Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 15. Diuretic Agents

Diuretic Agents: Introduction

Each segment of the nephron—proximal convoluted tubule (PCT), thick ascending limb of the loop of Henle (TAL), distal convoluted tubule (DCT), and cortical collecting tubule (CCT)—has a different mechanism for reabsorbing sodium and other ions. The subgroups of the sodium-excreting diuretics are based on these sites and processes in the nephron. Several other drugs alter water excretion predominantly. The effects of the diuretic agents are predictable from a knowledge of the function of the segment of the nephron in which they act.

High-Yield Terms to Learn

Bicarbonate diuretic A diuretic that selectively increases sodium bicarbonate excretion. Example: a carbonic anhydrase inhibitor Diluting segment A segment of the nephron that removes solute without water; the thick ascending limb and the distal convoluted tubule are active salt-absorbing segments that are not permeable by water Hyperchloremic metabolic acidosis A shift in body electrolyte and pH balance involving elevated chloride, diminished bicarbonate concentration, and a decrease in pH in the blood. Typical result of bicarbonate diuresis Hypokalemic metabolic alkalosis A shift in body electrolyte balance and pH involving a decrease in serum potassium and an increase in blood pH. Typical result of loop and thiazide diuretic actions Nephrogenic diabetes insipidus Loss of urine-concentrating ability in the kidney caused by lack of responsiveness to antidiuretic hormone (ADH is normal or high) Pituitary diabetes insipidus Loss of urine-concentrating ability in the kidney caused by lack of antidiuretic hormone (ADH is low or absent) Potassium-sparing diuretic A diuretic that reduces the exchange of potassium for sodium in the collecting tubule; a drug that increases sodium and reduces potassium excretion. Example: aldosterone antagonists. Uricosuric diuretic A diuretic that increases uric acid excretion, usually by inhibiting uric acid reabsorption in the proximal tubule. Example: ethacrynic acid

Renal Transport Mechanisms & Diuretic Drug Groups

The kidney filters both inorganic and organic solutes at the glomerulus and must recover a significant percentage of these substances before excretion in the urine. The major transport mechanisms for the recovery of ions and water in the various segments of the nephron are shown in Figure 15-1. Because the mechanisms for reabsorption of salt and water differ in each of the 4 major tubular segments, the diuretics acting in these segments each have differing mechanisms of action. Most diuretics act from the luminal side of the membrane and must be present in the urine. They are filtered at the glomerulus, and some are also secreted by the weak acid-secretory carrier in the proximal tubule. An exception is the aldosterone receptor antagonist group (eg, spironolactone and eplerenone), drugs that enter the collecting tubule cell from the basolateral side and bind to the cytoplasmic aldosterone receptor.

FIGURE 15-1

Tubule transport systems in the kidney and sites of action of diuretics. Circles with arrows denote known ion cotransporters that are targets of the diuretics indicated by the numerals. Question marks denote preliminary or incompletely documented suggestions for the location of certain drug effects.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 15-1.)

Proximal Convoluted Tubule (PCT)

This segment carries out isosmotic reabsorption of amino acids, glucose, and numerous cations. It is also the major site for sodium chloride and sodium bicarbonate reabsorption. The proximal tubule is responsible for 60-70% of the total reabsorption of sodium. No currently available drug directly acts on NaCl reabsorption in the PCT. The mechanism for bicarbonate reabsorption is shown in Figure 15-2. Bicarbonate itself is poorly reabsorbed through the luminal membrane, but conversion of bicarbonate to carbon dioxide via carbonic acid permits rapid reabsorption of the carbon dioxide. Bicarbonate can then be regenerated from carbon dioxide within the tubular cell and transported into the interstitium. Sodium is separately reabsorbed from the lumen in exchange for hydrogen ions and transported into the interstitial space by the sodium-potassium pump (Na+/K+ ATPase). Carbonic anhydrase, the enzyme required for the bicarbonate reabsorption process on the brush border and in the cytoplasm, is the target of carbonic anhydrase inhibitor diuretic drugs. Active secretion and reabsorption of weak acids and bases also occurs in the proximal tubule. Most weak acid transport occurs in the straight S2 segment, distal to the convoluted part. Uric acid transport is especially important and is targeted by some of the drugs used in treating gout (Chapter 36). Weak bases are transported in the S1 and S2 segments.

FIGURE 15-2

Mechanism of sodium bicarbonate reabsorption in the proximal tubule cell. NHE3, Na+/H+ exchanger 3; CA, carbonic anhydrase.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 15-2.)

