Water constitutes about 60% of the average adult body weight and is responsible for many physiological processes in the human body. Thus, fluid and electrolyte homeostasis is critical for human survival as exemplified by the potentially devastating consequences of fluid imbalance. The balance of total body fluid is an extremely well-regulated process which ensures the maintenance of a balance between fluid gain and loss through different physiological mechanisms such as neural regulation of thirst, hormonal regulation (vasopressin and natriuretic peptides), management through the skin, hemodynamic changes, and renal control of salt and water excretion. In particular, renal excretion of urine also ensures the elimination of products of metabolic activity and excess electrolytes in addition to water, thus maintaining fluid homeostasis. Fluid balance so inextricably links with electrolyte balance both in the intracellular (rich in K+ ions) and extracellular (rich in Na+ & Cl- ions) compartments, that unsurprisingly, trading of electrolytes is the core strategy of renal fluid regulation. Drugs that affect renal regulation of electrolyte excretion have the greatest effect in terms of the quantity of fluid control and thus water homeostasis.
Diuretics are drugs that pharmacologically tilt the renal fluid regulation in favor of excretion of water and electrolytes. Thus, diuretics are substances that increase the production and volume of urine. This class of drugs achieves this objective primarily by suppressing receptors that aid in reabsorption of Na+, the most abundant extracellular cation, from the renal tubules, thereby increasing the osmolality of the renal tubules and consequently suppressing water reabsorption. Osmotic diuretics cause a direct increase in luminal hyperosmolarity in the renal tubules without affecting electrolyte balance, whereas aquaretics are substances that act directly by only affecting the excretion of water.
This comprehensive review addresses all the relevant aspects of diuretic therapy, emphasizing the understanding of the basic pharmacophysiological mechanisms of drug action and that of adverse effects but also to more pragmatic aspects of dosing as well. Diuretics fall into several classes and subcategories depending on their mechanism and site of their action along the nephron. The classification is presented in Table 1, which lists all the available individual drugs in all the different classes, their peculiarities, chemical nature, their major site of action along the nephron, diuretic target molecule, and the percentage of Na+ reabsorption blocked. Additionally, Table 1 also gives information (to put things in a broader perspective) about miscellaneous agents that do not have a conspicuous diuretic action and are not used for diuresis, but they do have some diuretic effect which is noticeable which must be taken into account during therapy with these agents.
Diuresis is necessary for a variety of non-edematous and edematous conditions, which require clearing out excess water when the body abnormally sequesters fluid in third space in the form of edema. Indications for each individual drug is given below in tables 2 through 5. The quintessential of edematous conditions is heart failure (HF) where the inefficiency of the heart’s pumping ability results in:
1. Decreased renal perfusion leading to activation of the renin-angiotensin-aldosterone-system (RAAS) and
2. Long-standing venous stasis leading to extravasation of fluid into the interstitial space, both of which lead to intravascular volume expansion and result in signs of congestion such as weight gain, dyspnea, and generalized edema.
Pulmonary edema, most commonly resulting from HF, is also an indication for diuretic use. Loop diuretics (due to their greater effectiveness) are the cornerstone of diuretic therapy in symptomatic HF, with furosemide being the most widely used loop diuretic (albeit Torsemide with better pharmacological properties remains underexploited and a comparison trial, TRANSFORM-HF, is currently underway) according to both New York Heart Association (NYHA) and European Society of Cardiology (ESC). These agents are started at lower doses and titrated upwards and monitored through urine output and body weight measurements. Addition of thiazide diuretics (metolazone, hydrochlorothiazide) to loop diuretics can help in relieving symptoms when loop diuretics are not sufficient in HF as detailed below in the administration section. Aldosterone receptor antagonists (ARA) reduce the mortality and morbidity of advanced systolic HF and in patients with ejection fraction less than 35% falling into NYHA-HF classification categories II-IV. This effect is because aldosterone escapes suppression on chronic use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), whereas the addition of ARAs can protect from the effects of aldosterone in such patients.
Diuretics, along with salt restriction, are also recommended as the first-line therapy in ascites due to liver cirrhosis. In cirrhotic ascites, spironolactone is the drug of choice for initial therapy (due to its antiandrogenic effect), although a loop diuretic may be added as an adjunct if the treatment fails or can be added at the outset in synergistic combination therapy. In both HF and cirrhosis, renal dysfunction contributes to the pathophysiology through further activation of RAAS to increase the retention of fluid. Fluid overload that develops in renal insufficiency or acute kidney injury patients increases mortality, and loop diuretics are the favored initial therapy in these patients though renal replacement therapy is the long-term solution. Nephrotic syndrome (NS) characterized by hypoalbuminemia, proteinuria, and hyperlipidemia is an edematous condition that requires diuretic therapy. Activation of epithelial Na+ channels (ENaCs) in the collecting ducts is the mechanism of edema formation in NS, while RAAS activation could also play a minor role. All the diuretics are serum albumin-bound, and hence hypoalbuminemia in NS decreases the load of diuretic delivered to the renal tubules. Co-administration of albumin with furosemide or a combination of furosemide and ENaC inhibitor such as triamterene has shown some success in kidney disease patients with hypoalbuminemia. A gain-of-function mutation in ENaC receptors clinically causes Liddle syndrome for which ENaC inhibitor amiloride is the treatment of choice.
