Diuretics

by David Rosenblum November,18

Diuretics

Classification

1. High efficacy diuretics (inhibitor of Na⁺-K⁺-2Cl^– cotransport)

Sulphamoyl derivatives: Furosemide, bumetanide, torasemide

2. Medium efficacy diuretics (inhibitors of Na⁺-Cl^– symport)

Benzothiadiazines (thiazides)

Hydrochlorothiazide, benzthiazide, hydroflumethiazide, bendroflumethiazide

Thiazide like (related heterocyclics)

Chlorthalidone, metolazone, xipamide, indapamide, clopamide

3. Weak or adjunctive diuretics

Carbonic anhydrase inhibitor Acetazolamide
Potassium sparing diuretics

i. Aldosterone antagonist:Spironolactone, eplerenone ii. Inhibitors of renal epithelial Na+ channel: Triamterene, amiloride

Osmotic diuretic: Mannitol, isosorbide, glycerol

High ceiling (loop) diuretics [inhibitors of Na⁺-K⁺-2Cl^– cotransport]

Furosemide

Rapidly acting highly efficacious oral diuretic
Maximal natriuretic effect is much greater than that of any other classes
Effective even in patients with relatively severe renal failure
Onset of action is prompt (iv 2-5 min, im 10-20 min, oral 20-40 min) and duration short (3-6 min)
Major site of action is thick ascending loop of Henle. A minor component of action is on proximal tubule also.
Furosemide is a weak carbonic anhydrase inhibitor, it increases HCO₃^– excretion as well
It also causes acute changes in renal and systemic hemodynamics. Renal blood flow is transiently increased and there is redistribution of blood flow from outer to midcortical zone; GFR remains unaltered
It causes prompt increase in systemic venous capacitance and decreases left ventricular filling pressure
It increases Ca2+ excretion as well as Mg2+ excretion, it raises blood uric acid level
A small rise in blood sugar level is noted after regular use of furosemide
It is rapidly absorbed orally but bioavailability is 60%.
Lipid solubility is low and it is highly bound to plasma proteins
It is partly conjugated with glucuronic acid and mainly excreted unchanged by glomerular filteration as well as tubular excretion
Dose: usually 20-80 mg once daily in the morning. In renal insufficiency, up to 200 mg 6 hourly can be given by im or iv route
High dose furosemide is logical and effective therapy for severe cardiac failure and relatively safe when administered cutiously. The maximal dose is probably no less than that used in renal failure. ⁽¹⁾
Furosemide is used in the long term management of congestive heart failure. The adverse effects include RAAS activation, urinary Mg2+ and Ca2+ excretion, reduction in intracellular cations and thiamine deficiency. ⁽²⁾
A single dose of 80 mg of furosemide produces a natriuretic response in a 24 hour period equivalent to that achieved with a single oral dose of 100 mg of hydrochlorothiazide or a single dose of 2.0 cc of mercaptomerin given intramuscularly. ⁽³⁾
Furosemide stimulates prostaglandin E2 synthesis, a potent dilator of the patent ductus srteriosus and the administration of furosemideto any preterm infants should be carefully weighed against the risk of precipitation of symptomatic patent ductus arteriosus. Infants with low birth weight treated with chronic furosemide are at risk for the development of intra-renal calcifications. ⁽⁴⁾
Furosemide alters the organ of corti mechanics and causes sensorineural hering deficits. ⁽⁵⁾
Kidneys are responsible for 85% of furosemide total clearance, either via excretion (43%) or biotransformation (42%) and that probenecid inhibits both processes. ⁽⁶⁾
Furosemide does not reduce mortality in patients with acute kidney injury. In patients with acute lung injury without haemodynamic instability, furosemide may be useful in acheiving fluid balance to facilitate mechanical ventilation according to the lung protective ventilation strategy. ⁽⁷⁾
There is an oubain-insensitive transport process that facilitates the inward cotransport of Na+ and K+ ions and that can produce the net movement of both ions. The cotransport process is inhibited by furosemide. ⁽⁸⁾
The use of furosemide in the management of hypercalcemia should no longer be recommended. ⁽⁹⁾
Furosemide infusion therapy is associated with moderately negative cumulative fluid balances, electrolyte shifts and mild transient worsening of renal function. ⁽¹⁰⁾
Furosemide does not act on the proximal tubule. It inhibits the transport on the ascending limb of Henle’s loop. The urine flow rate furing furosemide closely approximates volume delivery out of the proximal tubule. ⁽¹¹⁾
The addition of albumin to a furosemide infusion does not enhances diuresis obtained with furosemide alone in critically ill patients. ⁽¹²⁾
Furosemide in continuous perfusion is not associated with a significant reduction in risk of mortality as compared to bolus administration in critically ill patients hospitalised in ICU. ⁽¹³⁾
The renal medullary and papillary concentrations of sodium and urea are depressed by furosemide. It reduce the permeability of collecting duct to water. ⁽¹⁴⁾
Furosemide is an inhibitor of thyroxine hormone in serum and high dose treatment with furosemide can lower total thyroxine and increase its free fraction in vivo. The sampling of thyroid tests from intravenous sites where furosemide has been administered should be discouraged.⁽¹⁵⁾
Furosemide use should not be considered as a major risk factor for the development of aminoglycoside induced nephrotoxicity or auditory toxicity. ⁽¹⁶⁾
Furosemide is used for prevention of epistaxis and exercise induced pulmonary hemorrhage (EIPH) in horses. ⁽¹⁷⁾
Continuous infusion following a single loading dose is the preferred method for administration of furosemide in patients with congestive heart failure. ⁽¹⁸⁾
Closely monitored use of iv furosemide with human albumin for treatment of cirrhotic ascites is effective an dsuperior to oral diuretics and it reduces the need for LVP. ⁽¹⁹⁾
Furosemide exerts an antihypertensive effect similar to that of other widely used sulfonamide diuretics, and therefore appears to be na effective agent for treatment of mild to moderate hypertension. ⁽²⁰⁾
The pharmacokinetics and pharmacodynamics of furosemide and torasemide are markedly altered in patients with diuretic resistant ascites. ⁽²¹⁾

