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Chapter: Essential pharmacology : Diuretics

Based on the diuretic action of calomel, organomercurials given by injection were introduced in the 1920s and dominated for nearly 40 years. The CAse inhibitors were developed in the 1950s from the observation that early sulfonamides caused acidosis and mild diuresis.



These are drugs which cause a net loss of Na+ and water in urine.


Based on the diuretic action of calomel, organomercurials given by injection were introduced in the 1920s and dominated for nearly 40 years. The CAse inhibitors were developed in the 1950s from the observation that early sulfonamides caused acidosis and mild diuresis. The first modern orally active diuretic chlorothiazide was discovered in 1957, and by early 1960s its congeners (thiazide diuretics) were already in common use. Availability of furosemide and ethacrynic acid by mid 1960s revolutionized the pattern of diuretic use. The K+ sparing diuretics spironolactone and triamterene were developed in parallel to these.


Diuretics are among the most widely prescribed drugs. Application of diuretics to the management of hypertension has outstripped their use in edema. Availability of diuretics has also had a major impact on the understanding of renal physiology.




1. High Efficacy Diuretics (Inhibitors of Na+K+2Cl¯ cotransport)


Sulphamoyl derivatives

Furosemide, Bumetanide, Torasemide


2. Medium Efficacy Diuretics (Inhibitors of Na+Cl¯ symport)


a.         Benzothiadiazines (Thiazides)

Hydrochlorothiazide, Benzthiazide, Hydroflumethiazide, Clopamide


b.         Thiazide Like (Related Heterocyclics)

Chlorthalidone, Metolazone, Xipamide, Indapamide.


3. Weak Or Adjunctive Diuretics


a. Carbonic Anhydrase Inhibitors



b. Potassium Sparing Diuretics


i.Aldosterone Antagonist: Spironolactone

ii.Inhibitors Of Renal Epithelial Na+ Channel: Triamterene, Amiloride.


c. Osmotic Diuretics

 Mannitol, Isosorbide, Glycerol


Other high ceiling diuretics, viz. ethacrynic acid and organomercurials (mersalyl) are only historical.



(Inhibitors of Na+K+2Cl¯ Cotransport)


Furosemide (Frusemide) Prototype drug


The development of this orally and rapidly acting highly efficacious diuretic was a breakthrough. Its maximal natriuretic effect is much greater than that of other classes. The diuretic response goes on increasing with increasing dose: upto 10 L of urine may be produced in a day. It is active even in patients with relatively severe renal failure. The onset of action is prompt (i.v. 2–5 min., i.m. 10–20 min., oral 20–40 min.) and duration short (3–6 hours).



The major site of action is the thick AscLH (site II) where furosemide inhibits Na+ K+2Cl¯ cotransport (Fig. 41.1). A minor component of action on PT has also been indicated. It is secreted in PT by organic anion transport and reaches AscLH where it acts from luminal side of the membrane. It abolishes the corticomedullary osmotic gradient and blocks positive as well as negative free water clearance. K+ excretion is increased mainly due to high Na+ load reaching DT. However, at equinatriuretic doses, K+ loss is less than that with thiazides.


Furosemide has weak CAse inhibitory action and increase HCO3¯ excretion as well; urinary pH may rise but the predominant urinary anion is Cl¯; acidosis does not develop. Its action is independent of acidbase balance of the body and it causes little distortion of the same; mild alkalosis occurs at high doses.


In addition to its prominent tubular action, furosemide causes acute changes in renal and systemic haemodynamics. After 5 min of i.v. injection, renal blood flow is transiently increased and there is redistribution of blood flow from outer to midcortical zone; g.f.r. generally remains unaltered due to compensatory mechanisms despite increased renal blood flow. Pressure relationship between vascular, interstitial and tubular compartments is altered, the net result of which is decreased PT reabsorption. The intrarenal haemodynamic changes are brought about by increased local PG synthesis.


Intravenous furosemide causes prompt increase in systemic venous capacitance and decreases left ventricular filling pressure, even before the saluretic response is apparent. This action also appears to be PG mediated and is responsible for the quick relief it affords in LVF and pulmonary edema.


