Introduction

Idiopathic edema is a poorly understood disorder that affects primarily women and causes salt retention and edema in the absence of cardiac, renal, hepatic, or thyroid disease. Despite many studies of the various factors controlling the renal handling of sodium and water, the disease remains idiopathic (see Table 1). It may represent a heterogenous collection of edematous disorders since a variety of abnormalities have been discovered in different subsets of patients. A uniform explanation for...

Pathophysiology

Hyperuricemia is a common complication of diuretic therapy in general (Table 1). In most mammals, uric acid undergoes bidirectional transport in the proximal nephron, i.e., both tubular reabsorption and secretion as reviewed previously (see Chapters II and IIIA). In man, net urate reabsorption occurs and is highly dependent on the filtered load, luminal concentration of urate, and luminal flow rate. Most commonly used diuretic agents can alter uric acid transport along the nephron, leading to...

Treatment Of Ascites And Edema In Patients With Hepatic Cirrhosis [35

Salt restriction and diuretics may be used in patients with cirrhosis to reduce mechanical derangements and enhance patient comfort. However, these treatments do not correct or reverse the underlying hepatic abnormalities. The therapeutic goal of such therapy is the reestablishment of salt and water balance at more clinically acceptable levels of ascites and edema. Complete elimination of detectable edema and ascites is rarely possible or desired. Indeed, attempts to eliminate completely edema...

References

H. (1971, reprint of original 1889 edition). Outlines of the History of Medicine and the Medical Profession. R. E. Kreiger, Huntington, NY. 2. Bartram, E. A. (1932). Experimental observations on the effect of various diuretics when injected directly into one renal artery of the dog. J. Clin. Invest. 11, 1197-1219. 3. Berglund, H., Medes, G., Huber, G. C., Longcope, W. T., and Richards, A. N. (Eds.) (1935). The Kidney in Health and Disease. Lea & Febiger, Philadelphia. 4. Beyer, K....

Central Nervous System

Mannitol is an osmotic diuretic which is utilized clinically to decrease intracranial pressure. This agent is administered as a hypertonic solution such that an osmotic gradient is created favoring the movement of water from the brain parenchyma into the intravascular compartment across the blood-brain barrier. As long as the blood-brain barrier is intact, mannitol is effective in decreasing the water content of the brain, thereby reducing intracranial pressure (see Table 1). When the integrity...

Inhibitors Of Carbonic Anhydrase Pharmacokinetics and Pharmacodynamics

These agents are now most frequently used for glaucoma, but they represent a milestone in the development of diuretics. Modern diuretic therapy was launched when it was noted that sulfanilamide caused a diuresis rich in sodium bicarbonate. Chemical modification of this compound resulted in current carbonic anhydrase inhibitors such as acetazolamide, and subsequently thiazide, and loop diuretics. Little is known of the pharmacokinetics or pharmacodynamics of carbonic anhydrase inhibitors. The...

Collecting Duct

The collecting duct consists of a series of subsegments. Following the connecting tubule, there is the initial cortical collecting tubule (segment prior to the confluence of multiple tubules), followed by the cortical collecting duct, the outer medullary collecting duct (divided into outer stripe and inner stripe segments), and the inner medullary or papillary collecting duct. In general, these segments are similar, but significant differences exist. Below we describe some of the general...

Acknowledgments

Appreciation is expressed to Agnes C. Buffone for preparation of the manuscript and to the members of the renal research group at Tulane for providing assistance and suggestions. Dr. Jules Puschett provided very helpful consultations. Some of the illustrations were prepared by Betsy Ewing and Dr. Lisa M. Harrison-Bernard. The author's research activities in the area of renal hemodynamics and experimental hypertension have been supported by research grants from the National Heart Lung and Blood...

Renal Electrolyte Transport and Its Regulation

Alpern,* Gerhard Giebisch,t and Donald W. Seldin* * Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235 and 'Department of Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06510 In this chapter we review how the kidney transports electrolytes and water, and how these processes are regulated. The chapter will then form the basis for an understanding of the multiplicity of diuretic effects, many...

Effect Of Nsaids On Diuretic Stimulated Renin Release

Indomethacin has been shown to attenuate the increase in plasma renin activity which follows furosemide, hydrochlorothiazide and even spironolactone administration in man 10 . The time course of this inhibition is rapid and occurs independently of diuretic effects on sodium excretion or measurable change in vascular volume. Therefore it seems likely that the inhibition of renin release is due to direct effects on the juxtamedullary apparatus. As aldosterone levels following diuretic...

Suggested Reading Osmotic Diuretics

S. (1979). Luminal influences on potassium secretion Sodium concentration and fluid flow rate. Am. J. Physiol 236, F192-F205. 2. Reineck, H. J., Osgood, R. W., Ferris, T. F., and Stein, J. H. (1975). Potassium transport in the distal tubule and collecting duct of the rat. Am. J. Physiol. 229,1403-1409. 3. Mathisen, O., Raeder, M., and Kiil, F. (1981). Mechanism of osmotic diuresis. Kidney Int. 19, 431-437. 4. Mavichak, V., and Sutton, R. A. L. (1986). Osmotic...

Distal Convoluted Tubule and Connecting Tubule

The distal tubule consists of several short nephron segments. The first of these is the distal convoluted tubule. While early micropuncture studies used this term to apply to the entire surface distal nephron beginning with the macula densa and ending with the confluence of multiple nephrons into the cortical collecting duct, more recent nomenclature defines this segment more narrowly. The distal convoluted tubule is a segment of approximately 0.5 mm in length that contains one cell type,...

Plasma Volume

In patients with hypertension addition of an ACE inhibitor to patients receiving chronic diuretic therapy does not appear to alter plasma volume 48 . In patients with untreated heart failure plasma and extracellular fluid volume are expanded 1 , However, in patients treated optimally with diuretics plasma volume may be normal or reduced and extracellular fluid volume normal or only slightly increased 3, 14 . Addition of an ACE inhibitor causes an acute fall in hematocrit, indicating acute...

