Diuretics: A Nephrologist’s Perspective

INTRODUCTION

While research in the arena of nephrology has made great strides and pharmacotherapeutic strategies continue to develop apace, renal disorders inflict a high burden of disease among individuals across the globe. They remain a leading cause of morbidity and mortality, attracting worldwide attention to the epidemiology, risk factors and treatment modalities.¹Cases A. Recent advances in nephrology: highlights from the 35th annual meeting of the American society of nephrology. Drugs Today (Barc). 2002 Dec;38(12):797-805.   ²Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int Suppl. 2007 Nov;(107):S4-9.   ³Trifiro G, Sultana J, Giorgianni F, Ingrasciotta Y, Buemi M, Muscianisi M, Tari DU, Perrotta M, Canale V, Arcoraci V, Santoro D. Chronic Kidney Disease Requiring Healthcare Services: A New Approach to Evaluate Epidemiology of Renal Disease. BioMed Research International. 2014;2014:268362.   ⁴Anand S, Khanam MA, Saquib J, Saquib N, Ahmed T, Alam DS, Cullen MR, Barry M, Chertow GM. High prevalence of chronic kidney disease in a community survey of urban Bangladeshis: a cross-sectional study. Globalization and Health. 2014;10:9.   Despite nephrology being a specialty since the 1970s, literature on the spectrum of renal diseases in India has been limited.⁵Agarwal SK, Dash SC. Spectrum of renal diseases in Indian adults. J Assoc Physicians India. 2000 Jun;48(6):594-600.    To address this scarcity of data, a study⁶Aggarwal HK, Yashodara BM, Nand N, Sonia, Chakrabarti D, Bharti K. Spectrum of renal disorders in a tertiary care hospital in Haryana. J Assoc Physicians India. 2007 Mar;55:198-202.   was conducted by Aggarwal and coworkers to ascertain the spectrum of renal disorders in India. The results revealed chronic kidney disease (CKD) to be the most common disease accounting for 56.02% cases, followed by nephrotic syndrome (22.36%), acute renal failure (12.84%), acute nephritic syndrome (6.75%) and asymptomatic urinary abnormality (0.99%; figure 1). In addition, the chief causes of CKD were found to be chronic glomerulonephritis (39.32%) and diabetic nephropathy (19.16%) while those of primary nephrotic syndrome were minimal change disease and

membranoproliferative glomerulonephritis.⁶Aggarwal HK, Yashodara BM, Nand N, Sonia, Chakrabarti D, Bharti K. Spectrum of renal disorders in a tertiary care hospital in Haryana. J Assoc Physicians India. 2007 Mar;55:198-202.    Besides India, a large number of other developing nations are afflicted by the tremendous burden of renal diseases. Onwukwe and colleagues⁷Odenigbo C, Oguejiofor O, Onwubuya E, Onwukwe Ch. The prevalence of chronic kidney disease in apparently healthy retired subjects in asaba, Nigeria. Ann Med Health Sci Res. 2014 Jul;4(Suppl 2):S128-32.    assessed the prevalence of CKD in Nigeria and demonstrated it to be 43.5% in the general population, 40.7% in the elderly subpopulation; and 49.1% in the non-elderly individuals (figure 2). Moreover, a greater predilection toward women was observed (women: 64.3%; men: 33.33%). Accumulating evidences also highlight a similar trend of CKD prevalence in the high-income countries such as the US.⁸Almirall J, Vaqueiro M, Antón E, Baré ML, González V, Jaimez E, Gimeno C; Centros de Asistencia Primaria (Grupo del proyecto “D’AVIS”). Prevalence of chronic kidney disease in community-dwelling elderly and associated cardiovascular risk factors. Nefrologia. 2005;25(6):655-62.   ⁹Grams ME, Chow EK, Segev DL, Coresh J. Lifetime incidence of CKD stages 3-5 in the United States. Am J Kidney Dis. 2013 Aug;62(2):245-52.   ¹⁰Ryan TP, Sloand JA, Winters PC, Corsetti JP, Fisher SG. Chronic kidney disease prevalence and rate of diagnosis. Am J Med. 2007 Nov;120(11):981-6.    It is noteworthy that the risk factors of renal diseases have also been under active investigation, with diabetes, hypertension, advanced age, family history and anemia identified as few of the most important.¹¹Vassalotti JA, Fox CH, Becker BN. Risk factors and screening for chronic kidney disease. Adv Chronic Kidney Dis. 2010 May;17(3):237-45.   ¹²Iseki K, Kohagura K. Anemia as a risk factor for chronic kidney disease. Kidney Int Suppl. 2007 Nov;(107):S4-9.    Based on the accruing data, a pragmatic approach for prompt diagnosis and treatment of renal disorders is warranted. Among a plethora of drug classes available, diuretics play a pivotal role in the management of renal diseases.¹³Cadwallader AB, de la Torre X, Tieri A, Botre F. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis. Br J Pharmacol. 2010 Sep;161(1):1-16.   ¹⁴Risler T, Krämer B, GA. The efficacy of diuretics in acute and chronic renal failure. Focus on torasemide. Drugs. 1991;41 Suppl 3:69-79.    Information available from several studies provides undisputed evidence in support of their utility for the treatment of diseases characterized by excessive extracellular fluid, including CKD, nephrotic syndrome, cirrhosis and heart failure.¹⁵Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2011 Dec 20;8(2):100-9.    This review emphasizes on the significant role of diuretics in renal disorders.

