loop agents and thiazides in combination often produce diuresis when neither agent acting alone is even minimally effective. There are several reasons for this phenomenon.


Pharmacology_Katzung

Pharmacology_Katzung. First, salt reabsorption in either the TAL or the DCT can increase when the other is blocked. Inhibition of both can therefore produce more than an additive diuretic response. Second, thiazide diuretics often produce a mild natriuresis in the proximal tubule that is usually masked by increased reabsorption in the TAL. The combination of loop diuretics and thiazides can therefore reduce Na+ reabsorption, to some extent, from all three segments. Metolazone is the thiazide-like drug usually used in patients refractory to loop agents alone, but it is likely that other thiazides at equipotent doses would be just as effective. Moreover, metolazone is available only in an oral preparation, whereas chlorothiazide can be given parenterally.


Pharmacology_Katzung

Pharmacology_Katzung. The combination of loop diuretics and thiazides can mobilize large amounts of fluid, even in patients who have not responded to single agents. Therefore, close hemodynamic monitoring is essential. Routine outpatient use is not recommended but may be possible with extreme caution and close follow-up. Furthermore, K+ wasting is extremely common and may require parenteral K+ administration with careful monitoring of fluid and electrolyte status. The first large-scale randomized controlled trial of combination loop and thiazide diuretic therapy in patients with heart failure is currently under way in the CLOROTIC (Combination of Loop with Thiazide-type Diuretics in Patients with Decompensated Heart Failure) trial. Clinical experience suggests that in outpatients, adverse effects of thiazides as add-on therapy to loop diuretics can be mitigated by infrequent low-dose therapy. Add-on diuretic therapy with metolazone is started at 2.5 mg weekly and titrated up slowly as needed, with close


Pharmacology_Katzung

Pharmacology_Katzung. as add-on therapy to loop diuretics can be mitigated by infrequent low-dose therapy. Add-on diuretic therapy with metolazone is started at 2.5 mg weekly and titrated up slowly as needed, with close monitoring of the patient’s blood pressure and serum potassium concentration.


Pharmacology_Katzung

Pharmacology_Katzung. POTASSIUM-SPARING DIURETICS & PROXIMAL TUBULE DIURETICS, LOOP AGENTS, OR THIAZIDES Hypokalemia often develops in patients taking carbonic anhydrase inhibitors, loop diuretics, or thiazides. This can usually be managed by dietary NaCl restriction or by taking dietary KCl supplements. When hypokalemia cannot be managed in this way, the addition of a K+-sparing diuretic can significantly lower K+ excretion. Although this approach is generally safe, it should be avoided in patients with renal insufficiency and in those receiving angiotensin antagonists such as ACE inhibitors, in whom life-threatening hyperkalemia can develop in response to K+-sparing diuretics. A summary of the effects of diuretics on urinary electrolyte excretion is shown in Table 15–2. A common reason for diuretic use is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases that reduce blood flow to the kidney.


Pharmacology_Katzung

Pharmacology_Katzung. A common reason for diuretic use is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases that reduce blood flow to the kidney. This reduction is sensed as insufficient effective arterial blood volume and leads to salt and water retention, which expands blood volume and eventually causes edema formation. Judicious use of diuretics can mobilize this interstitial edema without significant reductions in plasma volume. However, excessively rapid diuretic therapy may compromise the effective arterial blood volume and reduce the perfusion of vital organs. Therefore, the use of diuretics to mobilize edema requires careful monitoring of the patient’s hemodynamic status and an understanding of the pathophysiology of the underlying illness.


Pharmacology_Katzung

Pharmacology_Katzung. When cardiac output is reduced by heart failure, the resultant changes in blood pressure and blood flow to the kidney are sensed as hypovolemia and lead to renal retention of salt and water. This physiologic response initially increases intravascular volume and venous return to the heart and may partially restore the cardiac output toward normal (see Chapter 13).