Consequences of Diuretic Induced Hypokalemia

The most serious potential complication of diuretic-induced hypokalemia is the development of arrhythmias. This complication is particularly true for patients taking cardiac glycosides as the presence of hypokalemia can precipitate digitalis toxicity. A controversial issue has centered around whether diuretic-induced hypokalemia can give rise to fatal arrhythmias. In several large trials involving therapy of patients with mild hypertension, higher rates of cardiac mortality primarily...

Sodium Chloride

A. (1992). Sodium chloride transport Distal nephron. In The Kidney (D. W. Seldin and G. Giebisch, eds.), pp. 2003-2040. Raven, New York. 2. Reeves, W. B., and Andreoli, T. E. Sodium chloride transport in the loop of Henle. In The Kidney (D. W. Seidin, G. Giebisch, Eds.), pp. 1975-2002. Raven Press, New York. 3. Weinstein, A. M. (1992). Sodium and chloride transport Proximal nephron. In The Kidney (D. W. Seldin and G. Giebisch, Eds.), pp. 1925-1974. Raven Press,...

Calcium Transport

Calcium homeostasis is maintained by the kidney excreting an amount of Ca2+ equal to that which is absorbed from the GI tract. Approximately 60 of plasma Ca2+ is ultrafilterable (that fraction not bound to albumin), including both ionized Ca2+ and Ca2+ complexed to anions such as phosphate, citrate, HC03 and sulfate. Once filtered, approximately 65 of Ca2+ is reabsorbed in the proximal tubule (Fig. 12). In the proximal tubule, Ca2+ reabsorption and Na + reabsorption are regulated in parallel,...

Intestine

On a daily basis the small and large intestine absorbs a large quantity of salt and water as well as dietary nutrients. Many of the transport mechanisms involved in this absorptive process are similar, if not identical, to ones present in the kidney. Several diuretics have been shown to interact with these transport processes in the intestine. For the most part, diuretic therapy is not associated with clinically evident gastrointestinal manifestations however, administration of diuretics have...

Ivb

Diuretic Agents Clinical Physiology and Pharmacology Copyright 1997 by Academic Press. All rights of reproduction in any form reserved. I I Control I Indomethacin Y A Meclofenamate * p< .05 vs Control for same group I I Control I Indomethacin Y A Meclofenamate * p< .05 vs Control for same group FIGURE 1. Effect of two structurally distinct prostaglandin synthesis inhibitors on the acute natriuretic response to different classes of diuretics in the rat. Only mannitol natriuresis was not...

Hyponatremia Incidence

Recently, diuretics have been identified as the cause or at least a major contributing factor in over half the patients hospitalized for severe chronic hyponatremia 8, 24 . Every diuretic can be associated with hyponatremia, either alone or in combination with other diuretics. Although a common complication, it is usually mild. Diuretic-induced hyponatremia is usually seen with thiazide diuretics, including metolazone 2, 3, 8 . Since loop diuretics impair both the renal concentrating and...

Diuretics and Glaucoma

Baylor University Medical Center, Dallas, Texas 77030 Glaucoma is a series of eye diseases characterized by increased intraocular pressure, optic nerve degeneration, and visual field defects 3, 4, 8 . It is one of the leading causes of blindness in the United States. The incidence of the disease increases with advancing age and ranges from 1 to 5 of adults over the age of 40. The disease is insidious in its origin and most patients are asymptomatic until late in the course of the illness. By...

Mechanisms Of Hypertension

Siderable variation in sodium intake and level of BP. There is some evidence that subjects can be divided according to their BP response to sodium into those who are sodium-sensitive and those who are not. Thus, abnormal handling of sodium may be a factor in the etiology of hypertension in salt-sensitive individuals in terms of both enhanced renal absorption and vascular effects through impaired Na+ K+ ATPase activity. Inhibition of Na+ K+ ATPase by an endogenous digitalis-like factor in...

Cardiovascular

Diuretics affect the cardiovascular system in several ways. The effects of diuretics on the peripheral vasculature are reviewed in detail elsewhere in this book and will only be summarized here. Furosemide has been shown to decrease left ventricular filling pressure and increase venous capacitance within minutes of administration, well before a diuretic response is apparent. This venodilatory response has, in part, been attributed to the release of vasodilatory prostaglandins from the kidney....

Extrarenal Generation of Metabolic Alkalosis

Extrarenal factors may also be responsible for the generation of metabolic alkalosis (Table 1). Acid loss, as in vomiting, can be a source of new bicarbonate added to the blood. Alkali gain, as in the milk-alkali syndrome or use of injectable NaHC03 during cardiopulmonary resuscitation, may also generate metabolic alkalosis. Acid may also be translocated within the body, producing acidosis in one compartment and alkalosis in the other. This may occur with severe potassium deficiency. Finally,...

Treatment

Monitoring plasma sodium concentration for the first few days of diuretic therapy is prudent. This is especially true in elderly women, patients who ingest large volumes of water, or patients on nonsteroidal anti-inflammatory drugs. If hyponatremia develops, the treatment consists of stopping the diuretic, water restriction, and replacement of any sodium deficit by administering isosmotic saline (see Chapter VC1). This does not apply to edematous states (e.g., heart failure, cirrhosis with...

Hypokalemia

Clinical trials in hypertensives treated with thiazide and furosemide have shown a close association between the development of glucose intolerance and hypokalemia. In fact the development of glucose intolerance during diuretic therapy was shown to be both time- and dose-related and was reversible after discontinuation of diuretic despite prolonged use (up to 14 years), indicating a metabolic and not a tissue toxic effect of the drug. In addition, in some studies, glucose intolerance has been...

Proximal Tubule

Approximately 50 of filtered NaCl and 70-90 of filtered NaHC03 are reabsorbed in the proximal tubule. The proximal tubule is subdivided into three segments, the most proximal S1 the middle S2, and the terminal S3 segment. In Diuretic Agents Clinical Physiology and Pharmacology Copyright 1997 by Academic Press. All rights of reproduction in any form reserved. general, Na + transport mechanisms are qualitatively similar in these segments, but differ quantitatively. Transport rates in Si are most...