Furosemide increases Ca2+ excretion (contrast thiazides which reduce it) as well as Mg2+ excretion. It tends to raise blood uric acid level by competing with its proximal tubular secretion as well as by increasing reabsorption in PT which is a consequence of reduced e.c.f. volume.


The magnitude of hyperuricaemia is lower than that with thiazides. Hyperglycaemic action of furosemide is also less marked than thiazides.


Molecular Mechanism Of Action:


A glycoprotein with 12 membrane spanning domains has been found to function as the Na+K+2Cl¯ cotransporter in many epithelia performing secretory/ absorbing function, including AscLH. Recently, distinct absorptive or secretory isoforms of Na+K+2Cl¯ cotransporter have been isolated. The former is exclusively expressed at the luminal membrane of thick AscLH—furosemide attaches to the Cl¯ binding site of this protein to inhibit its transport function. The secretory form is expressed on the basolateral membrane of most glandular and epithelial cells.




Furosemide is rapidly absorbed orally but bioavailability is about 60%. In severe CHF oral bioavailability may be markedly reduced. Lipidsolubility is low, and it is highly bound to plasma proteins. It is partly conjugated with glucuronic acid and mainly excreted unchanged by glomerular filtration as well as tubular secretion. Some excretion in bile and directly in intestine also occurs. Plasma t½ averages 1–2 hour but is prolonged in patients with pulmonary edema, renal and hepatic insufficiency.


Dose Usually 20–80 mg once daily in the morning. In renal insufficiency, upto 200 mg 6 hourly has been given by i.m./i.v. route. In pulmonary edema 40–80 mg may be given i.v.


LASIX 40 mg tab., 20 mg/2 ml inj. LASIX HIGH DOSE 500 mg tab, 250 mg/25 ml inj; (solution degrades spontaneously on exposure to light), SALINEX 40 mg tab, FRUSENEX 40, 100 mg tab.




It is similar to furosemide in all respects, but is 40 times more potent. It induces very rapid diuresis and is highly effective in pulmonary edema. However, the site of action, ceiling effect, renal haemodynamic changes and duration of action are similar to furosemide. A secondary action in PT has also been demonstrated. It may act in some cases not responding to furosemide. Hyperuricaemia, K+ loss, glucose intolerance and ototoxicity are claimed to be less than with furosemide. However, it may rarely cause myopathy.


Bumetanide is more lipidsoluble, 80–100% bioavailable orally, extensively bound to plasma proteins, partly metabolized and partly excreted unchanged in urine. Its accumulation in tubular fluid is less dependent on active secretion. Plasma t½ ~60 min, gets prolonged in renal and hepatic insufficiency.


Dose: 1–5 mg oral OD in the morning, 2–4 mg i.m./i.v., (max. 15 mg/day in renal failure).


BUMET, 1 mg tab., 0.25 mg/ml inj.


Torasemide (Torsemide)


Another high ceiling diuretic with properties similar to furosemide, but 3 times more potent. Oral absorption is more rapid and more complete. The elimination t½ (3.5 hours) and duration of action (4–8 hours) are longer. Torasemide has been used in edema and in hypertension.

Dose: 2.5–5 mg OD in hypertension; 5–20 mg/day in edema; upto 100 mg BD in renal failure.


DIURETOR 10, 20 mg tabs, DYTOR 10, 20, 100 mg tabs.


Use Of High Ceiling Diuretics


a)  Edema Diuretics are used irrespective of etiology of edema—cardiac, hepatic or renal. The high ceiling diuretics are preferred in CHF for rapid mobilization of edema fluid (see Ch. No. 37). Thiazides may be used for maintenance, but often prove ineffective and high ceiling drugs are called in. For nephrotic and other forms of resistant edema, the high ceiling diuretics are the drugs of choice. In chronic renal failure massive doses have to be used, but they continue to be effective while thiazides just do not produce any action. In impending acute renal failure, loop diuretics may decrease the need for dialysis.


b)  Acute Pulmonary Edema (Acute LVF, Following MI): Intravenous administration of furosemide or its congeners produces prompt relief. This is due to vasodilator action that precedes the saluretic action. Subsequently, decrease in blood volume and venous return is responsible for the improvement.


c)   Cerebral Edema: Though osmotic diuretics are primarily used, furosemide may be combined to improve efficacy.


d)  Hypertension: High ceiling diuretics are indicated only in presence of renal insufficiency, CHF, in resistant cases or hypertensive emergencies; otherwise thiazides are preferred.


e)   Along with blood transfusion in severe anaemia, to prevent vascular overload.


f)     Hypercalcaemia and renal calcium stones: because furosemide and its congeners increase calcium excretion and urine flow, they may help to reduce serum calcium level. Excess salt that is lost must be replaced.