Bumetanide

Similar to furosemide in all respects, but is 40 times more potent
It induces very rapid diuresis and is highly effective in pulmonary edema
More lipid soluble, oral bioavailability is 80-100%
It is preferred for oral use in severe CHF
It is extensively bound to plasma proteins, partly metabolized and partly excreted unchanged in urine.
Plasma t ½ is 60 min, it gets prolonged in renal and hepatic insufficiency
Dose: 1-5 mg oral OD in the morning, 2-4 mg im/iv
Compared to continuous infusion furosemide, Furosemide + metolazone or continuous infusion bumetanide is associated with greater increase in urine output in patients with acute heart failure. ⁽²²⁾
The peak rate of diuretic response and the total response for 6 hours after drug ingestion is greater with bumetanide compared to furosemide with respect to urinary volume and sodium excretion. ⁽²³⁾
Bumetanide is an effective diuretic for the treatment of ascites in patients with liver disease. ⁽²⁴⁾
Bumetanide has a rapid action virtually complete in 4 hr with an effect on water and electrolyte excretion similar to that of furosemide. It is highly potent and effective in controlling edema. There are low incidence of electrolyte complications and no other biochemical abnormalities or haematological complications. It is well tolerated by the patients. ⁽²⁵⁾
The effective dose ratio of bumetanide: furosemide is 1:25 in patients with congestive heart failure. ⁽²⁶⁾
Bumetanide is a promising novel therapeutic agent to treat autism. ⁽²⁷⁾
The continuous iv infusion of bumetanide may result in severe disabling musculoskeletal symptoms. The reaction appears to be dose related, without specific risk factors and is reversible on discontinuation of the infusion. ⁽²⁸⁾
Bumetanide should be considered for the management of patients with hypokalemic periodic paralysis due to sodium channel mutations. ⁽²⁹⁾
Bumetanide in doses varying from 0.015 mg/kg to 0.10 mg/kg is an effective diuretic for long term use in infants with congenital heart disease presenting with cardiac failure. ⁽³⁰⁾
Bumetanide used in combination with phenobarbital is more effective in neonatal seizures due to hypoxic encephalopathy. ⁽³¹⁾