Kallikrein Kinin System

Kallikreins are serine protease enzymes that act on kininogens (a2-glyco-proteins) to form bradykinin and kallidin, which have powerful vasodilator and natriuretic actions. Their vasodilator action is mediated, in part, by their effects on endothelial cells to stimulate NO formation and release. Infusion of bradykinin intravenously or into the renal artery increases RBF and sodium excretion with lesser effects on GFR. Renal kallikrein is produced by the distal nephron and released into the...

Sympathetic Nervous System

Diuretics increase plasma noradrenaline in patients with hypertension, probably a baroreflex response to a tendency for plasma volume to fall acutely. In patients with untreated heart failure diuretics may reduce plasma noradrenaline though this has not been subject to controlled studies 6 , In patients treated with diuretics chronically sympathetic activity is generally increased and plasma noradrenaline rises further on administration of a diuretic 15 . ACE inhibitors can reduce basal...

Stomach

Carbonic anhydrase is present in high concentrations in the gastric epithelium, where it plays a major role in gastric acid secretion. Inhibition of this enzyme has been shown to inhibit basal and stimulated gastric acid secretion in both experimental animals and in humans. In fact, acetazolamide has been used in the treatment of patients with peptic ulcer with a reported response rate of greater than 90 . In parietal cells, protons derived from water molecules are secreted into the gastric...

Interaction With Spironolactone

Although plasma aldosterone is initially reduced by ACE inhibitors, during long-term therapy plasma aldosterone rises again. The rise in aldosterone can be suppressed, to a large extent by increasing the dose of ACE inhibitor 10 , or the effects of aldosterone can be blocked by an antagonist. The rise in potassium during ACE inhibition is one potential mechanism for the secondary rise in aldosterone. Alternatively, breakthrough of ACE inhibition may lead to a resumption of angiotensin II...

Treatment Of Hypertension

The goals of treatment are to reduce BP and the risk of cardiovascular events, but to minimize adverse effects and facilitate patient compliance. Treatment can be divided into nonpharmacological and pharmacological 11 . Both forms of therapy rely heavily on patient education and good communication between doctor and patient. Nonpharmacological measures have the advantages of minimal cost and lack of side-effects, although compliance is not necessarily better. Current generally agreed-upon...

Maximum Osmotic Diuresis Is Linked to Amount Filtered

As described above, mannitol and other osmotic diuretics are freely filtered at the glomerulus and are not appreciably absorbed during their passage through the nephron or, in the case of urea, exceed the ability of the tubular transport mechanisms to reabsorb them. Consequently, the filtered load of the osmotic diuresis increases proportionately with the plasma concentration. The rate of urine flow is ultimately a function of the rate at which fluid is reabsorbed from the renal tubules. Hence,...

Direct Tubular Effects of Diuretics

Favors fluid reabsorption in the proximal tubule and as a result inhibit fluid reabsorption in this segment. Decreased fluid transport leads to a fall in the luminal Na concentration and creates an unfavorable diffusion gradient for Na reabsorption. As a result, there is a sharp increase in delivery of Na and water to downstream nephron segments. Since filtered K is isotonically reabsorbed in the proximal nephron in rough proportion to bulk fluid transport, inhibition of fluid transport results...

Cr

OH generated within the cell by apical membrane H + secretion reacts with C02 to form HC03 , which exits across the basolateral membrane on a C1 HC03 exchanger. CI which enters the cell on the exchanger recycles across a basolateral membrane CI channel. The fate of K + which enters the cell on the H K ATPase, is not clear. Carbonic anhydrase catalyzes the conversion of C02 and OH to HC03 in the cell. Electrogenic H + secretion generates a lumen positive voltage which...

Acute Renal Failure From Diuretic And Nsaid Administration

Acute renal failure has been reported in two healthy volunteers taking indomethacin and triamterene as part of a drug study, in one patient taking this combination, and recently in a man with mild hypertension taking ibuprofen and the combination of hydrochlorothiazide and triamterene who had been strenuously exercising. The latter individual underwent a renal biopsy which showed acute tubular necrosis (ATN). All patients subsequently recovered renal function in a time course consistent with...

Effects of Increased Distal Delivery

The rejection of NaCl by proximal tubules and loops of Henle results in increased delivery of fluid and greater tubular flow rates to more distal nephron segments. The consequence of such augmented distal delivery is enhanced potassium secretion. The magnitude of potassium secretion by distal tubules and collecting ducts is regulated, in part, by the supply of sodium reaching these nephron locations and flow of tubular fluid through them. Increases in net sodium absorption, for instance, are...

The Epithelial Na Channel Genes and Proteins

Molecular cloning and human genetics have provided important insights regarding Na+ reabsorption by collecting ducts. As with the other transporters described above, this work has uncovered the molecular identity of the Na+ channel mediating reabsorption and has also begun to define the molecular site of channel inhibition by amiloride. Na+ Channel Genes and Tissue Expression The amiloride-sensitive epithelial Na+ channel is formed by the assembly of three homologous subunits (Table 3)...

Autoregulatory Mechanisms

Consideration of the forces operating at the glomerular and peritubular capillaries reveals that even relatively small changes in the pressures and flows can cause substantial alterations in filtered and reabsorbed volumes. To minimize the effects of external disturbances such as changes in arterial perfusion pressure, the renal vasculature has powerful mechanisms that maintain a stable intrarenal hemodynamic environment and a controlled filtered load. Through active adjustments of smooth...

The Potassium Sparing Diuretics

The potassium-sparing diuretics, amiloride, triamterene, and spironolactone, cause a greater increase in Na than Ca clearance, i.e., reducing the ratio of Ca clearance to Na clearance 37, 39 . Amiloride, like the thiazides, has been shown to cause absolute reduction in Ca clearance. The mechanism, however, appears to be different from that of the thiazides since the effect of the two diuretics is additive 15 . In perfusion studies, the effect of amiloride is mainly observed in the latter half...