Forced diuresis with saline and furosemide infusion is no longer recommended to treat poisonings.



(Inhibitors of Na+Cl¯ symport)


Chlorothiazide was synthesized as a CAse inhibitor variant which produced urine that was rich in Cl¯, and diuresis occurred in alkalosis as well as acidosis. A large number of congeners were developed subsequently and the thiadiazine ring was replaced by other heterocyclic rings, but the type of activity remained the same. The important features of agents marketed in India are presented in Table 41.1.



These are medium efficacy diuretics with primary site of action in the cortical diluting segment or the early DT (Site III). Here they inhibit Na+–Cl¯ symport at the luminal membrane. They do not affect the corticomedullary osmotic gradient indicating lack of action at the medullary thick AscLH. Positive free water clearance is reduced (very dilute urine cannot be passed in the absence of ADH), but negative free water clearance (in the presence of ADH) is not affected. This strengthens the view that the site of action is in between thick AscLH and late DT. These drugs gain access to their site of action via organic acid secretory pathway in PT and then along the tubular fluid to early DT, where they bind to specific receptors located on the luminal membrane. Like the Na+ K+2Cl¯ cotransporter, the Na+Cl¯ symporter is also a glycoprotein with 12 membrane spanning domains that binds thiazides but not furosemide or any other class of diuretics. It has been cloned and shown to be selectively expressed on the luminal membrane in the DT. The site of action of thiazide diuretics is shown in Fig. 41.2.



Some of the thiazides and related drugs have additional CAse inhibitory action in PT; intensity of this action differs among different compounds (Table 41.1), but it is generally weak and clinically insignificant. However, it may confer some proximal tubular action to the compounds.


Under their action, increased amount of Na+ is presented to the distal nephron, more of it exchanges with K+ urinary K+ excretion is increased in parallel to the natriuretic response. The maximal diuresis induced by different agents falls in a narrow range; though potency (reflected in daily dose) differs markedly. Nevertheless, they are moderately efficacious diuretics because nearly 90% of the glomerular filtrate has already been reabsorbed before it reaches their site of action. They have a flat dose response curve; little additional diuresis occurs when the dose is increased beyond 100 mg of hydrochlorothiazide or equivalent. They do not cause significant alteration in acid-base balance of the body.


By their action to reduce blood volume, as also intrarenal haemodynamic changes, they tend to reduce g.f.r. This is one reason why thiazides are not effective in patients with low g.f.r. They decrease renal Ca2+ excretion and increase Mg2+ excretion by a direct distal tubular action. They also decrease urate excretion by the same mechanism as furosemide.


The extrarenal actions of thiazides consist of a slowly developing fall in BP in hypertensives and elevation of blood sugar in some patients due to decreased insulin release which probably is a consequence of hypokalaemia.




All thiazides and related drugs are well absorbed orally; are administered only by this route. Their action starts within 1 hour, but the duration varies from 8–48 hours (Table 41.1). The more lipidsoluble agents have larger volumes of distribution (some are also tissue bound), lower rates of renal clearance and are longer acting. The protein binding is also variable. Most of the agents undergo little hepatic metabolism and are excreted as suCh. No. They are filtered at the glomerulus as well as secreted in the PT by organic anion transport. Tubular reabsorption depends on lipid solubility: the more soluble ones are highly reabsorbed—prolonging duration of action.


Chlorthalidone It is a particularly long acting agent with a t½ 40–50 hours, used exclusively as antihypertensive.


Metolazone In common with loop diuretics, it is able to evoke a clinically useful response even in severe renal failure (g.f.r. ~15 ml/min), and has marked additive action when combined with furosemide. An additional proximal tubular action has been demonstrated; PO4 reabsorption that occurs in PT is inhibited. It is excreted unchanged in urine.


Xipamide It has a pronounced diuretic action similar to low doses of furosemide. Because of longer duration of action—hypokalemia is more prominent.


