Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Diuretics Donald G. Vidt MD To cite this article: Donald G. Vidt MD (1976) Diuretics, Postgraduate Medicine, 59:5, 143-151, DOI: 10.1080/00325481.1976.11714362 To link to this article: http://dx.doi.org/10.1080/00325481.1976.11714362
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Date: 16 January 2017, At: 02:28
• The introduction in 1958 of chlorothiazide as the first truly effective oral diuretic marked the onset of a new era in the treatment of edematous conditions and hypertension. Diuretics are now among the most commonly used therapeutic agents. The development of new, more patent agents has increased the complexity of management. The clinician must understand the mechanisms by which diuretics exert their effects and the pathologie conditions under which they can be used and must appreciate their potential disadvantages, side effects, and interactions with other drugs. Action of Diuretics on the Kidney
The four major sites of diuretic action along the nephron are the proximal tubule, the medullary and cortical segments of the thick ascending limb of Henle's loop, and the distal tubule (figure 1). Proximal tubule-In the proximal tubule, 60% ta 75% of the glomerular filtrate is reabsorbed isotonically (ie, sodium and other solutes move with water in isotonie proportions). Amino acids, glucose, and much of the calcium and phosphorus are also reabsorbed at this site. Thus, quantitatively, proximal tubular function is very significant. Inhibition of net proximal tubular transport does not increase urine flow ta the degree that might be expected, because the portion of nephron distal ta the proximal tubule has a high reserve capacity, permitting it, when necessary, ta reabsorb a larger-than-normal amount of sodium and chloride. Thus, inhibition of distal transport mechanisms generally produces more effective diuresis than can be accomplished at the proximal site. Ascending limb of Henle' s loop-The ascending limb of Henle's loop is responsible for reabsorption of approximately 15% ta 30% of the filtered Joad. Sodium chloride is actively transported from the tubular lumen of the medullary segment of the thick ascending limb, which is relatively impermeable ta water. Studies have suggested that active transport of chloride is the key process here and is possibly coupled with transport of 1 sodium. The same basic process occurs in bath the medullary and the cortical segments of the thick ascending limb. However, transport inhibition will have very different consequences on the final concentration of urine, depending on the segment in which the inhibition occurs. ~
Vot. 59 o No. 5o May 1976 o POSTGRADUATE MEDICINE
diuretics use and misuse Donald G. Vidt, MD The Cleveland Clinic Foundation Cleveland
con si der What are the major sites of diuretic action along the nephron? What are the pathologie conditions for which specifie diuretics may be effective? What are the most serious side effects of diuretics?
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Figure 1. Major sites of diuretic action along the nephron: proximal tubule (1 ), medullary segment of the thick ascending limb of Henle's loop (2), cortical segment of the thick ascending limb of Henle's loop (3), and distal tubule (4).
Solute reabsorption from the medullary thick ascending limb leads to dilution oftubular contents, while deposition of sodium chloride in the interstitium without an osmotically equivalent amount of water produces a hypertonie medullary interstitium. Fluid passing dawn the collecting duct will osmotically equilibrate with the hypertonie medullary interstitium and form concentrated urine under the influence of antidiuretic hormone. Interference with the function of the medullary segment of thick ascending limb results in inability to concentrate the urine. Henle's loop emerging into the cortex contains a dilute tubular fluid which is further diluted in the cortical segment of the thick ascending limb by further outward transport of sodium chloride without water. Inhibition of sodium reabsorption at this site would impair the ability to form a maximally dilute urine.
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Distal tubule-The dilute tubular fluid passes to the distal convoluted tubule. Under the influence of aldosterone, sodium is reabsorbed at this site in exchange for potassium or hydrogen ions. Whether potassium or hydrogen is secreted for each absorbed sodium ion is dictated by the patient's acid-base balance and serum potassium concentration. Inhibition of this ion exchange pump leads to increased sodium loss, while potassium and hydrogen are conserved. Cllnical Implications of Dluretlc Therapy
For purposes of this discussion, diuretics are grouped into six categories: osmotic agents, carbonic anhydrase inhibitors, organomercurials, thiazides and related sulfonamide derivatives, furosemide and ethacrynic acid (loop diuretics), and potassiumsparing agents (distal tubular diuretics). Table l outlines the preparations available and the
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dosages which are usually administered. Osmotic diuretics-Mannitol is the prototype of the osmotic agents. Under normal physiologie conditions its principal site of action is the proximal tubule, where it osmotically prevents the normal obligatory reabsorption of filtrate. Experimental studies 1 • 2 have demonstrated an increase in the medullary blood flow during mannitol diuresis and a marked reduction in medullary hypertonicity. Reduction in interstitial solute concentration reduces the driving force for water reabsorption in the descending limb of Henle's loop, thus allowing a larger volume offiltrate to reach the distal tubule and collecting duct. Here, the higher flow rate of filtrate, the restraining effect of mannitol, and reduced medullary interstitial concentration combine to decrease the water and sodium reabsorption at these distal sites. The major use of mannitol toda y is in states of acute renal insufficiency, law renal perfusion, or both. Mannitol is effective in restoring glomerular filtration rate during and after transient hypotension and is often used prophylactically where hypotension or sudden reduction in renal perfusion can be anticipated. A high concentration of mannitol in the extracellular fluid compartment and the accompanying increased osmolality induce a shift of water from the cells ta expand the volume and dilute the sodium concentration of the extracellular fluid. The clinical implications of a sudden shift in water may be significant. Pulmonary edema may be precipitated in patients with incipient cardiac failure. Even when underlying heart disease is absent, administration of large amounts of mannitol ta patients with oliguria and acute tubular necrosis or obstructive uropathy may lead ta pulmonary congestion. 3 In patients with oligurie renal failure who have received large amounts of mannitol, significant increase in plasma osmolality may occur and hyponatremia secondary ta water redistribution may be misinterpreted. Carbonic anhydrase inhibitors-These agents prevent the generation and tubular secretion of hydrogen ions in the proximal
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tubule, thereby also reducing sodium reabsorption. The result is less hydrogen ion formation and increased loss of potassium in the distal tubule. 4 Acetazolamide is the most commonly used carbonic anhydrase inhibitor. It is relatively nontoxic, but its value is limited by law potency and the rapid development of tolerance by patients receiving it for more than 48 hours. Carbonic anhydrase inhibitors may be particularly useful as adjunctive therapy in correcting metabolic alkalosis by providing increased bicarbonate excretion and may be used ta potentiate the effectiveness of organomercurials, thiazides, furosemide, ethacrynic ac id, or spironolactone. When used for these purposes they are best administered intermittently for one or two days each week. They may be used as an adjunct in the treatment of acute hyperuricemia or in the chemotherapy of hematopoietic neoplasms. Where high rates of urie acid excretion may be anticipated, an alkaline urine should be encouraged since alkalinity greatly increases the solubility of urie acid. Organomercurial diuretics-Although the organomercurials are nonselective inhibitors binding ta most sulfhydryl-containing proteins within renal tubular cells, their main effect is exerted via inhibition of sodium and chloride reabsorption in the medullary and cortical segment of the thick ascending limb ofHenle's loop. 5 Ta a lesserextent, the cation exchange pump in the distal tubule is inhibited and the diuresis produced may not carry the degree ofkaliuresis associated with patent diuretics, such as ethacrynic acid or furosemide. Several disadvantages have limited the use of organomercurials in recent years, and they are rarely used today. They are less effective in achieving diuresis in congestive heart failure than furosemide or ethacrynic acid, they must be administered intramuscularly, and they are not effective in metabolic alkalosis. Organomercurials should not be administered intravenously because instances of sudden death, presumably of cardiac origin, have been reported. Their repeated use in patients
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lt is generally agreed that a diuretic agent should be included in every antihypertensive regimen.
