Diuretics and Renal Pharmacology

Diuretics and Renal Pharmacology

Butch Kukanich and Deborah T. Kochevar

This chapter presents the physiological basis for fluid and electrolyte balance, including discussion of selected renal mechanisms for regulation of water, sodium, chloride, potassium, hydrogen, and bicarbonate. In this chapter these concepts will be extended in order to understand the mechanism of action, therapeutic uses, and side effects of diuretic agents and renal pharmacology. Diuretic agents are used to mobilize tissue fluid, most often in the treatment of edema of cardiac, renal, or hepatic origin. The history of diuretics dates back to consumption by Paleolithic humans of caffeine-containing plants. Besides xanthine derivatives such as caffeine, osmotic diuretics were clinically important prior to the 20th century. The use of mercurial diuretics, now therapeutically obsolete, began in the early 1900s and was followed by introduction of the first modern diuretic, acetazolamide, in the mid-1950s. By the late 1950s and early 1960s the formulary of modern diuretics included chlorothiazide, furosemide, and potassium-sparing diuretics (Morrison, 1997). These drugs and their relatives constitute the mainstays of diuretic treatment. Finally, the renin–angiotensin–aldosterone system will be discussed, which can be activated by different mechanisms resulting in local and systemic effects including vascular and renal effects.

Renal Physiology

Nephron Function

Knowledge of renal anatomy and physiology is essential to understanding the mechanism of action of diuretic drugs. Although a thorough review of these topics is beyond the scope of this text, a brief overview of nephron function is provided. The basic functional unit of the kidney is the nephron, which consists of a filtering apparatus, the glomerulus, connected to an extended tubular structure that reabsorbs and conditions the glomerular ultrafiltrate to produce urine. Each kidney is composed of thousands of nephron units. Figures 24.1 and 24.2 are drawings of single nephron units, indicating the broad subdivisions of nephron segments and the sites of action of diuretic agents. This diagram provides the simplest nomenclature for nephron segments. As knowledge of the function and epithelial morphology of each segment has increased, the tubular portion of the nephron has been subdivided into approximately 14 shorter segments referred to by a standardized nomenclature (Kriz and Kaissling, 1992).

Diagram shows anatomy of nephron having efferent arteriole, afferent arteriole, interlobular artery, et cetera.

Figure 24.1 Anatomy of the nephron and associated structure. Source: http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22@7.30. Used under CC BY 4.0 https://creativecommons.org/licenses/ by/4.0/.

Diagram shows location within nephron having glomerulus, proximal tubule, distal tubule, osmotic diuretics, et cetera.

Figure 24.2 Locations within the nephron where diuretic agents exert their effects.

Blood flow through the kidney goes from the renal artery into smaller arteries until it reaches the afferent arteriole (Figure 24.1). The afferent arteriole becomes the glomerular capillaries (where glomerular filtration occurs) then the efferent arterioles. The efferent arterioles carry blood into the peritubular capillaries, which surround the renal tubules and is where the majority of the glomerular filtrate (water, electrolytes, glucose, etc.) is reabsorbed.

Formation of urine starts in the glomerulus, where a portion of plasma water is filtered through fenestrated glomerular capillary endothelial cells, a basement membrane, and, finally, filtration slit diaphragms formed by the visceral epithelial cells that cover the basement membrane on its urinary space side. The filtrate collects in Bowman’s space, a double-walled invagination that surrounds the glomerular capillaries. From Bowman’s capsule the filtered fluid passes into the proximal tubule and begins its passage through the renal tubular system. Small solutes (e.g., sodium, chloride, glucose) are actively filtered with plasma water while larger elements, such as protein, blood cells, and macromolecules, are retained within the glomerular capillaries. The rate of filtration in each nephron is a function of hydrostatic pressure in the glomerular capillaries, hydrostatic pressure from the ultrafiltrate in Bowman’s space, mean colloid osmotic pressure in the glomerular capillaries, colloid osmotic pressure of the ultrafiltrate in Bowman’s space, and the properties of the filtering membrane. Hydrostatic pressures are the pressures of the fluid against the surface membrane; in the glomerular capillaries, hydrostatic pressure is determined by capillary blood pressure and in the Bowman’s space by the pressure of the ultrafiltrate. The primary constituent of the glomerular capillary colloid osmotic pressure is albumin in the plasma and there is little colloidal osmotic pressure in normal urine produced by healthy glomeruli. The colloid osmotic pressure in the plasma is higher than the glomerular filtrate, resulting in an opposing force to filtration. The net filtration pressure (Figure 24.3) is determined by the following relationship:

numbered Display Equation

Diagram shows glomerular net filtration pressure having blood hydrostatic pressure, blood colloid osmotic pressure, and capsular pressure.

