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...

As An Adjunct To Dialysis

Loop diuretics have also been administered to patients with end-stage renal disease on maintenance dialysis in an attempt to reduce interdialytic weight gains, prevent heart failure or pulmonary congestion, and control blood pressure without unpalatable limitations in fluid or sodium intake. It has also been suggested that this strategy could reduce the number of hypotensive episodes which occurred during hemodialysis during removal of excess fluid. The ma jority of these studies have been...

Chronic Renal Failure

The common denominator in chronic renal failure, irrespective of its cause, is reduced renal blood flow and glomerular filtration rate. To maintain the proper milieu interieur the kidney, responding to hemodynamic, neural, and humoral signals, undergoes some very significant alterations in its reabsorptive and secretory functions. In order to continue excretion of the ingested sodium in the diet, the diseased kidney with a reduced number of functioning nephrons, reabsorbs less of the filtered...

Nsaids Effects On Diuretic Excretion Of Other Solutes

The effect of NSAIDs on diuretic stimulated excretion of other solutes has not been extensively examined. The kalurietic effects of loop diuretics during NSAID administration have been reported to be unaltered in some studies and reduced in others 2, 10, 11 , Even in the latter cases the reduction in potassium excretion is usually quite modest compared with the reduction in sodium excretion. Greater reductions in potassium excretion have been reported in association with significant reductions...

References

H. (1993). A comparison between the effect of topical and systemic carbonic anhydrase inhibitors on aqueous humor secretion. Exp. Eye Res. 57(1), 67-78. 2. Cotton, P. (1993). Focus in glaucoma may change from keeping fluid out to letting fluid out. J. Am. Med. Assoc. 269, 2711. 3. Dunsfield, T. S. (1993). Drug treatment of glaucoma. Am. Pharm. 33, 43-52. 4. Everitt, D. E., and Avorn.J. (1990). Systemic effects of medications used to treat glaucoma Ann. Intern. Med....

Pharmacokinetic Mechanisms for Diuretic Antagonism

Most studies examining pharmacokinetic interactions between NSAIDs and diuretics have focused on indomethacin and furosemide. In these studies it has been noted that indomethacin induces an 18 to 40 reduction in plasma furosemide clearance 2 . In man, this results from a large reduction in furosemide's renal clearance and a smaller insignificant decrease in nonrenal clearance (primarily liver and intestine). In the dog, significant decreases in both renal and nonrenal clearances have been...

Ca2 Channel Antagonists and Other Direct Vasodilators

The natriuresis caused by agents that directly increase GFR may be due largely to their hemodynamic effects. Calcium channel blockers or antagonists refer to a large class of drugs that directly interfere with entry of Ca2+ via voltage-dependent calcium channels. Thus, calcium channel blockers will directly vasodilate preglomerular arterioles, leading to increases in RBF and GFR and will also block vasoconstrictor responses to agents that activate L-type voltage-dependent Ca2+ channels. As...

Endogenous Ouabain

In the 1960s and 1970s, de Wardener and colleagues developed evidence for the existence of various natriuretic factors, which could stimulate salt excretion in the setting of volume expansion by inhibition of tubule Na K ATPase 16 . While numerous extracts of plasma and urine from volume expanded animals inhibited Na K ATPase activity and reduced transepithelial Na+ transport in a number of renal model epithelia, the identity of these factors remained unclear 16 , Recent studies have provided...

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...

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...

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...

Clinical Significance

The incidence of insulin resistance without overt hyperglycemia is unknown, but overt hyperglycemia occurs in about 15 of patients treated with thiazide diuretics. The incidence of hyperglycemia caused by loop diuretics is lower because these agents tend to cause less potassium wastage than thiazides. Glucose concentrations are mildly elevated (120-150 mg dl) in most cases however, severe hyperglycemia with glycosuria can be precipitated even by mild to moderate (25-50 mg day) doses of...