Pharmacology_Katzung

Pharmacology_Katzung. If the underlying disease causes cardiac output to deteriorate despite expansion of plasma volume, the kidney continues to retain salt and water, which then leaks from the vasculature and becomes interstitial or pulmonary edema. At this point, diuretic use becomes necessary to reduce the accumulation of edema, particularly in the lungs. Reduction of pulmonary vascular congestion with diuretics may actually improve oxygenation and thereby improve myocardial function. Reduction of preload can reduce the size of the heart, allowing it to work at a more efficient fiber length. Edema associated with heart failure is generally managed with loop diuretics. In some instances, salt and water retention may become so severe that a combination of thiazides and loop diuretics is necessary.


Pharmacology_Katzung

Pharmacology_Katzung. In treating the heart failure patient with diuretics, it must always be remembered that cardiac output in these patients is being maintained in part by high filling pressures. Therefore, excessive use of diuretics may diminish venous return and further impair cardiac output. This is especially critical in right ventricular heart failure. Systemic, rather than pulmonary, vascular congestion is the hallmark of this disorder. Diuretic-induced volume contraction predictably reduces venous return and can severely compromise cardiac output if left ventricular filling pressure is reduced below 15 mm Hg (see Chapter 13). Reduction in cardiac output, resulting from either left or right ventricular dysfunction, also eventually leads to renal dysfunction resulting from reduced perfusion pressures.


Pharmacology_Katzung

Pharmacology_Katzung. Diuretic-induced metabolic alkalosis, exacerbated by hypokalemia, is another adverse effect that may further compromise cardiac function. This complication can be treated with replacement of K+ and restoration of intravascular volume with saline; however, severe heart failure may preclude the use of saline even in patients who have received excessive diuretic therapy. In these cases, adjunctive use of acetazolamide helps to correct the alkalosis. Another serious toxicity of diuretic use in the cardiac patient is hypokalemia. Hypokalemia can exacerbate underlying cardiac arrhythmias and contribute to digitalis toxicity. This can usually be avoided by having the patient reduce Na+ intake while taking diuretics, thus decreasing Na+ delivery to the K+-secreting collecting tubule. Patients who do not adhere to a low Na+ diet must take oral KCl supplements or a K+-sparing diuretic.


Pharmacology_Katzung

Pharmacology_Katzung. Recently, there has been interest in the use of vaptans in heart failure, not only to treat hyponatremia but also to treat volume overload. Electrolyte dysfunction is less likely with a combination of diuretics and vaptans as opposed to higher doses of the diuretics alone. A variety of diseases interfere with the kidney’s critical role in volume homeostasis. Although some renal disorders cause salt wasting, most cause retention of salt and water. When renal failure is severe (GFR < 5 mL/min), diuretic agents are of little benefit, because glomerular filtration is insufficient to generate or sustain a natriuretic response. However, a large number of patients, and even dialysis patients, with milder degrees of renal insufficiency (GFR of 5–15 mL/min), can be treated with diuretics with some success.


Pharmacology_Katzung

Pharmacology_Katzung. There is still interest in the question as to whether diuretic therapy can alter the severity or the outcome of acute renal failure. This is because “nonoliguric” forms of acute renal insufficiency have better outcomes than “oliguric” (<400–500 mL/24 h urine output) acute renal failure. Almost all studies done to address this question have shown that diuretic therapy helps in the short-term fluid management of some of these patients with acute renal failure, but that it has no impact on the long-term outcome.


Pharmacology_Katzung

Pharmacology_Katzung. Many glomerular diseases, such as those associated with diabetes mellitus or systemic lupus erythematosus, exhibit renal retention of salt and water. The cause of this sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation and tubular function through release of vasoconstrictors, prostaglandins, cytokines, and other mediators. When edema or hypertension develops in these patients, diuretic therapy can be very effective. Certain forms of renal disease, particularly diabetic nephropathy, are frequently associated with development of hyperkalemia at a relatively early stage of renal failure. This is often due to type IV renal tubular acidosis. In these cases, a thiazide or loop diuretic will enhance K+ excretion by increasing delivery of salt to the K+secreting collecting tubule.


