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The Pharmacology of Newer Diuretics

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The Pharmacology of Newer Diuretics View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by VCU Scholars Compass The Pharmacology of Newer Diuretics ALBERT J. WASSERMAN Department of Medicine, Medical College of Virginia, Richmond Diuretics continue to be among The problem is one of developing the commonest of all prescribed circulatory collapse, shock. The items. Until recently, the physician only treatment advisable then is needed to have little concern about the infusion of salt-poor albumin. the dose of the agent he was choos­ Such episodes have been reported ing because firstly, the dose-re­ with some real frequency. The sponse curve tended to be startl­ problem of inducing excessive po­ ingly flat, and secondly, there was tassium loss is primarily related to little chance of inducing an exces­ the patient who is also taking di­ sive diuresis, regardless of dose. gi talis and who becomes much Now that furosemide (Lasix) and more susceptible to the ectopic ac­ ethacrynic acid (Edecrin) have be­ tivity of the cardiac glycosides. Hy­ come available, we find that one pochloremia will induce diuretic must indeed titrate the dose to the refractoriness to mercurials, but particular patient, and must appre­ not to these new agents. In spite of ciate for the first time the compli­ electrolyte derrangements and in cations which can result from an spite of reduction in renal blood excessive diuresis. Finally, with the flow, furosemide and ethacrynic availability of triamterene and MK- acid will continue to exert diuretic 870 ( Colectril, not yet available), effects. Hyponatremia may develop, one must appreciate the import­ particularly in the patient who is ance of the distal tubular mechan­ having a marked saluresis and who ism for potassium for sodium ex­ replaces the volume with tap water. change. The additive effect of these The cause of muscle cramps, the exchange inhibitors can be of con­ weakness, the "washed-out" feel­ siderable clinical usefulness. ing, is still not clear, but the symp­ toms are well-recognized in pa­ Adverse Effects of Diuretics tients in whom a marked prompt diuresis ensues. The relationship to Figure 1 illustrates the excessive thrombosis and the development of diuresis which can result from the gout are not clear, but there is newer, more potent diuretics. This some circumstantial evidence sug­ R_atient was hospitalized and started gesting that these can occur during on what seemed like a reasonable diuresis. In summary, one must dose of ethacrynic acid, but she avoid having too rapid and too lost 35 pounds in four days. For­ massive a diuresis. tunately, this patient had no ad­ Table 2 suggests some measures verse effects, but this is the very to avoid adverse effects of diuretics. circumstance in which the series The most important is the first: of adverse effects shown in table 1 choose a sub-maximally effective can occur. The most important of dose. This requires knowing some­ these is hypovolemia. This is par­ thing about the dose response to ticularly likely to occur in the pa­ these new agents. The only way to tient with cirrhosis or nephrosis. judge the response, of course, is to 82 MCV QUARTERLY 3(2): 82-90, 1967 A. J. WASSERMAN TABLE 1 c::i Results of Excessive Diuresis ~ 1. Hypovolemia a. Reduction in renal blood flow b. Circulatory collapse • ! :::·:·:::::::::::·:::::·:::::::.::::::::::::::::::"d 2. Hypokalemia ~ fI '··································•• !.l..••. "."." .••..ii" .•.•...i:.•. •.• .•.•• .}"::::::: .. ...........· .·.·.·: ..... ~....- ....-... -.....- ....- ...- ....- ....- ....- ....- ....- .,.,-.,.,-.,.,-...: ) ~h: ~000 a. Digitalis intoxication li.i 3. Hypochloremia • a. Mercurial refractoriness \. 4. Hyponatremia a. Water intoxication 190- • 5. Muscle cramps 6. Weakness • 7. ? Thromboses 8. Acute gout 180- " \ • TABLE 2 1701- \ Routine Measures on Initiating a Diuresis • 1. Choose a submaximal diuretic dose. \ 2. Record weights and fluid bal- 160- • ance. 3. Restrict activity. 4. Reduce sodium intake. 5. Restrict fluids to 1 to 1.5 liters, --.--·, I I I I I I I I ~ especially the day after diuresis. 150 ~~~~~~~-'-~~-'-"· ~~- 6. Watch blood Na, K, Cl, HCOs, I 3 5 7 9 urea and hematocrit. TIME-DAYS Fig. 1- An excessively rapid response to ethacrynic acid. record weights and fluid balance. ing a poor response, they should vantage with the exception of a Weights must be recorded by every be checked. With the new agents more prolonged activity. In this out-patient who is taking diuretics which continue to be effective even sense it more closely resembles for their diuretic properties. If a in the face of electrolyte abnormal­ chlorthalidone. It has no other ad­ poor response from the diuretic ities, it is necessary to check them vantages and no other disadvan­ occurs, restnctmg the patient's with some regularity, like once ev­ tages. physical activity during the day ery week or two. will often enhance the diuresis, Furosemide since in heart failure, physical ac­ Quinethazone