Indapamide It has little diuretic action in the usual doses, probably because it is highly lipidsoluble, is extensively metabolized and only small quantity of unchanged drug is present in the tubular fluid. However, it retains antihypertensive action and is used for that purpose only.





Edema: Thiazides may be used for mild-to-moderate cases. For mobilization of edema fluid more efficacious diuretics are preferred, but thiazides may be considered for maintenance therapy. They act best in cardiac edema, less effective in hepatic or renal edema. They are powerless in the presence of renal failure. Cirrhotics often develop refractoriness to thiazides due to development of secondary hyperaldosteronism.


Hypertension:  Thiazides and related diuretics, especially chlorthalidone are one of the first line drugs (Ch. No. 40).


Diabetes Insipidus: They reduce urine volume (see Ch. No. 42).


Hypercalciuria with recurrent calcium stones in the kidney. Thiazides act by reducing Ca2+ excretion.


Complications Of High Ceiling And Thiazide Type Diuretic Therapy


Most of the adverse effects of these drugs are related to fluid and electrolyte changes caused by them. They are remarkably safe in low doses used over short periods. Many subtle metabolic effects have been reported in their long-term use as antihypertensives at the relatively higher doses used in the past (see Ch. No. 40).


1. Hypokalaemia:  This is the most significant problem. It is rare at low doses, but may be of grave consequence when brisk diuresis is induced or on prolonged therapy, especially if dietary K+ intake is low. Degree of hypokalaemia appears to be related to the duration of action of the diuretic; longer acting drugs causing more K+ loss. The usual manifestations are weakness, fatigue, muscle cramps; cardiac arrhythmias are the serious complications. Hypokalaemia is less common with standard doses of high ceiling diuretics than with thiazides, possibly because of shorter duration of action of the former which permits intermittent operation of compensatory repletion mechanisms. It can be prevented and treated by:


(a) High dietary K+ intake or

(b) Supplements of KCl (24–72 mEq/day) or

(c) Concurrent use of K+ sparing diuretics.


Measures (b) and (c) are not routinely indicated, but only when hypokalaemia has been documented or in special risk situations, e.g. cirrhotics, cardiac patients—especially post MI, those receiving digitalis, antiarrhythmics, or tricyclic antidepressants and elderly patients.


Serum K+ levels are only a rough guide to K+ depletion, because K+ is primarily an intracellular ion. Nevertheless, an attempt to maintain serum K+ at or above 3.5 mEq/L should be made.


Combined tablets of diuretics and KCl are not recommended because:


·            they generally contain insufficient quantity of K+ (8–12 mEq only).

·            may cause gut ulceration by releasing KCl at one spot.

·            K+ is retained better if given after the diuresis is over.


K+ sparing diuretics are more efficacious and more convenient in correcting hypokalaemia than are K+ supplements. ACE inhibitors/AT1 antagonists given with thiazides tend to prevent development of hypokalaemia.


Alkalosis may occur with hypokalaemia, because more H+ exchanges with Na+ in DT when less K+ is available for exchange.


2. Acute Saline Depletion: Over enthusiastic use of diuretics, particularly high ceiling ones, may cause dehydration and fall in BP (especially in erect posture). Serum Na+ and Cl¯ levels remain normal because isotonic saline is lost. It should be treated by saline infusion.


3. Dilutional Hyponatraemia: Occurs in CHF patients when vigorous diuresis is induced with high ceiling agents, rarely with thiazides. Kidney tends to retain water, though it is unable to retain salt due to the diuretic; e.c.f. gets diluted, hyponatraemia occurs and edema persists despite natriuresis. Patients feel very thirsty. Treatment of this distortion of fluidelectrolyte balance is difficult: withhold diuretics, restrict water intake and give glucocorticoid which enhances excretion of water load. If hypokalaemia is present, its correction helps.


4. GIT and CNS Disturbances: Nausea, vomiting and diarrhoea may occur with any diuretic. Headache, giddiness, weakness, paresthesias, impotence are occasional complaints with thiazides as well as loop diuretics.


5. Hearing Loss: Occurs rarely, only with high ceiling diuretics and when these drugs are used in the presence of renal insufficiency. Increased

salt content of endolymph and a direct toxic action on the hair cells in internal ear appear to be causative.