Figure 24.3 The glomerular net filtration pressure. Source: http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482 e3e22@7.30. Used under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Changes in glomerular capillary hydrostatic pressure (e.g., hyper- or hypotension), blood colloid osmotic pressure (e.g., hypoalbuminemia), and ultrafiltrate hydrostatic pressure (e.g., albuminuria) can have profound effects on glomerular filtration.

Ultrafiltrate from the glomerulus enters the proximal tubule from Bowman’s capsule. By the time urine exits the distal tubule and collecting duct, better than 99% of ultrafiltrate volume will be reabsorbed. Figure 24.4 summarizes the characteristics of reabsorption in broad sections of the renal tubules.

Diagram shows ion and water movement in nephron having with glucose, amino acids, protein, vitamins, lactate, urea, uric acid, et cetera.

Figure 24.4 Nephron ion and water movement. Source: http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482 e3e22@7.30. Used under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

The proximal convoluted tubule (PCT) reabsorbs the majority of sodium (∼60% that enters the nephron) by various transporters and water passively follows and is eventually absorbed into the peritubular capillaries by osmosis. Nearly 100% of the glucose, amino acids, and other substances such as vitamins are also reabsorbed in the PCT by various transporters. Animals with hyperglycemia (e.g., diabetes mellitus) may have large amounts of glucose in the nephron, which exceeds the transport capacity of the active transporters to reabsorb from the nephron and glycosuria can occur. Approximately 90% of bicarbonate is reabsorbed in the PCT through the activity of the enzyme carbonic anhydrase (CA) (Figure 24.5). In the nephron bicarbonate combines with a hydrogen ion to produce carbonic acid. Carbonic acid is converted to water and carbon dioxide by CA and carbon dioxide freely diffuses into the PCT cell. Carbon dioxide in the PCT cell then combines with water to form carbonic acid, catalyzed by CA, and the carbonic acid dissociates into bicarbonate and a hydrogen ion effectively transporting bicarbonate from the nephron into the PCT cell. Bicarbonate is then cotransported with sodium to the interstitial fluid where it can diffuse into the peritubular capillaries. Carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide) exert their primary effects in the PCT, but also have effects on the distal convoluted tubule (DCT).

Diagram shows proximal convoluted tube having peritubular capillary with interstitial fluid and proximal tubule with renal tubule cell and tubular fluid.

Figure 24.5 Reabsorption of bicarbonate from the proximal convoluted tubule, the primary location of carbonic anhydrase inhibitor effects.

The Loop of Henle consists of a thick descending loop, thin descending loop, thin ascending loop, and thick ascending loop. Water pores (aquaporins) are present in the thin descending loop that allow water to osmotically move out of the nephron into the interstitial space, which is hyperosmolar (up to four times osmolarity as the original nephron contents). Reabsorption of sodium, potassium, and chloride from the nephron into the renal tubule cell by the sodium-potassium-2-chloride (Na+/K+/2Cl) cotransporter occurs in the thick ascending loop. Sodium is then transported from the cell to the interstitial fluid by the sodium/potassium ATPase and chloride follows sodium through chloride channels to the interstitial fluid (Figure 24.6). The thick ascending loop is impermeable to water. The high osmolarity of the interstitial fluid is thus maintained by the net movement of sodium and chloride from the nephron to the interstitial fluid, which transports a large portion of the sodium and chloride (∼35% of the original ultrafiltrate) (Figure 24.7).

Diagram shows ion movement in proximal convoluted tube having thick ascending limb and proximal tubule with renal tubule cell and tubular fluid.

Figure 24.6 Ion movement in the thick ascending loop, the primary location of furosemide effects.

Diagram shows Henle countercurrent loop having several levels of urea with interstitial osmolality.

Figure 24.7 The loop of Henle countercurrent multiplier system and osmolality of the interstitial fluid and tubular fluid. Source: http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22@7.30. Used under CC BY 4.0 https://creativecommons.org/ licenses/by/4.0/.