table 1. classification of diuretics used in clinical practice Type of agent
Generic name
Commercial preparation
Usualdaily dosage (oral)
Osrnotlc dluretlc
Mannitol
Osmitrol
25-100 gm• (IV)
Carbonic anhydrase inhlbitor
Acetazolamide
Diamox
250-500 mg
Organomercurlal diu retie
Mercaptomerin
Thiomerin
1-2 ml (lM)
Diuril
250-1 ,500 mg
Thiazlde and related sulfonamlde derivatives Benzothiadiazine compounds
Chlorothiazide Hydrochlorothiazide
Bendroflumethiazide Methyclothiazide Hydroflumethiazide Benzthiazide Polythiazide Cyclothiazide Trichlormethiazide Phlhaiimidine compound Quinazoline compounds Loop dluretlcs Anlhranilic acid compound (sulfonamide derivative) Phenoxyacelic acid derivative Potasslum-sparlng agents (distal tubule diuretics)
Esidrix } HydroDiuril Oretic Naturetin
25-150 mg 5-15 mg
Aquatensen} Enduron
5-15 mg
Diucardin} Saluron Exna Renese Anhydron
26-150 mg 25-150 mg 2-B mg 2-6 mg 2-B mg
Chlorthalidone
Metahydrin} Naqua Hygroton
Quinelhazone Metolazone
Hydromox Zaroxolyn
50-150 mg 2.5-10 mg
Furosemide
Las ix
40 mg-1 gm (or more)
Ethacrynic acid
Edecrin
50 mg-1 gm (or more)
Spironolactone Triamterene
Aldactone Dyrenium
50-200 mg 100-200 mg
50-100 mg
*5%-25% solutions available.
with rel1,jll insufficiency may lead to mercurial toxicity. The renal failure and hemorrhagic cystitis that have been reported with repeated use are probably consequences of heavymetal poisoning, which results from continued administration when renal excretion is impaired. Failure to achieve a diuretic response with an organomercurial should signal the clinician to stop administration of the drug, search for an explanation for the therapeutic failure, and consider other diuretic agents.
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Thiazides and related sulfonamide derivatives-The principal inhibitory effect of these agents is on the cortical segment of the thick ascending limb of Henle's loop. Thiazides also have a carbonic anhydrase inhibitory action which is of little clinical signifie ance. Chlorothiazïde is the prototype of this group of diuretics. The many derivatives developed subsequently are more patent by weight but appear not ta have more diuretic potency or a greater margin of safety, when used in recommended dosages, than does chlorothiazide. Adverse effects-Thiazides have been associated with a large variety of adverse effects, sorne of little clinical importance. The most significant are electrolyte abnormalities: metabolic alkalosis, hypokalemia, and hyponatrernia. Metabolic alkalosis due ta chloride and potassium depletion (hypochloremichypokalemic alkalosis) occurs secondary ta increased delivery of sodium ta the distal tubule, where increased exchange of sodium for potassium occurs under the influence of aldosterone. The resultant hypokalemia increases proximal reabsorption of bicarbonate, further aggravating the existing alkalosis. Thiazides are usually administered in edematous states, such as congestive heart failure, nephrotic syndrome, and hepatic cirrhosis with ascites, and in the presence of secondary hyperaldosteronism, conditions under which sensitivity of the distal tubule ta increased sodium delivery may be increased. Metabolic alkalosis secondary ta increased water excretion (contraction alkalosis) pla ys a raie in perpetuating alkalosis secondary ta thiazide administration. Patients with alkalosis and volume contraction require restriction offluid volume and appropriate electrolyte replacement. Occasionally, ammonium chloride may be needed ta correct the alkalosis. Hypokalemia secondary ta thiazide administration may induce myocardial irritability in patients with myocardial disease. Appropriate measures should be taken ta prevent hypokalemia during diuretic therapy in these
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patients, and serum potassium levels should be monitored at regular intervals. Hyponatremia, although much more cornmon in association with the patent loop diuretics, may be induced by prolonged use of thiazide diuretics. It is usually of dilutional type, due to impaired free water clearance and unrestricted fluid intake. Serum sodium concentration is law, but total body sodium is generally increased. Therefore, differentiatian of dilutional hyponatremia from a sodium depletion state due to profuse diuresis is important, since appropriate therapy of the two conditions is quite different. Thiazide diuretics may cause hyperuricemia, mainly due to volume contraction and increased proximal reabsorption of urie acid. Inhibition of urie acid secretion may also be a factor. The rise in blood urea nitrogen leve! results from volume contraction and decreased glomerular filtration rate and is most apparent in patients with marginal renal reserve function. Asymptomatic hyperuricemia düring chronic therapy with thiazides does not require specifie treatment. If gout develops, allopurinol is added to the regimen, plus colchicine to control acute symptoms. Sorne clinicians prefer to add allopurinol if the urie acid leve! exceeds 10 mg/100 ml. Hypercalcemia may be attributed in part to volume contraction with increased proximal reabsorption of calcium. Thiazides also appear to potentiate the renal effects of parathormone on calcium reabsorption. 6 • 7 Photosensitivity is a rare side effect of the sulfonamide diuretics, ie, thiazides, chlorthalidone, quinethazone, metolazone, and the loop diuretic furosemide. Significant hyperglycemia, also rare, is an indirect effect of chronic volume depletion, since it results in part from hypokalemia. Neither diabetes nor goutis a contraindication to the use of a thiazide diuretic. Suitable dietary manipulations and prevention of hypokalemia will usually prevent undue hyperglycemia in the diabetic patient, and allopurinol should be included in the regimen of patients with gout. Other side effects of minor consequence
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include gastrointestinal irritation, weakness, oral sensation of dry mou th or bad tas te, leukopenia, thrombocytopenia, pancreatitis, purpura without thrombocytopenia, and skin rash. Benefits of chronic use-The modest volume contraction produced with chronic use of the thiazides may have salutary effects in sorne nonedematous states. 7 In nephrogenic diabetes insipidus, thiazides may reduce urinary volume by as much as 50%. The glomerular filtration rate is decreased with increased proximal reabsorption of filtrate, Jess filtrate reaches the distal reabsorption sites, and thus, Jess water is excreted. Decreased calcium excretion may be beneficiai in the treatment ofhypercalciuria. In the therapy of renal tubular acidosis (proximal type), the volume contraction produced by thiazides reduces the bicarbonate leak, thus partially restoring serum bicarbonate levels. Use in hypertension-Thiazides are the primary diuretics used in treatment of hypertension. They, as weil as the other oral diuretics, reduce blood pressure by depleting the volume of plasma and of extracellular fluid initially. With chronic use, they appear to reduce vascular reactivity to sympathetic stimulation, which prevents the sympathetic nervous system from compensating for a small but definite reduction in plasma volume. It is generally agreed that a diuretic agent should be included in every antihypertensive regimen. In uncomplicated mild or moderate hypertension, it may be the only agent needed to normalize blood pressure. Hypokalemia may occur in antihypertensive therapy with thiazide diuretics but is generally not significant enough to require replacement therapy. If the serum potassium leve! falls below 3 mEq/liter or if symptoms occur that are attributable to hypokalemia, such as weakness or muscle cramping, the clinician may give supplemental potassium, add a potassium-sparing diuretic to the regimen, or restrict sodium intake to further minimize potassium Joss at the distal tubular exchange site. Furosemide and ethacrynic acid ( loop
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Because of their potency and rapid onset of action, loop diuretics are particularly useful in situations where fluid overload poses an immediate threat.
