Intensive Diuretic Therapy High Doses Combinations and Constant Infusions

West Haven VA Center for the Study and Treatment of Kidney Disease, West Haven, Connecticut 06516 Yale University School of Medicine, New Haven, Connecticut 06520 and West Haven VA Medical Center, West Haven, Connecticut 06516 An edematous patient may be deemed resistant to diuretic drugs when moderate doses of a loop diuretic do not achieve the desired extracellular fluid (ECF) volume reduction. As shown in Fig. 1, the natriuretic dose-response curve for loop diuretics is sigmoidal the...

Pathogenesis Of Ams [1114

It is highly likely that the pulmonary, peripheral, and cerebral forms of high altitude sickness share similar pathogenic mechanisms of impaired acclimatization (Fig. 1). Patients susceptible to AMS tend to demonstrate less weight loss than normal, do not diurese adequately and may actually gain weight they Hypoxia + Delayed Ventilatory Acclimatization Hypoxia + Delayed Ventilatory Acclimatization FIGURE 1. Pathogenesis of AMS. PAP, pulmonary artery pressure PVP, pulmonary venous pressure ANF,...

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...

Suggested Reading

J., and Warnock, D. G. (1994). Brief report Liddle's syndrome revisited A disorder of sodium reabsorption in the distal tubule. New Engl. J. Med. 330, 178. 2. Griffing, G. T., Cole, A. G., Aurecchia, S. A. et al (1982). Amiloride in primary hyperaldoster-onism. Clin. Pharmacol. Theraupeut. 31, 56. 3. Harrington, J. T., Hulter, H. N., Cohen, J. J., and Madias, N. E. (1986). Mineralocorticoid-stimulated renal acidification The critical role of dietary sodium. Kidney...

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...

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...

Maintenance of Metabolic Alkalosis

Reduced effective arterial blood volume is the mechanism responsible for the maintenance of metabolic alkalosis in the majority of patients (Table 2). The mechanisms by which volume contraction maintains metabolic alkalosis have TABLE 2 Maintenance of Metabolic Alkalosis Increased proximal bicarbonate reabsorption Reduced effective arterial blood volume Potassium deficiency Increased pCO 2 concentration Increased distal bicarbonate reabsorption Persistent mineralocorticoid excess Potassium...

References

Albright, F., Henneman, P., Benedict, P. H., and Forbes, A. P. (1953). Idiopathic hypercalciuria A preliminary report. Proc. R. Soc. Med. 46,1077-1081. 2. Bilezikian, J. P. (1993). Management of hypercalcemia. J. Clin. Endo. Metab. 77, 1445-1449. 3. Borghi, L., Meschi, T., Guerra, A., and Novarini, A. (1993). Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. J. Cardiovasc. Pharm. 22 (Suppl. 6), S78-S86. 4. Breslau, N. A., Moses, A. M.,...

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,...

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....

Transplantation Delayed Graft Function

Transplantation of cadaveric kidneys is beset with a significant problem with the potential of adversely affecting transplant outcome. Difficulties derive from the periods of warm and cold ischemia that precede transplantation. The incidence of delayed graft function (defined as failure of the graft to function promptly following transplantation), usually requiring dialysis, varies widely. It may be encountered in as few as 10 of patients in some programs, but in as many as 50 of patients in...

Diuretic Pharmacokinetic And Pharmacodynamics In Renal Insufficiency

Both pharmacokinetic and pharmacodynamic mechanisms contribute to the reduced efficacy of loop diuretics in chronic renal disease. Several pharmacokinetic mechanisms limit delivery of diuretic to its active site. First, as renal blood flow is reduced in parallel to glomerular filtration rate (GFR), delivery of diuretic to the organic acid transport system in the proximal tubule is delayed. Additionally some uremic toxins are organic anions and can competitively inhibit tubular diuretic...

Chronic Adaptations

When diuretics reduce ECF volume effectively, NaCl balance gradually returns to neutral despite continued diuretic administration (see Fig. 1 13, 42 ). This braking phenomenon occurs when the magnitude of natriuresis following each diuretic dose declines. Several factors, acting in concert, may participate in chronic adaptation (see Fig. 3). A critical factor that is necessary for the braking phenomenon to occur is a decline in the ECF volume. Wilcox and coworkers showed that the magnitude of...