Potassiumretaining Diuretics Spironolactone

The disposition of spironolactone is complex and not completely elucidated. In addition, it is not clear whether spironolactone itself or one or more metabolites is the predominant active compound. Spironolactone (half-life of about 1.5 hr) is rapidly converted to canrenone and other metabolites, including 7a-thiomethylspirolactone and a 6a-hydroxy-7a-thiomethylspirolactone 10 , all of which have half-lives of about 15 hr. Early studies using combinations of radiolabeled drug and fluorimetric...

Effect on Intestinal Calcium Absorption

The effect of thiazide diuretics on intestinal calcium absorption is not clear. Thiazide has been associated with no change, a fall, or a rise in intestinal calcium absorption in patients with idiopathic hypercalciuria. However, it has been shown that the effect of thiazide on intestinal calcium absorption was selective in hypercalciuric patients with calcium nephrolithiasis 20 . In renal leak hypercalciuria (RH), thiazide typically reduces the fractional calcium reabsorption, commensurate with...

Calcium Phosphate Magnesium

E. (1992). Renal regulation of calcium balance. In The Kidney (D. W. Seldin and G. Giebisch, eds.), pp. 2375-2394. Raven, New York. 2. Murer, H., and Biber, J. (1992). Renal tubular phosphate transport Cellular mechanisms. In The Kidney (D. W. Seldin and G. Giebisch, eds.), pp. 2481-2510. Raven, New York. 3. Quamme, G. A. (1992). Magnesium Cellular and renal exchanges. In The Kidney (D. W. Seldin and G. Giebisch, eds.), pp. 2339-2356. Raven, New York.

Aldosterone and Cortisol Excess

In situations of aldosterone excess causing hypertension, there is usually an adrenal cortical adenoma (Conn's syndrome) or bilateral adrenal hyperplasia. Aldosterone promotes sodium retention and potassium excretion, leading to slight hypernatremia, extracellular volume (ECV) expansion, hypertension, and hypokalemic alkalosis. Unlike secondary causes of hyperaldosteronism, such as renal artery stenosis, in which aldosterone and renin levels are high, in primary hyperaldosteronism, renin is...

Thiazide or Thiazidelike Diuretics Affecting Distal Convoluted Tubule Salt Transport

A. (1995). Cellular calcium transport in renal epithelia Measurement, mechanisms, and regulation. Physiol. Rev. 75,429-471. 2. Gesek, F. A., and Friedman, P. A. (1995). Sodium entry mechanisms in distal convoluted tubule cells. Am. J. Physiol. 268, F89-F98. 3. Lemmink, H. H., van den Heuvel, L. P. W. J., van Dijk, H. A., Merkx, G. F. M., Smilde, T. J., Taschner, P. E. M., Monnens, L. A. H., Hebert, S. C., and Knoers, N. V. A. M. (1996). Linkage of Gitelman...

Diuretics and Cerebral Edema

Baylor University Medical Center, Dallas, Texas 77030 Cerebral edema is defined as an increase in the volume of the brain due to an increase in brain water content 4 . The water content of the brain in health is about 80 of wet weight for the gray matter and 70 of wet weight for the white matter. For the same degree of cerebral edema only small increases in brain water occur in the gray matter, while much larger increases in brain water occur in the white matter. Therefore, most of the...

Effect on Renal Calcium Transport

Under most physiological conditions, renal sodium and calcium reabsorption proceed in parallel 18 . However, under certain physiological, pathophysiological, or pharmacological conditions, the renal absorption of calcium and sodium may be dissociated. It has been shown that this relationship can be dissociated by administration of certain drugs such as thiazide diuretics or amiloride 9 . Thiazide diuretics, either alone or in combination with amiloride, reduced renal calcium excretion,...

Potassiumsparing Diuretics

One of the side-effects of diuretics is the excessive excretion of potassium caused by the increased delivery of sodium to the distal tubule, in a setting of increased levels of aldosteronism associated with the underlying disease state or induced by volume depletion secondary to successful diuresis. While potassium losses could be clinically managed by potassium supplementation, it prompted the quest for agents that could block the distal secretion of potassium by interfering with the...

Loop Diuretics

Loop diuretics are potent inhibitors of magnesium reabsorption 11 , having a proportionately greater effect on magnesium than on sodium and calcium reabsorption and, therefore, may contribute to hypomagnesemia secondary to renal magnesium wasting in a variety of clinical settings. The severity of the magnesium depletion that occurs with furosemide administration probably depends on the patient's magnesium intake (from food, intravenous fluid, etc), as well as on the frequency of furosemide...

Diuretics in the Treatment of Metabolic Alkalosis

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235 After correcting the underlying cause, the initial goal in the treatment of metabolic alkalosis is to remove those factors that are responsible for maintaining the alkalosis. In some circumstances, diuretic therapy may be the preferred method of achieving this goal. When utilizing this approach, however, one needs to consider carefully both the type of diuretic to be used as well as the...

Management of Hypertension

Hypertension in chronic renal insufficiency has been shown to respond to treatment with loop diuretics, either given alone or in combination with thiazide diuretics. A number of authors report success with the combined use of furosemide and hydrochlorothiazide 3 ormetolazone 32 . Whether these agents exert their hypotensive effect exclusively by inducing natriuresis and are thereby useful in patients with advanced renal failure and in patients undergoing dialysis is a matter of controversy....

Volume Expansion with Mineralocorticoid Suppression

In the setting of significant renal disease bicarbonate clearance will be decreased and severe metabolic alkalosis may occur following exogenous bicarbonate administration. Similarly, renal insufficiency is a critical event in the pathogenesis of milk-alkali syndrome. In this syndrome consumption of large quantities of milk and calcium containing antacids will result in hypercalcemia and metabolic alkalosis. Liddle's syndrome has all the clinical features of primary mineralocorticoid excess and...