The thick ascending limb of the loop of Henle is of particular importance since this is the site of action of the most effective diuretic drugs (i.e., loop diuretics, furosemide). Approximately 25% of filtered solutes are reabsorbed in the loop of Henle, and most of this reabsorption occurs in the thick ascending limb. The thick ascending loop connects with the distal convoluted tubule to make a critical contact with the afferent arteriole through a cluster of specialized epithelial cells, referred to as the macula densa, which monitors the sodium and tubular flow rates and is discussed in more detail in Section Renin–Angiotensin–Aldosterone System (Figure 24.8). Water, sodium, chloride, bicarbonate, and calcium are reabsorbed in the DCT. Sodium/chloride symporters transport sodium and chloride from the nephron into the DCT cells and are sensitive to the thiazide diuretics (Figure 24.9). Aldosterone enhances sodium and water reabsorption in the DCT and collecting duct by increasing the amount of sodium/potassium ATPase transporters moving sodium out of the nephron and chloride follows along with water. Spironolactone, an aldosterone antagonist, is a diuretic that exerts its effects in the DCT and the collecting duct. Parathyroid hormone (PTH) receptors on the DCT when bound by PTH insert calcium channels on the luminal surface to enhance recovery of calcium from the tubules.

Diagram shows anatomy of glomerulus, macula densa, with podocyte, proximal convoluted tubule, macula densa, et cetera.

Figure 24.8 Anatomy of the glomerulus, macula densa, juxtaglomerular cells and renal vasculature. Source: http://cnx.org/contents/14fb4ad7-39a1-4eee-ab6e-3ef2482e3e22@7.30. Used under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/.

Diagram shows ion movement  of thiazide diuretic effect having peritubular capillary with interstitial fluid.

Figure 24.9 Ion movement in the distal convoluted tubule, the primary location of thiazide diuretic effects.

The collecting duct produces the final effects on urine volume based on plasma osmolarity. More water is reabsorbed if the plasma osmolarity is high (e.g., dehydration) and more water is lost if the plasma osmolarity is low (e.g., overhydration). Two main cell types are present in the collecting duct, the principal cells and intercalated cells. The principal cells possess channels for the recovery or loss of sodium and potassium and the intercalated cells secrete or absorb acid and bicarbonate. Intercalated cells are important factors in regulating urine (and plasma) pH through absorption of bicarbonate and excretion of hydrogen ions. Antidiuretic hormone (ADH, arginine vasopressin, or specifically in swine lysine vasopressin) is released from the posterior pituitary gland when plasma osmolarity increases with an effect of increasing water reabsorption in the collecting duct through aquaporins (water channels). Antidiuretic hormone stimulates aquaporin channels to be inserted on the apical side (tubular side) of the principal cells, resulting in water movement from the nephron into the principal cells due to an osmotic gradient. Different aquaporin channels on the basolateral cell membrane allow water movement from the cell into the interstitial space by osmotic movement. The water than diffuses into the peritubular capillaries and reenters the circulation. Alcohol (ethanol) consumption decreases ADH resulting in a diuretic effect, which is observed in animals treated for ethylene glycol toxicity. Aldosterone also produces an effect on the collecting duct, resulting in increased sodium reabsorption from the collecting duct by sodium/potassium channels and sodium/potassium ATPases. Water passively follows sodium, resulting in a net increased reabsorption of sodium and water and net excretion of potassium. Spironolactone administration results in inhibition of aldosterone leading to loss of sodium and water and retention of potassium from the collecting duct and is often referred as a “potassium-sparing” diuretic.

Factors Regulating Renal Function

Renin–Angiotensin–Aldosterone System

The macula densa is located at the junction of the thick ascending limb and distal convoluted tubule and sits between the afferent and efferent arterioles. Together with the juxtaglomerular cells, which produce renin, these components form the juxtaglomerular apparatus (Figure 24.8). Increased reabsorption of Na and Cl detected by the macular densa results in inhibition of renin release into the efferent arteriole by the juxtaglomerular cells through activation of adenosine (A1) receptors. Conversely, decreased reabsorption of Na and Cl detected by the macular densa stimulates renin release into the efferent arterial through prostaglandins (PGE2, PGI2). Renin release is also enhanced when low blood pressure is detected by intrarenal baroreceptors, triggering the release of prostaglandins (PGE2, PGI2). Renin release can also be stimulated by an extrarenal mechanism, sympathetic nerve stimulation of β1 receptors on the juxtaglomerular cells.

Renin release from the juxtaglomerular cells results in a cascade of events known as the renin–angiotensin–aldosterone system (RAAS) (Figure 24.10). Renin converts angiotensinogen, which is released from the liver, to angiotensin I (ATI). Angiotensin I is converted to angiotensin II (ATII) by angiotensin converting enzymes (ACE) located in the lungs. Angiotensin II is a vasoconstrictor, which binds to AT receptors in the vasculature resulting in increased vascular tone and increased blood pressure. Angiotensin II also stimulates the release of aldosterone from the adrenal cortex, which enhances sodium and subsequently water reabsorption in the distal convoluted tubule and collecting ducts, increasing circulating blood volume and blood pressure.