Pharmacology_Katzung

Pharmacology_Katzung. Patients with renal diseases leading to the nephrotic syndrome often present complex problems in volume management. These patients may exhibit fluid retention in the form of ascites or edema but have reduced plasma volume due to reduced plasma oncotic pressures. This is very often the case in patients with “minimal change” nephropathy. In these patients, diuretic use may cause further reductions in plasma volume that can impair GFR and may lead to orthostatic hypotension. Most other causes of nephrotic syndrome are associated with primary retention of salt and water by the kidney, leading to expanded plasma volume and hypertension despite the low plasma oncotic pressure. In these cases, diuretic therapy may be beneficial in controlling the volume-dependent component of hypertension.


Pharmacology_Katzung

Pharmacology_Katzung. In choosing a diuretic for the patient with kidney disease, there are a number of important limitations. Acetazolamide must usually be avoided because it causes NaHCO3 excretion and can exacerbate acidosis. Potassium-sparing diuretics may cause hyperkalemia. Thiazide diuretics are thought to be ineffective when GFR falls below 30 mL/min, although the exact GFR at which they no longer prove to be beneficial is still a matter of debate. In addition, it has been found that thiazides can be used to significantly reduce the dose of loop diuretics needed to promote diuresis in a patient with a GFR of 5–15 mL/min. Thus, high-dose loop diuretics (up to 500 mg/d of furosemide) or a combination of metolazone (5–10 mg/d) with furosemide (40–80 mg/d) may be useful in treating volume overload in dialysis or predialysis patients. Finally, although excessive use of diuretics can impair renal function in all patients, the consequences are obviously more serious in patients with underlying renal


Pharmacology_Katzung

Pharmacology_Katzung. dialysis or predialysis patients. Finally, although excessive use of diuretics can impair renal function in all patients, the consequences are obviously more serious in patients with underlying renal disease.


Pharmacology_Katzung

Pharmacology_Katzung. Liver disease is often associated with edema and ascites in conjunction with elevated portal hydrostatic pressures and reduced plasma oncotic pressures. Mechanisms for retention of Na+ by the kidney in this setting include diminished renal perfusion (from systemic vascular alterations), diminished plasma volume (due to ascites formation), and diminished oncotic pressure (hypoalbuminemia). In addition, there may be primary Na+ retention due to elevated plasma aldosterone levels.


Pharmacology_Katzung

Pharmacology_Katzung. When ascites and edema become severe, diuretic therapy can be very useful. However, cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels. In contrast, cirrhotic edema is unusually responsive to spironolactone and eplerenone. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. However, considerable caution is necessary in the use of aldosterone antagonists in cirrhotic patients with even mild renal insufficiency because of the potential for causing serious hyperkalemia.


Pharmacology_Katzung

Pharmacology_Katzung. It is important to note that, even more than in heart failure, overly aggressive use of diuretics in this setting can be disastrous. Vigorous diuretic therapy can cause marked depletion of intravascular volume, hypokalemia, and metabolic alkalosis. Hepatorenal syndrome and hepatic encephalopathy are the unfortunate consequences of excessive diuretic use in the cirrhotic patient. Vaptans are relatively contraindicated in patients with liver disease because a study of tolvaptan in treating patients with autosomal dominant polycystic kidney disease resulted in increased transaminases in some patients treated with high-dose tolvaptan. Low-dose tolvaptan, however, may prove to be useful in treating some patients with cirrhosis (those who do not have ongoing liver damage) who suffer from hyponatremia or fluid overload.


Pharmacology_Katzung

Pharmacology_Katzung. Idiopathic edema (fluctuating salt retention and edema) is a syndrome found most often in 20to 30-year-old women. Despite intensive study, the pathophysiology remains obscure. Some studies suggest that surreptitious, intermittent diuretic use may actually contribute to the syndrome and should be ruled out before additional therapy is pursued. While spironolactone has been used for idiopathic edema, it should probably be managed with moderate salt restriction alone if possible. Compression stockings have also been used but appear to be of variable benefit.


Pharmacology_Katzung

Pharmacology_Katzung. The diuretic and mild vasodilator actions of the thiazides are useful in treating virtually all patients with essential hypertension and may be sufficient in many (see also Chapter 11). Although hydrochlorothiazide is the most widely used diuretic for hypertension, chlorthalidone may be more effective because of its much longer half-life. Loop diuretics are usually reserved for patients with mild renal insufficiency (GFR < 30–40 mL/min) or heart failure. Moderate restriction of dietary Na+ intake (60–100 mEq/d) has been shown to potentiate the effects of diuretics in essential hypertension and to lessen renal K+ wasting. A K+-sparing diuretic can be added to reduce K+ wasting.