Thiazides are the best first choice for hypertension, as concluded in a recent Cochrane review, and chlorthalidone is the best first-line agent among all the anti-hypertensive compared according to the 2017 American college of cardiology (ACC) hypertension guidelines. Chlorthalidone, with its longer duration of action and longer half-life, at lower doses, was found to significantly reduce the risk of cardiovascular (CV) events when compared to other anti-hypertensive medications. Indapamide has lower metabolic adverse effects when compared to chlorthalidone due to its non-interference in lipid or glucose metabolism and much safer for use in hypertension, making it suitable for patients with diabetes. Direct vasodilatory effects of thiazide-like diuretics also contribute to the lowering of blood pressure (BP) on long term therapy. On the other hand, loop diuretics may be the preferred agent when hypertension is associated with chronic kidney disease (CKD) or glomerular filtration rate (GFR) less than or equal to 30 mL/min (though some recent reports still favor thiazides in this setting) and potassium-sparing diuretics (PSD) are used in hypertensive patients with K+ or Mg2+ loss..
Thiazide-related reabsorption of calcium might be advantageous in nephrolithiasis and hypercalciuria, whereas loop diuretics cause calciuresis and therefore are suitable for use in symptomatic hypercalcemia patients. Diabetes insipidus, a polyuric disease, results in a loss of dilute urine with low sodium levels, and paradoxically thiazide diuretics can help by increasing distal tubule Na+ excretion, which compensatively increases water and Na+ reabsorption in the proximal tubule (PT); thus impairing the maximum diluting capacity of kidneys. Acetazolamide, the only carbonic anhydrase inhibitor available, induces metabolic acidosis by increased bicarbonate excretion and is used as a prophylaxis in high altitude sickness where it counteracts the hypoxia-induced respiratory alkalosis raising the PaO2 and with similar logic its use is warranted in reversing metabolic alkalosis. Acetazolamide effectively reduces the intraocular pressure and is used for short-term therapy for open-angle glaucoma when topical therapy is not feasible. There is inconclusive evidence “for” or “against” the use of diuretics in Ménière disease.
Osmotherapy is the mainstay of medical therapy for raised intracranial pressure (ICP) after traumatic brain injury and cerebral edema. Hyperosmolar therapy with mannitol reduces elevated ICP rapidly in less than an hour though a rebound (an initial increase of ICP) is a possibility. Mannitol also promotes diuresis in acute renal failure and to excrete toxic metabolites and substances. Though hypertonic saline similarly is used to treat high ICP and sometimes has demonstrated greater efficiency than mannitol is not considered a diuretic.
Diuretics can also be employed less commonly in the active elimination of toxic substances by forced diuresis, which increases urine volume per unit time. Clinicians employ loop diuretics along with alkalinization of the urine in forced alkaline diuresis in the treatment of salicylate, phenobarbital, and lithium poisoning. Loop diuretics (along with salt tablets) are also used as a second-line therapy to decrease urine concentration in the syndrome of inappropriate antidiuretic hormone secretion (SIADH), where the mainstay of therapy is the restriction of water intake. The loop diuretic bumetanide has shown effectiveness as an anti-seizure drug and is used in temporal lobe epilepsy in addition to other central nervous system pathologies such as autism and schizophrenia.
Almost all diuretics act by targeting ion transport receptors that are present on the luminal surface in the renal tubules, except for ARAs, which act on cytosolic steroid receptors. All the diuretics are bound to albumin, and as glomerular filtration excludes macromolecules such as albumin, active secretion of diuretic agents into the lumen is a prerequisite for their action. ARAs reach the distal tubule via the blood and act on the mineralocorticoid receptor (MR) in the cytoplasm of the principal cells. Diuretics, which are acidic (loop, thiazides, and acetazolamide) or basic (ENaC inhibitors), are secreted respectively via the organic anion or organic cation transporters (OATs, OCTs), located on the basolateral surface of cells in the straight segment of PT.
For a thorough understanding of the diuretic action and its adverse effects, certain general principles regarding renal physiology are critical. The following section will explain the mechanisms of action of different diuretics, starting with a brief physiological introduction of the concerned portion of the renal tubule followed by the mechanism of action of the particular diuretic.
In the Bowman’s capsule, plasma from the renal artery passes through the three-layered glomerular ultrafiltration system and delivers an ultrafiltrate that is isotonic to that of plasma. The contiguous PT reabsorbs about 60 to 70% of the filtered load, including Na+, water along with bicarbonates (HCO3+), organic solutes (glucose and amino acids), electrolytes, and other substances. Such massive reabsorptive capacity occurs with the help of the specific transport receptors in the brush border cells, which increases the surface area of the PTs yielding a fluid, in the end, that is isotonic (300 mOsm/kg) with the plasma. Na+ in the filtrate gets reabsorbed and enters the cell in exchange for H+ (present inside the cells) through Na+-H+ exchanger (NHE3) present in the luminal membrane and maintains electrical neutrality across the membrane. The H+ ions that reached the lumen combine with the filtered HCO3+ ions to form carbonic acid (H2CO3) in the lumen and this breaks down into H2O and CO2 with the help of the enzyme carbonic anhydrase present on the luminal side of the brush border cell. CO2 diffuses back into the cell, and H2O is reabsorbed via aquaporin-1 channels into the cell, both of which combine to form H2CO3 with the help of cellular carbonic anhydrase, which further catalyzes them to form HCO3+ and H+ ions inside the cells. Almost 80% of filtered HCO3+ is reabsorbed in the PT cells in this way and exits the basolateral membrane along with Na+ (that entered via NHE3 channels) through the Na+/HCO3+ co-transporter (NBCe1). Na+-K+-ATPase pump avidly depletes the excess cellular Na+ ions along the basolateral membrane while also providing the energy for NHE3 channels by creating low Na+ levels inside the cell. The renal reabsorption of HCO3+ and secretion of H+ ions play an important role in acid-base homeostasis and steady maintenance of pH in the body.