Characteristics of Diuretic Induced Hypokalemia

The degree of hypokalemia associated with use of diuretics varies according to the agent used. In hypertensive patients taking thiazide diuretics, the serum potassium concentration falls on average by 0.5 mEq liter. This decline can be as high as 0.9 mEq liter with use of the long acting thiazide, chlorthalidone. While loop diuretics are more potent natriuretic agents, they typically result in a milder degree of hypokalemia as the average decline in the serum potassium concentration is 0.3 mEq...

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...

Renal Calcium Handling

The normal human adult kidneys filter approximately 170 liters of water and 10 g of calcium per day. The final urine contains nearly 1.5 liters of water and 200 mg calcium daily. Thus, 99 of filtered water and 98 of filtered calcium are normally reabsorbed by the renal tubules 16 . Most of the filtered calcium is reabsorbed from the lumen of the proximal tubules and returned to the circulation. Micropuncture studies have shown that approximately 60 of the filtered calcium is absorbed by the end...

Thick Ascending Limb

The thick ascending limb (TAL) begins at the junction between the inner and the outer medulla for deep nephrons and at the tip of the loop of Henle for more superficial nephrons. The thick ascending limb includes medullary and cortical segments and ends at the juxtaglomerular apparatus, where the nephron abuts against its own glomerulus. Figure 7 shows a cell model that includes mechanisms for NaCl and NaHC03 absorption in the thick ascending limb. The mechanism of NaCl absorption begins, once...

Urea and Uric Acid

A rise in blood urea nitrogen (BUN) is commonly seen with diuretic therapy and is a useful warning of excessive dosage, especially when compared with the plasma creatinine level, which begins to rise only if there is significant ECV depletion and developing prerenal failure. Hyperuricemia is due to a combination of enhanced proximal tubule absorption secondary to ECV contraction and competition between uric acid and diuretic secretion along the proximal tubule. Hyperuricemia is considered by...

Agents Which Primarily Increase Free Water Clearance

The kidney increases plasma osmolality by excreting a urine which is dilute with respect to the plasma (increased free water excretion) and reduces plasma osmolality by excreting a urine which is concentrated with respect to the plasma (increased free water reabsorption). As shown in Fig. 1, the nephron dilutes the urine by reabsorbing solute (predominantly NaCl) without water primarily in the thick ascending limb (TAL). In the absence of ADH, this dilute urine is mostly excreted. The...

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...

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...

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...

Summary

Adequate renal perfusion pressure is essential to achieve diuretic-induced natriuresis. Hypotension and shock limit renal perfusion, but in many critically ill patients, renal perfusion pressure may not be reflected by the mean arterial pressure, owing to renal artery stenosis or vasoactive drug use. Adrenergic agonists, especially dopamine, have proven useful in increasing urinary salt and water excretion. In some situations, dopamine appears to have unique effects on the kidney. In patients...

Volume Expansion with Mineralocorticoid Excess

These conditions are associated with a primary increase in mineralocorticoid activity. Increased mineralocorticoid activity is considered primary in that it persists in the face of activation of the control system normally responsible for its suppression, an expansion of the effective extracellular fluid volume. As long as dietary sodium is normal, distal delivery of sodium salts will be plentiful and, as a result, urinary potassium and net acid excretion are increased, result ing in potassium...

Pathophysiology

An exaggerated diurnal weight gain is a feature of idiopathic edema normal women gain approximately 0.6 kg during the day, whereas women with idiopathic edema gain more than 1.4 kg 1 , Concern about weight can lead to intermittent fasting and binging in some patients which may be a factor in causing the edema. Fasting suppresses the sympathetic nervous system, and the natriuresis of fasting is in part due to decreased renal sympathetic nerve activity. Carbohydrate feeding results in increased...

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...