Pathophysiology of Severe Hypercalcemia

Most causes of severe hypercalcemia are associated with increased osteoclastic bone resorption. The osteoclast is activated by substances like PTH, PTH-related protein, and other osteoclast activators. The activated osteoclast leads to excessive bone resorption and the release of Ca from bone into the extracellular fluid. Excessive absorption of Ca from the gastrointestinal tract is not usually an important mechanism although it can play a role in states of vitamin D excess. Hypercalcemia...

Clinical Consequences

The incidence of spironolactone-induced gynecomastia in men is dose related (Fig. 3). It is estimated that 50 of men treated with Si50 mg day of spironolactone will develop gynecomastia. The degree of gynecomastia varies con- FIGURE 3. Incidence of gynecomastia according to dose of spironolactone. From Juenema-tire, et al. siderably from patient to patient but in most instances causes mild symptoms. Associated breast tenderness is common but an inconsistent feature. Regression of gynecomastia...

Antiandrogenic Effects

Caminos-Torres, R., Ma, L., and Snyder, R J. Gynecomastia and semen abnormalities induced by spironolactone in normal men. J. Clin. Endocrinol. Metab. 45, 255. 2. Dorfman, R. I. (1970). Biological activity of antiandrogens. Br. J. Derm. 82 (Suppl. 6), 3-8. 3. Dupont, A. (1985). Disappearance of spironolactone-induced gynecomastia during treatment with potassium canrenoate. The Lancet September, 731. 4. Juenemaitre, X., Chatellier, G., Kreft-Jais, C. et al. (1987). Efficacy and tolerance of...

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...

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...

The Nature Of Hypertension

Hypertension is a raised systemic arterial blood pressure (BP). However, BP is a continuously distributed variable and the numerical boundary between nor-motension and hypertension is arbitrary and is based on the increasing cardiovascular risk, in particular stroke, as BP rises (Fig. 1) 7 . A WHO-based classification of hypertension is shown in Table 1. Considering end-point trials of cardiovascular risk (more specifically, stroke), it is now widely accepted that maintaining BP below 140 90 mm...

Use Of Albumin And Diuretics For Edema Treatment

Although the combination of albumin and diuretics has been used in the treatment of nephrotic edema for over 25 years, few studies have critically examined the response to this therapy. Most studies report using 0.5-1.0 g kg body weight of 20-25 albumin administered over 30-60 min followed by a 30-min infusion of 1-2 mg kg furosemide. This therapy is then repeated daily or every other day as needed to achieve the desired degree of weight loss. Average weight losses of 1.2 to 2.5 of the initial...

Diuretic Use In Essential Hypertension During Pregnancy

Hypertension in pregnancy represents a risk factor to the mother and fetus even in the absence of preeclampsia. Women with essential hypertension should continue taking their usual anti-hypertensive medications, including diuretics, during pregnancy. Angiotensin converting enzyme inhibitors are an exception and are contraindicated in pregnancy. In one study of women with essential hypertension, diuretics were stopped and the results compared to women who continued diuretic use throughout...

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...

Use of Diuretics in the Treatment of Hypertension in Renal Impairment

Hypertension is a consequence of renal impairment and if untreated accelerates the decline in renal function to end-stage renal failure. Moreover, hyperlipidemia and glucose intolerance are more common in chronic renal failure, and cardiovascular morbidity and mortality are significantly increased, particularly in patients on dialysis in whom BP control is often difficult. The major cause of hypertension in renal failure is sodium retention and ECV expansion, so-called volume-dependent...

Effects of Disease

Few studies have assessed the pharmacokinetics and pharmacodynamics of thiazide diuretics in the clinical conditions in which they are used. In general, changes seem to be similar to those discussed with loop diuretics. No studies have assessed pharmacodynamics. Patients with decreased renal function have slowed elimination of tizolemide and trichlormethiazide with an inverse correlation of elimination half-life with creatinine clearance. This effect would presumably result in a diminished peak...