Pharmacology_Katzung

Pharmacology_Katzung. There has been debate about whether thiazides should be used as the initial therapy in the treatment of hypertension. Their modest efficacy sometimes limits their use as monotherapy. However, a very large study of over 30,000 participants has shown that inexpensive diuretics like thiazides result in outcomes that are similar or superior to those found with ACE inhibitor or calcium channel-blocker therapy. This significant result reinforces the importance of thiazide therapy in hypertension.


Pharmacology_Katzung

Pharmacology_Katzung. Although diuretics are often successful as monotherapy, they also play an important role in patients who require multiple drugs to control blood pressure. Diuretics enhance the efficacy of many agents, particularly ACE inhibitors. Patients being treated with powerful vasodilators such as hydralazine or minoxidil usually require simultaneous diuretics because the vasodilators cause significant salt and water retention. There is also growing evidence showing that spironolactone may be the most effective single agent in the therapy of drug-resistant hypertension, and this effect may extend to dialysis patients.


Pharmacology_Katzung

Pharmacology_Katzung. Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. Although there are numerous medical conditions (hyperparathyroidism, hypervitaminosis D, sarcoidosis, malignancies, etc) that cause hypercalciuria, many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the DCT and thus reduce the urinary Ca2+ concentration. Fluid intake should be increased, but salt intake must be reduced, since excess dietary NaCl will overwhelm the hypocalciuric effect of thiazides. Dietary Ca2+ should not be restricted, as this can lead to negative total body Ca2+ balance. Calcium stones may also be caused by increased intestinal absorption of Ca2+, or they may be idiopathic. In these situations, thiazides are also effective but should be used as adjunctive therapy with other measures.


Pharmacology_Katzung

Pharmacology_Katzung. Hypercalcemia can be a medical emergency (see Chapter 42). Because loop diuretics reduce Ca2+ reabsorption significantly, they can be quite effective in promoting Ca2+ diuresis. However, loop diuretics alone can cause marked volume contraction. If this occurs, loop diuretics are ineffective (and potentially counterproductive) because Ca2+ reabsorption in the proximal tubule would be enhanced. Thus, saline must be administered simultaneously with loop diuretics if an effective Ca2+ diuresis is to be maintained. The usual approach is to infuse normal saline and furosemide (80–120 mg) intravenously. Once the diuresis begins, the rate of saline infusion can be matched with the urine flow rate to avoid volume depletion. Potassium chloride may be added to the saline infusion as needed.


Pharmacology_Katzung

Pharmacology_Katzung. Diabetes insipidus is due to either deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic diabetes insipidus [NDI]). Administration of supplementary ADH or one of its analogs is effective only in central diabetes insipidus. Thiazide diuretics can reduce polyuria and polydipsia in nephrogenic diabetes insipidus, which is not responsive to ADH supplementation. Lithium, used in the treatment of manic-depressive disorder, is a common cause of NDI, and thiazide diuretics have been found to be helpful in treating it. This seemingly paradoxical beneficial effect of thiazides was previously thought to be mediated through plasma volume reduction, with an associated fall in GFR, leading to enhanced proximal reabsorption of NaCl and water and decreased delivery of fluid to the downstream diluting segments. However, in the case of Li+-induced NDI, it is now known that HCTZ causes increased osmolality in the inner medulla (papilla)


Pharmacology_Katzung

Pharmacology_Katzung. and decreased delivery of fluid to the downstream diluting segments. However, in the case of Li+-induced NDI, it is now known that HCTZ causes increased osmolality in the inner medulla (papilla) and a partial correction of the Li+-induced reduction in aquaporin-2 expression. HCTZ also leads to increased expression of Na+ transporters in the DCT and CCT segments of the nephron. Thus, the maximum volume of dilute urine that can be produced is significantly reduced by thiazides in NDI. Dietary sodium restriction can potentiate the beneficial effects of thiazides on urine volume in this setting. Serum Li+ levels must be carefully monitored in these patients, because diuretics may reduce renal clearance of Li+ and raise plasma Li+ levels into the toxic range (see Chapter 29). Lithium-induced polyuria can also be partially reversed by amiloride, which blocks Li+ entry into collecting duct cells, much as it blocks Na+ entry. As mentioned above, thiazides are also beneficial in other forms of