Acetazolamide, the only CAI, acts on this segment. Acetazolamide interferes non-competitively with both the luminal and cellular carbonic anhydrase enzymes resulting in impairment of Na+, HCO3+, and water reabsorption. Though acetazolamide targets the proximal portion of the renal tubule, where the majority of the Na+ ions undergo reabsorption, compensatory processes develop in the distal portions to reabsorb the increased distally delivered Na+ ions. These processes include the Na+ reabsorption mechanisms in the loop of Henle, the distal convoluted tubule (DCT), the activation of tubuloglomerular feedback (TGF), and in amiloride-sensitive distal nephron (ASDN) through ENaCs. Increased HCO3+ leads to alkaline diuresis, causing decreased serum HCO3+ levels which further undermines the substrate availability for carbonic anhydrase mediated Na+ reabsorption in the PTs resulting in decreased efficiency of acetazolamide.
Acetazolamide acts on carbonic anhydrase, causing loss of HCO3+ ions in the urine leading to metabolic acidosis. The physiological response of the body to compensate for this loss of HCO3+ ions is by decreasing the levels of CO2, in other words, by causing respiratory alkalosis; this takes place by hyperventilation, which leads to increased expiration of CO2 leading to higher partial pressures of O2 in the arterial blood. As high altitude is a low O2 environment, the action of acetazolamide decreases the incidence of tissue hypoxia in high altitudes. Thus it is the drug of choice in altitude sickness.
The cortical proximal convoluted tubule descends into the outer medulla to continue as the thin descending limb of the loop of Henle, forms a hairpin loop in the inner medulla, and ascends back as thin and thick portions of the ascending limb of the loop and reaches back to the cortex. This structural arrangement is critical for the urinary concentrating ability of the kidney achieved by the countercurrent multiplier system of the loop of Henle. Electroneutral Na+-K+-2Cl- co-transporter 2 (NKCC2) present in the apical surface of thick ascending limb (TAL) reabsorbs 25 - 30% of the filtered Na+ into the cells. The driving force for this action is the favorable low Na+ concentration in the tubular cells achieved by the Na+-K+-ATPase antiporter pump present in the basolateral membrane. This channel pumps 3 Na+ out of the cell (into the interstitium) for every 2 K+ that comes into the cell. Excess chloride from the cells is transported via the chloride-specific channels (ClC-Ka and ClC-Kb), also on the basolateral side, which requires Barttin beta-subunits for their action. Renal outer medullary K+ (ROMK) channel present in the luminal membrane, in turn, secretes and recycles back the K+ from the cell into the lumen with the help of ATP. Collectively, this not only results in creating a hyperosmolar medullary interstitial environment but also a luminal positive charge that repels luminal cations Na+, Ca2+, and Mg2+ via the paracellular pathway into the interstitium. Of note, TAL, devoid of aquaporins, is impermeable to water, and reabsorption of only the tubular solutes leads to dilution resulting in a hypotonic fluid inside the lumen (thus aka diluting segment). The thin descending segment of the loop is permeable to water, and the hyperosmolarity in the medulla draws the water out of this segment through the aquaporin-1 channels resulting in a hypertonic tubular fluid. As this tubular fluid flows continuously in the loop, repeated actions in thick and thin limbs create an osmolar gradient in the length of the medulla with concentrations in the inner medulla that can reach up to 1200 mOsm/kg of H2O. Loop diuretics act on this segment.
Loop diuretics act principally by blocking the electroneutral NKCC2 (isoform in the kidneys) channels located on the luminal (apical) membrane of the TAL. Every loop diuretics have distinct chemical structures, but all are anions that assists them in blocking the chloride-binding site of the translocation pocket of the NKCC2 transmembrane receptor. Blockage of NKCC2 action in the TAL results in inhibition of Na+, K+, and 2Cl- reabsorption and reduced interstitial tonicity, thereby thwarting the countercurrent mechanism of urinary concentration. Within the lumen, however, the dilution function of the TAL is compromised and results in excess Na+ delivery to the distal tubules by which one would expect would lead to an activation of the tubuloglomerular feedback (TGF) mechanism. TGF is a mechanism that is activated when macula densa, specialized epithelial cells in the distal tubule, senses increased NaCl levels in the lumen and causes constriction of afferent glomerular arterioles, thereby reducing the GFR. It turns out macula densa cells also contain the NKCC2 symporters, and their antagonism by loop diuretics causes decreased salt sensing ability in these cells, which results in inhibition of the TGF mechanism. Low-salt or diuretic volume depletion also induces the release of renin activating the RAAS pathway, which helps maintain GFR by increasing BP. Loop diuretics are the most potent among all the diuretics as they inhibit the largest amount of Na+ reabsorption (25% of filtered Na+). High efficiency of loop diuretics results from profound diuretic action and therefore has acquired the tag of “high-ceiling” and “high-efficiency” diuretics.
Acute tolerance to loop diuretics occurs within sometime after dosing and can cause a ‘braking phenomenon,’ which is rebound retention of Na+ due to increased reabsorption from the distal tubules, while chronic tolerance can occur due to distal tubular structural adaptation by the kidneys to increase Na+ retention. Acute tolerance can be overcome by choosing the correct dosage, frequency of dosing, the timing of diet, and dietary salt restriction. Chronic tolerance in HF may cause diuretic resistance leading to refractory HF, and this can sometimes be overcome by increasing the dose of loop diuretics, co-administering thiazide-like diuretics along with loop diuretics to perform a sequential nephron blockade and/or dopamine can be administered to improve renal perfusion. Also, the combination of acetazolamide and loop diuretics has demonstrated effectiveness in diuretic resistance as acetazolamide can overcome the proximal tubular Na+ reabsorption.