Flow chart shows renin-angiotensin-aldosterone system having cells, different staged of angiotensin, vasodilation, et cetera.

Figure 24.10 Schematic of the renin–angiotensin–aldosterone system.

ATII increases vascular tone by multiple mechanisms. ATII produces direct vasoconstriction through AT receptors, resulting in the rapid pressor response. Peripheral sympathetic neurotransmission is enhanced by ATII, resulting in increased release of norepinephrine from nerve terminals. Centrally mediated enhanced sympathetic outflow is also stimulated by ATII. ATII also stimulates catecholamine release from the adrenal medulla.

ATII has affects on renal function. ATII stimulates Na+/K+ exchange in the PCT, which increases the reabsorption of Na+, Cl, and HCO3+ (Figure 24.5). The expression of the Na+/glucose transporter in the PCT


is increased with low concentrations of ATII. The activity of Na+/K+/2Cl transporter in the thick ascending limb is also enhanced. ATII stimulates the release of aldosterone, which acts at the DCT and collecting ducts to enhance retention of Na+ and water while increasing elimination of K+. The vasoconstriction induced by ATII in most cases decreases GFR by affecting the afferent arteriole greater than the efferent arterial. However, during renal hypotension ATII affects the efferent arterial to a greater extent than the afferent, resulting in increased GFR. Administration of ACE inhibitors during renal hypotension increases the risk of acute renal failure.

The RAAS production of ATII is also associated with altered cardiovascular structures. Increased cardiac afterload, due to increased vascular tone, and increased preload, due to aldosterone-mediated sodium and water retention, contribute to cardiac remodeling and hypertrophy. Direct effects of ATII on cardiac myocytes, vascular smooth muscle, and fibroblasts also result in cardiac hypertrophy and remodeling and vascular remodeling resulting in increased vascular wall thickness and decreased vascular compliance.

Renin release is modulated by feedback inhibition. Angiotensin II stimulates AT receptors on the juxtaglomerular cells decreasing the release of renin and is known as the short negative feedback loop. Increases in blood pressure due to ATII vasoconstriction results in decreased sympathetic tone and subsequently β1 receptor stimulation. Increases in afferent arterial pressures decrease renin release and is termed the long loop negative feedback.

The RAAS is classically described as an endocrine system response as described above in this section, but locally active and alternative pathways for angiotensin synthesis are present. ACE is present throughout the vascular system in endothelial cells and circulating renin can be stored in the endothelial cells, which can subsequently locally activate the RAAS (Mompeón et al., 2015). Addition tissues (brain, vasculature, heart, adrenal glands, etc.) can produce renin, AT, or ACE that affect local tissue function and structure (Bader and Ganten, 2008). There are also other enzymes that can contribute to the metabolism of angiotensinogen to ATI and ATII. Chymases are enzymes implicated in production of ATII from angiotensin in tissues that can be refractory to ACE inhibitor therapy. There appears to be species-specific differences and the overall contribution to ATII formation appears much less than ACE (Aramaki et al., 2003; Campbell, 2012).

Sympathetic Nervous System

The kidneys are innervated by the sympathetic nervous system. Adrenergic α1-receptor activation results in vasoconstriction of the afferent arterial resulting in decreased blood flow, decreased hydrostatic pressure in the glomerulus, and decreased glomerular filtration rate. Sympathetic β1 receptors are also located on the macula densa, which stimulate renin release and activation of the RAAS.

Antidiuretic Hormone

Osmoreceptors are specialized cells in the hypothalamus that are sensitive to changes in blood osmolarity (primarily influenced by sodium ion concentration). If blood osmolarity increases, typically due to sodium ingestion or water deprivation), ADH is released from the posterior pituitary with its primary effects on the collecting duct cells to increase water reabsorption from the tubular fluid by inserting aquaporins on the apical (lumen) side of the cells. ADH release is controlled by a negative feedback loop in which low blood osmolarity detected by the osmoreceptors inhibits the release of ADH. Diabetes insipidus is a disease characterized by insufficient production of ADH, resulting in blood hyperosmolarity. Ethanol, which is used in the management of ethylene glycol toxicity, inhibits the release of ADH, which can cause diuresis. ADH is also known as vasopressin as high concentrations result in vasoconstriction.