Suggested Readings

Ayalon, A., Corcia, A., Klemperer, G., and Caplan, S. R. (1980). Suppression of gastric acid secretion by furosemide in isolated gastric mucosa of guinea pig. Am. J. Physiol 239, G532-G535. 2. Bickler, P. E., Litt, L., Banville, D. L., and Severinghaus, J. W. (1988). Effects of acetazolamide on cerebral acid-base balance. J. App. Physiol 65, 422-427. 3. Bickler, P. E., Litt, L., and Severinghaus, J. W. (1988). Effects of acetazolamide on cerebrocort-ical NADH and blood volume. J. App. Physiol...

Loop Diuretics

The use of loop diuretics is commonly associated with the development of metabolic alkalosis (Fig. 2). Loop diuretics inhibit salt transport in the thick ascending limb of Henle, resulting in a reduction in the extracellular fluid volume. The contraction of extracellular fluid around a fixed concentration of bicarbonate will cause the bicarbonate concentration to rise. This effect has been called a contraction alkalosis. The magnitude by which this mechanism contributes to the alkalosis is...

Immediate Adaptations

About 25 mol of sodium are filtered every day by the kidneys in a normal human. Because dietary salt intake on a Western diet is typically 130-260 mmol daily, approximately 3 pounds of salt (17 mol 1 kg NaCl) must be reabsorbed every day by the renal tubules to maintain salt balance. All sodium chloride reabsorption along the mammalian nephron is driven by the action of Na K ATPase, which is present along the basolateral cell membrane of most renal epithelial cells. Transepithelial sodium...

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...

Renal Transport Of Anionic Diuretics

Three steps are necessary to effect tubular secretion of organic anions. First, the anionic compound must be delivered to the basolateral surface of the proximal tubule cell second, the anionic compound must be transported into the cell across the basolateral membrane and third, the anionic compound must be transported across the brush border membrane into the tubule lumen. Most investigations of these processes relating to anionic diuretic secretion have used furosemide and chlorothiazide as...

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...

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,...

Use Of Diuretics In Nephrotic Syndrome

The subset of patients with chronic renal disease who have nephrotic syndrome provide an additional challenge to effective diuretic therapy. In patients with this condition blunted responses to diuretics are frequently observed early in the course of the disease when GFRs are normal or only modestly reduced. Both pharmacodynamic and pharmacokinetic mechanisms account for diuretic resistance in nephrotic syndrome. Most pharmacokinetic studies have focused on the effect of reductions in serum...

Carbonic Anhydrase Inhibitors

The last of the diuretic agents to be discovered by serendipity were the carbonic anhydrase inhibitors. Their subsequent development was to mark the entry of organic chemists into a new era characterized by diuretic design rather than fortuitous discovery. The observation in 1937 that patients receiving one of the new antimicrobials, sulfanilamide, developed metabolic acidosis was to pave the way for the recognition of its diuretic property. Carbonic anhydrase had been discovered in 1932. In...

Acidifying Salts And Potassium Salts

The diuretic effect of acidifying salts was described at the end of World War I. The two principal agents used were calcium chloride and ammonium chloride. Calcium chloride was the weaker of the two when it was shown that its intravenous use resulted in calcification of the heart and soft tissues it quickly fell out of favor, while oral ammonium chloride remained in use. However, when it became evident that the large doses (600 g) of ammonium chloride necessary for effective diuresis were...

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...

Acetazolamide

The diuretic which is most commonly associated with the development of metabolic acidosis is acetazolamide. This diuretic acts by inhibiting the enzyme carbonic anhydrase. Given the central role that this enzyme plays in bicarbonate reabsorption in the proximal tubule, administration of this diuretic leads to the development of metabolic acidosis by disrupting the process of bicarbonate reclamation. The mechanism by which acetazolamide leads to inhibition of bicarbonate reabsorption is directly...

Salt Restriction And Diuretic Therapy [3033

Contraction of extracellular fluid (ECF) and plasma volumes can be achieved with dietary salt restriction and diuretic therapy. This may be of great benefit to patients with chronic or acute congestive heart failure. Volume contraction reduces central and pulmonary venous capillary pressures which reverses pulmonary congestion and edema, as well as peripheral edema, ascites, and hepatic congestion. ECF and plasma volumes can be manipulated by varying salt intake. When normal individuals switch...