Torasemide

Properties similar to furosemide but 3 times more potent
oral absorption is more rapid and more complete
The elimination t ½ (3.5 hours) and duration of action (4-8 hours) are longer
Torasemide treatment can ameliorate cardiac sympathetic nerve acticvity and left ventricular remodelling in patients with congestive heart failure. ⁽³²⁾
The pharmacokinetics and pharmacodynamics of torsemide is markedly altered in patients with diuretic resistant ascites. ⁽³³⁾
Congestive heart failure patients treated with torasemide gain a higher benefit in quality of lifev than furosemide treated patients, due to torasemide’s dual effect on both clinical status and social function. ⁽³⁴⁾
Torasemide inhbits trancardiac extraction of aldosterone in patients with congestive heart failure. ⁽³⁵⁾
In hypertensive patients with mild and clinically stable heart failure, long term administration of prolonged release formulation of torasemide is not associated with significant effects on myocardial fibrosis. ⁽³⁶⁾
Torasemide is 5 times more potent as furosemidde. Renal clearance and the fraction of unchanged drug appearing in the urine is decreased with higher doses. Probenecid pretreatment decreases both urine volume and sodium excretion. ⁽³⁷⁾
Torasemide transport by organic anion transporters contributes to hyperuricemia. ⁽³⁸⁾
Torasemide can be safely used and appears to be effective for treatment of heart failure in children. ⁽³⁹⁾
Oral or iv administration of 20 mg torasemide has good bioavailability (greater than 91%). Its biologic half lifeis 2.5 h with a distribution volume of 180 ml/kg and body clearance of 0.8 ml.min. ⁽⁴⁰⁾
Torasemide could reverse myocardial fibrosis and reduce collagen type I synthesis in patients with congestive heart failure. ⁽⁴¹⁾
Indomethacin reduces the natriuretic response to torasemide in humans. Dietary sodium restriction is a significant determinant of the interaction between NSAIDs and loop diuretics in healthy volunteers. ⁽⁴²⁾
Compared to furosemide treated patients, torasemide treated patients are less likely to be readmitted for heart failure and for all cardiovascular causes and arev less fatigued. ⁽⁴³⁾

Uses of high ceiling diuretics

Edema
Acute pulmonary edema (acute LVF, following MI)
Cerebral edema
Hypertension
Along with blood transfusion in severe anemia to prevent volume overload
Hypercalcemia of malignancy

Thiazide and related diuretics

These are medium efficacy diuretics with primary site of action in the cortical diluting segment or the early DT
They inhibit Na⁺-Cl^– symport at the luminal membrane
Some thiazides have additional CAse inhibitory action on PT.
They reduce blood volume as well as intrarenal hemodynamic changes, thus causes reduction in GFR
They are well absorbed orally.
Their action starts within 1 hour, but duration varies from 6-48 hours
The more lipid soluble agents have larger volumes of distribution, lower rates of renal clearance and are longer acting
Most agents undergo little hepatic metabolism and are excreted as such
They are filtered at the glomerulus as well as secreted in PT by organic anion transport
Tubular reabsorption depends on lipid solubility: the more lipid soluble ones are highle reabsorbed – prolonging duration of action
The elimination t ½ of hydrochlorothiazide is 3-6 hours, but action persists longer (6-12 hours)
Hydrochlorothiazide is a well established diuretic and antihypertensive agent which promotes natriuresis by acting on the distal renal tubule. Metoprolol extended release hydrochlorothiazide is more effective than monotherapy and allows a low dose multidrug regimen as an alternative to high dose monotherapy, thereby minimizing the dose related side effects ⁽⁴⁴⁾
The antihypertensive efficacy of hydrochlorothiazide in a daily dose of 12.5 to 25 mg is inferior to that of all other drug classes. Thus it is an inappropriate first line drug for the treatment of hypertension. ⁽⁴⁵⁾
Chlorthalidone is 1.5 to 2.0 times as potent as hydrochlorothiazide and it has much longer duration of action. ⁽⁴⁶⁾
The addition of 25,50 and 100 mg losartan to 25 mg hydrochlorothiazide produces a significant and dose related reduction in blood pressure and is well tolerated. ⁽⁴⁷⁾
Lisinopril is as effective as hydrochlorothiazide in treating obese patients with hypertension. It has a more rapid rate of response and offers advantages in patients at high risk of metabolic disorders. ⁽⁴⁸⁾
Vitamin D3 supplementation up to 4000 IU in hydrochlorothiazide users is associated with a rise in serum calcium but a low frequency of hypercalcemia. ⁽⁴⁹⁾
Several novel gene regions were associated with hydrochlorothiazide induced uric acid elevation in Africans Americans (LUC7L2, COX18/ANKRD17, FTO, PADI4 and PARD3B) and one region was associated with these elevations in Caucasians (GRIN3A). ⁽⁵⁰⁾
Benazepril- amlodipine combination is superior to the benazepril-hydrochlorothiazide combination in reducing cardiovascular events in patients with hypertension. ⁽⁵¹⁾
Bullous Pemphigoid is induced by hydrochlorothiazide therapy. ⁽⁵²⁾
In older patients with hypertension and > 1 other coronary heart disease risk factor, amlodipine or lisinopril is no better than chlorthalidone in lowering the risk of CHD or other cardiovascular disease events. ⁽⁵³⁾
Azilsartan. chlorthalidone can be considered an antihypertensive therapy option in patients for whom combination therapy is required (blood pressure > 20 mmHg systolic or > 10 mmHg diastolic above goal). ⁽⁵⁴⁾
Chlorthalidone for treatment of hypertension in older adults is associated with greater incidence of electrolyte abnormalities, particularly hypokalemia. ⁽⁵⁵⁾
There is an increased risk of hyponatremia with chlorthalidone relative to hydrochlorothiazide at equal milligram-to-milligram dose per day. ⁽⁵⁶⁾
There is an increase in serum lipids during the treatment of hypertension with chlorthalidone. ⁽⁵⁷⁾
Chlorthalidone and amlodipine is associated with lower visit-to-visit variability of systolic blood pressure than lisinopril. ⁽⁵⁸⁾
In Patients with hypertension already taking hydrochlorothiazide, switching to chlorthalidone further reduce systolic and diastolic blood pressures without clinically significant changes in renal function or electrolyte levels. ⁽⁵⁹⁾
Chlorthalidone is best in preventing heart failure in patients with hypertension. ⁽⁶⁰⁾
Agranulocytosis occurs secondary to chlorthalidone therapy in patients with hypertension. ⁽⁶¹⁾
Diminished response to norepinephrine may be a factor responsible for the antihypertensive efefct encountered after prolonged administration of chlorthalidone or hydrochlorothiazide. ⁽⁶²⁾
The hypertensive patients who donot achieve the target blood pressures on telmisartan and hydrochlorothiazide can be switched on to the temisartan and chlorthalidone combination. This is effective and well tolerated. ⁽⁶³⁾
Chlorthalidone is superior to hydrochlorothiazide in preventing cardiovascular outcomes. This may be due to pleiotropic effects of alternative medicines ot to hydrochlorothiazide’s short duration of action. ⁽⁶⁴⁾
Chlorthalidone is an effective antihypertensive in metabolic syndrome. ⁽⁶⁵⁾
In patients withg moderate to advanced chronic kidney disease with poorly controlled hypertension, chlorthalidone ignificantly reduce the blood pressure via volume contraction. ⁽⁶⁶⁾