Mutation of NKCC2 channels causes Type I Bartter’s syndrome, which is usually present at birth and characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and nephrocalcinosis.
The distal convoluted tubule (DCT) starts at the macula densa and ends at the collecting duct, and 5 to 10% of the filtered Na+ load is reabsorbed here via the NaCl co-transporter (NCC). NCC channels can be activated by aldosterone, insulin, vasopressin, and angiotensin II, leading to increased NaCl reabsorption. NCC is an electroneutral Na+ and Cl- symporter, expressed throughout the DCT, and like NKCC2, derives its energy from low cellular Na+ achieved by basolateral Na+-K+-ATPase pump. As NCC channels are the predominant mechanism for Na+ reabsorption in DCT, this segment is endowed with abundant mitochondria to supply ATP for the pump. Reabsorbed Na+ exits the cell via the basolateral Na+-K+ pump into the interstitium, while Cl- is transported to the interstitium via the basolateral ClC-Kb and K+-Cl- co-transporter4 (KCC4). Tubular K+ secretion occurs through both ROMK and “maxi”-K+ channels in high-flow conditions and only through ROMK in low-flow conditions. In contrast to TAL, 10% of both Ca2+ and Mg2+ reabsorption occurs only via active transport via transient receptor potential (TRP) channel subfamilies. The early portion of DCT (with only NCC channels) has a zero potential, while the late DCT has a luminal negative voltage due to the presence of electrogenic ENaC channels here. Due to the absence of aquaporins, it is considered the terminal diluting segment of the nephron and dilutes the urine further before it reaches the next segment. Thiazide diuretics and ENaC inhibitors act on this segment.
Thiazide diuretics are superior to any other diuretic agent for hypertension treatment and subdivide into two subcategories, i.e., thiazide-type and thiazide-like diuretics. Thiazide-like diuretics are so-called because they lack the benzothiadiazine backbone (thus the chemical properties associated with it), which is characteristic of Thiazide-type agents. Among the Thiazides, thiazide-like drugs are exceptional and better than thiazide-type diuretics in handling high BP with the least adverse effects such as metabolic or electrolyte disturbances.
In the DCTs, the most abundant Na+ reabsorption occurs through the NCC channels, which are the lone targets of thiazide diuretics. Thiazides exert their action by competitively binding to the chloride binding site of the NCC’s transmembrane domain and inhibiting the Na+ reabsorption. The important role of NCC channels is well-established as in patients with loss-of-mutation of this channel causes Gitelman syndrome manifesting with hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria, and lower systemic BP. Gordon’s syndrome is the inverse of Gitelman’s phenotype in that they cause gain-of-function mutation of NCC leading to salt retention and is treatable with thiazides.
TGF mechanism is not inhibited by thiazides (in contrast with loop agents) as the anatomical positioning of DCTs is after the macula densa. Increased renin secretion by thiazides is mediated only through volume depletion rather than low-salt delivery to the macula densa, as in loop diuretics.
Low-dose thiazide-like agents are considered as the best antihypertensive agent as it lowers BP on chronic use irrespective of volume depletion. Though the exact mechanism is still unclear, it is theorized to occur through direct endothelial or vascular smooth muscle-mediated vasodilation (probably by altering Ca2+ regulation), reverse whole body regulation, and/or renal autoregulation.
Connecting tubules are short segments of renal tubules connecting the DCT with the collecting duct. Collecting duct forms the concluding segment of the nephron and receives only about 10% of the glomerular filtrate, and the Na+ reabsorptive capacity of this segment varies significantly from 1 to 5%. Aquaporin-2 is the subtype of aquaporins expressed in both connecting tubules and collecting duct, and their density is the highest in the medullary collecting duct. The antidiuretic hormone vasopressin acts only on the aquaporin-2 subtype of aquaporin channels located in the distal nephron and does not bind to the aquaporin-1 channels located in the proximal nephron.
Apart from these structural segments, there is a functional segment of the distal nephron comprising of late DCT, connecting tubules, and collecting ducts (both cortical and medullary) are referred to as the aldosterone-sensitive distal nephron (ASDN). The principal cells are one of the major epithelial cell types located in ASDN and identify with the cytoplasmic MR for aldosterone and luminal membrane ENaC receptors. ENaC receptors expressed in ASDN are responsible for the final fine-tuning of the tubular fluid and accounts for reabsorption of about 3% of the filtered Na+ load. The energy required for the function of ENaC derives from the electrochemical gradient created by the basolateral Na+-K+-ATPase pump. Increased reabsorption of Na+ through electrogenic ENaC creates a more negative luminal potential, which paves the way for the cells to secrete K+ through the luminal ROMK channels, which express specifically in ENaC positive cells. Alpha-intercalated cells, however, are responsible for H+ secretion in response to luminal negative charge causing tubular acidification via the proton pump H+-ATPase. Both the types of PSDs act on the ASDN segment.
PSD, as the name suggests, overcomes the increased loss of K+ ions in the urine, thereby preventing hypokalemia, a predominant side effect of other diuretics. ENaC inhibitors and ARAs, two subcategories belonging to this class, are structurally different, and they target different types of receptors. ENaC inhibitors are pteridine analogs and are secreted in the PTs to reach the tubular lumen to bind to ENaC receptors located in the principal cells of ASDN, while ARAs are synthetic steroid analogs and bind to the cytoplasmic MR. Notwithstanding these differences, K+ retaining ability of both the subtypes of this class at the end is by their action on ENaC receptors, while the ENaC inhibitors achieve this by acting directly to suppress these receptors, ARAs act indirectly by suppressing the aldosterone-induced proteins which increase production, redistribution (from the cytosol to membrane) and activation of ENaC receptors.