DIURETICS: AT A GLANCE

Diuretics are a heterogenous class of drugs that are of paramount importance in both prevention and treatment of renal diseases.¹³Cadwallader AB, de la Torre X, Tieri A, Botre F. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis. Br J Pharmacol. 2010 Sep;161(1):1-16.   ¹⁶Ernst ME, Gordon JA. Diuretic therapy: key aspects in hypertension and renal disease. J Nephrol. 2010 Sep-Oct;23(5):487-93.    These are further classified into different types; categorization of diuretics on the basis of their efficacy has been summarized in table 1.¹⁷Drugs acting on the kidney. Chapter 8 In Pharmacological Classification of Drugs. KD Tripathi. 4th Edition. Jaypee Brothers Medical Publishers (P) Ltd. 2010.    As these agents can be used either as monotherapy or in combination, a comprehensive knowledge about the clinical pharmacology of each class of drug is essential for effective management of renal diseases.¹⁵Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2011 Dec 20;8(2):100-9.   ¹⁸Padilla MC, Armas-Hernández MJ, Hernández RH, Israili ZH, Valasco M. Update of diuretics in the treatment of hypertension. Am J Ther. 2007 Mar-Apr;14(2):154-60.   ¹⁹Swan SK. Diuretic strategies in patients with renal failure. Drugs. 1994 Sep;48(3):380-5.    In addition, an understanding of the factors that aid in determining a patient’s response to a diuretic is a prerequisite for accurate use of drugs.¹⁵Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2011 Dec 20;8(2):100-9.   

Diuretics primarily cause increase in urinary flow rate and sodium excretion in order to maintain normal volume and composition of body fluids.¹³Cadwallader AB, de la Torre X, Tieri A, Botre F. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis. Br J Pharmacol. 2010 Sep;161(1):1-16.   ¹⁵Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2011 Dec 20;8(2):100-9.    As a threshold amount of diuretic is required to obtain the desired natriuretic effect, therefore modifications in the pharmacokinetic and pharmacodynamic parameters occurring in the presence of several renal diseases necessitate careful dose titrations and adjustment.¹⁶Ernst ME, Gordon JA. Diuretic therapy: key aspects in hypertension and renal disease. J Nephrol. 2010 Sep-Oct;23(5):487-93.   