Prostaglandins Thromboxanes and Other Arachidonic Acid Metabolites

Renal eicosanoids are synthesized from arachidonic acid at several sites within the kidney and influence renal vascular resistance, arterial pressure, and sodium and water excretion. Administration of PGE2 or PGI2 (prostacyclin) into the renal artery causes vasodilation, while thromboxane A2 and leukotrienes C4 and D4 constrict the renal vasculature. Endoperoxides (PGE2, PGF2a, PGI2, and thromboxane A2) are synthesized by the cyclooxygenase enzymatic pathway, whereas the leukotrienes are formed...

Morbidity And Mortality

Diuretics reduced the risk of stroke and the magnitude of benefit is close to what is predicted by the fall in blood pressure. In contrast the reduction in coronary events and overall mortality is less than expected. This could reflect the benefits of blood pressure reduction being balanced by adverse metabolic effects including, possibly, neuroendocrine activation. Patients with left ventricular dysfunction requiring treatment with a diuretic have a worse prognosis than those that do not 45 ....

Clinical Applications

Furosemide is known to be a potent natriuretic agent. It also increases calcium excretion in direct proportion to sodium excretion 15 , The use of repeated doses of furosemide in conjunction with intravenous replacement of saline has been used as the first approach in treatment of the hypercalcemia of malignancy 15 . In subjects with hypoparathyroidism, furosemide causes a significant increase in urinary calcium excretion and consequently a significant fall in serum ionized calcium. However, in...

Renal Hemodynamic Effects

Diuretics tend to increase renal blood flow acutely in normal subjects and patients with hypertension, probably through prostaglandin mediated pathways 15, 29 , Renal vascular resistance must fall substantially as renal perfusion pressure will fall due to the diuretic. Frusemide may also redistribute blood flow toward the renal cortex 15 . During longer term therapy RAAS activation, resulting in a preferential increase in efferent arteriolar tone, may reverse the direct pharmacological effect...

Diuretic Therapy of Acute Pulmonary Edema [6

Acute pulmonary edema is an obvious clinical indication for aggressive diuretic therapy. Loop diuretics of the furosemide class are particularly useful for the treatment of acute pulmonary edema for two reasons (i) their acute potent diuretic effect and (ii) their capacity to rapidly produce acute venodilation by a nondiuretic mechanism. Diuresis reduces ECF and plasma volumes, cardiac inflow (preload), and left ventricular end-diastolic pressures. This reduces pulmonary capillary hydrostatic...

Hemodynamic Consequences Of Diuretics That Counteract Natriuretic Response

Except for agents that directly cause renal arteriolar vasodilation or interfere with the transmission of tubuloglomerular feedback signals, most other diuretics have a greater potential for causing reductions in renal hemodynamics and GFR by causing release of vasoconstrictor factors or by increasing the activity of the tubuloglomerular feedback mechanism. As already mentioned, nonspecific indirect effects to reduce RBF also result if diuretic therapy leads to excessive sodium loss and marked...

Antiandrogenic Effects Introduction

Mineralocorticoid antagonists are weak diuretics that act by inhibiting the effect of aldosterone on sodium transport in the cortical collecting duct of the kidney. In the kidney, mineralocorticoid specificity is a result of the action of 11 3-hydroxysteroid dehydrogenase which converts glucocorticoids to meta bolites for which the mineralocorticoid has low affinity. However, mineralo-corticoids are not metabolized by this enzyme and therefore bind to the mineralocorticoid receptor in the renal...

Mercurials

Mercury has an ancient medical history. Depending on the compound prescribed, it had been used as a cathartic (mercurous chloride), as an antiseptic (bichloride of mercury), and as an anti-syphilitic (first as a mercuric compound, and then as organic mercurials such as was introduced by Paul Ehrlich (1854-1915) in the form of the magic bullets, arsphenamine and neoarsphena-mine). The diuretic properties of mercury were recognized by Paracelsus, in his quest for specific remedies derived from...

Carbonic Anhydrase Inhibitors

K., and Rector, F. C.,Jr. (1991). Renal acidification mechanisms. In The Kidney (B. M. Brenner and F. C. Rector, Jr., eds.), pp. 318-379. W. B. Saunders Co., Philadelphia, PA. 2. Brown, D., Zhu, X. L., and Sly, W. S. (1990). Localization of membrane-associated carbonic anhydrase type IV in kidney epithelial cells. Proc. Natl. Acad. Sei. USA 87, 7457-7461. 3. Maren, T. H. (1967). Carbonic anhydrase Chemistry, physiology, and inhibition. Physiol. Rev. 47, 595-781. 4....

ACE Inhibitors and Ang Ii Receptor Antagonists

Angiotensin antagonists represent a major category of antihypertensive agents that exert their influence by interfering with the multiplicity of actions of ANG II on the systemic circulation as well as on the kidney (Fig. 5). There are a large number of ACE inhibitors and a growing number of nonpeptide ANG II receptor antagonists. Of the two main classes of ANG II receptors, the AT receptor has been identified to be responsible for mediating most of the renal vascular and tubular effects. Thus,...

Children

The pharmacokinetics and pharmacodynamics of loop diuretics have not been rigorously assessed in healthy children. Neonates who received furosemide via transplacental passage after their mothers received it for toxemia of pregnancy show prolonged elimination half-lives, which correlated inversely with gestational age. This observation probably represents the immaturity of the kidney at the various stages of development of the neonate. Newborns have prolonged elimination half-lives of...

Role of Bone

Approximately 60 of body stores of magnesium are in bone, of which about 50 are on bone crystal surfaces and readily available for mobilization in the event of magnesium depletion. It has been suggested that in hypomagnesemic states there is altered bone solubility leading to enhanced release of magnesium ion from crystal surfaces to correct hypomagnesemia. The hypocalcemia that occurs in magnesium depletion has been attributed in part to exchange of calcium for magnesium on the surface of...