diuretic s)-These agents are dissimilar in structure but are considered together because of their similarity in physiologie action. Both are potent diuretics, theireffect resulting from inhibition of sodium reabsorption in the medullary and cortical segments of the thick ascending limb of Henle's Joop. 8 • 9 When the filtered Joad is adequate, diuresis may be massive and the increased sodium delivered to the aldosterone-sensitive distal tubule may induce large !osses of potassium. Both agents are relatively effective, even in the presence of underlying electrolyte or acid-base imbalance. Therefore, diuresis can be expected, if dosage is sufficient, in patients with metabolic or respiratory acidosis, or in patients with hyponatremia, hypokalemia, or hypochloremia. Since the Joop diuretics inhibit sodium reabsorption in both segments of the thick ascending limb of Henle's loop, they inhibit the maximal diluting and concentrating ability of the kidney. Thus, both agents reduce the capacity of the kidney to regulate tonicity of body fluids and subject the patient to risks resulting from an imbalance between volume of water ingested and that needed to cover solute excretion and insensible !osses. The clinical implications are such that neither agent should be the initial diuretic used unless short-term benefits outweigh the potential clinical consequences of massive diuresis. Because oftheir potency and rapid onset of action, these agents are particularly useful in situations where fluid overload poses an immediate threat. In the patient with acute left ventricular failure, for example, 40 to 80 mg offurosemide given intravenously can make a significant difference in outcome. Diuresis ensues within minutes, peaks in 30 minutes to two hours, and is an important adjunct to digitalis and other measures in the treatment of this medical emergency. The broad dose-related response to these agents also makes them useful in conditions, including renal insufficiency, where the filtered Joad of sodium is greatly reduced. Should the thiazides or other diuretics fail to produce diuresis, a Joop diuretic may be substituted. In patients with refractory edema,
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doses of both ethacrynic acid and furosemide exceeding 1.0 gm/day have been used. For patients requiring longer term therapy, intermittent administration may effectively promote negative sodium balance and minimize the risks of severe electrolyte abnormalities. In a few patients with refractory anasarca, the effect of furosemide or ethacrynic acid on sodium excretion may be potentiated by concomitant administration of a thiazide, carbonic anhydrase inhibitor, organomercurial, or spironolactone. The potential for producing significant electrolyte imbalance poses a real danger with the use of high doses of loop diuretics, particularly in the long-term management of patients with chronic congestive heart failure or other refractory edematous states. Dilutional hyponatremia should be suspected when a patient who stiJl has obvious fluid retention stops responding to the diuretic. Serum sodium concentration is usually below 130 mEq/Jiter, and dilutio-nal reduction in serum proteins and red cell volume is evident. Water intake should be restricted and diuretic therapy suspended until the serum sodium value ri ses to at !east 135 mEq/liter. Chronic sodium and fluid volume depletion may be produced by a combination of overly rigorous sodium restriction and chronic therapy with potent loop diuretics. Serum sodium concentration is very low (Il 0 to 120 mEq/Jiter) and azotemia is usually present. Patients are hypotensive, lethargie, confused, and dehydrated and require careful replacement of sodium chloride and water for restoration of effective circulating volume. In the evaluation of acute urinary suppression (oliguria), furosemide has been used to help distinguish between ischemie tubular necrosis and prerenal azotemia with oliguria. Furosemide given intravenously in a dose of 40 to 80 mg, with or without a concomitant test dose of mannitol, may produce a rise in urinary volume when oliguria has a prerenal basis. The use of ethacrynic ac id and, to a Jesser extent, furosemide has been associated with ototoxicity which is usually transient but has been implicated in permanent hearing
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Joss. 10 • 11 The risk with either agent appears to be increased in patients with renal insufficiency, especially when intensive therapy with high doses is used. Other side effects, similar to those of thiazides, may occur, ie, hyperuricemia and azotemia due to a decrease in circulating blood volume and decreased glomerular filtration rate. There have been a few reports of altered carbohydrate metabolism, but the incidence is even Jess than is seen with thiazides. As with many other drugs, various idiosyncratic reactions have been reported. Potassium-sparing agents-These agents act on the distal tubule to increase sodium excretion minimally while conserving potassium and hydrogen by inhibiting the cation exchange pump; thus, the term ''potassiumsparing diuretics.'' The diuretic properties of spironolactone result from its structural similarity to aldosterone, which enables it to competitively inhibit binding of aldosterone to cellular receptors, preventing aldosterone stimulation of distal sodium reabsorption. Triamterene, which is chemically unrelated, also interferes with sodium reabsorption and excretion of potassium and hydrogen ions in the distal nephron but exerts its effect even in the absence of aldosterone. 9 • 12 These agents are most useful when administered concomitantly with diuretics that act proximal to the site of sodium-potassium exchange in the distal tubule. Their principal advantage is reduction of the potassium Joss induced by the more patent, proximally acting diuretics. Thus, they may potentiate the effectiveness of organomercurials, thiazides, or loop diuretics. Spironolactone is especially useful in combination with other diuretics in clinical states with secondary hyperaldosteronism, such as chronic congestive heart failure, the nephrotic syndrome, or cirrhosis with refractory tluid retention. In hypertensive patients treated chronically with thiazide diuretics, potassium-sparing agents may be added to the regimen if avoidance of hypokalemia seems desirable, particularly if digitalis glycosides are also being given. Patients with chronic, decompensated cirrhosis and portal hypertension are exquis-
Vol. 59 • No. 5o May 1976 o POSTORADUATE MEDICINE
Donald G. Vidt Dr. Vidt is head of the section of clinical hypertension and nephrology, The Cleveland Clinic Foundation, Cleveland.