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...

Ventilatory Acclimatization And Acidbase Homeostasis At Altitude [11

Upon exposure to high altitude, a drop in arterial P02 or 02 saturation stimulates peripheral chemoreceptors and produces an immediate increase in ventilation which raises alveolar P0z (PAo2) back toward normal. The beneficial effect of hyperventilation on oxygenation is offset by the rapid development of hy-pocapnia and respiratory alkalosis which in turn blunts further ventilatory response. A biologic compromise is quickly reached where PAo2 is only partially restored and the changes in...

Diet and Bed Rest

The safest and most conservative treatment of cirrhotic ascites and edema is the institution of bed rest and a low salt diet. This regimen will produce significant clinical improvement in 20-30 of cirrhotic patients 7 . Bed rest reduces lower extremity venous pooling, shifts some blood from splanchnic to central vessels, and expands the EABV. Although bed rest clearly promotes diuresis and natriuresis, it is only a temporizing maneuver. Restricting salt intake below the rate of renal excretion...

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...

Renal Function In Heart Failure

About 20 of the cardiac output is normally delivered to the kidneys and virtually all of the renal blood flow (> 98 ) passes first through the glomeruli. Hydrostatic pressures within glomerular capillaries are regulated by constriction, or dilation, of preglomerular afferent arterioles and postglomerular efferent arterioles and by contraction or relaxation of periglomerular capillary mesangial cells. The hydrostatic pressures, surface area, and epithelial hydraulic permeability of glomerular...

Medical Therapy Of Glaucoma

Medical treatment for glaucoma involves multiple medications (Table 2) 3, 5, 10 . The principal goal of medical treatment is lowering of intraocular pressure. Local administration of cholinergic agents, beta-adrenergic blockers, and alpha- 1. Cholinergic agents (pilocarpine) 2. Beta-adrenergic antagonist agents (timolol) 3. Alpha-adrenergic agents (epinephrine) a. Osmotic diuretics (mannitol) b. Loop diuretics (ethacrynic acid) 5. Ocular (ciliary) carbonic anhydrase inhibitors adrenergic...

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...

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...

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,...

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...

Pharmacokinetics and Pharmacodynamics

Table 2 summarizes pharmacokinetic data in healthy subjects for the most commonly used loop diuretics. These drugs are absorbed quickly with peak serum concentrations attained within 0.5-2 hr. Furosemide exhibits what are called absorption-limited kinetics wherein its rate of absorption is slower than the rate of elimination. This feature manifests clinically as a delay in the peak time at which furosemide appears in blood or urine. In turn, the onset of effect of furosemide after oral dosing...

Mediators Which Stimulate Renal Salt and Water Retention and Constrict Blood Vessels

Heart Failure Cycle

The major neurohormonal responses which increase renal salt and water retention and cause vasoconstriction are portrayed in Fig. 1. The low EABV associated with heart failure activates sympathetic adrenergic nerves and elevates systemic catecholamine levels which produce both systemic and cardiac effects. Systemic arteriolar constriction mitigates the fall in FIGURE 1. The pathophysiology of salt and water retention and edema formation in patients with heart failure. Only the vasoconstricting...

X

Model for NaCl absorption in the thick ascending limb of Henle. The mechanism of all salt reabsorption by the thick ascending limb of Henle is well understood and is shown schematically in the model depicted in Fig. 7. The thick ascending limb reabsorbs about 10-15 of the filtered NaCl. The entry of each sodium ion across the apical membrane of thick ascending limb cells is directly and tightly coupled to one potassium ion and two chloride ions by the Na K 2C1 cotransporter, a process...

Atrial Natriuretic Peptide and Related 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...

Continuous Diuretic Infusion

Bolus Infusion

For hospitalized patients who are resistant to diuretic therapy, another approach is to infuse diuretics continuously. Continuous diuretic infusions have several potential advantages over bolus diuretic administration. First, because they avoid troughs of diuretic concentration, they prevent intermittent periods of positive NaCl balance (postdiuretic NaCl retention). When short acting diuretics, such as the loop diuretics, are administered by bolus infusion or by mouth once or twice a day, a...