These drugs account for the inhibition of only 3% of the filtered Na+ load and are thus not very potent diuretics. ENaC inhibitors, amiloride, and triamterene are primarily used in situations to correct hypokalemia induced by other diuretics without mineralocorticoid excess. They are also used to treat hypomagnesemia that can occur with diuretics, antibiotics, chemotherapeutic drugs, and immunosuppressants. ENaC inhibitors are, therefore, both K+-sparing and Mg2+-sparing agents. Spironolactone being non-selective, also mediates its effect through its anti-androgenic activity and can be used in the treatment of androgen-excess syndromes such as hirsutism. Eplerenone is favored for the pharmacological treatment of primary aldosteronism due to its selective mineralocorticoid antagonism..
As opposed to other agents, osmotic diuretics do not interfere with electrolyte reabsorptive mechanisms, and their main diuretic action is mediated through increasing osmolarity of the tubular fluid in PT and TAL of the loop of Henle. Mannitol is freely filtered nonmetabolized sugar, which increases the osmolality of both plasma and renal tubular fluid, causing osmotic diuresis. Mannitol raises the serum osmolality and since it does not cross the blood-brain barrier causes a positive blood-cerebrospinal fluid osmotic-gradient resulting in brain dehydration (without affecting the brain blood flow), the effect required for reducing the intracranial pressure. Mannitol is poorly reabsorbed and causes a wash-out of medullary solute gradient inhibiting the countercurrent urinary concentration function, thus drawing water along with it to the collecting ducts. This osmotic effect is similar to that of excess tubular glucose due to diabetes mellitus leading to polyuria.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors are novel oral anti-diabetic medications that inhibit the low affinity, high capacity SGLT2 receptors in the PT. SGLT2 receptors are involved in the reabsorption of 90% of filtered glucose along with Na+ ions from the renal tubules and become overexpressed in Type-2 diabetes mellitus. By blocking these receptors, SGLT2 inhibitors increase glucose excretion in the urine, thereby increasing the tubular osmolarity, which in turn causes osmotic diuresis. These agents ending with the suffix –gliflozins, can thus cause diuresis, natriuresis (due to associated Na+ loss), and reduce extracellular fluid volume. The diuretic action of these agents is only transient due to the development of compensatory adaptive mechanisms to maintain fluid volume by the kidneys.
ACEIs and ARBs can cause natriuresis and diuresis primarily by blocking the production of the downstream molecules of the RAAS pathway, angiotensin II and aldosterone, which are involved in renal conservation of water and salt. Though the antihypertensive action of these drugs is primarily due to the systemic effects of BP reduction, diuretic actions also play a minimal role. They are sometimes combined with other diuretics to enhance the effect. Stronger alcoholic beverages (more than 13.5% alcohol), when consumed in moderation, can cause a transient diuretic effect without any electrolyte disturbances. Under conditions of hypohydration, alcohol does not induce any diuretic effect to restore fluid balance.
Conivaptan and tolvaptan are not classified under diuretics but are called aquaretics due to their effects in increasing only the water excretion without any saluretic action of a diuretic. Conivaptan (IV route only) acts nonselectively on both V1A & V2 vasopressin receptors, whereas tolvaptan (oral agent) is a selective antagonist of V2 vasopressin receptors. Arginine vasopressin agonist action on its receptor leads to increased expression of luminal aquaporin-2 channels (thus promoting water reabsorption), whereas its antagonism by aquaretics leads to enhanced aquaresis. Aquaretics, with their electrolyte-sparing effect, is currently indicated for use only in hyponatremia.
Diuretic administration is usually via the oral route, but when maximum potency is required, such as in cases of advanced HF, it can be given intravenously in a hospital setting. In such situations, continuous infusion over a specified period is preferable to bolus injections. Adverse effects (or complications) in a particular patient should be well-anticipated, and the choice of diuretic, the dose required, route of administration, and needed clinical improvement should all merit consideration before administering any diuretic agent.
Loop diuretics are more than 95% albumin-bound and reach peak concentrations in 30 min to 2 hours as they are absorbed swiftly with an oral bioavailability that exceeds 80% for bumetanide and torsemide while that of furosemide is the lowest at 50% on average. Loop diuretics are available in both oral and intravenous (IV) forms, and IV infusions can be for immediate effect. Furosemide is excreted unchanged in urine or through a renal metabolism, while bumetanide and torsemide undergo hepatic metabolism (hence respective organ damage will prolong their half-life). Torsemide has the longest half-life (3 to 4 hours) and the longest duration of action (12 hours) when compared to both furosemide and bumetanide, with the practicability of once-daily dosing. Torsemide absorption is not affected by food intake, while that of furosemide and bumetanide decreases dramatically and essential to be taken in an empty stomach. Since furosemide is the most commonly used agent, dose conversion between different loop diuretics is to be cautiously applied. In general, for oral diuresis 80 mg furosemide = 20 mg torsemide = 1 mg bumetanide are the conversion equivalents. While that for intravenous agents, 40 mg furosemide = 20 mg torsemide = 1 mg bumetanide are to be employed. Loop diuretics are threshold drugs meaning that no diuretic effect will occur below the threshold drug concentration. The threshold level also depends on different clinical conditions and could be different for different patients. Hence to achieve effective diuresis, different doses might be required to achieve the threshold level. The lowest dose that is clinically effective should be chosen for HF treatment. Frequency of dosing is also very important as loop diuretics with a shorter duration of action can cause post-diuretic Na+ retention (anti-natriuresis) as the diuretic effect wears off. Thus they are usually given on a twice-daily schedule.