itely sensitive to the kaliuretic effects of diuretics. Hepatic encephalopathy or coma may be precipitated or aggravated by uncontrolled hypokalemia. I consider the major potential complication with these agents to be hyperkalemia from drug-induced inhibition of potassium excretion in patients with normal or increased potassium intake. Hyperkalemia is likely to occur in patients with impaired renal function, a condition I considera contraindication to the use of potassium-sparing agents, al one or in conjunction with other diuretics. Use oftriamterene may be associated with gastrointestinal disturbances, while longterm use of spironolactone can result in gynecomastia in men or menstrual disturbances in women. Interaction of Diuretlcs With Other Drugs
Treatment of complex medical problems often necessitates the use of severa! drugs, and the clinician must be aware of documented and potential drug interactions. The interaction of thiazides and loop diuretics with digitalis glycosides is weil documented. The electrolyte disturbances, particularly hypokalemia, produced by these kaliuretic agents sensitize the myocardium to the effects of digitalis, so that an otherwise normal maintenance dose can produce digitalis toxicity, resulting in a potentially fatal arrhythmia or apparently refractory heart failure. The potassium-sparing agents spironolactone and triamterene could theoretically inhibit the action of the cardiac glycosides on the heart. In the treatment of hypertension, diuretics
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potentiate the effect of the vasodilating agents or sympathetic inhibiting agents-probably through a subtle decrease in circulating blood volume and reduction in vascular reactivity-and permit control of blood pressure with smaller doses of more patent agents. It is weil recognized that all vasodilating agents and ali sympathetic inhibiting agents, except propranolol, cause plasma volume expansion that may counteract their antihypertensive effect. The apparent resistance that often develops with the use of these agents alone is really a pseudoresistance that can be prevented by administration of a diuretic in sufficient dosage ta prevent plasma volume expans10n. In diabetes, the interaction of oral hypoglycemie agents or insulin with kaliuretic diuretics is recognized. 13 The production of hypokalemia is probably an essentia) step in the development of hyperglycemia. Likewise, uricosuric drugs may interact with ali thiazides, furosemide, or ethacrynic acid. Thiazide produces hyperuricemia either directly by competitively inhibiting urie acid secretion or indirectly by enhancing renal tubular reabsorption of urie acid .14 There are a number of other, Jess wellrecognized drug interactions. Carbonic anhydrase inhibitors and thiazides render the urine alkaline, resulting in an increased proportion of un-ionized drugs, such as amphetamines, quinidine, and tricyclic antidepressants.15 Renal tubular reabsorption of these agents is enhanced and serum levels may be increased. During therapy with methenamine compounds, urinary pH must be kept below 5.5 ta effect conversion of methenamine ta free formaldehyde. Nitrofurantoins are also more active in an acid urine. Thus, diuretics that render" the urine alkaline may have an effect on the function of these urinary chemotherapeutic agents. Thiazide diuretics and turosemide reportedly increase responsiveness ta nondepolarizing muscle relaxants such as tubocurarine and gallamine.
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Ethacrynic acid should be administered with caution ta patients on warfarin anticoagulants, because it has been shawn in vitro ta displace warfarin from human albumin binding sites, 16 an interaction which may be important clinically. Ethacrynic acid may also potentiate the risk of ototoxicity when given with aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, streptomycin). Impaired renal function enhances the danger of nerve deafness when these agents are used, alone or in combination. Aspirin has been proposed ta displace spironolactone as a competitor with aldosterone for receptor sites in the distal renal tubule, with a resultant reversai of the natriuresis produced by spironolactone. Conclusions
It is apparent that the large number of diuretics available today enables the clinician ta mobilize edema fluid from patients with heart failure or other fluid retention states, ta control blood pressure effectively in many pa" tients with hypertension, and ta manage many nonedematous states more successfully. The potency of sorne of these agents and their varied effects on renal tubular transport necessitate a cautious approach based on an understanding of their mechanisms of action. By selectively choosing different diuretics or diuretic combinations, the clinician can achieve the desired diuretic effect and prevent many of the electrolyte and acid-base derangements th at accompany diuretic therapy. Selectivity of usage based on knowledge of the practical clinical pharmacology of these agents will also minimize the occurrence of side effects and avoid undesirable drug Interactions. • Address reprint requests ta Donald G. Vidt, MD, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation. 9500 Euclid Ave, Cleveland, OH 44106. ReadySource on cardiovascular therapeutics appears on page 194.
CME Credit Quiz on cardiovascular therapeutics begins on page 201.
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References 1. Goldberg M, Ramirez MA: Effects of saline and mannitol diuresis on the renal concentrating mechanism in dogs: Alterations in renal tissue solutes and water. Clin Sei Mol Med 32:475-493. 1967 2. Velasquez MT. Notargiacomo AV. Cohn 1N: Comparative effects of saline and mannitol on renal cortical blood flow and volume in the dog. Am 1 Physiol224:322, 1973 3. Gennari F1, Kassirer 1P: Osmotic diuresis. N Engl1 Med 291:714-720. 1974 4. Maren TH: Carbonic anhydrase: Chemistry. physiology. and inhibition. Physiol Rev 47:595-781. 1967 5. Levitt MF, Goldstein MH. Lenz PR. et al: Mercurial diuretics. Ann NY Ac ad Sei 139:375-387, 1966 6. Paloyan E, Farland M. Pickleman 1R: Hyperparathyroidism coexisting with hypertension and prolonged thiazide administration. 1AMA 210: 1243, 1969 7. Maninez-Maldonado M. Eknoyan G. Suki WN: Diuretics in nonedematous states: Physiologie basis for the clinical use. Arch Intern Med 131:797-808. 1973 8. Kim KE, Onesti G. Moyer 1H, et al: Ethacrynic acid and furosemide: Diuretic and hemodynamic effects and clinical uses. Am 1 Cardial 27:407-415. 1971
9. Frazier HS, Yager H: The clinical use of diuretics. N Engl 1 Med 288:455-457, 1973 1O. Meriwether WD, Mangi R1. Serpick AA; Deafness following standard intravenous dose of ethacrynic acid. 1AMA 216:795-798. 1971 Il. Lloyd-Mostyn RH. Lord 11: Ototoxicity of intravenous frusemide. Lance! 2:1156-1157. 1971 12. Liddle GW: Aldosterone antagonists and triamterene. Ann NY Acad Sei 139:466-470, 1966 13. Rapoport Ml, Hurd HF: Thiazide-induced glucose intolerance treated with potassium. Arch ln te rn Med 113:405-409, 1964 14. Steele TH, Oppenheimer S: Factors affecting urate excretion following diuretic administration in man. Am 1 !VIed 47:564-574, 1969 15. Gerhardt RE, Knouss RF. Thyrum PT. et al: Quinidine excretion in aciduria and alkaluria. Ann Intem Med 71 :927-933. 1969 16. Sellers EM, Koch-Weser 1: Displacement of warfarin from human albumin by diazoxide and ethacrynic, mefenamic, and nalidixic ac ids. Clin Pharmacol Ther Il :524529, 1970
COMINGIN---------------------
COM ING IN---------------------
ipma annals
diet and health
from the 60th annual postgraduate medical assembly
Postmenopausal Gynecology Edward A. Banner, MD Mayo Clinic and Mayo Foundation Rochester, Minnesota
Vol. 59 o No. 5 o May 1976 • POSTGRADUATE MEDICINE
special series
Diet in the Cause and Management of Gastrointestinal Diseases Robert C. Dunkerley, MD G. Dewey Dunn, MD Frederick A. Wilson, MD Veterans Administration Hospital Nashville, Tennessee
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Diuretics Donald G. Vidt MD To cite this article: Donald G. Vidt MD (1976) Diuretics, Postgraduate Medicine, 59:5, 143-151, DOI: 10.1080/00325481.1976.11714362 To link to this article: http://dx.doi.org/10.1080/00325481.1976.11714362
Published online: 07 Jul 2016.