Pharmacology_Katzung

Pharmacology_Katzung. can also be partially reversed by amiloride, which blocks Li+ entry into collecting duct cells, much as it blocks Na+ entry. As mentioned above, thiazides are also beneficial in other forms of nephrogenic diabetes insipidus. It is not yet clear whether this is via the same mechanism that has been found in Li+-induced NDI. Acetazolamide has also shown efficacy in treating polyuria in nephrogenic diabetes insipidus with fewer adverse events.


Pharmacology_Katzung

Pharmacology_Katzung. Aldosterone antagonists have been shown to be cardioprotective in patients with heart disease. In addition, they may exert an additional benefit in lowering albuminuria in patients with diabetes and microalbuminuria. Their use has been limited in patients with renal dysfunction because of the increased risk of inducing hyperkalemia. Finerenone may afford similar cardiac and renal protection with a lower risk for hyperkalemia. • Brinzolamide, dorzolamide: Topical for glaucoma SGLT2 INHIBITORS •CanagliflozinInhibition of sodium/glucose cotransporter (SGLT2) in the PCT results in decreased Na+ and glucose reabsorption Inhibition of glucose reabsorption lowers serum glucose concentration, and reduced Na+ reabsorption causes mild diuresis Diabetes mellitus; approved for the treatment of hyperglycemia, not as a diuretic Available orally. Half-life 10–12h•notrecommendedin severe renal or liver disease •Dapagliflozin, empagliflozin: similar to canagliflozin


Pharmacology_Katzung

Pharmacology_Katzung. Bumetanide, torsemide: Sulfonamide loop agents like furosemide Ethacrynic acid: Not a sulfonamide but has typical loop activity and some uricosuric action Pulmonary edema, peripheral edema, heart failure, hypertension, acute hypercalcemia, anion overdose Oral and parenteral preparations • duration of action 2–4 h • Toxicity: Ototoxicity, hypovolemia, K wasting, hyperuricemia, hypomagnesemia Inhibition of the Na/Cl transporter in the distal convoluted tubule Hypertension, mild heart failure, nephrolithiasis, nephrogenic diabetes insipidus • Toxicity: Hypokalemic metabolic alkalosis, hyperuricemia, hyperglycemia, hyponatremia Metolazone: Popular for use with loop agents for synergistic effects Chlorothiazide: Only parenteral thiazide available (IV) Chlorthalidone: Long half-life (50–60 h) due to binding to red blood cells Eplerenone: Like spironolactone, more selective for aldosterone receptor Triamterene: Mechanism like amiloride, much less potent, more toxic


Pharmacology_Katzung

Pharmacology_Katzung. Eplerenone: Like spironolactone, more selective for aldosterone receptor Triamterene: Mechanism like amiloride, much less potent, more toxic POTASSIUM-SPARING DIURETICS •SpironolactonePharmacologic antagonist of aldosterone in collecting tubules•weakantagonismof androgen receptors Reduces Na retention and K wasting in kidney•poorlyunderstoodantagonismofaldosterone in heart and vessels Aldosteronism from any cause •hypokalemiaduetoother diuretics •postmyocardialinfarction Slow onset and offset of effect•duration24–48h•Toxicity: Hyperkalemia, gynecomastia (spironolactone, not eplerenone)•additiveinteraction with other K-retaining drugs •AmilorideBlocks epithelial sodium channels in collecting tubules Reduces Na retention and K wasting •increaseslithiumclearanceHypokalemia from other diuretics •reduceslithium-induced polyuria •Liddle’ssyndromeOrallyactive•duration24h•Toxicity: Hyperkalemic metabolic acidosis Acetazolamide Generic, Diamox