Uses of thiazide diuretics

Edema
Hypertension
Diabetes insipidus
Hypercalciuria

Complications of high ceiling and thiazide type diuretic therapy

Hypokalemia
Acute saline depletion
Dilutional hyponatremia
GIT and CNS disturbances
Hearing loss
Allergic manifestations
Hyperuricemia
Hyperglycemia and hyperlipidemia
Hypocalcemia
Magnesium depletion
Thiazides have aggravated renal insufficiency, by reducing GFR
Brisk diuresis induced in cirrhotics may precipitate mental disturbances and hepatic coma. It may be due to hypokalemia, alkalosis and increased blood NH₃ levels
Diuretics should be avoided in toxemia of pregnancy in which blood volume is low despite edema. Diuretics may further compromise placental circulation increasing the risk of miscarriage, fetal death

Drug interaction

Thiazide and high ceiling diuretics potentiate all other antihypertensives
Hypokalemia induced by these diuretics:
Reduces sulfonylurea action
Increase risk of polymorphic ventricular tachycardia due to drugs which prolong QT interaval
Enhance digitalis toxicity
High ceiling diuretics and aminoglycoside antibiotics are both ototoxic and nephrotoxic; produce additive toxicity
Cotrimoxazole given with diuretics cause high incidence of thrombocytopenia
Indomathacin and other NSAIDs diminish the action of high ceiling diuretics
Probenecid competitively inhibit tubular secretion of furosemide and thiazides; decreases their action by lowering concentration in the tubular fluid, while diuretics diminish uricosuric action of probenecid
Serum lithium level rises due to enhanced reabsorption of Li⁺ (and Na⁺) in PT

Resistance to high ceiling diuretics

Refractoriness is more common with thiazides, but occur in certain circumstances with high ceiling diuretics as well. The causes and mechanism of such resistance include:

Cause	Mechanism
Renal insufficiency	Decreases access of diuretics to its site of action due to low GFR and low proximal tubular secretion
Nephritic syndrome	Binding of diuretic to urinary protein, other pharmacodynamic causes
Cirrhosis of liver	Abnormal pharmacodynamics; hyperaldosteronism; mechanism not clear
CHF	Impaired oral absorption due to intestinal congestion, decreased renal blood flow and glomerular filteration, increased salt reabsorption in PT