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Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [FU Berlin]
Date: 16 January 2017, At: 02:28
• The introduction in 1958 of chlorothiazide as the first truly effective oral diuretic marked the onset of a new era in the treatment of edematous conditions and hypertension. Diuretics are now among the most commonly used therapeutic agents. The development of new, more patent agents has increased the complexity of management. The clinician must understand the mechanisms by which diuretics exert their effects and the pathologie conditions under which they can be used and must appreciate their potential disadvantages, side effects, and interactions with other drugs. Action of Diuretics on the Kidney
The four major sites of diuretic action along the nephron are the proximal tubule, the medullary and cortical segments of the thick ascending limb of Henle's loop, and the distal tubule (figure 1). Proximal tubule-In the proximal tubule, 60% ta 75% of the glomerular filtrate is reabsorbed isotonically (ie, sodium and other solutes move with water in isotonie proportions). Amino acids, glucose, and much of the calcium and phosphorus are also reabsorbed at this site. Thus, quantitatively, proximal tubular function is very significant. Inhibition of net proximal tubular transport does not increase urine flow ta the degree that might be expected, because the portion of nephron distal ta the proximal tubule has a high reserve capacity, permitting it, when necessary, ta reabsorb a larger-than-normal amount of sodium and chloride. Thus, inhibition of distal transport mechanisms generally produces more effective diuresis than can be accomplished at the proximal site. Ascending limb of Henle' s loop-The ascending limb of Henle's loop is responsible for reabsorption of approximately 15% ta 30% of the filtered Joad. Sodium chloride is actively transported from the tubular lumen of the medullary segment of the thick ascending limb, which is relatively impermeable ta water. Studies have suggested that active transport of chloride is the key process here and is possibly coupled with transport of 1 sodium. The same basic process occurs in bath the medullary and the cortical segments of the thick ascending limb. However, transport inhibition will have very different consequences on the final concentration of urine, depending on the segment in which the inhibition occurs. ~
Vot. 59 o No. 5o May 1976 o POSTGRADUATE MEDICINE
diuretics use and misuse Donald G. Vidt, MD The Cleveland Clinic Foundation Cleveland
con si der What are the major sites of diuretic action along the nephron? What are the pathologie conditions for which specifie diuretics may be effective? What are the most serious side effects of diuretics?
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Figure 1. Major sites of diuretic action along the nephron: proximal tubule (1 ), medullary segment of the thick ascending limb of Henle's loop (2), cortical segment of the thick ascending limb of Henle's loop (3), and distal tubule (4).
Solute reabsorption from the medullary thick ascending limb leads to dilution oftubular contents, while deposition of sodium chloride in the interstitium without an osmotically equivalent amount of water produces a hypertonie medullary interstitium. Fluid passing dawn the collecting duct will osmotically equilibrate with the hypertonie medullary interstitium and form concentrated urine under the influence of antidiuretic hormone. Interference with the function of the medullary segment of thick ascending limb results in inability to concentrate the urine. Henle's loop emerging into the cortex contains a dilute tubular fluid which is further diluted in the cortical segment of the thick ascending limb by further outward transport of sodium chloride without water. Inhibition of sodium reabsorption at this site would impair the ability to form a maximally dilute urine.
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Distal tubule-The dilute tubular fluid passes to the distal convoluted tubule. Under the influence of aldosterone, sodium is reabsorbed at this site in exchange for potassium or hydrogen ions. Whether potassium or hydrogen is secreted for each absorbed sodium ion is dictated by the patient's acid-base balance and serum potassium concentration. Inhibition of this ion exchange pump leads to increased sodium loss, while potassium and hydrogen are conserved. Cllnical Implications of Dluretlc Therapy
For purposes of this discussion, diuretics are grouped into six categories: osmotic agents, carbonic anhydrase inhibitors, organomercurials, thiazides and related sulfonamide derivatives, furosemide and ethacrynic acid (loop diuretics), and potassiumsparing agents (distal tubular diuretics). Table l outlines the preparations available and the
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dosages which are usually administered. Osmotic diuretics-Mannitol is the prototype of the osmotic agents. Under normal physiologie conditions its principal site of action is the proximal tubule, where it osmotically prevents the normal obligatory reabsorption of filtrate. Experimental studies 1 • 2 have demonstrated an increase in the medullary blood flow during mannitol diuresis and a marked reduction in medullary hypertonicity. Reduction in interstitial solute concentration reduces the driving force for water reabsorption in the descending limb of Henle's loop, thus allowing a larger volume offiltrate to reach the distal tubule and collecting duct. Here, the higher flow rate of filtrate, the restraining effect of mannitol, and reduced medullary interstitial concentration combine to decrease the water and sodium reabsorption at these distal sites. The major use of mannitol toda y is in states of acute renal insufficiency, law renal perfusion, or both. Mannitol is effective in restoring glomerular filtration rate during and after transient hypotension and is often used prophylactically where hypotension or sudden reduction in renal perfusion can be anticipated. A high concentration of mannitol in the extracellular fluid compartment and the accompanying increased osmolality induce a shift of water from the cells ta expand the volume and dilute the sodium concentration of the extracellular fluid. The clinical implications of a sudden shift in water may be significant. Pulmonary edema may be precipitated in patients with incipient cardiac failure. Even when underlying heart disease is absent, administration of large amounts of mannitol ta patients with oliguria and acute tubular necrosis or obstructive uropathy may lead ta pulmonary congestion. 3 In patients with oligurie renal failure who have received large amounts of mannitol, significant increase in plasma osmolality may occur and hyponatremia secondary ta water redistribution may be misinterpreted. Carbonic anhydrase inhibitors-These agents prevent the generation and tubular secretion of hydrogen ions in the proximal
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tubule, thereby also reducing sodium reabsorption. The result is less hydrogen ion formation and increased loss of potassium in the distal tubule. 4 Acetazolamide is the most commonly used carbonic anhydrase inhibitor. It is relatively nontoxic, but its value is limited by law potency and the rapid development of tolerance by patients receiving it for more than 48 hours. Carbonic anhydrase inhibitors may be particularly useful as adjunctive therapy in correcting metabolic alkalosis by providing increased bicarbonate excretion and may be used ta potentiate the effectiveness of organomercurials, thiazides, furosemide, ethacrynic ac id, or spironolactone. When used for these purposes they are best administered intermittently for one or two days each week. They may be used as an adjunct in the treatment of acute hyperuricemia or in the chemotherapy of hematopoietic neoplasms. Where high rates of urie acid excretion may be anticipated, an alkaline urine should be encouraged since alkalinity greatly increases the solubility of urie acid. Organomercurial diuretics-Although the organomercurials are nonselective inhibitors binding ta most sulfhydryl-containing proteins within renal tubular cells, their main effect is exerted via inhibition of sodium and chloride reabsorption in the medullary and cortical segment of the thick ascending limb ofHenle's loop. 5 Ta a lesserextent, the cation exchange pump in the distal tubule is inhibited and the diuresis produced may not carry the degree ofkaliuresis associated with patent diuretics, such as ethacrynic acid or furosemide. Several disadvantages have limited the use of organomercurials in recent years, and they are rarely used today. They are less effective in achieving diuresis in congestive heart failure than furosemide or ethacrynic acid, they must be administered intramuscularly, and they are not effective in metabolic alkalosis. Organomercurials should not be administered intravenously because instances of sudden death, presumably of cardiac origin, have been reported. Their repeated use in patients
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lt is generally agreed that a diuretic agent should be included in every antihypertensive regimen.