Effect on Bone

The direct effect of thiazide on bone metabolism has not been studied extensively. However, in two studies, one conducted in uremic patients undergoing hemodialysis, and the other in the normal thyroparathyroidectomized dogs, thiazide administration has resulted in hypercalcemia and increased osteocystic bone resorption, respectively 7 . In the former condition, potentiation of the skeletal effect of PTH has been suggested. However, in the latter situation due to the absence of parathyroid...

Hypokalemia and Hypomagnesemia

Mild hypokalemia (Plasma K 3.3-3.8 mmol liter 1) and metabolic alkalosis occurs in up to 20 of patients and will appear within the first 6 weeks of starting therapy. Significant hypokalemia (< 3.2 mmol liter-1) should not be ignored and warrants further investigation (e.g., underlying hyperaldosteron-ism) and or potassium supplementation (especially in elderly patients on di-goxin and those with a history of ischemic heart disease and liver cirrhosis). Hypokalemia is thought to predispose to...

Mediators Which Oppose Renal Salt Retention and Vasoconstriction

Activation of the above-described vasoconstricting and salt-retaining mechanisms is associated with simultaneous or sequential activation of opposing counterregulatory neurohormonal mediators. They modulate and reduce the intensity of vasoconstriction and renal salt retention. These counterregulatory mediators include atrial natriuretic peptides, vasodilatory prostanoids, dopamine, and nitric oxide. Over the past 15 years, a family of natriuretic peptides synthesized primarily by the heart has...

Neutral Diuresis

Neutral diuresis refers to the induction of a large urine output in an attempt to enhance the excretion of a drug or poison without pH dependent ion trapping effects. This treatment can be effective in the therapy of a drug overdose if the drug has a relatively small volume of distribution and is excreted by the kidneys TABLE 3 Drugs Whose Renal Excretion Is Enhanced by Neutral Diuresis Ethanol Methanol Ethylene glycol Lithium Meprobamate in substantial quantities. The diuresis can be initiated...

Renal Sodium And Water Handling

There are multiple possible sites of interaction of ACE inhibitors and diuretics on salt and water excretion. Both agents have effects on arterial (renal perfusion) pressure, an important determinant of salt and water excretion, and on renal hemodynamics. Diuretics increase angiotensin II and sympathetic activity, which may enhance proximal tubular sodium retention, and aldosterone, which enhances distal tubular sodium potassium exchange. In normal subjects there is some evidence that ACE...

Pharmacokinetics and Pharmacodynamics Table

The onset of effect of thiazide diuretics is fairly rapid, and peak concentrations of drug are attained within 1.5-4 hr with no differences among the agents (Table 6) 10 , with the possible exception of chlorthalidone, wherein a delayed peak effect has been reported (8-10 and 14 hr). These data disagree with an earlier report indicating peak effect in 1 to 3 hr the reasons for the discrepant data are unclear. After an oral dose, the amount of drug reaching the urine varies greatly among these...

Role of the Kidney

Kidney Central Role

Renal handling of magnesium involves filtration and renal tubular reabsorption. Tubular secretion of magnesium is negligible and contributes in only a minor way to overall magnesium balance. In man, 3500 mg of magnesium is filtered daily, and only 3 of this amount is excreted in urine (100-150 mg day), an amount equal to the daily net intestinal magnesium absorption 12 , Renal magnesium reabsorption has specific features when compared with that of sodium and calcium (Fig. 1) 6 . The...

Site and Mechanism of Diuretic Action

Hebert Dartmouth Medical School, Department of Pharmacology and Toxicology, Hanover, New Hampshire 03755-3835 and Vanderbilt University Medical School, Division of Nephrology, Diuretics are a diverse group of chemical compounds that share the ability to augment net renal sodium excretion. These agents are widely used in clinical medicine for the treatment of hypertension, pulmonary or cerebral edema, and other disorders that are characterized by the accumulation...

Use of Diuretics in the Treatment of Hypertension in Pregnancy

Hypertension in pregnancy can be broadly divided into preexisting hypertension (chronic hypertension), hypertension of pregnancy (usually appearing within the first trimester, but can develop at any time) and preeclampsia eclampsia (occurring in the third trimester). Preeclampsia is characterized by hypertension, proteinuria, edema, and hyperuricemia, with or without associated liver dysfunction and coagulopathy (HELLP syndrome hemolysis, elevated liver enzymes, and low platelets). Eclampsia is...

Vic

Tion of bicarbonate which has been consumed as a result of buffering of metabolic acids. Both of these processes are dependent upon hydrogen ion secretion. The process of bicarbonate reclamation occurs in the proximal tubule. This segment of the nephron has a high capacity for bicarbonate reabsorption and normally reabsorbs 80-90 of the 4500 mEq liter of bicarbonate filtered daily. The majority of bicarbonate reabsorption in this segment is mediated by proton secretion on the apical membrane...

Dietary Fat and Weight Gain

Dietary restriction of cholesterol and saturated fatty acid can mitigate and in some cases prevent increases in LDL-cholesterol, VLDL-cholesterol, and hypertriglyceridemia during thiazide therapy. In addition, increases in body weight during long-term treatment with diuretics tends to increase plasma cholesterol, whereas weight loss is associated with improvement in plasma lipids. Whether the changes in weight reflect attendant alterations in insulin resistance or dietary effects on lipid...

Clinical Presentations

The clinical features of diuretic-induced ATIN are summarized in Table 1. Furosemide, chlorothiazide, hydrochlorothiazide, and triamterene are the main agents reported to cause the syndrome. The onset of renal failure after initiating diuretic therapy is variable, ranging from 1 week to 14 months. Early reports of ATIN caused by diuretics included only patients with underlying renal disease however, it is clear that this disorder occurs in patients with normal renal function as well....