Carbonic Anhydrase Inhibitors

Acetazolamide

It is a sulfonamide derivative which non competitively but reversibility inhibits CAse (type II) in PT cells resulting in slowing of hydration of CO₂.
The net effect is inhibition of HCO₃^– reabsorption in PT.
The resulting alkaline diuresis is only mild
The secretion of H+ in DT and CD is also interfered
The urine produced under acetazolamide action is alkaline and rich in HCO₃^– and cause acidosis, less HCO₃^– is filtered at the glomerulus- less diuresis occurs
External action of acteazolamide is:
Lowering of intra ocular tension
Decreased gastric HCl and pancreatic NaHCO₃ secretion
Raised level of CO₂ in brain and lowering of pH
Alteration of CO₂ transport in lungs and tissues
Acetazolamide is well absorbed orally and excreted unchanged in urine. Action of a single dose lasts 8-12 hours
Acetazolamide 250 mg daily is the lowest effective dose to prevent acute mountain sickness. ⁽⁶⁷⁾
Acetazolamide, in a dose sufficient to inhibit the erythrocyte carbonic anhydrase induce a rapid and marked increase in cerebral blood flow (CBF), leaving cerebral metabolic rate for oxygen (CMRO2) unchanged. ⁽⁶⁸⁾
A single dose of acetazolamide effectively corrects metabolic alkalosis in critically ill patients by decreasing the serum SID (Strong Ion Difference). This effect is completely explained by the increased renal excretion ratio of sodium to chloride, resulting in an increase in serum chloride. ⁽⁶⁹⁾
The impact of acetazolamide on the haemodynamic alterations induced by hypobric hypoxia is considered among the beneficial effects of this drug in subjects prone to mountain sickness. ⁽⁷⁰⁾
Acetazolamide increases cerebral blood flow. The vasodilator response to acetazolamide did not change with age. ⁽⁷¹⁾
Acetazolamide inhibit the cerebrospinal fluid (CSF) flow and choroid plexus carbonic anhydrase enzyme. ⁽⁷²⁾
There is a significant effect of acetazolamide on bicarbonate, sodium and chloride reabsorption in the proximal tubule in the face of severe acidosis. The decrease in chloride reabsorption (and accompanying sodium) after acetazolamide is related to the decrease in bicarbonate reabsorption and the associated decrease in the transtubular chloride gradient. ⁽⁷³⁾
Acetazolamide induces cilio-choroidal effusion after cataract surgery. ⁽⁷⁴⁾
Acetazolamide an dsulfoaphane reduces the viability and growth of bronchial carcinoid cell lines. It can be used in the treatment of bronchial carcinoids. ⁽⁷⁵⁾
Acetazolamide is used in the treatment of hydrocephalus. ⁽⁷⁶⁾
Acetazolamide markedly depress volume flow and bicarbonate concentration in the stimulated pancreas with increase in chloride concentration. Concentrations of calcium, magnesium and total protein is increased. ⁽⁷⁷⁾
The intraocular tension even after 16 hours of administration of a single dose of acetazolamide is much below the initial level. The maximum effect is seen after 4-8 hours. Sustained release acetazolamide is recommended in the management of glaucoma as it assures uniform action. ⁽⁷⁸⁾
Low dose acteazolamide reverses periventricular white matter hyperintensities in idiopathic normal pressure hydrocephalus (iNPH). ⁽⁷⁹⁾
Uses:
Glaucoma
To alkalinize urine
Epilepsy acute mountain sickness
Periodic paralysis
Adverse effects
Acidosis, hypokalemia, drowsiness, paresthesia, fatigue, abdominal discomfort
Bone marrow depression
Contraindicated in liver disease, may precipitate hepatic coma
Acidosis likely to occur in patients with COPD