table 1. classification of diuretics used in clinical practice Type of agent
Generic name
Commercial preparation
Usualdaily dosage (oral)
Osrnotlc dluretlc
Mannitol
Osmitrol
25-100 gm• (IV)
Carbonic anhydrase inhlbitor
Acetazolamide
Diamox
250-500 mg
Organomercurlal diu retie
Mercaptomerin
Thiomerin
1-2 ml (lM)
Diuril
250-1 ,500 mg
Thiazlde and related sulfonamlde derivatives Benzothiadiazine compounds
Chlorothiazide Hydrochlorothiazide
Bendroflumethiazide Methyclothiazide Hydroflumethiazide Benzthiazide Polythiazide Cyclothiazide Trichlormethiazide Phlhaiimidine compound Quinazoline compounds Loop dluretlcs Anlhranilic acid compound (sulfonamide derivative) Phenoxyacelic acid derivative Potasslum-sparlng agents (distal tubule diuretics)
Esidrix } HydroDiuril Oretic Naturetin
25-150 mg 5-15 mg
Aquatensen} Enduron
5-15 mg
Diucardin} Saluron Exna Renese Anhydron
26-150 mg 25-150 mg 2-B mg 2-6 mg 2-B mg
Chlorthalidone
Metahydrin} Naqua Hygroton
Quinelhazone Metolazone
Hydromox Zaroxolyn
50-150 mg 2.5-10 mg
Furosemide
Las ix
40 mg-1 gm (or more)
Ethacrynic acid
Edecrin
50 mg-1 gm (or more)
Spironolactone Triamterene
Aldactone Dyrenium
50-200 mg 100-200 mg
50-100 mg
*5%-25% solutions available.
with rel1,jll insufficiency may lead to mercurial toxicity. The renal failure and hemorrhagic cystitis that have been reported with repeated use are probably consequences of heavymetal poisoning, which results from continued administration when renal excretion is impaired. Failure to achieve a diuretic response with an organomercurial should signal the clinician to stop administration of the drug, search for an explanation for the therapeutic failure, and consider other diuretic agents.
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Thiazides and related sulfonamide derivatives-The principal inhibitory effect of these agents is on the cortical segment of the thick ascending limb of Henle's loop. Thiazides also have a carbonic anhydrase inhibitory action which is of little clinical signifie ance. Chlorothiazïde is the prototype of this group of diuretics. The many derivatives developed subsequently are more patent by weight but appear not ta have more diuretic potency or a greater margin of safety, when used in recommended dosages, than does chlorothiazide. Adverse effects-Thiazides have been associated with a large variety of adverse effects, sorne of little clinical importance. The most significant are electrolyte abnormalities: metabolic alkalosis, hypokalemia, and hyponatrernia. Metabolic alkalosis due ta chloride and potassium depletion (hypochloremichypokalemic alkalosis) occurs secondary ta increased delivery of sodium ta the distal tubule, where increased exchange of sodium for potassium occurs under the influence of aldosterone. The resultant hypokalemia increases proximal reabsorption of bicarbonate, further aggravating the existing alkalosis. Thiazides are usually administered in edematous states, such as congestive heart failure, nephrotic syndrome, and hepatic cirrhosis with ascites, and in the presence of secondary hyperaldosteronism, conditions under which sensitivity of the distal tubule ta increased sodium delivery may be increased. Metabolic alkalosis secondary ta increased water excretion (contraction alkalosis) pla ys a raie in perpetuating alkalosis secondary ta thiazide administration. Patients with alkalosis and volume contraction require restriction offluid volume and appropriate electrolyte replacement. Occasionally, ammonium chloride may be needed ta correct the alkalosis. Hypokalemia secondary ta thiazide administration may induce myocardial irritability in patients with myocardial disease. Appropriate measures should be taken ta prevent hypokalemia during diuretic therapy in these
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patients, and serum potassium levels should be monitored at regular intervals. Hyponatremia, although much more cornmon in association with the patent loop diuretics, may be induced by prolonged use of thiazide diuretics. It is usually of dilutional type, due to impaired free water clearance and unrestricted fluid intake. Serum sodium concentration is law, but total body sodium is generally increased. Therefore, differentiatian of dilutional hyponatremia from a sodium depletion state due to profuse diuresis is important, since appropriate therapy of the two conditions is quite different. Thiazide diuretics may cause hyperuricemia, mainly due to volume contraction and increased proximal reabsorption of urie acid. Inhibition of urie acid secretion may also be a factor. The rise in blood urea nitrogen leve! results from volume contraction and decreased glomerular filtration rate and is most apparent in patients with marginal renal reserve function. Asymptomatic hyperuricemia düring chronic therapy with thiazides does not require specifie treatment. If gout develops, allopurinol is added to the regimen, plus colchicine to control acute symptoms. Sorne clinicians prefer to add allopurinol if the urie acid leve! exceeds 10 mg/100 ml. Hypercalcemia may be attributed in part to volume contraction with increased proximal reabsorption of calcium. Thiazides also appear to potentiate the renal effects of parathormone on calcium reabsorption. 6 • 7 Photosensitivity is a rare side effect of the sulfonamide diuretics, ie, thiazides, chlorthalidone, quinethazone, metolazone, and the loop diuretic furosemide. Significant hyperglycemia, also rare, is an indirect effect of chronic volume depletion, since it results in part from hypokalemia. Neither diabetes nor goutis a contraindication to the use of a thiazide diuretic. Suitable dietary manipulations and prevention of hypokalemia will usually prevent undue hyperglycemia in the diabetic patient, and allopurinol should be included in the regimen of patients with gout. Other side effects of minor consequence
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include gastrointestinal irritation, weakness, oral sensation of dry mou th or bad tas te, leukopenia, thrombocytopenia, pancreatitis, purpura without thrombocytopenia, and skin rash. Benefits of chronic use-The modest volume contraction produced with chronic use of the thiazides may have salutary effects in sorne nonedematous states. 7 In nephrogenic diabetes insipidus, thiazides may reduce urinary volume by as much as 50%. The glomerular filtration rate is decreased with increased proximal reabsorption of filtrate, Jess filtrate reaches the distal reabsorption sites, and thus, Jess water is excreted. Decreased calcium excretion may be beneficiai in the treatment ofhypercalciuria. In the therapy of renal tubular acidosis (proximal type), the volume contraction produced by thiazides reduces the bicarbonate leak, thus partially restoring serum bicarbonate levels. Use in hypertension-Thiazides are the primary diuretics used in treatment of hypertension. They, as weil as the other oral diuretics, reduce blood pressure by depleting the volume of plasma and of extracellular fluid initially. With chronic use, they appear to reduce vascular reactivity to sympathetic stimulation, which prevents the sympathetic nervous system from compensating for a small but definite reduction in plasma volume. It is generally agreed that a diuretic agent should be included in every antihypertensive regimen. In uncomplicated mild or moderate hypertension, it may be the only agent needed to normalize blood pressure. Hypokalemia may occur in antihypertensive therapy with thiazide diuretics but is generally not significant enough to require replacement therapy. If the serum potassium leve! falls below 3 mEq/liter or if symptoms occur that are attributable to hypokalemia, such as weakness or muscle cramping, the clinician may give supplemental potassium, add a potassium-sparing diuretic to the regimen, or restrict sodium intake to further minimize potassium Joss at the distal tubular exchange site. Furosemide and ethacrynic acid ( loop
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Because of their potency and rapid onset of action, loop diuretics are particularly useful in situations where fluid overload poses an immediate threat.