Pharmacology_Katzung

Pharmacology_Katzung. Acetazolamide Generic, Diamox Amiloride Generic, Midamor, combination drugs* Bendroflumethiazide Naturetin, combination drugs * Bumetanide Generic, Bumex Dapagliflozin Farxiga Chlorthalidone Generic, Hygroton, Thalitone, Chlorothiazide Generic, Diuril combination drugs * Demeclocycline Generic, Declomycin Dorzolamide (for ocular Generic, Trusopt Hydrochlorothiazide Generic, Esidrix, Hydro-DIURIL, combination drugs * Hydroflumethiazide Generic, Saluron Indapamide Generic, Lozol Mannitol Generic, Osmitrol Methazolamide (for ocular Generic, Neptazane conditions) Methyclothiazide Generic, Aquatensen, Enduron Metolazone Generic, Mykrox, Zaroxolyn (Note: Bioavailability of Mykrox is greater than that of Zaroxolyn) Polythiazide Renese, combination drugs * Spironolactone Generic, Aldactone, combination drugs* Torsemide Generic, Demadex Trichlormethiazide Generic, Diurese, Naqua, others


Pharmacology_Katzung

Pharmacology_Katzung. Polythiazide Renese, combination drugs * Spironolactone Generic, Aldactone, combination drugs* Torsemide Generic, Demadex Trichlormethiazide Generic, Diurese, Naqua, others Eplerenone Inspra Furosemide Generic, Lasix, others Tolvaptan Samsca Triamterene Dyrenium *Combination drugs: see Table 15–6. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981. Bakris GL et al: Effect of finerenone on albuminuria in patients with diabetic nephropathy. JAMA 2015;314:884. Berl T et al: Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705.


Pharmacology_Katzung

Pharmacology_Katzung. Berl T et al: Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705. Bokrantz T et al: Thiazide diuretics and fracture-risk among hypertensive patients. Results from the Swedish primary care cardiovascular database (SPCCD). J Hypertens 2015;33:e94. Brater DC: Mechanism of action of diuretics. UpToDate, 2013. http://www. uptodate.com. Brenner BM (editor): Brenner & Rector’s The Kidney, 8th ed. Saunders, 2008. Cefalu WT et al: Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATASU): 52 week results from a randomized, double-blind, phase 3 non-inferiority trial. Lancet 2014;382:941. Cooper BE: Diuresis in renal failure: Treat the patient, not the urine output. Crit Care Med 2009;37:761. Costello-Boerrigter LC, Boerrigter G, Burnett JC Jr: Revisiting salt and water retention: New diuretics, aquaretics, and natriuretics. Med Clin North Am 2003;87:475.


Pharmacology_Katzung

Pharmacology_Katzung. Costello-Boerrigter LC, Boerrigter G, Burnett JC Jr: Revisiting salt and water retention: New diuretics, aquaretics, and natriuretics. Med Clin North Am 2003;87:475. Ernst ME, Moser M: Use of diuretics in patients with hypertension. N Engl J Med 2009;361:2153. Forssmann W-G, Meyer M, Forsmann K: The renal urodilatin system: Clinical implications. Cardiovasc Res 2001;51(3):450. Ginés P, Schrier RW: Renal failure in cirrhosis. N Engl J Med 2009;361:1279. Hao C-M, Breyer MD: Physiological regulation of prostaglandins in the kidney. Annu Rev Physiol 2008;70:357. Hays RM: Vasopressin antagonists: Progress and promise. N Engl J Med 2006; 355:146. Hill JA, Yancy CW, Abraham WT: Beyond diuretics: Management of volume overload in acute heart failure syndromes. Am J Med 2006;119:S37. Kaplan NM: The place of diuretics in preventing cardiovascular events. J Hum Hypertens 2004;18:S29.


Pharmacology_Katzung

Pharmacology_Katzung. Kaplan NM: The place of diuretics in preventing cardiovascular events. J Hum Hypertens 2004;18:S29. Kim G-H et al: Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel. J Am Soc Nephrol 2004;15:2836. Klein JD, Sands JM: Urea transport and clinical potential of urearetics. Curr Opin Nephrol Hypertens 2016;25:1. Lee C, Burnett J: Natriuretic peptides and therapeutic applications. Heart Fail Rev 2007;12:131. Matsue Y et al: Clinical effectiveness of tolvaptan in patients with acute heart failure and renal dysfunction: AQUAMARINE study. J Card Fail 2016;22:423. Na KY et al: Upregulation of Na+ transporter abundance in response to chronic thiazide or loop diuretic treatment in rats. Am J Physiol 2003;284:F133.