Carbonic Anhydrase Inhibitors

Prototypes and Mechanism of Action

Acetazolamide is the prototypic agent. These diuretics are sulfonamide derivatives. The mechanism of action is inhibition of carbonic anhydrase in the brush border and cytoplasm (Figure 15-2). Carbonic anhydrase is also found in other tissues and plays an important role in the secretion of cerebrospinal fluid and aqueous humor. Acetazolamide inhibits carbonic anhydrase in all tissues of the body.

Effects

The major renal effect is bicarbonate diuresis (ie, sodium bicarbonate is excreted); body bicarbonate is depleted, and metabolic acidosis results. As increased sodium is presented to the cortical collecting tubule, some of the excess sodium is reabsorbed and potassium is secreted, resulting in significant potassium wasting (Table 15-1). As a result of bicarbonate depletion, sodium bicarbonate excretion slows—even with continued diuretic administration—and the diuresis is self-limiting within 2-3 days. Secretion of bicarbonate into aqueous humor by the ciliary epithelium in the eye and into the cerebrospinal fluid by the choroid plexus is reduced. In the eye, a useful reduction in intraocular pressure can be achieved. In the central nervous system (CNS), acidosis of the cerebrospinal fluid results in hyperventilation, which can protect against high-altitude sickness. The ocular and cerebrospinal fluid effects are not self-limiting.

TABLE 15-1 Electrolyte changes produced by diuretic drugs.

Amount in Urine Group NaCl NaHCO3

K+

Body pH Carbonic anhydrase inhibitors    Acidosis Loop diuretics  —  Alkalosis Thiazides  ,—  Alkalosis K+-sparing diuretics

 —  Acidosis

Clinical Uses

A major application of carbonic anhydrase inhibitors is in the treatment of severe acute glaucoma (see Table 10-3). Acetazolamide must be administered orally or parenterally, but topical analogs are now available (dorzolamide, brinzolamide) for chronic use in the eye. Carbonic anhydrase inhibitors are also used to prevent acute mountain (high-altitude) sickness. These agents are used for their diuretic effect only if edema is accompanied by significant metabolic alkalosis.

Toxicity

Drowsiness and paresthesias are commonly reported after oral therapy. Cross-allergenicity between these and all other sulfonamide derivatives (other sulfonamide diuretics, hypoglycemic agents, antibacterial sulfonamides) is uncommon but does occur. Alkalinization of the urine by these drugs may cause precipitation of calcium salts and formation of renal stones. Renal potassium wasting may be marked. Patients with hepatic impairment often excrete large amounts of ammonia in the urine in the form of ammonium ion. If they are given acetazolamide, alkalinization of the urine prevents conversion of ammonia to ammonium ion. As a result, they may develop hepatic encephalopathy because of increased ammonia reabsorption and hyperammonemia.

Thick Ascending Limb of the Loop of Henle (TAL)

This segment pumps sodium, potassium, and chloride out of the lumen into the interstitium of the kidney. It is also a major site of calcium and magnesium reabsorption, as shown in Figure 15-3. Reabsorption of sodium, potassium, and chloride are all accomplished by a Na+/K+/2Cl- carrier, which is the target of the loop diuretics. This cotransporter provides part of the concentration gradient for the countercurrent concentrating mechanism in the kidney and is responsible for the reabsorption of 20-30% of the sodium filtered at the glomerulus. Because potassium is pumped into the cell from both the luminal and basal sides, an escape route must be provided; this occurs into the lumen via a potassium-selective channel. Because the potassium diffusing through these channels is not accompanied by an anion, a net positive charge is set up in the lumen. This positive potential drives the reabsorption of calcium and magnesium.

FIGURE 15-3

Mechanism of sodium, potassium, and chloride reabsorption by the transporter NKCC2 in the thick ascending limb of the loop of Henle. Note that pumping of potassium into the cell from both the lumen and the interstitium would result in unphysiologically high intracellular K+ concentration. This is avoided by movement of K+ down its concentration gradient back into the lumen, carrying with it excess positive charge. This positive charge drives the reabsorption of calcium and magnesium.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 15-3.)