diuretic s)-These agents are dissimilar in structure but are considered together because of their similarity in physiologie action. Both are potent diuretics, theireffect resulting from inhibition of sodium reabsorption in the medullary and cortical segments of the thick ascending limb of Henle's Joop. 8 • 9 When the filtered Joad is adequate, diuresis may be massive and the increased sodium delivered to the aldosterone-sensitive distal tubule may induce large !osses of potassium. Both agents are relatively effective, even in the presence of underlying electrolyte or acid-base imbalance. Therefore, diuresis can be expected, if dosage is sufficient, in patients with metabolic or respiratory acidosis, or in patients with hyponatremia, hypokalemia, or hypochloremia. Since the Joop diuretics inhibit sodium reabsorption in both segments of the thick ascending limb of Henle's loop, they inhibit the maximal diluting and concentrating ability of the kidney. Thus, both agents reduce the capacity of the kidney to regulate tonicity of body fluids and subject the patient to risks resulting from an imbalance between volume of water ingested and that needed to cover solute excretion and insensible !osses. The clinical implications are such that neither agent should be the initial diuretic used unless short-term benefits outweigh the potential clinical consequences of massive diuresis. Because oftheir potency and rapid onset of action, these agents are particularly useful in situations where fluid overload poses an immediate threat. In the patient with acute left ventricular failure, for example, 40 to 80 mg offurosemide given intravenously can make a significant difference in outcome. Diuresis ensues within minutes, peaks in 30 minutes to two hours, and is an important adjunct to digitalis and other measures in the treatment of this medical emergency. The broad dose-related response to these agents also makes them useful in conditions, including renal insufficiency, where the filtered Joad of sodium is greatly reduced. Should the thiazides or other diuretics fail to produce diuresis, a Joop diuretic may be substituted. In patients with refractory edema,
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doses of both ethacrynic acid and furosemide exceeding 1.0 gm/day have been used. For patients requiring longer term therapy, intermittent administration may effectively promote negative sodium balance and minimize the risks of severe electrolyte abnormalities. In a few patients with refractory anasarca, the effect of furosemide or ethacrynic acid on sodium excretion may be potentiated by concomitant administration of a thiazide, carbonic anhydrase inhibitor, organomercurial, or spironolactone. The potential for producing significant electrolyte imbalance poses a real danger with the use of high doses of loop diuretics, particularly in the long-term management of patients with chronic congestive heart failure or other refractory edematous states. Dilutional hyponatremia should be suspected when a patient who stiJl has obvious fluid retention stops responding to the diuretic. Serum sodium concentration is usually below 130 mEq/Jiter, and dilutio-nal reduction in serum proteins and red cell volume is evident. Water intake should be restricted and diuretic therapy suspended until the serum sodium value ri ses to at !east 135 mEq/liter. Chronic sodium and fluid volume depletion may be produced by a combination of overly rigorous sodium restriction and chronic therapy with potent loop diuretics. Serum sodium concentration is very low (Il 0 to 120 mEq/Jiter) and azotemia is usually present. Patients are hypotensive, lethargie, confused, and dehydrated and require careful replacement of sodium chloride and water for restoration of effective circulating volume. In the evaluation of acute urinary suppression (oliguria), furosemide has been used to help distinguish between ischemie tubular necrosis and prerenal azotemia with oliguria. Furosemide given intravenously in a dose of 40 to 80 mg, with or without a concomitant test dose of mannitol, may produce a rise in urinary volume when oliguria has a prerenal basis. The use of ethacrynic ac id and, to a Jesser extent, furosemide has been associated with ototoxicity which is usually transient but has been implicated in permanent hearing
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Joss. 10 • 11 The risk with either agent appears to be increased in patients with renal insufficiency, especially when intensive therapy with high doses is used. Other side effects, similar to those of thiazides, may occur, ie, hyperuricemia and azotemia due to a decrease in circulating blood volume and decreased glomerular filtration rate. There have been a few reports of altered carbohydrate metabolism, but the incidence is even Jess than is seen with thiazides. As with many other drugs, various idiosyncratic reactions have been reported. Potassium-sparing agents-These agents act on the distal tubule to increase sodium excretion minimally while conserving potassium and hydrogen by inhibiting the cation exchange pump; thus, the term ''potassiumsparing diuretics.'' The diuretic properties of spironolactone result from its structural similarity to aldosterone, which enables it to competitively inhibit binding of aldosterone to cellular receptors, preventing aldosterone stimulation of distal sodium reabsorption. Triamterene, which is chemically unrelated, also interferes with sodium reabsorption and excretion of potassium and hydrogen ions in the distal nephron but exerts its effect even in the absence of aldosterone. 9 • 12 These agents are most useful when administered concomitantly with diuretics that act proximal to the site of sodium-potassium exchange in the distal tubule. Their principal advantage is reduction of the potassium Joss induced by the more patent, proximally acting diuretics. Thus, they may potentiate the effectiveness of organomercurials, thiazides, or loop diuretics. Spironolactone is especially useful in combination with other diuretics in clinical states with secondary hyperaldosteronism, such as chronic congestive heart failure, the nephrotic syndrome, or cirrhosis with refractory tluid retention. In hypertensive patients treated chronically with thiazide diuretics, potassium-sparing agents may be added to the regimen if avoidance of hypokalemia seems desirable, particularly if digitalis glycosides are also being given. Patients with chronic, decompensated cirrhosis and portal hypertension are exquis-
Vol. 59 • No. 5o May 1976 o POSTORADUATE MEDICINE
Donald G. Vidt Dr. Vidt is head of the section of clinical hypertension and nephrology, The Cleveland Clinic Foundation, Cleveland.