Potassium sparing diuretics

Aldosterone antagonist: Spironolactone

It is a steroid
It penetrates the late DT and CD cells and acts by combining with an intracellular mineralocorticoid receptor (MR) – induces the formation of aldosterone induced proteins (AIPs)
The AIPs promote Na⁺ reabsorption and K⁺ secretion
Spironolactone acts from the interstitial side of the tubular cell, combines with MR and inhibits the formation of AIPs in a competitive manner
Under normal circumstances, it increases Na⁺ and decreases K⁺ excretion
The oral bioavailability is 75%
It is highly bound to plasma proteins and completely metabolized in the liver, converted to active metabolite, the most important is Canrenone that is responsible for 1/2 – 2/3 of its action in vitro
T ½ is 1-2 hours and dose is 25-50 mg BD-QID
Oral spironolactone can be used in teenage girls for the treatment of acne vulgaris. ⁽⁸⁰⁾
Blockade of aldosterone receptors by spironolactone can substantially reduce the risk of both morbidity and death among patients with severe heart failure. ⁽⁸¹⁾
The use of spironolactone reduces left ventricular mass and improves arterial stiffness in early stage chronic kidney disease (CKD). ⁽⁸²⁾
Us eof spironolactone is associated with an incidence of adverse events which may have impact on treatment compliance in patients with heart failure. ⁽⁸³⁾
Spironolactone is an appropriate antihypertensive medication to add to treatment of patients with resistant hypertension (>3 antihypertensive medications at optimal doses). ⁽⁸⁴⁾
There is no evidence of increased risk of breast, uterus, ovarian and cervical cancer with spironolactone use. ⁽⁸⁵⁾
Spironolactone is more effective both as a diuretic and in conserving potassium compared to amiloride in hypertensive patients with thiazide-induced hypokalemia. ⁽⁸⁶⁾
Long term aldosterone receptor blockade improves the left ventricular diastolic function but did not affect maximal exercise capacity, patient symptoms or quality of life in patients with heart failure with preserved ejection fraction. ⁽⁸⁷⁾
Aldosterone contributes to vascular and soft tissue calcification. Spironolactone ameliorates PIT1-dependent vascular osteoinduction. ⁽⁸⁸⁾
Early treatment with lisinopril and spironolactone preserves cardiac and skeletal muscle in Duchenne muscular dystrophy mice. ⁽⁸⁹⁾
Spironolactone lowers the blood pressure especially in patients with aldosterone excess. ⁽⁹⁰⁾
Spironolactone prevents cardiac hypertrophy and decreases left ventricular ejection fraction in patients undergoing peritoneal dialysis without significant adverse effects. ⁽⁹¹⁾
Uses:
To counteract K+ loss due to thiazide and loop diuretics
Edema
Hypertension
CHF
Interactions:
Given with K+ supplements- hyperkalemia can occur
Aspirin blocks the spironolactone action by inhibiting the tubular secretion of its active metabolite Canrenone
Hyperkalemia occurs in patients receiving ACE inhibitors/ ARB
Spironolactone increases plasma digoxin concentration
Adverse effects
Drowsiness, ataxia, mental confusion
Epigastric distress and loose motion
Gynaecomastia, decreased libido, erectile dysfunction in males
Breast tenderness, menstrual irregularities in women
Hyperkalemia, acidosis in cirrhotics
Peptic ulcer is aggravated

Eplerenone

Newer more selective aldosterone antagonist, having lower affinity to other steroidal receptors
Much less likely to cause hormonal disturbances like gynaecomastia, menstrual irregularities, impotence etc
Risk of hyperkalemia and gi isturbances are similar to spironolactone
Well absorbed orally, inactivated in liver by CYP3A4, and excreted in urine as well as feces
Eplerenone is more selective with fewer side effects, but it is not proven to be superior to that of spironolactone. The American College of Cardiology recommends trying spironolactone first and then switching to eplerenone if patients develop gynecomastia, menstrual irregularities or impotence. ⁽⁹²⁾
Eplerenone ina dose 50-400 mg once daily is well tolerated and effective in reducing BP in patients with mild to moderate hypertension during a 24 h period. ⁽⁹³⁾
Eplerenone reduces both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms. ⁽⁹⁴⁾
Eplerenone doe not appear to be more effective in reducing clinical events compared to other older, less expensive aldosterone antagonists. ⁽⁹⁵⁾
Endothelial progenitor cells (EPCs) play a significant role in reendothelialization and vascular repair. Patients with chronic heart failure treated with eplerenone show higher numbers of EPCs. ⁽⁹⁶⁾
Eplerenone reduces risk of cardiovascular death or hospitalization in heart failure patients with reduced ejection fraction. ⁽⁹⁷⁾
Renal dysfunction with elevated albuminuria is seen in primary aldosteronism patients. Aldosterone antagonist eplerenone or spironolactone treatment is effective in preserving renal function. ⁽⁹⁸⁾
Eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension. ⁽⁹⁹⁾
Eplerenone regresses rapid pacing-induced electrical delays, inflammatory cytokine gene activation and fibrosis in heart failure. Ventricular arrhythmia vulnerability in heart failure is correlated with the extent of fibrosis and electrical activation delays during premature excitation. ⁽¹⁰⁰⁾
The major metabolic pathways were 6β- and/ or 21-hydroxylation and 3-keto reduction. The primary metabolic products excreted in urine and feces include 6β- hydroxy-EP, 6β-21OHEP, 21-OHEP and 2α,3β 21-OHEP. ⁽¹⁰¹⁾
The anti-fibrotic effect of eplerenone appears to be unrelated to its effect on blood pressure. Eplerenone inhibits renal inflammation, interstitisal cell proliferation, phenotypic changes in interstitial cells and reduces oxidative stress. ⁽¹⁰²⁾
Specifically indicated in
Moderate to severe CHF
Post infarction left ventricular dysfunction
Hypertension