CKD causes a diuretic resistant state both by reducing maximal natriuresis induces a shift in the diuretic dose-response curve rightward and downward. Loop diuretics are the primary agents used in CKD, and higher starting doses are the recommendation. For furosemide, this is in the range of 40 to 80 mg is recommended for stages 4 and 5 of CKD, whereas the usual 20 to 40 mg is recommended in stage 1 through 3 of CKD. Also, continuous infusion of loop agents is recommended in hospitalized patients (to overcome anti-natriuresis), which is particularly important in CKD patients.
All thiazides are sulfonamide derivatives that are readily absorbed from the gastrointestinal (GI) tract after oral administration. The oral bioavailability of thiazides ranges from 50 to 95%, and for the two most frequently used agents, hydrochlorothiazide and chlorthalidone, it is 70% and 65%, respectively. Once in the plasma, thiazides are plasma albumin-bound and do not undergo any metabolism prior to excretion and are secreted unchanged via urine and feces. The only exception is indapamide, a thiazide-like diuretic, which undergoes extensive hepatic metabolism, and less than 7% is excreted in the urine.
Chlorthalidone, with a half-life of approximately 42 hours, has a larger volume of distribution than its thiazide-type counterpart hydrochlorothiazide because they bind to red blood cell (RBC) carbonic anhydrase and are sequestered in these cells reaching a concentration 7 to 10 times more than that of plasma. Thus RBCs act as a reservoir, and the drug is released into the plasma gradually, which can be utilized clinically by a once-daily dosing regimen. Hydrochlorothiazide, in contrast, has a shorter half-life of about 6 to 9 hours, but this increases with long term dosing, and some studies thus recommend once-daily dosing for this drug as well. Hydrochlorothiazide is a pregnancy category B medication. While loop diuretics are recommended in all stages of CKD, Thiazides are advised only in stages 1 to 3. The risk of metabolic side effects increases at higher doses of thiazides and is usually not preferred near the maximum dose range. Dosage for the most common indications of the individual thiazide diuretics appear in Table 3.
ENaC inhibitor amiloride does not undergo any metabolic transformation in the body, while triamterene is metabolized into a sulfate ester by extensive hepatic metabolism. Thus in patients with liver pathology amiloride is preferred, half of which is excreted in the urine unmetabolized while the other half passes through the feces. However, amiloride must be avoided in patients with renal dysfunction as it is excreted through tubular secretion, and due to its longer half-life, the drug can accumulate in the body in such patients and predispose to life-threatening hyperkalemia. Though comfortable once-daily dosing is possible with amiloride, its peer triamterene needs twice-daily dosing, and both these drugs have an oral bioavailability of approximately 50%. Amiloride being pregnancy category B medication, is safer to use for the treatment of Liddle syndrome in pregnant patients.
ARA spironolactone largely undergoes metabolism in the liver into its active form canrenone, which is more than 90% bound to plasma proteins. The oral bioavailability of spironolactone varies from 60 to 90%, while that of eplerenone is about 69%. Eplerenone undergoes a hepatic metabolism as well, but there are no active metabolites and is 50% bound to albumin in the serum, and about 67% is excreted in the urine while 32% passes through the feces. Food intake does not interfere with the absorption of these drugs, and taking it with food can, in effect, reduce gastric irritation and adverse symptoms associated with it. Dosage for the most common indications of the individual PSDs appear in Table 4.
Acetazolamide, the only diuretic CAI, is well absorbed from the GI tract, not metabolized, and is 93% protein-bound in the plasma. The onset of action of the oral form is 1 to 1.5 h with an oral bioavailability of almost 100%. It has a plasma half-life of 13 hours, and twice-daily dosing is recommended. Almost 90% of the drug is excreted in the urine by tubular secretion and is not effective in renal insufficiency.
Mannitol is poorly absorbed when given orally, and hence it is administered only via intravenous route as a bolus and hence has a bioavailability of 100%. Once in the plasma, mannitol, being an osmotic substance, draws fluid into the plasma, decreasing the blood viscosity and thereby the hematocrit. Mannitol is freely filtered with limited reabsorption, and it undergoes only slight metabolism in the liver to glycogen. The majority of the rest (more than 90%) is excreted unchanged in the urine with an elimination half-life reported from 70 to 150 minutes. Dosage for the most common indications of the individual CAIs and osmotic diuretics appear in Table 5.
General Adverse Effects
The most common adverse effect for any diuretic is mild hypovolemia, which can lead to transient dehydration and increased thirst. When there is an over-treatment with a diuretic, this could lead to severe hypovolemia, causing hypotension, dizziness, and syncope. More generalized side-effects of diuretic agents include headache, urinary frequency, restlessness, weakness, fatigue, and lethargy. GI disturbances like nausea, vomiting, constipation, diarrhea, anorexia, and abdominal pain can occur with loop diuretics and PSDs than any other diuretic group.
Electrolyte abnormalities are commonly associated with all the diuretic agents, and their mechanisms of such effect are well-established, and these mechanisms are explained under the respective class of diuretics below. To give broader picture hypokalemia, for example, is caused by all the diuretics except PSDs, which causes hyperkalemia. Acid-base disorders usually accompany the electrolyte derangement due to their close association with their reabsorption in the renal tubules. Metabolic disturbances can lead to derangement of glucose, uric acid, or lipid levels with certain diuretics and are individually discussed. Other rare adverse effects include impotence, hyperglycemic hyperosmolar non-ketotic syndrome, skin reactions, aplastic anemia, thrombocytopenia, agranulocytosis, hemolytic anemia, muscle cramps, and myalgia. In general, adverse effects are dose-dependent and are higher with loop diuretics as they have the most significant diuretic effect. With controlled low-dose formulations, adverse effects have reduced substantially, especially with thiazide diuretics.