Besides, these agents reduce excretion of protein in urine, and lower the risk of developing hyperkalemia.¹³Cadwallader AB, de la Torre X, Tieri A, Botre F. The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis. Br J Pharmacol. 2010 Sep;161(1):1-16.   ¹⁵Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2011 Dec 20;8(2):100-9.    However, adverse events associated with the use of diuretics involving uric acid, Na⁺ and K⁺ axes, are a cause of considerable concern.¹⁵Sica DA. Diuretic use in renal disease. Nat Rev Nephrol. 2011 Dec 20;8(2):100-9.    The most common complications include hypokalemia, intravascular volume depletion and azotemia, ototoxicity (usually with loop-acting diuretics), hyperlipidemia, acute pancreatitis, hyperkalemia (often with potassiumsparing drugs), and acidosis (with carbonic anhydrase inhibitors), which in turn demand careful alteration in dose quantity and frequency.²⁰Suki WN. Use of diuretics in chronic renal failure. Kidney Int Suppl. 1997 Jun;59:S33-5.   ²¹Odvina CV, Mason RP, Pak CY. Prevention of thiazide-induced hypokalemia without magnesium depletion by potassium-magnesium-citrate. Am J Ther. 2006 Mar-Apr;13(2):101-8.   

Furthermore, diuretic resistance defined as the diminished pharmacological response or diminished natriuresis, to a given dose of a diuretic, is often witnessed in clinical practice, especially in cases of CKD. A shift in the dose-response curve relating urinary diuretic excretion rates (dose) with sodium excretion (response) is used to demonstrate the phenomenon of diuretic resistance. The various factors that contribute to this state include reduced renal blood flow and sodium filtration, accumulation of organic acids that inhibit tubular secretion of the diuretic, and inadequate cumulative sodium excretion to meet patients’ needs. On the other hand, the pharmacological response of the remaining nephrons to diuretic agents remains intact. Thus, diuretic administration strategies that consider altered pharmacological responses in patients with renal failure are imperative in order to institute an effective and safe treatment. Moreover, such strategies must be revised timely by the nephrologists as renal function changes over time.¹⁹Swan SK. Diuretic strategies in patients with renal failure. Drugs. 1994 Sep;48(3):380-5.   ²²Ellison DH. Diuretic resistance: physiology and therapeutics. Semin Nephrol. 1999 Nov;19(6):581-97.   

Mechanism of action of diuretics: An overview

Diuretics are considered one of the most important drugs of the therapeutic armamentarium for several renal diseases. An enlarging body of evidence suggests that all diuretics act chiefly by inhibiting reabsorption of sodium in the nephron at four major sites. Due to difference in their site and mechanism of action, they exhibit variations in their pharmacological properties and clinical indications. Classical clearance methodology for the determination of diuretic mechanism and site of action takes into account four kinds of observations including impact of diuretic agents on the concentrating and diluting mechanism; evaluation of the pattern of anionic excretion produced by the drug; determination of the drug’s action on acid excretion and on acid-base status; and assessment of the effects of the diuretic on potassium excretion. Reviewed herein are the properties of different classes of diuretics and their action on each nephron segment that governs salt and water reabsorption.²³Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin Drug Saf. 2010 Mar;9(2):243-57.   ²⁴Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med. 1976 Apr;59(4):105-10.   ²⁵Puschett JB. Sites and mechanisms of action of diuretics in the kidney. J Clin Pharmacol. 1981 Nov-Dec;21(11-12 Pt 2):564-74.   ²⁶Materson BJ. Insights into intrarenal sites and mechanisms of action of diuretic agents. Am Heart J. 1983 Jul;106(1 Pt 2):188-208.   ²⁷Davies DL, Wilson GM. Diuretics: mechanism of action and clinical application. Drugs. 1975;9(3):178-226.   ²⁷Kokko JP. Site and mechanism of action of diuretics. Am J Med. 1984 Nov 5;77(5A):11-7.   