6. Allergic Manifestations: Rashes, photosensitivity occur, especially in patients hypersensitive to sulfonamides. Blood dyscrasias are rare; any diuretic may be causative.


7. Hyperuricaemia: Long-term use of higher dose thiazides in hypertension has caused rise in blood urate level. This is uncommon now due to use of lower doses (see Ch. No. 40). Furosemide produces a lower incidence of hyperuricaemia. This effect can be counteracted by allopurinol. Probenecid is better avoided, because it may interfere with the diuretic response, particularly of loop diuretics.


8. Hyperglycaemia and Hyperlipidemia: Have occurred in the use of diuretics as antihypertensive (see Ch. No. 40). These metabolic changes are minimal at low doses now recommended.


9. Hypercalcaemia: Occurs with thiazides, while hypocalcaemia occurs with high ceiling diuretics when these are administered chronically.


10. Magnesium Depletion: It may develop after prolonged use of thiazides as well as loop diuretics, and may increase the risk of ventricular arrhythmias, especially after MI or when patients are digitalized. K+ sparing diuretics given concurrently minimise Mg2+ loss.


11. Thiazides have sometimes aggravated renal insufficiency, probably by reducing g.f.r.


12. Brisk diuresis induced in cirrhotics may precipitate mental disturbances and hepatic coma. It may be due to hypokalaemia, alkalosis and increased blood NH3 levels.


13. Diuretics should not be used in toxaemia of pregnancy in which blood volume is low despite edema. Diuretics may further compromise placental circulation miscarriage, foetal death. Thus, diuretics are contraindicated in pregnancy induced hypertension.




1. Thiazides and high ceiling diuretics potentiate all other antihypertensives. This interaction is intentionally employed in therapeutics.


2. Hypokalaemia induced by these diuretics:


·      Enhances digitalis toxicity.

·      Increases the incidence of polymorphic ventricular tachycardia due to quinidine and other antiarrhythmics.

·      Potentiates competitive neuromuscular blockers and reduces sulfonylurea action.


3. High ceiling diuretics and aminoglycoside antibiotics are both ototoxic and nephrotoxic; produce additive toxicity; should be used together cautiously.


4. Cotrimoxazole given with diuretics has caused higher incidence of thrombocytopenia.


5. Indomethacin and other NSAIDs diminish the action of high ceiling diuretics. Inhibition of PG synthesis in the kidney, through which furosemide and related drugs induce intrarenal haemodynamic changes which secondarily affect salt output, appears to be the mechanism. Antihypertensive action of thiazides and furosemide is also diminished by NSAIDs.


6. Probenecid competitively inhibits tubular secretion of furosemide and thiazides: decreases their action by reducing the concentration in the tubular fluid, while diuretics diminish uricosuric action of probenecid.


7. Serum lithium level rises when diuretic therapy is instituted. This is due to enhanced reabsorption of Li+ (and Na+) in PT.


Resistance To High Ceiling Diuretics


Refractoriness (progressive edema despite escalating diuretic therapy) is more common with thiazides, but occurs under certain circumstances with high ceiling diuretics as well. The causes and mechanism of such resistance include:



Long-term use of loop diuretics causes distal nephron hypertrophy resistance. Addition of metolazone, or to some extent a thiazide, which act on distal tubule overcome the refractoriness in many cases. Further increase in dose and/or fractionation of daily dose may restart diuresis. Bedrest may also help.




Carbonic anhydrase (CAse) is an enzyme which catalyses the reversible reaction H2O + CO2 ←→ H2CO3. Carbonic acid spontaneously ionizes H2CO3←→H+ +HCO¯3  (Fig. IX.2). Carbonic anhydrase thus functions in CO2  and HCO3¯ transport and in H+ ion secretion. The enzyme is present in renal tubular cell (especially PT) gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBC. In these tissues a gross excess of CAse is present, more than 99% inhibition is required to produce effects.




It is a sulfonamide derivative which noncompetitively but reversibly inhibits CAse in PT cells resulting in slowing of hydration of CO2 decreased availability of H+ to exchange with luminal Na+ through the Na+H+ antiporter. Inhibition of brush border CAse retards dehydration of H2CO3 in the tubular fluid so that less CO2 diffuses back into the cells. The net effect is inhibition of HCO¯ (and accompanying Na+) reabsorption in PT prompt but mild alkaline diuresis ensues.