Loop Diuretic-specific Effects
Electrolyte abnormalities are the most common adverse effects associated with chronic thiazide therapy in hypertension. They occur most commonly with longer-acting agents such as chlorthalidone and metolazone, but this is mitigated to an extent with low-dose strategy.
Potassium-sparing Diuretic Specific Effects
More generalized and less common side-effects of K+-sparing agents include headache, fatigue, and GI disturbances like nausea, vomiting, constipation, diarrhea, anorexia, and abdominal pain.
ENaC Inhibitor Specific Effects
Aldosterone Receptor Antagonist Specific Effects
Carbonic Anhydrase Inhibitor Specific Effects
Osmotic Diuretic Specific Effects
Severe dehydration or established anuria is a contraindication for any type of diuretic. Patients with known hypersensitivity to any of the diuretic agents are contraindicated to receive the same drug. Diuretics are contraindicated in severe electrolyte derangement and should not be administered until a detected electrolyte abnormality is corrected.
Loop and thiazide diuretics are contraindicated in patients already diagnosed with gout.
Loop diuretics (except ethacrynic acid), thiazide diuretics, and CAIs are all sulfonamide derivatives and were generally regarded as contraindicated in sulfa-allergy patients. Recent evidence suggests otherwise, and several reports of instances of uneventful use of sulfa-diuretic use in documented sulfa-allergy patients exist. In conclusion, only a low-risk of cross-allergenicity between sulfonamide antibiotics and sulfonamide non-antibiotics and diuretics can be prescribed with caution in sulfa-allergic patients. Notwithstanding, documented allergy to any of the sulfonamide diuretic agents themselves should be considered an absolute contraindication, and for sulfonamide non-antibiotics, it is a relative contraindication.
Loop diuretics are contraindicated in patients with hypokalemia (only to be administered after correction), severe hyponatremia, hypotension, azotemia, oliguria/anuria, and hepatic coma. It is also contraindicated in any situation where fluid depletion is foreseen, such as surgery. Furosemide and bumetanide are pregnancy category C, while torsemide is category B and relatively safe in pregnancy.
Thiazide diuretics induce hyperglycemia, but are these agents contraindicated in hypertensive patients for the risk of new-onset diabetes or worsening of preexisting diabetes? Thiazides are of crucial importance as first-line therapy in patients with hypertension; a condition treated primarily to reduce the high risk of CV mortality. To compare the two important drugs in this class, chlorthalidone (thiazide-like diuretic) has demonstrated superiority to hydrochlorothiazide (thiazide-type diuretic) in reducing systolic BP levels and in achieving target BP values. Also, chlorthalidone, in comparison to other anti-hypertensives, has been repeatedly shown in various clinical trials to reduce the risk of adverse CV events greatly. Also, chlorthalidone has shown to cause the fewest clinical events of diabetes in contrast to any other anti-hypertensive. In a hypertensive population with preexisting diabetes, the salutary anti-hypertensive effects of low-dose (12.5 mg) chlorthalidone outweighs the risk of glucose intolerance and will particularly benefit young and non-obese patients. The 2018 ESC guidelines on hypertension give the highest class I recommendation for the use of thiazide/thiazide-like diuretics along with a RAS blocker in the treatment of diabetics with hypertension.
Guidelines advised against the use of thiazides in patients with severe stage 4 or stage 5 CKD (see Table 2), though recent reports are in favor of its use as anti-hypertensive (even if GFR less than 30 mL/min) as the BP-lowering mechanism of thiazides are not related to their diuretic function in the kidney. Nevertheless, thiazides are contraindicated when the diuresis is the predominant action required in patients with CKD, where loop diuretics are preferred. The only exception is metolazone, a thiazide diuretic that can be used for diuresis in CKD.
K+-sparing diuretics are contraindicated in hyperkalemia (K+ levels more than 5 mEq/L) until the underlying pathology is corrected. PSDs are contraindicated in advanced renal failure or CKD as these patients are at risk of hyperkalemia; this is particularly true when GFR <30 mL/min/1.73 m^2 corresponding to CKD stages 4 and 5. Spironolactone is pregnancy category C, and along with triamterene should be avoided in pregnancy while eplerenone is category B medications.
In hyperchloremic metabolic acidosis (see adverse effects), acetazolamide is contraindicated, and extreme caution should be exercised in the severe chronic obstructive pulmonary disease when considering acetazolamide for treatment.
The kidneys primarily excrete mannitol, and in patients with renal impairment, it should be used with caution as it can cause osmotic nephropathy. Intravascular volume overload due to mannitol may be of concern in cardiac and renal failure patients and are hence contraindicated in such patients. Mannitol should is not for use in patients with active cranial bleeding, severe dehydration, and in patients with hypersensitivity history to its use. When using mannitol in treating patients with anuria, it requires an initial test dose to verify the diuretic response.
Salicylates can displace acetazolamide from plasma protein, thereby causing an increase in free acetazolamide in the plasma leading to toxicity secondary to RBC carbonic anhydrase inhibition. Acetazolamide should not be used to alkalinize urine following salicylate overdose since it may worsen metabolic acidosis.
Prostaglandins are involved in the modulation of systemic and renal vasodilation, GFR, RAAS, water, and salt secretion. Their blockade by nonsteroidal anti-inflammatory drugs (NSAIDs) in a patient with hypertension could suppress the effects of anti-hypertensive medications, including that of diuretics. NSAIDs are not very influential in regulating renal functions under normal circumstances, but they can blunt the natriuretic response, reduce GFR and suppress renin production when used along with loop or thiazide diuretics and can cause acute renal failure.