Proximal convoluted tubule (PCT): Diuretics that usually target PCT include osmotic diuretics such as mannitol which cause osmotic diuresis and increases renal blood flow; drugs that interfere with the adenyl cyclase system such as xanthines; and carbonic anhydrase inhibitors such as acetazolamide which increase solute-free water generation, induce phosphaturia and enhance bicarbonate excretion, alkalinize the urine, and cause kaliuresis. In addition, some thiazide and thiazide-like diuretics have a secondary site of action in the PCT based on either carbonic anhydrase inhibition or other mechanisms, such as inhibition of sodium phosphate reabsorption.²⁴Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med. 1976 Apr;59(4):105-10.   ²⁵Puschett JB. Sites and mechanisms of action of diuretics in the kidney. J Clin Pharmacol. 1981 Nov-Dec;21(11-12 Pt 2):564-74.   ²⁹Lang F. Osmotic diuresis. Ren Physiol. 1987;10(3-4):160-73.   

Loop of Henle: Loop diuretics such as furosemide and ethacrynic acid act at the ascending limb of Henle’s loop. These drugs impair Na⁺/K⁺/Cl^– co-transport in the ascending limb of Henle’s loop to inhibit reabsorption of sodium and chloride. This in turn reduces both solute-free water generation and extraction of tubular water from the collecting duct. These agents cause increments in the excretion of sodium in the urine by 15-25% of filtered load, therefore considered the most effective natriuretic agents. These diuretics are also referred as high ceiling diuretics. In addition, they are potent, have a early onset of action, and tend to have a short duration of effect.²⁴Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med. 1976 Apr;59(4):105-10.   ²⁵Puschett JB. Sites and mechanisms of action of diuretics in the kidney. J Clin Pharmacol. 1981 Nov-Dec;21(11-12 Pt 2):564-74.   ³⁰Allison ME, Shilliday I. Loop diuretic therapy in acute and chronic renal failure. J Cardiovasc Pharmacol. 1993;22 Suppl 3:S59-70.   ³¹Gamba G, Friedman PA. Thick ascending limb: the Na(+):K (+):2Cl (-) cotransporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch. 2009 May;458(1):61-76.   ³²Schlatter E, Greger R, Weidtke C. Effect of “high ceiling” diuretics on active salt transport in the cortical thick ascending limb of Henle’s loop of rabbit kidney. Correlation of chemical structure and inhibitory potency. Pflugers Arch. 1983 Mar 1;396(3):210-7.   

Early distal convoluted tubule (DCT): The thiazides and thiazide like drugs like metolazone act in the early portion of the distal convolution. They block Na⁺/Cl^– co-transport and increase sodium chloride and water excretion. Increased Na+ that reaches the DCT stimulates an exchange with K+/H+ that results in loss of these ions. This leads to increased potassium excretion via the sodium-potassium exchange mechanism and often results in hypokalemia. These agents are capable of increasing urinary sodium by 5-8% of the filtered load. Most of them seem to reach a dose-response plateau beyond which little additional effect is obtained by escalating the dose. Investigators have suggested that most of them are likely to demonstrate low efficacy with decline in glomerular filtration rate, except for metolazone and indapamide.²⁴Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med. 1976 Apr;59(4):105-10.   ²⁵Puschett JB. Sites and mechanisms of action of diuretics in the kidney. J Clin Pharmacol. 1981 Nov-Dec;21(11-12 Pt 2):564-74.   ³³Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014 Dec 5;9(12):2147-63.   ³⁴Cyclothiazide. Available at: http://pubchem.ncbi.nlm.nih.gov/compound/cyclothiazide#section=Top. Accessed on: 20.2.2015.   ³⁵Reungjui S, Pratipanawatr T, Johnson RJ, Nakagawa T. Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Curr Opin Nephrol Hypertens. 2008 Sep;17(5):470-6.   