itely sensitive to the kaliuretic effects of diuretics. Hepatic encephalopathy or coma may be precipitated or aggravated by uncontrolled hypokalemia. I consider the major potential complication with these agents to be hyperkalemia from drug-induced inhibition of potassium excretion in patients with normal or increased potassium intake. Hyperkalemia is likely to occur in patients with impaired renal function, a condition I considera contraindication to the use of potassium-sparing agents, al one or in conjunction with other diuretics. Use oftriamterene may be associated with gastrointestinal disturbances, while longterm use of spironolactone can result in gynecomastia in men or menstrual disturbances in women. Interaction of Diuretlcs With Other Drugs
Treatment of complex medical problems often necessitates the use of severa! drugs, and the clinician must be aware of documented and potential drug interactions. The interaction of thiazides and loop diuretics with digitalis glycosides is weil documented. The electrolyte disturbances, particularly hypokalemia, produced by these kaliuretic agents sensitize the myocardium to the effects of digitalis, so that an otherwise normal maintenance dose can produce digitalis toxicity, resulting in a potentially fatal arrhythmia or apparently refractory heart failure. The potassium-sparing agents spironolactone and triamterene could theoretically inhibit the action of the cardiac glycosides on the heart. In the treatment of hypertension, diuretics
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potentiate the effect of the vasodilating agents or sympathetic inhibiting agents-probably through a subtle decrease in circulating blood volume and reduction in vascular reactivity-and permit control of blood pressure with smaller doses of more patent agents. It is weil recognized that all vasodilating agents and ali sympathetic inhibiting agents, except propranolol, cause plasma volume expansion that may counteract their antihypertensive effect. The apparent resistance that often develops with the use of these agents alone is really a pseudoresistance that can be prevented by administration of a diuretic in sufficient dosage ta prevent plasma volume expans10n. In diabetes, the interaction of oral hypoglycemie agents or insulin with kaliuretic diuretics is recognized. 13 The production of hypokalemia is probably an essentia) step in the development of hyperglycemia. Likewise, uricosuric drugs may interact with ali thiazides, furosemide, or ethacrynic acid. Thiazide produces hyperuricemia either directly by competitively inhibiting urie acid secretion or indirectly by enhancing renal tubular reabsorption of urie acid .14 There are a number of other, Jess wellrecognized drug interactions. Carbonic anhydrase inhibitors and thiazides render the urine alkaline, resulting in an increased proportion of un-ionized drugs, such as amphetamines, quinidine, and tricyclic antidepressants.15 Renal tubular reabsorption of these agents is enhanced and serum levels may be increased. During therapy with methenamine compounds, urinary pH must be kept below 5.5 ta effect conversion of methenamine ta free formaldehyde. Nitrofurantoins are also more active in an acid urine. Thus, diuretics that render" the urine alkaline may have an effect on the function of these urinary chemotherapeutic agents. Thiazide diuretics and turosemide reportedly increase responsiveness ta nondepolarizing muscle relaxants such as tubocurarine and gallamine.
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Ethacrynic acid should be administered with caution ta patients on warfarin anticoagulants, because it has been shawn in vitro ta displace warfarin from human albumin binding sites, 16 an interaction which may be important clinically. Ethacrynic acid may also potentiate the risk of ototoxicity when given with aminoglycoside antibiotics (kanamycin, gentamicin, neomycin, streptomycin). Impaired renal function enhances the danger of nerve deafness when these agents are used, alone or in combination. Aspirin has been proposed ta displace spironolactone as a competitor with aldosterone for receptor sites in the distal renal tubule, with a resultant reversai of the natriuresis produced by spironolactone. Conclusions
It is apparent that the large number of diuretics available today enables the clinician ta mobilize edema fluid from patients with heart failure or other fluid retention states, ta control blood pressure effectively in many pa" tients with hypertension, and ta manage many nonedematous states more successfully. The potency of sorne of these agents and their varied effects on renal tubular transport necessitate a cautious approach based on an understanding of their mechanisms of action. By selectively choosing different diuretics or diuretic combinations, the clinician can achieve the desired diuretic effect and prevent many of the electrolyte and acid-base derangements th at accompany diuretic therapy. Selectivity of usage based on knowledge of the practical clinical pharmacology of these agents will also minimize the occurrence of side effects and avoid undesirable drug Interactions. • Address reprint requests ta Donald G. Vidt, MD, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation. 9500 Euclid Ave, Cleveland, OH 44106. ReadySource on cardiovascular therapeutics appears on page 194.
CME Credit Quiz on cardiovascular therapeutics begins on page 201.
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References 1. Goldberg M, Ramirez MA: Effects of saline and mannitol diuresis on the renal concentrating mechanism in dogs: Alterations in renal tissue solutes and water. Clin Sei Mol Med 32:475-493. 1967 2. Velasquez MT. Notargiacomo AV. Cohn 1N: Comparative effects of saline and mannitol on renal cortical blood flow and volume in the dog. Am 1 Physiol224:322, 1973 3. Gennari F1, Kassirer 1P: Osmotic diuresis. N Engl1 Med 291:714-720. 1974 4. Maren TH: Carbonic anhydrase: Chemistry. physiology. and inhibition. Physiol Rev 47:595-781. 1967 5. Levitt MF, Goldstein MH. Lenz PR. et al: Mercurial diuretics. Ann NY Ac ad Sei 139:375-387, 1966 6. Paloyan E, Farland M. Pickleman 1R: Hyperparathyroidism coexisting with hypertension and prolonged thiazide administration. 1AMA 210: 1243, 1969 7. Maninez-Maldonado M. Eknoyan G. Suki WN: Diuretics in nonedematous states: Physiologie basis for the clinical use. Arch Intern Med 131:797-808. 1973 8. Kim KE, Onesti G. Moyer 1H, et al: Ethacrynic acid and furosemide: Diuretic and hemodynamic effects and clinical uses. Am 1 Cardial 27:407-415. 1971
9. Frazier HS, Yager H: The clinical use of diuretics. N Engl 1 Med 288:455-457, 1973 1O. Meriwether WD, Mangi R1. Serpick AA; Deafness following standard intravenous dose of ethacrynic acid. 1AMA 216:795-798. 1971 Il. Lloyd-Mostyn RH. Lord 11: Ototoxicity of intravenous frusemide. Lance! 2:1156-1157. 1971 12. Liddle GW: Aldosterone antagonists and triamterene. Ann NY Acad Sei 139:466-470, 1966 13. Rapoport Ml, Hurd HF: Thiazide-induced glucose intolerance treated with potassium. Arch ln te rn Med 113:405-409, 1964 14. Steele TH, Oppenheimer S: Factors affecting urate excretion following diuretic administration in man. Am 1 !VIed 47:564-574, 1969 15. Gerhardt RE, Knouss RF. Thyrum PT. et al: Quinidine excretion in aciduria and alkaluria. Ann Intem Med 71 :927-933. 1969 16. Sellers EM, Koch-Weser 1: Displacement of warfarin from human albumin by diazoxide and ethacrynic, mefenamic, and nalidixic ac ids. Clin Pharmacol Ther Il :524529, 1970
COMINGIN---------------------
COM ING IN---------------------
ipma annals
diet and health
from the 60th annual postgraduate medical assembly
Postmenopausal Gynecology Edward A. Banner, MD Mayo Clinic and Mayo Foundation Rochester, Minnesota
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special series
Diet in the Cause and Management of Gastrointestinal Diseases Robert C. Dunkerley, MD G. Dewey Dunn, MD Frederick A. Wilson, MD Veterans Administration Hospital Nashville, Tennessee
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