Systemic Hemodynamic Responses And Conclusions

Many patients receiving diuretic therapy are hypertensive and a long-term goal of the therapy is to achieve sustained reductions in arterial pressure to normo-tensive levels. Indeed, monotherapy with diuretics has long been shown to be an effective treatment for many hypertensive patients. In more resistant cases, combinations of either ACE inhibitors or calcium antagonists with a diuretic have been effective in treating resistant patients. While the antihypertensive mechanisms for agents that...

Complications Of Albumin And Diuretic Combinations

Administration of albumin with diuretics may be associated with a number of complications. The most frequently reported problem is hypertension. The acute onset of hypertension of sufficient severity to require treatment is reported in between 10 and 46 of treatment courses with albumin and loop diuretics in some series 6, 14 . Additionally, over one-third of already hypertensive individuals will require upward adjustment of their medications to maintain blood pressure control during treatment...

Goals of Therapy for Severe Hypercalcemia

There are four basic goals of therapy for severe hypercalcemia Restore Adequate Hydration The initial approach to all severely hypercalcemic individuals is hydration with saline. Rehydration alone will reduce serum Ca by 1.5 to 2.0 mg dl. Expansion TABLE 1 Goals of Therapy in Severe Hypercalcemia of intravascular volume also leads to increased renal Ca clearance. The choice of saline enhances renal Ca clearance further by virtue of the obligatory link, in this situation, between sodium and...

Shortterm Adaptations Postdiuretic Nacl Retention

The half-life of most diuretics (especially the loop diuretics see Chapter IVA) is relatively short. Thus, serum diuretic concentrations are often below the natriuretic threshold during a portion of each day, except when the drugs are infused constantly. Even during continuous diuretic infusion, however, water and solute losses will decline as ECF volume falls 7 . This second type of adaptive response to diuretic administration occurs after the peak natriuresis has occurred and is most...

Clinical and Experimental Data

Eabv Liver

A number of human and animal studies have been undertaken to determine which salt and water retaining hypothesis is most consistent with the observed facts. In 1968, Eisenberg measured the blood volume of nephrotic patients and FIGURE 2. The overflow hypothesis renal salt and water retention in nephrotic syndrome. The pathology which produces increased glomerular permeability also produces intrarenal alterations which directly increase the reabsorption of salt and water by the kidney. Edema...

Management of Hypercalcemia Based on Severity

Management of the Patient with Mild Hypercalcemia The most common cause of calcium levels within 1 mg dl above the upper limit of normal is primary hyperparathyroidism. If the normal range of serum Ca concentration is 8.5-10.5 mg dl, most patients with primary hyperparathyroidism will show Ca levels between 10.6 and 11.5 mg dl. Even with mild hypercalcemia, if such a patient suffers from any of the adverse consequences of hyperparathyroidism such as kidney stones, recurrent ulcers, or...

Digitalis

The most important contribution of herbal medicine to the materia medica of the 18th century was foxglove. The purple foxglove, a rather common plant growing throughout the greater part of Europe, is not mentioned by the founding father of herbal medicine, Dioscorides, or in any of the ancient herbals. In the Middle Ages, Welsh physicians employed the foxglove for the preparation of external remedies. It was then known as foxes-glew or foxes-music, because of its resemblance to an ancient...

Cardiovascular Capacitance

Relationships between sodium balance and arterial pressure. such as enhanced production of endogenous vasodilator substances and adaptation of baroreflex activity have also been suggested to contribute to the reduced arterial pressure. In uncomplicated essential hypertensive subjects, effective antihypertensive action is usually associated with a sustained moderate reduction of extracellular fluid and plasma volumes. Thus, the correction of arterial pressure and effective blood volume...

The Overflow Hypothesis

Heart Failure Overflow

The underfill hypothesis has been challenged on several fronts. Lieberman, Levy, their co-workers, and others have advanced clinical and experimental data which challenge the early sequence shown in Fig. 1 15,16 . Careful studies of dogs with experimental cirrhosis and patients with early hepatic cirrhosis demonstrate that renal salt and water retention can develop prior to the formation of ascites or edema. The classic underfill hypothesis requires that ascites and or edema develop first, to...

Atrial Natriuretic Peptide and Related Peptides

Structure Natriuretic Peptides

The original peptide (see Fig. 4) was discovered by purification of atrial extracts which exhibited striking diuretic and natriuretic properties 6, 58 . Atrial natriuretic peptide is stored in secretory granules of the atrial myocyte as a 126-amino-acid propeptide (pro-ANP) which is cleaved during or soon after secre- FIGURE 4. Structure of human atrial natriuretic peptide (human ANP) and urodilatin (Human URO). Darkened amino acid residues on human URO represent an amino terminal extension...

Calcium Activation Mechanisms

Renal blood flow and intrarenal capillary dynamics are regulated by a variety of mechanisms that control vascular smooth muscle and mesangial cell contractile activity. As with other vascular smooth muscle cells, contraction of renal vascular cells is elicited primarily by increases in intracellular Ca2+ activity. Although extracellular fluid Ca2+ is in the millimolar range, cytosolic Ca2+ is maintained at considerably lower levels, (about 10 7 M) through active extrusion of Ca2+ from the cell...

Insulin Resistance

As already mentioned the insulin-resistant state associated with hypertension may be aggravated by therapy with potassium wasting diuretics. In this regard, several authors have suggested that the responses are in part explained by insulin resistance. Increased plasma insulin levels can increase hepatic VLDL production, thereby giving rise to both hypertriglyceridemia as well as increased LDL via intravascular catabolism of VLDL by lipoprotein lipase which is stimulated by insulin. Further,...

Prevention and Treatment of Diuretic Induced Hypokalemia

The first approach to preventing diuretic-induced hypokalemia is to use the lowest dose possible (Table 1). With regard to thiazide diuretics, the majority of the blood pressure lowering effect is seen at doses of 12.5-25 mg day. At higher doses, further blood pressure lowering is minimal, but rather, metabolic side-effects such as hypokalemia, hyperglycemia, and hypercholesterolemia become more prevalent. Dietary manipulations can also be utilized in the prevention and treatment of...