Cylcooxygenase (COX) exists as at least two distinct enzymes (COX1, COX2) and is described in detail in Chapter 20. Both COX isoforms are constitutively expressed in the kidneys, but COX2 expression can be induced to produce substantial local effects within the kidneys during periods of hypotension or decreased blood flow. Eicosanoids, products of COX, can exert prominent roles in renal physiology during certain conditions including hypotension (cardiac disease, vasodilation), hypovolemia (dehydration, hemorrhage), and hyponatremia. COXs produce a variety of eicosanoids, including prostaglandin E2 (PGE2), prostaglandin F (PGF), prostacyclin (PGI2), and thromboxane (TBXA2) with resultant effects in the kidney. The eicosanoids can produce afferent arteriole vasodilation (PGE2, PGI2) locally antagonizing the effects of systemic vasoconstriction such as sympathetic stimulation, ATII, and vasopressin. Eicosanoids enhance renin release (PGE2, PGI2), but renin release is not solely dependent on prostaglandins. Eicosanoids enhance elimination of sodium and water (PGE2, PGI2, PGF) through inhibition of Na+/K+ ATPase activity and aquaporin activity. Prostaglandins (PGE2, PGI2) also produce local vasodilation to maintain medullary blood flow during states of systemic vasoconstriction. Therefore it is not surprising that COX inhibitors can have profound renal effects, with renal adverse effects of nonsteroidal antiinflammatory drugs being the second most common organ system affected with adverse effects.

Renal Epithelial Transport

The presence of anion and cation transporters is essential for most highly protein-bound diuretic drugs to gain access to their site of action, the lumen of the renal tubule. Loop and thiazide diuretics and carbonic anhydrase inhibitors are secreted through the organic acid pathway, and amiloride and triamterene via an organic base transporter (Brater, 1998). Renal insufficiency accompanied by reduced creatinine clearance decreases delivery of diuretic drugs to their secretory site and hence to their site of action. Accumulation of endogenous organic acids during chronic renal failure may result in competition with diuretics for transport at proximal tubule secretion sites (Brater, 1993). Other transporters, including the p-glycoprotein efflux pump, breast cancer resistance protein (BRCP), multidrug and toxin extrusion proteins (MATE1, MATE2-K), and multidrug resistance proteins (MRP2, MRP4), are located in the proximal tubule that contribute to transport of drug into the urine functioning as a mechanism of drug clearance (2013).

Principles of Diuretic Use


The current therapeutic goal of diuretic use is increased excretion of sodium followed by water. The degree of sodium loss in the urine (referred to as natriuresis or, in combination with chloride, saluresis) varies with the mechanism of action of the drug. All except osmotic diuretics inhibit specific enzymes, transport proteins, hormone receptors, or ion channels that function, directly or indirectly, in renal tubular sodium reabsorption. Although saluresis is the primary clinical goal, diuretics also alter elimination of other ions to varying degrees (e.g., K+, H+, Ca2+, Mg2+, Cl, HCO3, phosphates) and may affect renal hemodynamics. Diuretic-induced depletion of circulating blood volume may lead to adverse effects such as electrolyte imbalances and dehydration if therapy is not well monitored. Older animals and those with cardiac or renal disease are also at increased risk for adverse effects if diuretic-induced hypovolemia goes untreated. Because these groups are also the primary target groups for diuretic use, rational use of diuretic drugs is essential. Table 24.1 summarizes selected features of diuretic drugs most commonly used in veterinary medicine.

Table 24.1 The effect of diuretics on water and electrolyte elimination

            H20 Na+ K+ Cl Mg2+ Ca2+ HCO3 H2PO4 H+
Carbonic anhydrase inhibitors + + ++ 0−+ +/− 0 ++ ++
Osmotic diuretics ++ ++ + + ++ + + + ?

Loop diuretics (Na+K+2Cl symport)

++ ++ ++ ++ ++ ++ 0−+ 0−+ +
Thiazide diuretics (Na+/Cl symport) + + ++ + +


0−+ 0−+ +
K+-sparing (Na+ channel) + + + + 0
Aldosterone antagonists + + + 0 ? + ?

++, large increase in elimination; +, increase in elimination; 0, little to no change in elimination; − decreased elimination; +/− variable effect; ? effect unknown.