Loop Diuretics

Prototypes and Mechanism of Action

Furosemide is the prototypical loop agent. Furosemide, bumetanide, and torsemide are sulfonamide derivatives. Ethacrynic acid is a phenoxyacetic acid derivative; it is not a sulfonamide but acts by the same mechanism. Loop diuretics inhibit the cotransport of sodium, potassium, and chloride (NKCC2, Figure 15-3). The loop diuretics are relatively short-acting (diuresis usually occurs over a 4-h period following a dose).

Effects

The loop of Henle is responsible for a significant percentage of total renal sodium chloride reabsorption; therefore, a full dose of a loop diuretic produces a massive sodium chloride diuresis if glomerular filtration is normal and blood volume may be significantly reduced. If tissue perfusion is adequate, edema fluid is rapidly excreted. The diluting ability of the nephron is reduced because the loop of Henle is the site of significant dilution of urine. Inhibition of the Na+/K+/2Cl- transporter also results in loss of the lumen-positive potential, which reduces reabsorption of divalent cations as well. As a result, calcium excretion is significantly increased. Ethacrynic acid is a moderately effective uricosuric drug if blood volume is maintained. The presentation of large amounts of sodium to the collecting tubule may result in significant potassium wasting and excretion of protons; hypokalemic alkalosis may result (Table 15-1). Loop diuretics also have potent pulmonary vasodilating effects; the mechanism is not known.

Prostaglandins are important in maintaining glomerular filtration. When synthesis of prostaglandins is inhibited, for example, by nonsteroidal anti-inflammatory drugs (Chapter 36), the efficacy of diuretics—especially loop diuretics—decreases.

Clinical Use

The major application of loop diuretics is in the treatment of edematous states (eg, heart failure, ascites). They are particularly valuable in acute pulmonary edema, in which the pulmonary vasodilating action plays a useful role. They are sometimes used in hypertension if response to thiazides is inadequate, but the short duration of action of loop diuretics is a disadvantage in this condition. A less common but important application is in the treatment of severe hypercalcemia (eg, that induced by malignancy). This life-threatening condition can often be managed with large doses of furosemide together with parenteral volume and electrolyte (sodium and potassium chloride) replacement. It should be noted that diuresis without volume replacement results in hemoconcentration; serum calcium concentration then will not diminish and may even increase further.

Toxicity

Loop diuretics usually induce hypokalemic metabolic alkalosis (Table 15-1). Because large amounts of sodium are presented to the collecting tubules, wasting of potassium (which is excreted by the kidney in an effort to conserve sodium) may be severe. Because they are so efficacious, loop diuretics can cause hypovolemia and cardiovascular complications. Ototoxicity is an important toxic effect of the loop agents. The sulfonamides in this group may rarely cause typical sulfonamide allergy.

Distal Convoluted Tubule (DCT)

This segment actively pumps sodium and chloride out of the lumen of the nephron via the Na+/Cl- carrier shown in Figure 15-4. This cotransporter is the target of the thiazide diuretics. The distal convoluted tubule is responsible for approximately 5-8% of sodium reabsorption. Calcium is also reabsorbed in this segment under the control of parathyroid hormone (PTH). Removal of the reabsorbed calcium back into the blood requires the sodium-calcium exchange process discussed in Chapter 13.

FIGURE 15-4

Mechanism of sodium and chloride reabsorption by the transporter NCC in the distal convoluted tubule. A separate reabsorptive mechanism, modulated by parathyroid hormone (PTH), is present for movement of calcium into the cell from the urine. This calcium must be transported via the sodium-calcium exchanger back into the blood. R, PTH receptor.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 15-4.)

Thiazide Diuretics

Prototypes and Mechanism of Action

Hydrochlorothiazide, the prototypical agent, and all the other members of this group are sulfonamide derivatives. A few derivatives that lack the typical thiazide ring in their structure nevertheless have effects identical with those of thiazides and are therefore considered thiazide-like. Thiazides are active by the oral route and have a duration of action of 6-12 h, considerably longer than most loop diuretics. The major action of thiazides is to inhibit sodium chloride transport in the early segment of the distal convoluted tubule (NCC, Figure 15-4).

Effects

In full doses, thiazides produce moderate but sustained sodium and chloride diuresis. Hypokalemic metabolic alkalosis may occur (Table 15-1). Reduction in the transport of sodium from the lumen into the tubular cell reduces intracellular sodium and promotes sodium-calcium exchange at the basolateral membrane. As a result, reabsorption of calcium from the urine is increased, and urine calcium content is decreased—the opposite of the effect of loop diuretics. Because they act in a diluting segment of the nephron, thiazides may reduce the excretion of water and cause dilutional hyponatremia. Thiazides also reduce blood pressure, and the maximal pressure-lowering effect occurs at doses lower than the maximal diuretic doses (see Chapter 11). Inhibition of renal prostaglandin synthesis reduces the efficacy of the thiazides.