Inhibitors of renal epithelial Na⁺ channel

Triamterene and amiloride are two non steroidal organic bases
Decrease K⁺ excretion , accompanied by small increase in Na⁺ excretion
They are inhibitors of renal epithelial Na+ channel
Both triameterene and amiloride are used in conjunction with thiazide or high celining diuretics to prevent hypokalemia and slightly augment the natriuretic response
Hyperkalemia is the most important adverse effects
Hyperkalemia is more likely in patients with ACE inhibitors/ ARBs, β blockers, NSAIDs and in those with renal impairment
Both drugs elevate plasma digoxin level

Triameterene

Incompletely absorbed orally, partly bound to plasma proteins, largely metabolized in liver to to an active metabolite and excreted in urine
Plasma t ½ is 4 hours, effect of a single dose lasts 6-8 hours
Triamterene is safe and effective diuretic in patients with congestive heart failure. It itself does not produce kaliuresis and blocks thiazide-induced kaliuresis. Serum uric acid may rise slightly. ⁽¹⁰³⁾
Triamterene may cause interstitial nephritis in hypertensive patients. ⁽¹⁰⁴⁾
Triamterene may be a useful adjunct for thiazide treated hypertensive patients by decreasing the likelihood of complicating hypokalemia. ⁽¹⁰⁵⁾
Thiazide trimaterene treatment may offer an alternative in some patients with primary aldosteronism who do not tolrate spironolactone. ⁽¹⁰⁶⁾
Triamterne crystalline nephropathy can occur in patients taking the medication. It can cause tbulointerstitial insult leading to acute kidney injury through multiple mechanism. ⁽¹⁰⁷⁾
Triamterene therapy can induce nephrolithiasis in patients. ⁽¹⁰⁸⁾
The renal tubular secretion of trimaterne is mediated by the organic cation system, whereas for p-hydroxytriamterene sulfate its tubular secretion is via the organic anion system. Famotidine is a weaker inhibitor of the organic anion system. ⁽¹⁰⁹⁾
Triamterene is a valuable supplement to thiazides in long term antihypertnesive treatment. ⁽¹¹⁰⁾
A well formulated hydrochlorothiazide-triamterene combination tablet promotes plasma concentrations and urinary excretion of hydrochlorothiazide, triamterene and hydroxytriamterene sulfate.⁽¹¹¹⁾
The use of high dose triamterene and spironolactone protect against the hypokalemic and ECG sequelae of combined beta-agonist/diuretic therapy, whereas a conventional dose of triamterene had no effect. ⁽¹¹²⁾
Side effects:
Nausea, dizziness, muscle cramps, rise in blood urea
Impaired glucose tolerance
Photosensitivity
Urate level is not increased

Amiloride

10 times more than triamterene (dose 5-10 mg OD-BD)
At high doses, it also inhibits Na+ reabsorption in PT
It decreases Ca²⁺ and Mg²⁺ excretion but increases urate excretion
Hyoercalcemic action of thiazides is augmented, hyperuricemic action is pertly annulled
Only 1/4^th of the drug is absorbed
It is not bound to plasma proteins and not metabolized
t ½ is 20 hours and duration of action are longer than triamterene
Amiloride has an antiarrhythmic activity in the suppression of sustained ventricular tachyarrhythmias in postinfarction model. ⁽¹¹³⁾
Acid sensing ion channel (ASIC) are leading acid sensors in human nociceptors and that VR1 participate in the nociception mainly under acidic conditions. Direct infusion of acidic solutions into human skin causes localized pain, which is blocked by amiloride, an inhibitor of ASICs. ⁽¹¹⁴⁾
Amiloride slectively inhibits the urokinase-type plasminogen activator. It could prove useful in selectively controlling u-PA-catalyzed extracellular proteolysis. ⁽¹¹⁵⁾
Amiloride did not significantly protect against the bronchoconstriction induced by cold air hyperventilation challange (CAHC). Inhaled amiloride did not affect FEV1 in the hour after inhalation. ⁽¹¹⁶⁾
Amiloride induced reduction of lithium uptake in the principal cells of the collecting duct improves responsiveness to AVP-stmulated translocation of AQP2 to the apical membrane of the principal cells. ⁽¹¹⁷⁾
Amiloride sensitive Na⁺ channels appear to be expressed in cells that lack voltage-gated inward currents, likely the Type I taste cells. ⁽¹¹⁸⁾
Intrathecal pretreatment with naloxone completely blocks the antinociceptive effect of morphine and the amiloride-morphine mixture. Intrathecal pretreatment with yohimbine completely blocks the antinociceptive effect of clonidine and antagonize the effect of amiloride-clonidine mixture. There is no motor dysfunction or significant change in blood pressure or heart rate after intrathecal administration of amiloride, amiloride-morphine and amiloride-clonidine. The synergistic effect was observed after co-administration of amiloride and morphine or clonidine suggesting a functional interaction among calcium channels, μ-receptors and α2-receptors at the spinal cord level of the nociceptive processing system. ⁽¹¹⁹⁾
Amiloride and amiloride plus hydrochlorothiazide is effective as diuretic antihypertensive potassium conserving agents. ⁽¹²⁰⁾
Amiloride inhibits macropinocytosis by lowering submembranous pH and preventing Rac1 and Cdc42 signalling. ⁽¹²¹⁾
Topical amiloride may find potential applications in the treatment of dry eye syndromes. The increase of Schirmer test I scores after application of amiloride eye drops may be due to retention of secreted tears on the ocular surface through suppression of tear resorption from the conjunctiva. ⁽¹²²⁾
Side effects:
nausea, diarrhea
headache
Amiloride blocks entry of Li⁺ through Na⁺ channels in CD cells and mitigates diabetes insipidus induced by lithium