Edema Formation

The most common indication for diuretic use is removal of tissue edema. Understanding the physiological principles underlying edema formation depends upon an understanding of net capillary filtration. Similar to net filtration pressure in the glomeruli, net capillary filtration, or fluid flux out of a capillary, is dependent upon the plasma colloidal osmotic pressure retaining fluid, and hydrostatic pressure in the arterial capillary forcing fluid out of the capillary through fenestrations and pores. Since the arterial capillary hydrostatic pressure is greater than the plasma colloidal osmotic pressure in most tissues, a small amount of fluid moves from the vasculature into the interstitial space. However, on the venous capillary side, plasma osmotic pressure is greater than the venous hydrostatic pressure and fluid is reabsorbed from the interstitial space into the venous capillary in most tissues, resulting in little net fluid loss into the interstitial space. The lymphatics contribute to fluid absorption from the interstitial space, ensuring no accumulation of fluid in the interstitial space in healthy tissues.

If the fluid movement out of the capillaries exceeds absorption of fluid by venous capillaries and lymphatics, edema results. There can be numerous causes of edema including: lymphatic obstruction (i.e., neoplasia), decreased plasma osmotic pressure (i.e., hypoalbuminemia), and increased venous hydrostatic pressure (i.e., decreased cardiac contractility, excessive intravascular fluid volume). Additionally, the loss of capillary integrity (i.e., inflammation, neurogenic) can result in tissue edema and noncardiogenic pulmonary edema due to head trauma, seizures, and electrocution that occur as a result of poorly understood mechanisms. Therefore the cause of the edema should be identified prior to any therapy, including diuretics.

Congestive heart failure (CHF) is a complex pathophysiological process that begins with decreased cardiac output. The decreased cardiac output and decreased renal blood flow leads to activation of the renin–angiotensin–aldosterone system followed by renal retention of salt and water. High baroreceptor activity causes increased peripheral vascular resistance and increased ADH, which lead to further salt and water retention by the kidneys. Increased central venous pressure caused by increased left ventricular end-diastolic pressures cause increased capillary hydrostatic pressure. All of these factors lead to greater fluid flux out of vessels, resulting in edema related to cardiac disease.

Inhibitors of Carbonic Anhydrase


This class of drugs was discovered as a result of the observation that sulfanilamide chemotherapeutic agents were capable of causing metabolic acidosis by inhibition of carbonic anhydrase (CA). Screening of sulfanilamides resulted in identification of compounds whose predominant mechanism of action was CA inhibition. These drugs have been used sparingly in veterinary medicine as diuretics and are more commonly used for ophthalmic purposes as topical formulations. The prototype drug in this class, acetazolamide (Diamox®, Dazamide®), is available in tablets (125 and 250 mg), extended-release capsules (500 mg), and injectable (500 mg per vial). Other CA inhibitors include preparations for oral use, dichlorphenamide (Daranide®) and methazolamide (Neptazane®), and a topical drug, dorzolamide (Trusopt®), for ophthalmic use.

Mechanisms and Sites of Action

Renal Mechanisms

Drugs in this class are active in the CA-rich segments of the nephron, in particular the proximal tubule. Noncompetitive, reversible inhibition of CA located in the luminal and basolateral membranes (type IV CA) as well as in the cytoplasm (type II CA) results in decreased formation of carbonic acid from CO2 and H2O (see Figure 24.5 and equation below):

numbered Display Equation

Reduction in the amount of carbonic acid yields fewer H+ within proximal tubular cells. Because H+ is normally exchanged for Na+ from the tubular lumen by the Na+/H+ antiporter (also referred to as a Na+/H+ exchanger or NHE), less Na+ is reabsorbed and more is available to combine with urinary HCO3. The NHE maintains a low proton concentration in the cell so that H2CO3 ionizes spontaneously to form H+ and HCO3. This, in turn, creates an electrochemical gradient for HCO3 across the basolateral membrane that drives movement of HCO3 into the interstitial space. Diuresis is established when water is excreted with sodium bicarbonate that accumulates due lack of CA activity. As sodium bicarbonate is trapped in the urine and eliminated, less HCO3 is returned to plasma, and a systemic acidosis eventually develops. As a result of the systemic acidosis, H+ becomes available, Na+ reabsorption is reestablished, and diuresis decreases. Continual use of CA inhibitors is therefore self-limiting in terms of diuretic action. Diuresis induced by CA inhibitors is mild due to incomplete inhibition of CA, redundancy of Na+ transporting systems in the proximal tubule, and rescue of Na+ by reabsorption later in the distal tubule. Because intracellular K+ can, to some extent, substitute for H+ in the Na+ reabsorption step, CA inhibitors cause enhanced K+ excretion. As more Na+ is presented to the distal tubule, the potential for K+ wasting increases. CA inhibitors also decrease secretion of titratable acids and ammonia in the collecting duct (Jackson, 1996). For this reason, and due to the increased excretion of sodium bicarbonate, urine pH increases despite the decreasing systemic pH associated with CA inhibitor induced acidosis. This class of drugs has little, if any, effect on excretion of Ca2+ and Mg2+ but does enhance phosphate elimination.