Xanthines

For nearly four decades, beginning with the latter part of the 19th century and until the introduction of organomercurials, xanthines were the mainstay of diuretic therapy 3, 4, 22, 35 , The first xanthine to be used for its diuretic effect was caffeine in 1864. A resident physician in St. Petersburg, Russia, by the name of Koshlakoff, described a patient in severe congestive heart failure given citrated caffeine to improve cardiac function. One-quarter of a gram of citrated caffeine was given...

Clinical Implications of Thiazide Diuretics

Thiazide diuretics have been widely used for the medical management of hy-percalciuric calcium nephrolithiasis 19 . The main rationale for this treatment is the ability of thiazide to reduce calcium excretion and thereby lower the urinary saturation of stone-forming calcium salts (calcium oxalate and calcium phosphate). Thiazides also increase excretion of inhibitors of the crystallization of calcium salts (such as pyrophosphate, magnesium, and zinc). In several clinical trials, thiazides have...

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

Salt Poor Albumin For Ascites

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,...

Spironolactone Induced Gynecomastia

The pathophysiology of gynecomastia after spironolactone administration has been carefully studied in man. As noted above, spironolactone induces gynecomastia (and other antiandrogenic effects) principally by binding to cytosolic r SPIRONOLACTONE RECEPTOR COMPLEX FIGURE 2. Active androgens and more specifically 5a-dihydrotestosterone (DHT) interact with the androgen receptor (R) in target tissues to form hormone receptor complexes which activate protein synthesis. Low (50-75 mg) or high...

Nonthiazide Hypocalciuric Diuretics

In addition to the thiazides, certain nonthiazide diuretics such as amiloride or indapamide have been shown to have hypocalciuric effects. These agents may also be of use in the management of idiopathic hypercalciuria or hypoparathyroidism. Amiloride, an antikaliuretic diuretic agent, is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known antikaliuretic or diuretic agents. Compared to thiazide, it is a weak diuretic agent. Amiloride is not an aldosterone antagonist and its...

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...

Mechanism Of Action Of Amiloride Effect on Renal Calcium Transport

Amiloride Effect Tubule

Amiloride inhibits sodium transport in the late distal tubules, likely connecting tubules, and other epithelial cells by blocking sodium channels 4 . Recently, it has been shown that amiloride inhibits sodium entry into the cells and hyper-polarizes the luminal and basolateral membranes. The latter effect, in turn, stimulates calcium influx into the cells and produces a sustained rise of intracellular calcium concentration. Calcium influx and rise of intracellular calcium concentration is...

Clinical and Experimental Data

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...

Overhydration

University of Texas, Southwestern Medical Center, Dallas, Texas 75235-8856 Diuretics, especially thiazide diuretics, are a frequent cause of hyponatremia. Paradoxically, loop diuretics can be important adjuncts in the treatment of acute symptomatic hyponatremia, the syndrome of inappropriate secretion of antidiuretic hormone SIADH , and diabetes insipidus. Hyponatremia is caused by water retention due to a continued water intake more than the ability of the kidneys to excrete electrolyte-free...

Diuretics Acting in Late Distal Tubule and Collecting Duct

These diuretics, usually referred to as potassium-sparing diuretics, are divided into two main classes agents whose action does not depend on the inhibition of aldosterone and agents which are classical pharmacological competitive antagonists of aldosterone. Amiloride and triamterene are the main diuretics with action independent of the antagonism of aldosterone. Potassium sparing diuretics are usually administered concomitantly with more potent diuretics to counteract diuretic-induced...

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,...

Thiazide Diuretics

The main site of action of thiazides is at the proximal portion of the distal convoluted tubule. Distal tubular reabsorption of magnesium affects only 5- 10 of filtered magnesium 10 . Thus, the inhibition of this process cannot account for the increase in the renal magnesium excretion induced by the thiazide diuretics. It has been shown that urinary magnesium excretion after treatment with thiazides is significantly delayed with respect to the volume of sodium and chloride excreted in the...