Pharmacology_Katzung

Pharmacology_Katzung. Na KY et al: Upregulation of Na+ transporter abundance in response to chronic thiazide or loop diuretic treatment in rats. Am J Physiol 2003;284:F133. Nariai T et al: DSR-71167, a novel mineralocorticoid receptor antagonist with carbonic anhydrase inhibitory activity, separates urinary sodium excretion and serum potassium elevation in rats. Pharmacol Exp Ther 2015;354:2. Nijenhuis T et al: Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005;115:1651. Olde Engberink RHG et al: Effects of thiazide-type and thiazide-like diuretics on cardiovascular events and mortality. Hypertension 2015;65:1033. Schnermann J, Huang Y, Mizel D: Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Renal Physiol 2013;305:F1352.


Pharmacology_Katzung

Pharmacology_Katzung. Schnermann J, Huang Y, Mizel D: Fluid reabsorption in proximal convoluted tubules of mice with gene deletions of claudin-2 and/or aquaporin1. Am J Physiol Renal Physiol 2013;305:F1352. Shargorodsky M et al: Treatment of hypertension with thiazides: benefit or damage—Effect of lowand high-dose thiazide diuretics on arterial elasticity and metabolic parameters in hypertensive patients with and without glucose intolerance. J Cardiometab Syndr 2007;2:16. Shlipak MG, Massie BM: The clinical challenge of cardiorenal syndrome. Circulation 2004;110:1514. Sica DA, Gehr TWB: Diuretic use in stage 5 chronic kidney disease and end-stage renal disease. Curr Opin Nephrol Hypertens 2003;12:483. Takeuchi T et al: Diuretic effects of sodium-glucose cotransporter 2 inhibitor in patients with type 2 diabetes mellitus and heart failure. Int J Cardiol 2015;201:1. Tavares M et al: New pharmacologic therapies in acute heart failure. Crit Care Med 2008;36:S112.


Pharmacology_Katzung

Pharmacology_Katzung. Tavares M et al: New pharmacologic therapies in acute heart failure. Crit Care Med 2008;36:S112. Tovar-Palacio C et al: Ion and diuretic specificity of chimeric proteins between apical Na+-K+-2Cl− and Na+-Cl− cotransporters. Am J Physiol 2004;287:F570. Vaclavik J et al: Effect of spironolactone in resistant arterial hypertension: A randomized, double-blind, placebo-controlled trial (ASPIRANT-EXT). Medicine (Baltimore) 2014;93:e162. Vasilakou D et al: Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: A systematic review and meta-analysis. Ann Intern Med 2013;159:262. Verkman AS et al: Small-molecule inhibitors of urea transporters. Subcell Biochem 2014;73:165. Wakai A, Roberts I, Schierhout G: Mannitol for acute traumatic brain injury. Cochrane Database Syst Rev. 2007;1:CD001049. Wilcox C: New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol 2002;13:798.


Pharmacology_Katzung

Pharmacology_Katzung. Wilcox C: New insights into diuretic use in patients with chronic renal disease. J Am Soc Nephrol 2002;13:798. This patient demonstrates the dramatic diuresis that can be achieved in patients on chronic loop diuretic therapy after addition of a thiazide diuretic. The drop in systolic blood pressure and the weight loss are consistent with the rapid diuresis achieved in this patient, with hypovolemia follow-ing. This effect has now led to acute kidney injury in this patient with preexisting advanced kidney disease. This case demonstrates the need for very close monitoring of patients after addition of thiazide diuretics to chronic loop diuretic therapy (particularly if they have pre-existing chronic kid-ney disease). This is often best achieved in the inpatient setting. Histamine, Serotonin, Bertram G. Katzung, MD, PhD


Pharmacology_Katzung

Pharmacology_Katzung. Histamine, Serotonin, Bertram G. Katzung, MD, PhD A healthy 45-year-old physician attending a reunion in a vacation hotel developed dizziness, redness of the skin over the head and chest, and tachycardia while eating. A short time later, another physician at the table developed similar signs and symptoms with marked orthostatic hypotension. The menu included a green salad, sautéed fish with rice, and apple pie. What is the probable diagnosis? How would you treat these patients?