Secretion of H+ in DT and CD is also inhibited. Though H+ is secreted at this site by a H+ATPase, it is generated in the cell by CAse mediated reaction. As such, this is a subsidiary site of action of CAse inhibitors. When CAse inhibitors are given, the distal Na+ exchange takes place only with K+ which is lost in excess. For the same degree of natriuresis CAse inhibitors cause the most marked kaliuresis compared to other diuretics. The urine produced under acetazolamide action is alkaline and rich in HCO¯ which is matched by both Na+ and K+. Continued action of acetazolamide depletes body HCO3¯ and causes acidosis; less HCO3¯ (on which its diuretic action depends) is filtered at the glomerulus selflimiting diuretic action. The extrarenal actions of acetazolamide are:


·            Lowering of intraocular tension due to decreased formation of aqueous humour (it is rich in HCO¯)3.


·            Decreased gastric HCl and pancreatic NaHCO3 secretion: This action requires very high doses—clinically not significant.


·            Raised level of CO2 in brain and lowering of pH sedation and elevation of seizure threshold.


·            Alteration of CO2 transport in lungs and tissues: these actions are masked by compensatory mechanisms.




Acetazolamide is well absorbed orally and excreted unchanged in urine. Action of a single dose lasts 8–12 hours.




Because of selflimiting action, production of acidosis and hypokalaemia, acetazolamide is not used as diuretic. Its current clinical uses are:


1. Glaucoma: as adjuvant to other ocular hypotensives (see Ch. No. 10).

2. To alkalinise urine: for urinary tract infection or to promote excretion of certain acidic drugs.

3. Epilepsy: as adjuvant in absence seizures when primary drugs are not fully effective.

4. Acute mountain sickness: for symptomatic relief as well as prophylaxis. Benefit occurs probably due to reduced CSF formation as well as lowering of CSF and brain pH.

5. Periodic paralysis.


Dose: 250 mg OD–BD; DIAMOX, SYNOMAX 250 mg tab. IOPARSR 250 mg SR cap.


Adverse Effects are frequent.


Acidosis, hypokalaemia, drowsiness, paresthesias, fatigue, abdominal discomfort. Hypersensitivity reactions—fever, rashes. Bone marrow depression is rare but serious. It is contraindicated in liver disease: may precipitate hepatic coma by interfering with urinary elimination of NH3 (due to alkaline urine). Acidosis is more likely to occur in patients of COPD.


Some topical CAse inhibitors have been introduced for use in glaucoma (see Ch. No. 10).




These are either aldosterone antagonist or directly inhibit Na+ channels in DT and CD cells to indirectly conserve K+.


Spironolactone (Aldosterone antagonist)


It is a steroid, chemically related to the mineralocorticoid aldosterone. Aldosterone acts on the late DT and CD cells (Fig. 41.3) by combining with an intracellular mineralocorticoid receptor → induces the formation of ‘aldosterone-induced proteins’ (AIPs) which promote Na+ reabsorption by a number of mechanisms (see legend to Fig. 41.3) and K+ secretion. Spironolactone acts from the interstitial side of the tubular cell, combines with the mineralocorticoid receptor and inhibits the formation of AIPs in a competitive manner. It has no effect on Na+ and K+ transport in the absence of aldosterone, while under normal circumstances, it increases Na+ and decreases K+ excretion.



Spironolactone is a mild saluretic because majority of Na+ has already been reabsorbed proximal to its site of action. However, it antagonises K+ loss induced by other diuretics and slightly adds to their natriuretic effect. The K+ retaining action develops over 3–4 days. It increases Ca2+ excretion by a direct action on renal tubules.




The oral bioavailability of spironolactone from microfine powder tablet is 75%. It is highly bound to plasma proteins and completely metabolized in liver; converted to active metabolites, the most important of which is Canrenone that is responsible for 1/2–2/3 of its action in vivo. The t½ of spironolactone is 1–2 hours, while that canrenone is ~18 hours. It undergoes some enterohepatic circulation.


Dose: 25–50 mg BD–QID; ALDACTONE 25, 100 mg tabs.