When a thiazide is used with a loop diuretic, a synergistic effect occurs with marked diuresis.

Clinical Use

The major application of thiazides is in hypertension, for which their long duration and moderate intensity of action are particularly useful. Chronic therapy of edematous conditions such as mild heart failure is another application, although loop diuretics are usually preferred. Chronic renal calcium stone formation can sometimes be controlled with thiazides because of their ability to reduce urine calcium concentration.

Toxicity

Massive sodium diuresis with hyponatremia is an uncommon but dangerous early effect of thiazides. Chronic therapy is often associated with potassium wasting, since an increased sodium load is presented to the collecting tubules; the cortical collecting tubules compensate by reabsorbing sodium and excreting potassium. Diabetic patients may have significant hyperglycemia. Serum uric acid and lipid levels are also increased in some persons. Thiazides are sulfonamides and share potential sulfonamide allergenicity.

Cortical Collecting Tubule (CCT)

The final segment of the nephron is the last tubular site of sodium reabsorption and is controlled by aldosterone (Figure 15-5), a steroid hormone secreted by the adrenal cortex. This segment is responsible for reabsorbing 2-5% of the total filtered sodium under normal circumstances; more if aldosterone is increased. The reabsorption of sodium occurs via channels (not a transporter) and is accompanied by an equivalent loss of potassium or hydrogen ions. The collecting tubule is thus the primary site of acidification of the urine and the last site of potassium excretion. The aldosterone receptor and the sodium channels are sites of action of the potassium-sparing diuretics. Reabsorption of water occurs in the medullary collecting tubule under the control of antidiuretic hormone (ADH).

FIGURE 15-5

Mechanism of sodium, potassium, and hydrogen ion movement in the collecting tubule cells. Synthesis of Na+/K+ ATPase, and the epithelial sodium channels (ENaC) and potassium channels is under the control of aldosterone, which combines with an intracellular receptor, R, before entering the nucleus.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 15-5.)

Potassium-Sparing Diuretics

Prototypes and Mechanism of Action

Spironolactone and eplerenone are steroid derivatives and act as pharmacologic antagonists of aldosterone in the collecting tubules. By combining with and blocking the intracellular aldosterone receptor, these drugs reduce the expression of genes controlling synthesis of epithelial sodium ion channels (ENaC) and Na+/K+ ATPase. Amiloride and triamterene act by blocking the epithelial sodium channels in the same portion of the nephron (Figure 15-5). (These drugs do not block INa channels in excitable membranes.) Spironolactone and eplerenone have slow onsets and offsets of action (24-72 h). Amiloride and triamterene have durations of action of 12-24 h.

Effects

All drugs in this class cause an increase in sodium clearance and a decrease in potassium and hydrogen ion excretion and therefore qualify as potassium-sparing diuretics. They may cause hyperkalemic metabolic acidosis (Table 15-1).

Clinical Use

Potassium wasting caused by chronic therapy with loop or thiazide diuretics, if not controlled by dietary potassium supplements, usually responds to these drugs. The most common use is in the form of products that combine a thiazide with a potassium-sparing agent in a single pill.

Aldosteronism (eg, the elevated serum aldosterone levels that occur in cirrhosis) is an important indication for spironolactone. Aldosteronism is also a feature of heart failure, and spironolactone and eplerenone have been shown to have significant long-term benefits in this condition (Chapter 13). Some of this effect may occur in the heart, an action that is not yet understood.

Toxicity

The most important toxic effect of potassium-sparing diuretics is hyperkalemia. These drugs should never be given with potassium supplements. Other aldosterone antagonists (eg, angiotensin [ACE] inhibitors and angiotensin receptor blockers [ARBs]), if used at all, should be used with caution. Spironolactone can cause endocrine abnormalities, including gynecomastia and antiandrogenic effects. Eplerenone appears to have less endocrine effect.

Skill Keeper: Diuretic Combinations and Electrolytes

(See Chapter 13)

Describe the possible interactions of cardiac glycosides (digoxin) with the major classes of diuretics. The Skill Keeper Answer appears at the end of the chapter.