Extrarenal Actions

Other actions of CA inhibitors are related to the wide distribution of CA in body tissues including the eye, gastric mucosa, pancreas, central nervous system (CNS), and red blood cells. The most important therapeutic consequence is associated with CA inhibition in the eye. The ciliary processes of the eye mediate the formation of aqueous humor, which contains an abundance of osmotically active HCO3. This process is CA dependent and, when inhibited, leads to a decreased rate of formation of aqueous humor and subsequent reduction in intraocular pressure. Although not therapeutically relevant in veterinary medicine, CA inhibition in the CNS has been associated with anticonvulsant actions attributed to this class of drugs.

Absorption and Elimination

Limited information is available regarding pharmacokinetics of CA inhibitors in animals. The pharmacokinetics of acetazolamide in dogs administered an extended release product produced an approximately 7-hour half-life with a TMAX at 3 hours (Li et al., 2014). Acetazolamide gains access to the renal tubules via the organic acid secretion pathway. A dose of 22 mg/kg is reported to have an onset of action of 30 minutes, maximal effects in 2–4 hours, and a duration of action of 4–6 hours in small animals (Roberts, 1985). Oral absorption of drugs in this class is appears to be good in dogs. The oral bioavailability of acetazolamide is 25% in horses, with a terminal half-life of 7 hours (Alberts et al., 2000). Acetazolamide is eliminated primarily through the kidneys. The pharmacokinetics of methazolamide has not been reported in dogs, cats, or horses.

Toxicity, Adverse Effects, Contraindications, and Drug Interactions

Although CA inhibitors are sulfonamide derivatives, side effects commonly associated with sulfonamides are not reported or expected (Trepanier, 2004). CNS drowsiness and disorientation may occur as a result of inhibition of CA in the CNS. Because CA inhibitors decrease ammonia excretion, the severity of preexisting hepatic disease may be worsened and hepatic encephalopathy can be induced. Use is also contraindicated in patients with certain electrolyte disturbances (due to K+ and Na+ wasting) and those with metabolic or respiratory acidosis. Use in patients with severe pulmonary disease who cannot respond to drug-induced metabolic acidosis with respiratory compensation is also contraindicated. Because CA inhibitors alkalinize the urine, calcium phosphate calculi formation is enhanced, and excretion of weak organic bases is reduced. Rare blood dyscrasias associated with CA inhibitors have also been reported in the human, but not in the veterinary literature.

Therapeutic Uses

The primary indication for use of CA inhibitors is to inhibit production of aqueous humor and reduce intraocular pressure. Topical application of dorzolamide (q 8–12 h) produced similar reductions in intraocular pressure compared to oral methazolamide (5 mg/kg q 12 h) or the combination of topical and oral therapy (Gelatt and MacKay, 2001). The topical CA inhibitors therapy is preferred due to equivalent efficacy, lower potential for adverse effects, and lower cost than systemic administration. Acetazolamide (5–10 mg/kg PO q 8 h) and methazolamide (5 mg/kg PO q 12 h given two to three times daily) have been used previously in dogs for management of glaucoma. CA inhibitors have been administered to patients with hydrocephalus for short-term medical management, often in combination with furosemide, but long-term management with diuretics, in people, is often not successful (Thomas, 2010).

In human medicine, CA inhibitors have been used as an adjunctive therapy for epilepsy and in management of acute mountain (high-altitude) sickness. In both human and veterinary medicine, the use of CA inhibitors as diuretics has limited effectiveness due to the rapid development of tolerance. Theoretically, acetazolamide could be used to manage metabolic alkalosis, but this is not a typical clinical practice in veterinary medicine.

Osmotic Diuretics


Osmotic diuretics contain simple solutes of low molecular weight that are typically freely filtered by the glomerulus, undergo limited tubular reabsorption, and are pharmacologically inert. They increase serum and tubular fluid osmolarity resulting in fluid shifts. The most common osmotic diuretic is mannitol, a six-carbon nonmetabolized polyalcohol with a molecular weight of 182. Other agents include glycerin, isosorbide, urea, and hypertonic saline solutions. Because mannitol is the most commonly used osmotic diuretic in both human and veterinary medicine, subsequent discussion will focus primarily on this drug. Concentrated mannitol (15–25%) may crystallize at cooler temperatures, in which case the drug can often be resolubilized by warming the solution. Prior to administration, the solution should be cooled and any remaining crystals removed using an in-line intravenous (IV) filter. There are no veterinary-approved mannitol formulations available. For IV use in animals, the human formulations are used. Human products (Osmitrol®, Resectisol®) range from 5% (275 mOsm/l) to 25% (1375 mOsm/l) and are available for IV administration.