ALDACTIDE: Spironolactone 25 mg + hydroflumethiazide 25 mg tab. LACILACTONE, SPIROMIDE: Spironolactone 50 mg + furosemide 20 mg tab.




Spironolactone is a weak diuretic in its own right and is used only in combination with other more efficacious diuretics.


·          Edema: It is more useful in cirrhotic and nephrotic edema: aldosterone levels are generally high. It breaks the resistance to thiazide diuretics that develops due to secondary hyperaldosteronism and reestablishes the response. Thus, it is particularly employed in refractory edema.


·          To counteract K+ loss due to thiazide and loop diuretics.

·          Hypertension: Used only as adjuvant to thiazide to prevent hypokalaemia; has weak antihypertensive action of its own.


·          CHF: As additional drug to conventional therapy in moderate to severe CHF; can retard disease progression and lower mortality.




·     Given together with K+ supplements— dangerous hyperkalaemia can occur.

·     Aspirin blocks spironolactone action by inhibiting tubular secretion of canrenone.

·     More pronounced hyperkalaemia can occur in patients receiving ACE inhibitors/angiotensin receptor blockers (ARBs).

·     Spironolactone increases plasma digoxin concentration.


Adverse Effects


The side effects are drowsiness, confusion, abdominal upset, hirsutism, gynaecomastia, impotence and menstrual irregularities. Most serious is hyperkalaemia that may occur especially if renal function is inadequate. Acidosis is a risk, particularly in cirrhotics. Peptic ulcer may be aggravated.


Eplerenone is a recently developed more selective aldosterone antagonist, that is less likely to cause hormonal disturbances like gynaecomastia, impotence and menstrual irregularities.



Inhibitors Of Renal Epithelial Na+ Channel


Triamterene and amiloride are two nonsteroidal organic bases with identical actions. Their most important effect is to decrease K+ excretion, particularly when it is high due to large K+ intake or use of a diuretic that enhances K+ loss. This is accompanied by a small increase in Na+ excretion. The excess urinary Na+ is matched by Cl¯ and variable amounts of HCO3¯ ; urine is slightly alkalinized. The effect on urinary electrolyte pattern is superficially similar to spironolactone, but their action is independent of aldosterone.


Mechanism Of Action


The luminal membrane of late DT and CD cells expresses a distinct ‘amiloride sensitive’ or ‘renal epithelial’ Na+ channel through which Na+ enters the cell down its electrochemical gradient which is generated by Na+K+ ATPase operating at the basolateral membrane (Fig. 41.3). This Na+ entry partially depolarizes the luminal membrane creating a –15 mV transepithelial potential difference which promotes secretion of K+ into the lumen through K+ channels. Though there is no direct coupling between Na+ and K+ channels, more the delivery of Na+ to the distal nephron—greater is its entry through the Na+ channel—luminal membrane is depolarized more—driving force for K+ secretion is augmented. As such, all diuretics acting proximally (loop diuretics, thiazides, CAse inhibitors) promote K+ secretion. Amiloride and triamterene block the luminal Na+ channels— indirectly inhibit K+ excretion, while the net excess loss of Na+ is minor (most of it has already been reabsorbed).


The intercalated cells in CD possess an ATP driven H+ pump which secretes H+ ions into the lumen. This pump is facilitated by lumen negative potential. Amiloride, by reducing the lumen negative potential, decreases H+ ion secretion as well; predisposes to acidosis.


Both triamterene and amiloride are used in conjunction with thiazide type or high ceiling diuretics: prevent hypokalaemia and slightly augment the natriuretic and antihypertensive response. Risk of hyperkalaemia is the most important adverse effect of amiloride and triamterene. These drugs should not be given with K+ supplements; dangerous hyperkalaemia may develop. Hyperkalaemia is also more likely in patients receiving ACE inhibitors/ARBs, β blockers, NSAIDs and in those with renal impairment.


Both drugs elevate plasma digoxin levels.




It is incompletely absorbed orally, partly bound to plasma proteins, largely metabolized in liver to an active metabolite and excreted in urine. Plasma t½ is 4 hours, effect of a single dose lasts 6–8 hours.


Side Effects are infrequent: consist of nausea, dizziness, muscle cramps and rise in blood urea. Impaired glucose tolerance and photosensitivity are reported, but urate level is not increased.