tivity reduces renal blood fl.ow. The structural formula for furos­ Fluids need be restricted only if The first new agent to consider emide (Lasix) is shown in figure 3. the patient appears to be one who is quinethazone (Hydromox). Fig­ Furosemide has also been called has the habit of ingesting water ure 2 shows the structural formula fursemide and frusemide. This is following a marked diuresis. No for quinthazone. Note the similar­ an agent whose activity-structure simple rule can be offered for the ity to chlorthalidone (Hydroton) relationship is still not clear. Some frequency of determining serum and to chlorothiazide (Diuril). would suggest that it is the com­ electrolytes. If the patient is having Quinethazone is thus another one mon grouping with the thiazides; a marked response, they should be of the large group of thiazide de­ others would suggest that it is the checked. Obviously, if he is hav- rivatives. It has no particular ad- free carboxyl group which is re- 83 PHARMACOLOGY OF NEWER DIURETICS sponsible for its diuretic activity. 0 It is clear that it is different from II the thiazides in several ways. N c Cl / ~ Firstly, it is active in an animal in N~ I which there is no liver. The thia­ D- zides require the presence of the NH,- S:((J NH,-so, ~ =u liver before diuresis will ensue. II OH 0 Secondly, furosemide causes a de­ crease in bicarbonate excretion in QUINETHAZONE CHLORTHALIDONE contrast to the typical thiazides. Thirdly, there is a markedly dif­ ferent order of efficacy. Furose­ mide clearly works in the ascend­ ing loop of Henle. It probably works in the proximal tubule, al­ though animal micropuncture stud­ ies give contrary evidence. It has been said, though, and we have all CHLOROTHIAZIDE been taught, that some 80% of the normal glomerular filtration is re­ absorbed in the proximal tubule. Fig. 2-Structural formulae of quinethazone (I;:lydromox), chlorthalidone If a diuretic were 100% effective, (Hygroton), and chlorothiazide (Diuril). theoretically it could only increase urine output to 20% of the filtra­ tion rate if it had no activity in the proximal tubule. Furosemide can produce a diuresis of as much as one-half of the glomerular filtra­ tion rate, and this has been used as evidence that it must alter the proximal tubular reabsorption of salt and water. Figure 4 shows the human re­ sponse to furosemide contrasted with hydrochlorothiazide at 50 to 75 mg of each. Note that furose­ mide produces a larger diuresis, natriuresis and chloruresis, but im­ portantly, no greater kaluresis. For each milliequivalent of sodium ex­ creted, furosemide causes less po­ tassium excretion than do the thia­ zides. Furosemide is very rapidly ef­ fective, acting in minutes when given intravenously. Its maximum effect occurs within two hours when NH-CH, 0 given orally. The duration of effect is correspondingly short. The dose response curve is shown in figure 5. In the case of hydrochlorothia­ zide, increasing the dose from 50 to 100 mg causes only a modestly COOH H,N02S increased natriuresis, whereas in­ creasing the dose of furosemide Fig. 3-Furosemide (Lasix), 4-chloro-N-(2-furylmethyl)-5-sulfamoyl-anthranilic from 50 to 100 mg causes a very acid. considerable difference. Furose- A. J. WASSERMAN mide, therefore, differs in potency, that is, more diuresis per milligram, mEq/24 hours ml/24 hours but more importantly, it differs in 160 1600 efficacy, giving a maximum re­ sponse beyond what can be ac­ 140 1400 hieved with any of the thiazides. 120 1200 The toxicity of furosemide is still under investigation. Table 3 1.000 lists the toxic reactions. Rare hy­ persensitivities, usually rashes and BO 800 rare, not definitely causally-related alteration in blood counts have 600 been reported. Nausea and vomit­ 4()() ing appear to be clearly dose-re­ lated and will occur quite fre­ 20 200 quently at single doses exceeding • Lasix 200 mg. Furosemide causes hyper­ 'LJ Hydrochlorothiazide uricemia regularly and will precip­ Urine Na Cl K itate acute gout occasionally. Pan­ creatitis and hyperglycemia have Fig. 4-Urinary response to equal milligram doses of furosemide and hydro­ now been reported in association chlorothiazide (Reproduced with permission from International Furosemide with furosemide therapy, but are Symposium, fig. 27, 1963). not yet established clearly as caus­ ally related. The extent of the hyperglycemia appears to be con­ siderably less than .that which oc­ curs with the benzothiadiazines. The major problem with furose­ mide is excessive diuretic effect. This is the major adverse effect in the use of this agent. In summary, then, furosemide is some three to five times as effica­ cious as the thiazides and causes less potassium loss. Because it is so rapidly effective, it has been used Hydrochlorothiezide in the treatment of pulmonary lasix edema and in cerebral edema. It is /::,. Na+ mEq/5 hours 6. Na+ mEq/5 hours important to note that it has a 300 300 steep dose response curve and that it continues to be effective even in 250 250 the face of electrolyte derrange­ ment, hypovolemia, and azotemia.
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