Pharmacology_Katzung

Pharmacology_Katzung. It has long been known that many tissues contain substances that, when released by various stimuli, cause physiologic effects such as reddening of the skin, pain or itching, and bronchospasm. Later, it was discovered that many of these substances are also present in nervous tissue and have multiple functions. Histamine and serotonin (5-hydroxytryptamine, 5-HT) are biologically active amines that function as neurotransmitters and are also found in non-neural tissues, have complex physiologic and pathologic effects through multiple receptor subtypes, and are often released locally. Together with endogenous peptides (see Chapter 17), prostaglandins and leukotrienes (see Chapter 18), and cytokines (see Chapter 55), they constitute the autacoid group of drugs.


Pharmacology_Katzung

Pharmacology_Katzung. Because of their broad and largely undesirable peripheral effects, neither histamine nor serotonin has any clinical application in the treatment of disease. However, compounds that selectively activate certain receptor subtypes or selectively antagonize the actions of these amines are of considerable clinical value. This chapter therefore emphasizes the basic pharmacology of the agonist amines and the clinical pharmacology of the more selective agonist and antagonist drugs. Obesity, a poorly understood condition, appears to involve many receptors, including some histamine and serotonin receptors. It is discussed in a special section following the discussion of serotonin and its antagonists. The ergot alkaloids, compounds with partial agonist activity at serotonin and several other receptors, are discussed at the end of the chapter.


Pharmacology_Katzung

Pharmacology_Katzung. Histamine was synthesized in 1907 and later isolated from mammalian tissues. Early hypotheses concerning the possible physiologic roles of tissue histamine were based on similarities between the effects of intravenously administered histamine and the symptoms of anaphylactic shock and tissue injury. Marked species variation is observed, but in humans histamine is an important mediator of immediate allergic (such as urticaria) and inflammatory reactions, although it plays only a modest role in anaphylaxis. Histamine plays an important role in gastric acid secretion (see Chapter 62) and functions as a neurotransmitter and neuromodulator (see Chapters 6 and 21). Newer evidence indicates that histamine also plays a role in immune functions and chemotaxis of white blood cells. Histamine occurs in plants as well as in animal tissues and is a component of some venoms and stinging secretions.


Pharmacology_Katzung

Pharmacology_Katzung. Histamine occurs in plants as well as in animal tissues and is a component of some venoms and stinging secretions. Histamine is formed by decarboxylation of the amino acid l-histidine, a reaction catalyzed in mammalian tissues by the enzyme histidine decarboxylase. Once formed, histamine is either stored or rapidly inactivated. Very little histamine is excreted unchanged. The major metabolic pathways involve conversion to N-methylhistamine, methylimidazoleacetic acid, and imidazoleacetic acid (IAA). Certain neoplasms (systemic mastocytosis, urticaria pigmentosa, gastric carcinoid, and occasionally myelogenous leukemia) are associated with increased numbers of mast cells or basophils and with increased excretion of histamine and its metabolites.


Pharmacology_Katzung

Pharmacology_Katzung. Most tissue histamine is sequestered and bound in granules (vesicles) in mast cells or basophils; the histamine content of many tissues is directly related to their mast cell content. The bound form of histamine is biologically inactive, but as noted below, many stimuli can trigger the release of mast cell histamine, allowing the free amine to exert its actions on surrounding tissues. Mast cells are especially rich at sites of potential tissue injury— nose, mouth, and feet; internal body surfaces; and blood vessels, particularly at pressure points and bifurcations. Non-mast cell histamine is found in several tissues, including the brain, where it functions as a neurotransmitter. Strong evidence implicates endogenous neurotransmitter histamine in many brain functions such as neuroendocrine control, cardiovascular regulation, thermal and body weight regulation, and sleep and arousal (see Chapter 21).