Late DCT and collecting duct: Diuretics that work primarily in the distal tubule and collecting tubule include the aldosterone antagonists like spironolactone, and inhibitors of renal epithelial Na⁺ channel including triamterene and amiloride. Triamterene and spironolactone display mild efficacy as natriuretic agents as they augment fractional sodium excretion by only 2-3%. However, they are useful because of their marked ability to diminish urinary potassium excretion (potassium-sparing effect), either by a direct renal tubular effect (triamterene) or by competitive inhibition of aldosterone (spironolactone).²⁴Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med. 1976 Apr;59(4):105-10.   ²⁵Puschett JB. Sites and mechanisms of action of diuretics in the kidney. J Clin Pharmacol. 1981 Nov-Dec;21(11-12 Pt 2):564-74.   ²⁷Davies DL, Wilson GM. Diuretics: mechanism of action and clinical application. Drugs. 1975;9(3):178-226.    Figure 3 depicts the actions of various diuretics at different sites of the nephron.²³Sarafidis PA, Georgianos PI, Lasaridis AN. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin Drug Saf. 2010 Mar;9(2):243-57.   ²⁴Krumlovsky FA, del Greco F. Diuretic agents. Mechanisms of action and clinical uses. Postgrad Med. 1976 Apr;59(4):105-10.   ²⁵Puschett JB. Sites and mechanisms of action of diuretics in the kidney. J Clin Pharmacol. 1981 Nov-Dec;21(11-12 Pt 2):564-74.   ²⁶Materson BJ. Insights into intrarenal sites and mechanisms of action of diuretic agents. Am Heart J. 1983 Jul;106(1 Pt 2):188-208.   ²⁷Davies DL, Wilson GM. Diuretics: mechanism of action and clinical application. Drugs. 1975;9(3):178-226.   ²⁷Kokko JP. Site and mechanism of action of diuretics. Am J Med. 1984 Nov 5;77(5A):11-7.   ²⁹Lang F. Osmotic diuresis. Ren Physiol. 1987;10(3-4):160-73.   ³⁰Allison ME, Shilliday I. Loop diuretic therapy in acute and chronic renal failure. J Cardiovasc Pharmacol. 1993;22 Suppl 3:S59-70.   ³¹Gamba G, Friedman PA. Thick ascending limb: the Na(+):K (+):2Cl (-) cotransporter, NKCC2, and the calcium-sensing receptor, CaSR. Pflugers Arch. 2009 May;458(1):61-76.   ³²Schlatter E, Greger R, Weidtke C. Effect of “high ceiling” diuretics on active salt transport in the cortical thick ascending limb of Henle’s loop of rabbit kidney. Correlation of chemical structure and inhibitory potency. Pflugers Arch. 1983 Mar 1;396(3):210-7.   ³³Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014 Dec 5;9(12):2147-63.   ³⁴Cyclothiazide. Available at: http://pubchem.ncbi.nlm.nih.gov/compound/cyclothiazide#section=Top. Accessed on: 20.2.2015.   ³⁵Reungjui S, Pratipanawatr T, Johnson RJ, Nakagawa T. Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Curr Opin Nephrol Hypertens. 2008 Sep;17(5):470-6.   

COMPLICATIONS OF DIURETIC THERAPY: HYPOKALEMIA AS A COMMON MANIFESTATION

Evidence emerging from accrued clinical reports suggests hypokalemia to be a common complication of diuretic therapy, especially thiazide diuretics. Unlike loop diuretics, thiazides stimulate K⁺ secretion indirectly. Investigators have putatively suggested several underlying mechanisms leading to the development of hypokalemia in patients on thiazide diuretics, both at low and high doses. It results primarily from increased Na+ and fluid delivery, owing to upstream transport inhibition, along with enhanced aldosterone effect.

Hypokalemic effect of thiazides can also be ascribed to their ability to reduce luminal calcium level along distal tubules, which activates epithelial Na+ channels (which are inhibited by calcium) and in turn stimulates K⁺ secretion. Thiazide diuretics also induce adaptation primarily along the connecting and collecting tubule, where enhanced electrogenic Na+ reabsorption triggers K⁺ secretion. Lastly, thiazides also augment K+ secretion by activating flow-sensitive maxi-K⁺ channels that differ from the K⁺ secretory channels mentioned above, at the molecular level (figure 4). On the other hand, loop diuretics portray lower risk of hypokalemia which can be attributed to the facts that they increase distal calcium delivery, and the compensatory response to loop diuretics from increased electroneutral sodium chloride (NaCl) reabsorption in the DCT, which is less likely to enhance potassium secretion.³⁶Knochel JP. Diuretic-induced hypokalemia. Am J Med. 1984 Nov 5;77(5A):18-27.   ³⁷Kokot F, Hyla-Klekot L. Drug-induced abnormalities of potassium metabolism. Pol Arch Med Wewn. 2008 Jul-Aug;118(7-8):431-4.   ³⁸Ellison DH, Loffing J. Thiazide effects and adverse effects: insights from molecular genetics. Hypertension. 2009 Aug;54(2):196-202.   