Improvement in Diuretic Delivery

Loop diui tics as well as thiazides are highly bound to albumin in the plasma. This bind .ng confines the drug to the vascular space and facilitates diuretic delivery t > the peritubular space surrounding the proximal tubule. From this location t re diuretics are secreted into the proximal tubule lumen. Albumin also plays a role in regulating the rate of secretion of anionic loop diuretics into the proximal tubule. This effect is independent of its function as a carrier molecule. Thus albumin...

Improvement in Solute Delivery

For many years hypoproteinemic states have been assumed to be associated with reductions in effective intravascular volume. This event has been postulated to play a seminal role in the intense renal sodium retention associated with nephrotic syndrome and cirrhosis through activation of a number of volume sensitive neurohumoral mechanisms stimulating sodium reabsorption. Additionally changes in vascular volume could induce direct increases in peritubular physical forces favoring sodium uptake in...

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....

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...

Classification Of Glaucoma

Glaucoma is not a single disorder, but rather multiple disorders (Table 1). There are multiple classification schemes. Glaucoma can be classified into congenital glaucoma, primary glaucoma, and secondary glaucoma. Congenital glaucoma is caused by an abnormality in the aqueous humor outflow tract in the anterior chamber. There may be other associated developmental ocular abnormalities. Primary glaucoma is divided into two categories, primary open angle glaucoma, and primary closed angle...

Cirrhosis Table

In patients with cirrhosis who are hypoalbuminemic, protein binding is decreased with consequent effects on volume of distribution and clearance. Bioavailability is normal, though the rate of absorption is slowed. Overall, unless renal function is compromised, diuretic delivery into urine is normal (Tables 2 and 3) as such, resistance is pharmacodynamic in nature. The possible mechanisms for such resistance include increased solute reabsorption at the proximal or distal tubule and or...

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...

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...

Broader Definition Of Hypertension

'A low, or declining, diastolic blood pressure has been linked to vessel wall thickening associated with progression of atherosclerosis and therefore may be an indication of widespread arterial disease and increased risk of cardiovascular mortality. 65 70 75 80 85 90 95 100 105 110 115 FIGURE 3. The J-curve for cardiovascular mortality and diastolic blood pressure (DBP). Low DBP may be a consequence rather than a cause of increased mortality. 65 70 75 80 85 90 95 100 105 110 115 FIGURE 3. The...

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...

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,...

Filtration in Systemic Capillaries and Lymphatic Drainage [610

The total body capillary filtration rate (not including the glomerular filtration rate (GFR)) is about 10-15 ml min, or 15-20 liters day. About 90 of this filtered fluid is reabsorbed in more distal portions of the capillaries or by other low pressure capillaries. The remaining 10 of filtered fluid, about 2 liters day, returns from the interstitial space to the vascular compartment via lymphatic drainage. Systemic capillary filtration of 15-20 liters day represents less than 0.5 of total blood...

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...

Cirrhotic Patients Refractory to Combination Diuretics

The massive ascites and edema of some cirrhotic patients cannot be reduced despite the above therapeutic interventions. In such patients large volume paracentesis (5-8 liters) can alleviate many of the symptoms associated with tense ascites. In the past, large volume paracentesis was discouraged for fear that it would produce severe intravascular volume depletion and cardiovascular collapse. However, recent studies show that large volume paracentesis can be safely carried out 11 . Indeed,...

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...

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...

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...

Lasix Induced Bicarbonate Alterations

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...

Osmotic Agents

Friedrich (b. 1864) had recommended urea in relatively small doses (2-14 g day) for use in cardiac edema and cirrhotic ascites. In 1896, Georg Klemperer (1865-1946) used it successfully in cases of hepatic ascites, using larger doses (16-20 g day). In the same year, and again in 1921, Hermann Strauss emphasized the merits of urea as a diuretic when given in large doses. Franz Volhard (1872-1905) used doses of 40-60 g per day in the treatment of patients with renal disease...

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...

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...

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

Vascular Function Arteries

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

Indapamide Mechanism Action

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...