Potassium Sparing Diuretics

These diuretics are the sodium channel blockers amiloride and triamterene and the antialdosterone spironolactone. They all have weak natriuretic effects and are antikaliuretic (see Fig. 6). Spironolactone is specifically indicated in hypertension due to primary mineralocorticoid excess, although in adrenal hyperplasia and hyperaldosteronism amiloride may prove more effective in maintaining plasma potassium and controlling BP. The main problem with spironolactone is that doses above 100 mg daily...

Insulin Resistance Introduction

Thiazide diuretics remain the cornerstone of antihypertensive therapy and have been shown to reduce morbidity and mortality in hypertensive populations throughout the world. However, their use has been associated with a high incidence of endocrine disturbances including glucose intolerance. Glucose intolerance induced by thiazide diuretics was first reported in the late 1950s. Since then a variety of thiazides as well as loop diuretics have been reported to cause mild glucose intolerance, overt...

Mechanism of Hypokalemia Induced Glucose Intolerance

The precise molecular mechanism of hypokalemia-induced glucose intolerance is not completely understood however, the bulk of clinical and experimental evidence indicates that glucose-mediated beta cell insulin release plays a major role. Studies in normal volunteers have shown that thiazide-induced potassium deficiency sufficient to produce sustained hypokalemia is associated with decreased glucose utilization and subnormal plasma insulin response to hyperglycemia of 125 mg dl (hyperglycemic...

Renal Generation of Metabolic Alkalosis

Bicarbonate may be generated from renal or extrarenal sources (Table 1). The renal generation of bicarbonate involves, in general, three features (1) relatively high distal delivery of sodium salts (2) persistent mineralocorticoid exTABLE 1 Generation of Metabolic Alkalosis I. Excessive loss of acid Extrarenal Loss of acid into gastric juice vomiting, nasogastric suction Intestinal acid loss villous adenoma, congenital chloridorrhea Translocation of acid into cells K deficiency Renal Coupling...

Renal Salt and Water Retention [7

The presence of clinically apparent generalized edema represents the translocation of a large volume of fluid from the vascular to the interstitial space. If this occurs acutely, circulatory shock may result. This can occur when an acute increase in capillary permeability is produced by an allergic reaction or extensive burn. More commonly, edema develops relatively gradually and intravascular volume is maintained by avid renal salt and water retention. Consequently, in addition to the local...

The Use of Diuretics in the Treatment of Ascites and Edema in Hepatic Cirrhosis

Diuretics Right Heart Failure

Seldin* Department oj Internal Medicine, Baylor University Medical Center, Dallas, Texas 75246 and *University oj Texas Health Sciences Center, Dallas, Texas 75235 Cirrhosis of the liver is a major cause of salt and water retention. The tendency for accumulating fluid to localize in the peritoneal cavity is typical of cirrhosis and is far more pronounced than in congestive heart failure or the nephrotic syndrome. Although peripheral edema does occur with cirrhosis,...

Thiazidesensitive cotransporter mRNA

Effects of continuous loop diuretic infusion on rat kidney. Loop diuretic infusion increased the number of thiazide-sensitive Na Cl cotransporters (data from J. Am. Soc. Nephrol. 1 91 -98, 1990), the rate of thiazide-sensitive Na transport along the distal tubule (data from J. Clin. Invest. 83 113-126, 1989), the abundance of thiazide-sensitive Na-Cl cotransporter mRNA (A, furosemide-treated kidney cortex B, control kidney cortex Obermuller et al. Am. J. Physiol. 269 F900-F910, 1995,...

Pathophysiology Of Salt Retention And Edema The Underfill Vs Overflow Hypotheses

The accumulation of clinically significant systemic edema generally requires that the kidneys retain salt and water (the acute capillary leak syndromes are exceptions). Renal salt retention certainly develops in patients with nephrotic syndrome. The most proximal signal, or signals, responsible for the renal salt retention of these patients remain uncertain. The classic pathophysiologic explanation for the salt retention of nephrotic syndrome is the underfill hypothesis and follows the sequence...

Xanthines

Xanthine derivatives such as theophylline (see Fig. 9) have multiple actions on cells, including blockade of uptake of calcium into sarcoplasmic reticulum, inhibition of degradation of cyclic AMP and cyclic GMP by phosphodiesterase, and blockade of adenosine receptors 42 . The effects on calcium transport and cyclic nucleotide degradation occur at methylxanthine concentrations in the range of 0.5-1 mM, far above the therapeutic range of 20-50 fiM. By contrast, blockade of adenosine receptors...

Significance of Competition for Diuretic Secretion

Competitive inhibition between diuretics and other substances transported by the basolateral anion transporter has a number of clinical ramifications. Probenecid, the prototypic competitive inhibitor of basolateral anion transport, has been used by many investigators to determine the mode of entry of diuretics into the renal tubule lumen. Probenecid has been found to decrease the intensity of the natriuretic activity of chlorothiazide, hydrochlorothiazide, furose-mide, and piretanide,...

Volume Depletion and Increased Catecholamines

Volume depletion may reduce both renal blood flow and glomerular filtration rate, thereby reducing the filtered load of glucose and promoting hyperglycemia. In addition, it has been postulated that reduction in blood pressure and flow to muscle, the primary site of insulin-mediated glucose uptake, may be attributed to volume depletion. Thus volume depletion could reduce tissue sensitivity to insulin indirectly by limiting delivery to muscle bed. Increased plasma catecholamine levels...

Tubuloglomerular Feedback Mechanism

In addition to its role in mediating renal autoregulation, the TGF mechanism contributes significantly to the regulation of GFR and ultimately to the long-term control of sodium balance and extracellular fluid volume 4, 5, 38,39 . By operating in concert with glomerulotubular balance, the TGF mechanism stabilizes delivery of volume and solute to the distal nephron. As depicted in Fig. 3, flow-related changes in the tubular fluid composition at the macula densa are sensed and signals are...