Osmotic Diuretics

Prototypes and Mechanism of Action

Mannitol, the prototypical osmotic diuretic, is given intravenously. Other drugs often classified with mannitol (but rarely used) include glycerin, isosorbide (not isosorbide dinitrate), and urea. Because it is freely filtered at the glomerulus but poorly reabsorbed from the tubule, mannitol remains in the lumen and "holds" water by virtue of its osmotic effect. The major location for this action is the proximal convoluted tubule, where the bulk of isosmotic reabsorption normally occurs. Reabsorption of water is also reduced in the descending limb of the loop of Henle and the collecting tubule.

Effects

The volume of urine is increased. Most filtered solutes are excreted in larger amounts unless they are actively reabsorbed. Sodium excretion is usually increased because the rate of urine flow through the tubule is greatly accelerated and sodium transporters cannot handle the volume rapidly enough. Mannitol can also reduce brain volume and intracranial pressure by osmotically extracting water from the tissue into the blood. A similar effect occurs in the eye.

Clinical Use

The osmotic drugs are used to maintain high urine flow (eg, when renal blood flow is reduced and in conditions of solute overload from severe hemolysis or rhabdomyolysis). Mannitol and several other osmotic agents are useful in reducing intraocular pressure in acute glaucoma and intracranial pressure in neurologic conditions.

Toxicity

Removal of water from the intracellular compartment may cause hyponatremia and pulmonary edema. As the water is excreted, hypernatremia may follow. Headache, nausea, and vomiting are common.

Antidiuretic Hormone Agonists & Antagonists

Prototypes and Mechanism of Action

Antidiuretic hormone (ADH) and desmopressin are prototypical ADH agonists. They are peptides and must be given parenterally. Conivaptan and tolvaptan are ADH antagonists. Demeclocycline was previously used for this purpose. Lithium also has ADH-antagonist effects but is never used for this purpose.

ADH facilitates water reabsorption from the collecting tubule by activation of V2 receptors, which stimulate adenylyl cyclase via Gs. The increased cyclic adenosine monophosphate (cAMP) causes the insertion of additional aquaporin AQP2 water channels into the luminal membrane in this part of the tubule (Figure 15-6). Conivaptan is an ADH inhibitor at V1a and V2 receptors. Tolvaptan is a more selective V2 blocker with little V1 affinity. Demeclocycline and lithium inhibit the action of ADH at some point distal to the generation of cAMP and presumably interfere with the insertion of water channels into the membrane.

FIGURE 15-6

Mechanism of water transport across the membranes of collecting duct cells. Aquaporins 3 and 4 (AQP3, 4) are normally present in the basolateral membranes, but the luminal water channel, AQP2, is inserted only in the presence of ADH or similar antidiuretic peptides acting on the vasopressin V2 receptor.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 15-6.)

Effects and Clinical Uses

Agonists

ADH and desmopressin reduce urine volume and increase its concentration. ADH and desmopressin are useful in pituitary diabetes insipidus. They are of no value in the nephrogenic form of the disease, but salt restriction, water restriction, thiazides, and loop diuretics may be used. These therapies reduce blood volume, a very strong stimulus to proximal tubular reabsorption. The proximal tubule thus substitutes—in part—for the deficient concentrating function of the collecting tubule in nephrogenic diabetes insipidus.

Antagonists

ADH antagonists oppose the actions of ADH and other naturally occurring peptides that act on the same V2 receptor. Such peptides are produced by certain tumors (eg, small cell carcinoma of the lung) and can cause significant water retention and dangerous hyponatremia. This syndrome of inappropriate ADH secretion (SIADH) can be treated with demeclocycline and conivaptan. Lithium also works but has greater toxicity.

Toxicity

In the presence of ADH or desmopressin, a large water load may cause dangerous hyponatremia. Large doses of either peptide may cause hypertension in some persons.

Conivaptan and tolvaptan may cause demyelination with serious neurologic consequences if hyponatremia is corrected too rapidly. Conivaptan may cause infusion site reactions. In children younger than 8 years, demeclocycline (like other tetracyclines) causes bone and teeth abnormalities. Lithium causes nephrogenic diabetes insipidus as a toxic effect; because of its other toxicities, the drug is never used to treat SIADH.