General and Salt Restriction

Treatment of nephrotic edema should be directed principally at the underlying glomerular process whenever possible. For example, the most effective treatment for the salt retention and edema produced by minimal change nephropathy is a glucocorticoid induced remission. Similarly, the best treatment for edema associated with a toxin or drug induced nephropathy, is elimination of the inciting agent. However, very often the glomerular process cannot be promptly or completely corrected. Weeks or...

Lessons from Mutations in the Epithelial Na Channel SCNN Found in Human Disease

Mutations in the human ENaC subunit genes result in inherited diseases characterized by either gain-of-function or loss-of-function of the epithelial Na channel in distal convoluted tubules and collecting duct. Mutations causing overactivity of the Na channel result in NaCl retention and hypertension Liddle's syndrome , whereas other mutations leading to reduction or loss of channel activity result in renal salt wasting and hyperkalemic acidosis pseu-dohypoaldosteronism type I . These...

Distal and Hemodynamic Effects of Mannitol

Evidence now supports the conclusion that the proximal tubular actions of mannitol on sodium absorption are insufficient to account for its diuretic effect, especially when mannitol is administered as a hypertonic solution. Under these conditions the ensuing diuresis and sodium excretion are considerably greater than the relatively modest decline in proximal reabsorption. It is generally accepted that inhibition of absorption by thick ascending limbs accounts for the majority of the additional...

Toxic Agents Drug Overdose Poisons Contrast Media

Ratio Urinary Weak Acid

Nephrology Metabolism Division, Baylor University Medical Center, Dallas, Texas 75246 This chapter focuses on the use of diuretics in the management of life threatening poisonings, drug overdoses, and radiocontrast agent-induced disease. These problems occur relatively frequently and continue to be major challenges for clinicians. Radiocontrast-induced acute renal failure may occur in a hospital setting, especially in an age of more aggressive interventional radiological techniques. This...

Diuretics

When dietary salt restriction with, or without, additional bed rest does not adequately control edema, diuretic therapy is initiated. However, it must be emphasized that moderate dietary salt restriction continues to be an important component of therapy after diuretics are begun. The ingestion of a high salt diet together with diuretics will reduce their efficacy and increase the severity of adverse effects. The duration of action of many potent diuretics is relatively short. Daily or twice a...

The Overflow Hypothesis

Cirrhosis Edema

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...

Effects of Loop Diuretics on Renal Hemodynamics via the Tubuloglomerular Feedback Mechanism

As discussed in other chapters, loop diuretics such as furosemide and bume-tamide exert powerful actions to inhibit the Na' 2C1 K cotransporter in the ascending loop of Henle. Accordingly, loop diuretics markedly increase NaCl load to the macula densa. While this would be expected to stimulate the TGF mechanism and lead to vasoconstrictor signals from the macula densa to reduce blood flow and GFR, this does not occur because the TGF mechanism is interrupted by these diuretics. Indeed loop...

Dopamine And Dobutamine For Congestive Heart Failure

Acute dopamine infusion increases renal plasma flow, urinary sodium excretion rate, glomerular filtration rate, and the functional status of patients with moderate to severe congestive heart failure. These effects result from stimulation of dopamine receptors DA and DA2 as well as f3 adrenergic receptors. Beregovich and co-workers 2 studied the dose-related hemodynamic and renal effects of dopamine in patients with classes III and IV congestive heart failure see Fig. 5 . Cardiac output and...

Chlorothiazide

Karl Beyer Thiazide Diuretics

In 1943 Sharp amp Dohme Inc. merged with Merck and Company in 1952 to become Merck, Sharp and Dohme MSD had set up what came to be known as the Renal Program headed by Karl H. Beyer, a pharmacologist, and James M. Sprague, an organic chemist Fig. 6 . Prompted by the work of Roblin on heterocyclic sulfonamides, the renal team embarked on an exploration of other sulfonamide derivatives that could mobilize edema by the elimination of sodium with chloride, rather than bicarbonate. Starting with...