Mechanisms and Sites of Action

Hyperosmolar solutions exert part of their effects by establishing an osmotic gradient between plasma and extravascular fluid compartments resulting in fluid movement into the plasma. Acute effects of this gradient include decreases in hematocrit, blood viscosity, plasma sodium, plasma pH, and, to some degree, the volume of solid organs. Hence, parenchymal dehydration and acute hemodilution are theoretically related as long as the osmotically active particles are effectively separated by a relatively solute-impermeable barrier.

Renal Mechanisms

Initially, osmotic diuretics were thought to act primarily at the level of the proximal tubule by limiting the movement of water from the lumen into the interstitial space. Water retained in the tubular lumen diluted concentrations of sodium and other ions, reduced ion reabsorption, and promoted diuresis. It is now held that osmotic diuretics, in particular mannitol, have effects throughout the length of the tubule, with the most prominent action occurring in the loop of Henle. Sodium reabsorption is markedly reduced in the descending and thin limbs of the loop of Henle, as determined by studies in dogs and rats. Sodium load to the thick ascending limb of the loop of Henle and to the distal tubule is consequently increased, but the nephron fails to recapture the increased loads of salt and water. As demonstrated in the dog, sodium reabsorption is also thought to be directly inhibited in medullary collecting ducts (Better et al., 1997).

Other reported renal effects of mannitol include increases in cortical and medullary blood flow due to a decrease in renal vascular resistance, impairment of urinary concentration, reduction in medullary tonicity (also known as medullary washout), an increase in GFR during renal hypoperfusion (may vary according to species), and an increase in urinary excretion of other electrolytes (e.g., K+, Ca2+, Mg2+, phosphate, bicarbonate) (Better et al., 1997). Mannitol may also prompt the release of atrial natriuretic factor and vasodilatory prostaglandins and inhibition of renin release.

Extrarenal Mechanisms

The actions of mannitol extend beyond the renal effects and include changes in blood rheology, direct transient effects on vascular tone, and increases in cardiac output. In addition to decreasing the hematocrit by hemodilution, mannitol decreases the volume, rigidity, and cohesiveness of red blood cell membranes. The combination of reduced viscosity and reduced mechanical resistance presumably leads to enhanced blood flow. Mannitol-induced increases in cardiac output are thought to be related to reduced peripheral resistance and reduced afterload, a transient increase in preload, and mild positive inotropy. Mannitol may also exert a cytoprotective effect by acting as an oxygen-free radical scavenger (Paczynski, 1997).

Absorption and Elimination

Mannitol is not metabolized and is handled as an inert substance by the body. Studies in dogs and humans indicate that mannitol distribution and elimination follow a two-compartment model (Cloyd et al., 1986; Rudehill et al., 1993). The distribution half-life of intravenously administered mannitol is measured in minutes. Elimination half-life is dose dependent and ranges from 0.5 to 1.5 hours for doses between 0.25 and 1.5 g/kg. Mannitol is eliminated rapidly by the kidneys unless renal function is impaired. As a result, penetration of mannitol into tissues is limited by rapidly falling plasma concentrations. Mannitol is administered intravenously in a slow bolus over 15–30 minutes. Glycerin and isosorbide are administered orally. Of the available osmotic diuretics, only glycerin is eliminated by biotransformation.

Adverse Effects and Drug Interactions

Acute Adverse Effects

Pulse pressure and mean arterial blood pressure usually increase transiently with mannitol administration. However, acute hypotensive, hyponatremic effects of mannitol administration have been reported, especially subsequent to rapid infusion in dehydrated individuals. The mechanism for this acute vasodilatory effect is not well understood, but the problem can largely be prevented by appropriate rates of administration (0.25–1.5 g/kg over 15–30 min). Acute hyponatremia may account for the nausea and vomiting that are sometimes observed with mannitol infusion. Rapid expansion of plasma volume related to attraction of fluid into the vascular compartment may precipitate CHF or pulmonary edema in certain patient populations. However, because the drug is cleared rapidly this problem is not common unless renal function is impaired or underlying cardiac disease is present.

Dehydration and Electrolyte Disturbances

Stay updated, free articles. Join our Telegram channel

Feb 8, 2018 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Diuretics and Renal Pharmacology

Full access? Get Clinical Tree

Get Clinical Tree app for offline access