Skill Keeper Answer: Digitalis and Diuretics

(See Chapter 13)

Digoxin toxicity is facilitated by hypokalemia. Therefore, potassium-wasting diuretics (eg, loop agents, thiazides), which are often needed in heart failure, can increase the risk of a fatal digitalis arrhythmia. Carbonic anhydrase inhibitors, though also potassium-wasting agents, are rarely used for their systemic and diuretic effects and are therefore less likely to be involved in digitalis toxicity. The potassium-sparing diuretics, in contrast to the other groups, can be useful in preventing such interactions.

Checklist

When you complete this chapter, you should be able to:

 List 5 major types of diuretics and relate them to their sites of action.

 Describe 2 drugs that reduce potassium loss during sodium diuresis.

 Describe a therapy that reduces calcium excretion in patients who have recurrent urinary stones.

 Describe a treatment for severe acute hypercalcemia in a patient with advanced carcinoma.

 Describe a method for reducing urine volume in nephrogenic diabetes insipidus.

 List the major applications and the toxicities of acetazolamide, thiazides, loop diuretics, and potassium-sparing diuretics.

Drug Summary Table: Diuretic Agents

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Interactions Carbonic anhydrase inhibitors Acetazolamide Inhibits carbonic anhydrase. In proximal tubule, bicarbonate reabsorption is blocked and Na+ is excreted with HCO3 -. In glaucoma, secretion of aqueous humor is reduced, and in mountain sickness, metabolic acidosis increases respiration

Glaucoma, mountain sickness; edema with alkalosis Oral, parenteral Diuresis is self-limiting, but effects in glaucoma and mountain sickness persist Duration: 12 h Metabolic acidosis; sedation, paresthesias. Hyperammonemia in cirrhosis Dorzolamide, brinzolamide: Topical carbonic anhydrase inhibitors for glaucoma only Loop diuretics Furosemide, also bumetanide, torsemide Inhibit Na+/K+/2Cl- transporter in thick ascending limb of loop of Henle. Cause powerful diuresis and increased Ca2+ excretion

Heart failure, pulmonary edema, severe hypertension; other forms of edema Oral, parenteral Duration: 2-4 h Metabolic hypokalemic alkalosis; ototoxicity; hypovolemia; efficacy is reduced by nonsteroidal anti-inflammatory drugs. Sulfonamide allergy (rare). Ethacrynic acid: Like furosemide but not a sulfonamide and has some uricosuric effect Thiazide diuretics Hydrochlorothiazide, many other thiazides Inhibit Na+/Cl- transporter in distal convoluted tubule. Cause moderate diuresis and reduced excretion of calcium

Hypertension, mild heart failure, hypercalciuria with stones; syndrome of inappropriate ADH secretion Oral Duration: 8-12 h Metabolic hypokalemic alkalosis; early hyponatremia; increased serum glucose, lipids, uric acid; efficacy is reduced by nonsteroidal anti-inflammatory drugs. Sulfonamide allergy (rare). Chlorthalidone: Not a thiazide, but effects are indistinguishable from those of thiazides K+-sparing diuretics Spironolactone, eplerenone Steroid inhibitors of cytoplasmic aldosterone receptor in cortical collecting ducts; reduce K+ excretion

Excessive K+ loss when using other diuretics; aldosteronism

Oral Duration: 24-36, 48 h Hyperkalemia; gynecomastia (spironolactone only) Amiloride Inhibitor of ENaC epithelial sodium channels in cortical collecting duct, reduces Na+ reabsorption and K+ excretion

Excessive K+ loss when using other diuretics; usually in combination with thiazides

Oral Duration: 10-12 h Hyperkalemia Triamterene: Like amiloride Osmotic diuretics Mannitol Osmotically retains water in tubule by reducing reabsorption in proximal tubule, descending limb of Henle's loop, and collecting ducts; in the periphery, mannitol extracts water from cells Solute overload in rhabdomyolysis, hemolysis; brain edema with coma; acute glaucoma Intravenous; short duration Hyponatremia followed by hypernatremia; headache, nausea, vomiting ADH agonists Desmopressin, vasopressin Agonists at V1 and V2 ADH receptors, activate insertion of aquaporin water channels in collecting tubule; vasoconstriction

Pituitary diabetes insipidus Subcutaneous, nasal Duration: 2-3 h Hyponatremia; hypertension ADH antagonists Conivaptan Antagonist at V1a,V2 receptors

SIADH, hyponatremia Parenteral Duration: 6-10 h Infusion site reactions Demeclocycline: Used in SIADH, mechanism unclear

ADH, antidiuretic hormone; SIADH, syndrome of inappropriate antidiuretic hormone.



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