The ototoxic ability of loop diuretics can become potentiated with other ototoxic drugs such as aminoglycosides or platinum-containing chemotherapeutic compounds.
Diuretic-induced hypokalemia can increase the risk of digitalis-induced arrhythmia. Digoxin competes with K+ ions for its binding site on Na+-K+-ATPase pump in the heart, and thus in diuretic-induced hypokalemia, the action of digoxin is unopposed, leading to fatal arrhythmias. Although any diuretic causing hypokalemia can lead to this effect, loop diuretics carry the greatest risk when compared to other classes of diuretics, but as an individual agent, hydrochlorothiazide had the greatest risk. Hence the combination of hypokalemia-inducible diuretics and digoxin can be dangerous and must be avoided. Similarly, clinicians must avoid using quinidine because thiazide-induced hypokalemia can potentiate its cardiovascular effects.
Bendroflumethiazide can cause calcium retention, and care is necessary when administered along with calcium supplements or vitamin D. Thiazides can cause lithium accumulation when the drugs are co-administered as they can increase lithium reabsorption in the PT.
RAAS inhibiting agents like ACEIs, ARBs, beta-blockers, NSAIDs, or aliskiren can result in a small amount of potassium retention, and their concomitant use along with PSDs may cause hyperkalemia and hence a relative contraindication. PSDs apparently must not be administered along with another PSD to avoid the risk of dangerous hyperkalemia.
Diuretic treatment calls for careful assessment of extracellular fluid volume, urine output, electrolyte levels in plasma and urine, body weight, acid-base status, serum glucose, and BP regularly with particular emphasis on patients with cardiovascular, hepatic, renal or metabolic disorders and in elderly individuals. Prerenal azotemia is of concern due to diuretic-induced hypovolemia, and blood urea nitrogen and creatinine levels require monitoring.
Ototoxicity is a risk with the use of loop diuretics, and special precautions are necessary. Baseline auditory tests are necessary (especially when planning large bolus doses at high infusion rates), which will help evaluate on a case-by-case basis the effect of loop diuretics on auditory functions after a certain length of treatment. Periodic sequential monitoring of auditory functions is also advisable, and the possibility of switching to a different diuretic therapy should be contemplated in case of any adverse outcomes.
Clinical cardiac status should be assessed in patients on diuretics (especially MI, HF, or other cardiac conditions), as they are prone to develop HF due to the abrupt increase in the fluid shift between the compartments.
Failure of a diuretic agent to increase urine output should prompt cessation of the diuretic agent as it could be evidence of undiagnosed underlying renal pathology.
Frequent administration of mannitol can worsen cerebral edema and hence should be administered every 6 to 8 hours, as suggested in Table 4.
Diuretics are not highly controlled drugs and hence have a high probability for misuse, particularly with athletes who might abuse them for rapid weight loss or to conceal the presence of other banned drugs. The use of diuretics is prohibited in athletes. (Athletes require a prior exemption for therapeutic use in athletes) and is routinely screened for by the world anti-doping agency. Such abuse, if it persists chronically, can lead to detrimental effects on CV and thermoregulatory functions, which could lead to death when combined with excessive physical activity as encountered in athletes. People with bulimia nervosa can misuse diuretics (when they try to purge the food), and such use can lead to pseudo-Bartter syndrome. Psychotic patients also can abuse diuretics, along with laxatives .
Diuretics in Diagnosis
Reversible ototoxicity (manifested as sensory neural hearing loss, tinnitus) can be caused by ischemia in stria vascularis and by inhibition of NKCC1 channels in stria vascularis by loop diuretics which improves with discontinuation of the drug. Deafness and tinnitus from loop diuretics most frequently occur when administering large bolus doses in an acute setting, such as when using furosemide in acute kidney injury. The resulting ototoxicity is, therefore, due to the higher serum concentrations of the drug achieved. Ethacrynic acid is the most ototoxic drug in this group.
Diuretic-induced kidney injury has been reported, and it is most severe in elderly patients due to their decreased sensitivity of thirst response. Diuretics are also associated with increased risk when the renal blood flow is compromised in conditions such as congestive heart failure, hepatic cirrhosis, and nephrotic syndrome and can cause acute renal failure. Dose dependency also plays a factor as higher diuretic doses are associated with pathological injury of the glomerular basement membrane. Diuretics can lead to vacuolar degeneration of tubular epithelial cells, and hence their use with other nephrotoxic drugs should be contraindicated.
Patient education plays a crucial role and adequate knowledge of the adverse effects, dietary, and lifestyle modifications that are necessary while on diuretics. Patients (especially in an outpatient setting) must understand to report any type of changes in their compliance pattern or any adverse effect thereof. Adherence to strict treatment protocols and timely intake of the drug and avoidance of any overdosing when the patients miss their dosing will significantly improve the clinical course and the effectiveness of the diuretic agent.
Nurses, as immediate caregivers, should be cognizant of the adverse effects of diuretics and should be able to alert the treating clinician in case if a patient’s condition worsens. This situation is particularly true in the case of hospitalized patients in intensive care units where updating of urine output charts, daily body weight measurements, and periodic arterial blood gas analysis to ensure patient safety. In an outpatient setting, pharmacists play an essential role and should be vigilant to check any drug-drug interactions or incorrect dosage in the prescriptions. Diuretics are prescription-only drugs, and any over-the-counter request of these drugs should be refused and, if needed, be reported to avoid damage to health by suspected misusers of diuretics. Several health professionals, including clinicians, as well as specialists like cardiologists, otorhinolaryngologists, plus clinical pharmacists, nurses, and other healthcare workers, form part of the interprofessional team to operate in collaboration to avert any adverse outcome with diuretic therapy. [Level 5]
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