Dose: 50–100 mg daily; DITIDE, triamterene 50 mg + benzthiazide 25 mg tab;


FRUSEMENE, triamterene 50 mg + furosemide 20 mg tab.




It is 10 times more potent than triamterene (dose 5–10 mg OD–BD). At higher doses it also inhibits Na+ reabsorption in PT, but this is clinically insignificant. It decreases Ca2+ excretion and increases urate excretion. Thus, hypercalcaemic action of thiazides is augmented but hyperuricaemic action is partly annuled. A mild antihypertensive action is also reported.


Only ¼ of an oral dose is absorbed. It is not bound to plasma proteins and not metabolized. The t½ (10–20 hours) and duration of action are longer than triamterene.


BIDURET, KSPAR: Amiloride 5 mg + hydrochlorothiazide 50 mg tab, LASIRIDE, AMIMIDE amiloride 5 mg + furosemide 40 mg tab.


Usual side effects are nausea, diarrhoea and headache.


Amiloride blocks entry of Li+ through Na+ channels in the CD cells and mitigates diabetes insipidus induced by lithium.


Given as an aerosol it affords symptomatic improvement in cystic fibrosis by increasing fluidity of respiratory secretions.






Mannitol is a nonelectrolyte of low molecular weight (182) that is pharmacologically inert— can be given in large quantities sufficient to raise osmolarity of plasma and tubular fluid. It is not metabolized in the body; freely filtered at the glomerulus and undergoes limited reabsorption: therefore excellently suited to be used as osmotic diuretic. Mannitol appears to limit tubular water and electrolyte reabsorption in a variety of ways:


·            Retains water iso-osmotically in PT— dilutes luminal fluid which opposes NaCl reabsorption.


·      Inhibits transport processes in the thick AscLH by an unknown mechanism. Quantitatively this appears to be the most important cause of diuresis.


·          Expands extracellular fluid volume (because it does not enter cells, mannitol draws water from the intracellular compartment)—increases g.f.r. and inhibits renin release.

·            Increases renal blood flow, especially to the medulla—medullary hypertonicity is reduced—corticomedullary osmotic gradient is dissipated—passive salt reabsorption is reduced.


Though the primary action of mannitol is to increase urinary volume, excretion of all cations and anions is also enhanced.


Administration Mannitol is not absorbed orally; has to be given i.v. as 10–20% solution. It is excreted with a t½ of 0.5–1.5 hour.


MANNITOL 10%, 20%, in 100, 350 and 500 ml vac.




Mannitol is never used for the treatment of chronic edema or as a natriuretic. Its indications are:


·     Increased intracranial or intraocular tension (acute congestive glaucoma, head injury, stroke, etc.): by osmotic action it encourages movement of water from brain parenchyma, CSF and aqueous humour; 1–1.5 g/kg is infused over 1 hour as 20% solution to transiently raise plasma osmolarity. It is also used before and after ocular/brain surgery to prevent acute rise in intraocular/intracranial pressure.


·     To maintain g.f.r. and urine flow in impending acute renal failure, e.g. in shock, severe trauma, cardiac surgery, haemolytic reactions: 500–1000 ml of the solution may be infused over 24 hours. However, prognostic benefits in conditions other than cardiac surgery are still unproven. If acute renal failure has already set in, kidney is incapable of forming urine even after an osmotic load; mannitol is contraindicated: it will then expand plasma volume pulmonary edema and heart failure may develop.


·     To counteract low osmolality of plasma/e.c.f. due to rapid haemodialysis or peritoneal dialysis (dialysis disequilibrium).



Mannitol along with large volumes of saline was infused i.v. to produce ‘forced diuresis’ in acute poisonings in the hope of enhancing excretion of the poison. However, this has been found to be ineffective and to produce electrolyte imbalances. Not recommended now.

Mannitol is contraindicated in acute tubular necrosis, anuria, pulmonary edema; acute left ventricular failure, CHF, cerebral haemorrhage.


Headache due to hyponatraemia is common, nausea and vomiting may occur; hypersensitivity reactions are rare.


Isosorbide and Glycerol


These are orally active osmotic diuretics which may be used to reduce intraocular or intracranial tension. Intravenous glycerol can cause haemolysis.


Dose: 0.5–1.5 g/kg as oral solution.


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