Hepatobiliary System

Formation of bile involves the movement of water and electrolytes and other solutes from the sinusoidal blood or intracellular compartment into the canaliculus. Canalicular secretion of bile is made up of two major components. Active transport of bile acids into the bile canaliculus provides the osmotic driving force for movement of water and smaller solutes, giving rise to the bile acid-dependent component of canalicular bile. The osmotic drive for a second bile acid-independent component of...

Hypo and Hypernatremia

Hyponatremia is an important adverse effect of thiazide diuretics, especially if long-acting like chlorthalidone hypernatremia is more commonly seen with loop diuretics causing dehydration. Thiazide diuretics induce the excretion of more sodium than water, whereas the impairment of the cortico-medullary osmotic gradient by loop diuretics leads to a larger excretion of water than sodium loop diuretics are often used in the treatment of hyponatremia. Hyponatremia is also more likely to occur in...

Pharmacodynamic Mechanisms for Diuretic Antagonism

Since the clinically important diuretics work from the luminal side of the renal tubule, pharmacodynamic interactions between NSAIDs and diuretics can be FIGURE 2. Dose-response curve depicting the relationship between urinary sodium excretion and urinary furosemide excretion rates in volunteers before and after indomethacin administration. After indomethacin treatment subjects required greater rates of furosemide excretion to achieve any desired rate of sodium excretion. From Chennavasin P.,...

Pathophysiology Of Salt Retention And Edema The Underfill Vs Overflow Hypotheses

Edema Mechanism

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...

Chronic Diuretic Therapy for Heart Failure [3033

Patients with mild heart failure generally respond favorably to the initiation of a low salt diet and thiazide diuretics. The relatively long biologic half-life of this class of diuretics can produce an almost continuous diuretic effect which is generally advantageous. Hydrochlorothiazide, at a dose of 25-50 mg day, or equivalent doses of other thiazides, or thiazide-like diuretics, are reasonable choices. Loop diuretics generate more dramatic diuresis over a shorter period of time. However,...

Renal Transport Of Cationic Diuretics

The diuretics triamterene and amiloride exist in the blood as cations. These agents are secreted into the lumen of the renal tubule through an organic cation transport system. The cation transport system is also located in the proximal tubule. Evidence in almost all species demonstrates that this system is separate from the systems used to transport anions. Quantitative cation transport capacity, however, differs significantly between species. From studies in rabbits it appears that the cation...

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...

Apical K Channels

Electrophysiological experiments in rabbits and rats have identified two types of K channels that are involved in the K recycling process a channel with a 30-40 pS conductance low-conductance channel and another with a higher conductance of 70-80 pS moderate conductance channel . High conductance gt 100 pS , or maxi-K channels, have also been identified in apical membranes of rabbit thick ascending limb cells in culture and they are thought to function in cell volume regulation, but not in K...

The NaCl Cotransporter Gene and Protein

Thiazide Sensitive Nacl Cotransporter

Major advances have been made over the past few years in our understanding of the actions of thiazide diuretics and this is due in large part to the molecular identification of a family of cation chloride cotransporters to which the Na Cl transporter belongs see Table 2 . This information has enhanced our thinking about these transporter proteins. It is now clear that Na Cl cotransport activity represents the function of a single membrane protein belonging to the newly identified family of...

Salt And Diet

The role of dietary manipulation to treat dropsy had been practiced for centuries. It had been used, with varying degrees of success, by nature healers, herbalists, and medical practitioners 1,8,35 . The favorable results of these dietary regimens had been attributed to its various constituents asparagus, celery, berries , its limited fluid content dry diets , or high potassium content potato diet . Mention of an association between salt intake and fluid retention was made by Caelius Aurelianus...

History of Diuretics

Paracentesis Dropsy

Department of Medicine, Baylor College of Medicine, Houston, Texas 77030 Diuretics, as therapeutic agents that act on the kidney to increase salt and water excretion, have a relatively short history. On the other hand, the very reason for which diuretics were developed, i.e., mobilization of excess body fluids, has a long history which dates back to the beginnings of medicine. No history of diuretics would be complete without some consideration of this long prelude, which is particularly...