Furthermore, investigators have also identified several factors which may exacerbate hypokalemia in patients taking diuretics, including consumption of high salt diets, large urine volumes, metabolic alkalosis, increased aldosterone production, and the simultaneous use of two diuretics that act on different sites in the renal tubule.³⁶Knochel JP. Diuretic-induced hypokalemia. Am J Med. 1984 Nov 5;77(5A):18-27.   ³⁷Kokot F, Hyla-Klekot L. Drug-induced abnormalities of potassium metabolism. Pol Arch Med Wewn. 2008 Jul-Aug;118(7-8):431-4.    Hypokalemia in turn is known to impose potential danger in patients; cardiac arrhythmias being the most common. A study³⁹Ornato JP, Gonzalez ER, Starke H, Morkunas A, Coyne MR, Beck CL. Incidence and causes of hypokalemia associated with cardiac resuscitation. Am J Emerg Med. 1985 Nov;3(6):503-6.    by Beck and colleagues revealed that hypokalemia heightened the relative risk for cardiac arrest by 2.5 times. In addition, patients who were administered diuretics without K⁺ supplementation were associated with highest risk of arrest (4.4 times). Furthermore, as hypokalemia has been suggested to be a frequent complication of chronic thiazide diuretic therapy, the investigators of a study⁴⁰Hollifield JW, Slaton PE. Thiazide diuretics, hypokalemia and cardiac arrhythmias. Acta Med Scand Suppl. 1981;647:67-73.    assessed the influence of hypokalemia on the occurrence of premature ventricular contractions. The results showed a significant correlation between occurrence of premature ventricular contractions and decline in serum K⁺ levels. It was thus concluded that thiazide diuretics is one of the leading causes of hypokalemia. Moreover, the incidence of premature ventricular contractions is likely to rise with the severity of hypokalemia. Besides cardiac complications, hypokalemia as a result of diuretic therapy may even predispose to muscle weakness, rhabdomyolysis, glucose intolerance, and several untoward events that result directly from increased ammonia production, such as protein and nitrogen wasting and hepatic coma.³⁶Knochel JP. Diuretic-induced hypokalemia. Am J Med. 1984 Nov 5;77(5A):18-27.   ³⁷Kokot F, Hyla-Klekot L. Drug-induced abnormalities of potassium metabolism. Pol Arch Med Wewn. 2008 Jul-Aug;118(7-8):431-4.    This underscores the need for reinforcement of proper preventive and treatment strategies for obtaining desirable results, in terms of potassium concentrations.