Osmotic diuretics

Mannitol

Non electrolyte of low molecular eight that is pharmacologically inert
Can be given in large quantities sufficient to raise osmolarity of plasma and tubular fluid
It is minimally metabolized in the body, freelt filtered at the glomerulus and undergoes limited reabsorption
Actions include:
Retain water isoosmotically in PT
Inhibit transport process in the thick AcsLH
Expands extracellular fluid volume, increases GFR and inhibit rennin release
Increases renal blood flow, especially to the medulla- passive salt reabsorption is reduced
Mannitol is not well absorbed orally; has to be given iv as 10-20% solution
It is excreted with t ½ of 0.5-1.5 hour
Mannitol is used as diuretic to treat intractable edema states, to increase urine flow and flush out debris from the renal tubules in acute tubular necrosis and to increase toxin excretion in patients with barbiturates, salicylate and bromide intoxication. As an obligate extracellular solute, it is useful to ameliorate symptoms of the dialysis disequilibrium syndrome, to decrease cerebral edema following trauma or cerebrovascular accidents, and to prevent cell swelling related to renal ischemia following cross-clamping of the aorta. It is used as an osmotic agent in peritoneal dialysis, to maintain urine output in hemodialysis and to limit infarct size following acute myocardial infarction. ⁽¹²³⁾
Osmo-induced synthesis of the comaptible solute mannitol is by a two step pathway. Mannitol-1-phosphate dehydrogenase mediates the first step of this pathway, it is regulated by salinity on the transcriptional as well as on the activity level. ⁽¹²⁴⁾
The new hydration protocol comprising supplementation with magnesium and mannitol wiythout furosemide could prevent the nephrotoxicity induced by cisplatin and pemetrexed without affecting the treatment outcome in patients with advanced non small cell lun cancer. ⁽¹²⁵⁾
Mannitol therapy for raised intra cranial pressure (ICP) may reduce mortality rate more than pentobarbital. ICP directed mannitol treatment may be better than using clinical parameters alone. ⁽¹²⁶⁾
Mannitol and hypertonic saline can be used in a variety of disease states causing cerebral edema. ⁽¹²⁷⁾
Mannitol clearance is independent of dose. Only the 1.5-g/kg dose produced a sustained of serum osmolality, confirming the large doses are likely to result in prolonged hypertonic dehydration. ⁽¹²⁸⁾
The vasodilator response to mannitol in the ischemic rat kidney is mediated by increased prostaglandin (PGI2) activity. ⁽¹²⁹⁾
Acute intracranial hypertension may respond to intravenous mannitol, but frequent administration can cause cerebral edema or renal problems. ⁽¹³⁰⁾
Mannitol infusion in patients with acute intracerebral hemorrhage can improve cerebral blood flow in bilateral hemispheres and decrease intracranial pressure in the hemorrhagic hemisphere and in the nonhemorrhagic hemisphere. ⁽¹³¹⁾
The mannitol therapy should be guided by 12 hourly measurement of serum osmolality. Mannitol should be used for 48 hours only if facilities for measuring serum osmolality are not available. ⁽¹³²⁾
Mannitol and methacholine are therapeutically equivalent to identift exercise induced bronchoconstriction and clinical diagnosis of astham. Mannitol challange has the potential to replace other challanges for BHR. ⁽¹³³⁾
Adverse effects:
Headache
Nausea, vomiting
Hypersensitivity reactions
Uses:
Increased intracranial or intraocular tension (acute congestive glaucoma, head injury, stoke etc)
To maintain GFR and urine flow in impending acute renal failure (shock, severe trauma, cardiac surgery, hemolytic reactions)
To counteract low osmolality of plasma/ ecf due to rapid hemodialysis or peritoneal dialysis
Contraindicated in
Acute tubular necrosis
Anuria
Pulmonary edema
Acute left ventricular failure
CHF
Cerebral hemorrhage

References:

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