THERAPEUTIC APPROACH TO DIURETIC-INDUCED HYPOKALEMIA

Hypokalemia is a leading complication of diuretics, particularly thiazides. The body usually responds by tightly regulating feedback and feed-forward systems in order to maintain serum potassium levels within very narrow limits. Although the relation between symptomatic hypokalemia and severe potassium depletion is well established, chronic mild hypokalemia is associated with accelerated progression of CKD, worsened systemic hypertension, and high mortality rate. This delineates the need for an appropriate therapeutic strategy to correct hypokalemia and prevent its consequences, without provoking hyperkalemia.⁴¹Asmar A, Mohandas R, Wingo CS. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012 Sep;60(3):492-7.   ⁴²Kjeldsen K. Hypokalemia and sudden cardiac death. Exp Clin Cardiol. 2010 Winter;15(4):e96-9.    Apropos, potassium replacement therapy including potassium chloride supplements may be a promising approach.³⁵Reungjui S, Pratipanawatr T, Johnson RJ, Nakagawa T. Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Curr Opin Nephrol Hypertens. 2008 Sep;17(5):470-6.   ³⁹Ornato JP, Gonzalez ER, Starke H, Morkunas A, Coyne MR, Beck CL. Incidence and causes of hypokalemia associated with cardiac resuscitation. Am J Emerg Med. 1985 Nov;3(6):503-6.   ⁴¹Asmar A, Mohandas R, Wingo CS. A physiologic-based approach to the treatment of a patient with hypokalemia. Am J Kidney Dis. 2012 Sep;60(3):492-7.   ⁴³Bourke E, Delaney V. Prevention of hypokalemia caused by diuretics. Heart Dis Stroke. 1994 Mar-Apr;3(2):63-7.   ⁴⁵Chlorothiazide. Available at: http://pubchem.ncbi.nlm.nih.gov/compound/chlorothiazide#section=Toxicity. Accessed on: 25.2.2015.    Investigators have suggested that prophylactic administration of a potassium supplement such as potassium chloride may be required in patients with serum potassium level less than about 3 mEq/L.⁴⁶Jackson PR, Ramsay LE, Wakefield V. Relative potency of spironolactone, triamterene and potassium chloride in thiazide-induced hypokalaemia. Br J Clin Pharmac. 1982;14:257-263.    A wealth of data indicates several clinical benefits of potassium supplementation in maintaining normal potassium level. A study⁴⁶Jackson PR, Ramsay LE, Wakefield V. Relative potency of spironolactone, triamterene and potassium chloride in thiazide-induced hypokalaemia. Br J Clin Pharmac. 1982;14:257-263.    conducted by Wakefield and coworkers showed that potassium chloride was comparatively more effective in increasing plasma potassium level than placebo. Thus, considerable base of evidence suggests that either a low-salt diet rich in potassium, chloride and magnesium or potassium chloride supplements may help in preventing the episodes of hypokalemia.⁴³Bourke E, Delaney V. Prevention of hypokalemia caused by diuretics. Heart Dis Stroke. 1994 Mar-Apr;3(2):63-7.    This has been consistently reported by the findings of a study³⁹Ornato JP, Gonzalez ER, Starke H, Morkunas A, Coyne MR, Beck CL. Incidence and causes of hypokalemia associated with cardiac resuscitation. Am J Emerg Med. 1985 Nov;3(6):503-6.    which revealed that potassium supplementation appeared to be protective in patients on diuretics. Moreover, the investigators demonstrated that those who were administered diuretics without potassium supplementation were associated with highest risk of cardiac arrest (4.4 times high), thus underlining the importance of potassium supplementation.³⁵Reungjui S, Pratipanawatr T, Johnson RJ, Nakagawa T. Do thiazides worsen metabolic syndrome and renal disease? The pivotal roles for hyperuricemia and hypokalemia. Curr Opin Nephrol Hypertens. 2008 Sep;17(5):470-6.   ⁴⁵Chlorothiazide. Available at: http://pubchem.ncbi.nlm.nih.gov/compound/chlorothiazide#section=Toxicity. Accessed on: 25.2.2015.   

Potassium supplementation with diuretics

Considerable evidence suggests that amelioration of hypokalemia (serum potassium < 3.5 mmol/L) lowers BP in essential hypertensive patients receiving thiazide diuretics. This can be achieved via potassium supplementation in those who continue to take a constant amount of diuretic. The World Health Organization (WHO) guidelines on potassium intake recommends that adults (≥16 years of age) without compromised renal handling of potassium should consume > 90 mmol potassium/ day for beneficial effects on BP and reducing the risk of comorbid cardiovascular diseases. For children (2-15 years of age), potassium intake of at least 90 mmol/day should be adjusted downward, based on energy requirements of children relative to those of adults. The positive effect of potassium supplementation has been demonstrated in various randomized, double-blind trials. A systematic review of literature and meta-analysis provides strong evidence for this phenomenon by showing that increased potassium intake [90 mmol/day (3,510 mg/day) to 120 mmol/ day (4,700 mg/day)] reduces BP in individuals with hypertension, and has no adverse effect on blood lipid concentrations, catecholamine concentrations, or renal function in adults.⁴⁷Salem CB, Hmouda H, Bouraoui K. Drug-induced hypokalaemia. Curr Drug Saf. 2009;4(1):55- 61.   ⁴⁸Svetkey LP, Yarger WE, Feussner JR, DeLong E, Klotman PE. Double-blind, placebo-controlled trial of potassium chloride in the treatment of mild hypertension. Hypertension. 1987 May;9(5):444-50.   ⁴⁹Kaplan NM, Carnegie A, Raskin P, Heller JA, Simmons M. Potassium supplementation in hypertensive patients with diuretic-induced hypokalemia. N Engl J Med. 1985;312(12):746-9.   ⁵⁰Patki PS, Singh J, Gokhale SV, Bulakh PM, Shrotri DS, Patwardhan B. Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study. BMJ. 1990;301(6751):521-3.   ⁵¹Geleijnse JM, Kok FJ, Grobbee DE. Blood pressure response to changes in sodium and potassium intake: a metaregression analysis of randomised trials. J Hum Hypertens. 2003;17(7):471-80.   ⁵²Guideline: Potassium Intake for Adults and Children. Geneva: World Health Organization; 2012. Available at: http://apps.who.int/iris/bitstream/10665/77 986/1/9789241504829_eng.pdf. Accessed on: 20/7/2015.    which showed that increased potassium intake reduced systolic BP by 3.49 mmHg [95% confidence interval (CI) 1.82-5.15)] and diastolic BP by 1.96 mmHg (95% CI 0.86-3.06) in the overall adult population. It was thus suggested that increased potassium intake would have a positive impact on the prevention and control of elevated BP and stroke, in the absence of severely compromised renal function. To take this notion further, investigators assessed the effect of daily potassium intake on reducing BP in non-medicated normotensive or hypertensive patients, and determined the link between potassium intake, sodium-to-potassium ratio and reduction in blood pressure. Potassium supplementation resulted in reduction of SBP by 4.7 mmHg (95% CI 2.4-7.0) and DBP by 3.5 mmHg (95% CI 1.3-5.7) in all patients. The effect was found to be greater in hypertensive patients, with a reduction of SBP by 6.8 mmHg (95% CI 4.3-9.3) and DBP by 4.6 mmHg (95% CI 1.8-7.5). Moreover, a direct relation between increased daily potassium excretion and decreased sodium-to-potassium ratio with BP reduction was reported. Increased total daily potassium urinary excretion from 60 to 100 mmol/day and decrease of sodium-to-potassium ratio were believed to be the active players in obtaining the estimated effect.⁵⁴Binia A. Daily potassium intake and sodium-to-potassium ratio in the reduction of blood pressure: a meta-analysis of randomized controlled trials. J Hypertens. 2015 Aug;33(8):1509-20.    Various benefits of potassium chloride are mentioned in box 1.

CONCLUSION

The enormous burden of renal disorders necessitates the need for more aggressive health measures to stem the tide. Mounting evidences suggest the significant role of diuretics in the management of these disorders and associated comorbidities such as hypertension. Knowledge of the pharmacologic properties and mechanisms of action of diuretic agents is a prerequisite for the successful choice and effective clinical use of these agents. One of the most common adverse effects of the diuretics, typically thiazides, is potassium depletion (hypokalemia) which is frequently encountered in most of the patients. Potassium depletion may in turn result in life-threatening clinical conditions including cardiac arrhythmias and is particularly important in patients receiving cardiac glycosides because hypokalemia potentiates the cardiac toxicity of these agents, thereby leading to increased ventricular irritability. Thus, it may prove beneficial to pay more attention to hypokalemia and to maintain plasma potassium levels in the normal range. The literature is replete with the beneficial effects of potassium supplementation such as potassium chloride in maintaining normal potassium level in cases of diureticinduced hypokalemia.

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