Review Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy † 1. Introduction Pantelis A Sarafidis , Panagiotis I Georgianos & Anastasios N Lasaridis 2. Hypokalaemia Aristotle University of Thessaloniki, AHEPA Hospital, Section of Nephrology and Hypertension, 3. Hyperkalaemia 1st Department of Medicine, St. Kiriakidi 1, 54636, Thessaloniki, Greece 4. Hyponatraemia Importance of the field: As with all potent therapeutic agents, the use of 5. Disorders of magnesium diuretic compounds has been linked with several adverse effects that may homeostasis reduce quality of life and patient compliance and, in some cases, may be 6. Disorders of calcium associated with considerable morbidity and mortality. Among the various homeostasis types of adverse effects, disturbances of electrolyte and acid–base balance are 7. Acid–base disorders perhaps the most common, and some of them are the aetiological factors of other side effects (i.e., hypokalaemia causing ventricular arrhythmias or 8. Conclusion glucose intolerance). The mechanism and site of action and, therefore, the 9. Expert opinion pharmacological effects of each diuretic class largely determine the specific electrolyte or acid–base abnormalities that will accompany the use of each diuretic agent. Areas covered in the review: This article reviews the major electrolyte dis- turbances (hypokalaemia, hyperkalaemia, hyponatraemia, disorders of mag- nesium and calcium balance), as well as the acid–base abnormalities complicating the use of the various diuretic agents. What the reader will gain: The reader will gain insights into the pathogenesis of the diuretic-induced electrolyte and acid–base disorders together with considerations for their prevention and treatment. For personal use only. Take home message: Knowledge of the pharmacologic properties of each diuretic class and appropriate monitoring of patients under diuretic treatment represent the most important strategies to prevent the development of diuretic-related adverse events and their consequences. Keywords: diuretics, hyperkalaemia, hypokalaemia, hypomagnesaemia, hyponatraemia Expert Opin. Drug Saf. (2010) 9(2):259-273 Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Sydney 1. Introduction Diuretics are potent therapeutic tools that have been used broadly for > 50 years in the treatment of major diseases of internal medicine, such as hypertension and common oedematous disorders (cardiac failure, nephrotic syndrome, hepatic cir- rhosis). Certain diuretics have been also used for years in the treatment of more specific conditions, such as glaucoma, cerebral oedema, hypercalcaemia, hypercal- ciuria and diabetes insipidus [1-3]. Although providing important help in the treatment of many diseases, as in the case of all potent therapeutic agents, the clinical use of diuretics has the potential to cause several adverse effects. These may reduce quality of life and patient compliance and, in some cases, may be associated with considerable morbidity and mortality [4]. Among the various types of adverse effects, disturbances of electrolyte and acid–base balance are perhaps the most common, and some of them are the aetiological factors of other side effects (i.e., hypokalaemia being responsible for the genesis of ventricular arrhythmias or glucose intolerance). 10.1517/14740330903499257 © 2010 Informa UK Ltd ISSN 1474-0338 259 All rights reserved: reproduction in whole or in part not permitted Diuretics in clinical practice. Part II: electrolyte and acid-base disorders complicating diuretic therapy largely based on their mechanism of action. The mechanism Article highlights. and site of action of each diuretic class determine their . The specific electrolyte or acid–base abnormalities that pharmacological effects, natriuretic efficacy and specific clin- characterise each diuretic class can be largely anticipated ical indications, as well as several of their side effects [1,3]. from the pharmacologic mechanism of action and the nephron segment where each class of diuretics acts. Therefore, as in the case of pharmacological actions, the . Hypokalaemia is the most common electrolyte disorder specific electrolyte or acid–base abnormalities for each class linked to diuretic use and is associated with a number of of diuretics can be largely anticipated from the pharmacologic serious cardiac adverse consequences (arrhythmias, mechanism of action and the nephron segment where a class of sudden death); the lower doses at which thiazides and diuretics acts (Table 1) [5]. Based on this, strategies of adequate related agents are prescribed for hypertension treatment in the last years seem to have helped towards reduction in monitoring of diuretic treatment, appropriate dose adjust- the incidence of diuretic-induced hypokalaemia. ment and electrolyte replacement, when necessary, can prevent . Hyperkalaemia is a side effect of potassium-sparing the development and the consequences of electrolyte or diuretics. The increase in the use of aldosterone-blockers acid–base disorders and ensure patients’ safety. for conditions other than their traditional indications (i.e., This article represents the second part of a work on the heart failure) was associated with important increase of the incidence of diuretic-induced hyperkalaemia; thus, clinical use of diuretics that reports on the disturbances of careful use and appropriate dosing of these agents is electrolyte and acid–base balance complicating the use of required, especially in patients with additional risk factors diuretic agents and discusses strategies for their prevention for hyperkalaemia. and treatment. Diuretic-induced hyponatraemia is a very common electrolyte disorder, occurring mainly in out-patients under thiazide treatment. Severe hyponatraemia can have 2. Hypokalaemia serious consequences. Adequate monitoring of serum Na+ levels, especially in predisposed patients, is the most The secretion of K+ into the tubular lumen occurs mainly in appropriate strategy to prevent the development of this the cortical collecting duct and to a lesser extent at the final side effect during diuretic treatment. segment of the distal convoluted tubule and the connecting . Chronic treatment with thiazide and loop diuretics can 2+ 2+ tubule, following the lumen negative electric gradient due to produce small reductions in serum Mg levels; as Mg + homeostasis plays a major role in several actions at cellular Na reabsorption [3,6]. A number of different factors can level, attention needs to be paid to the detection and participate in increased K+ secretion and consequently K+ appropriate correction of Mg2+ depletion during depletion and hypokalaemia during diuretic therapy. First, diuretic treatment. increased flow-dependent Na+ delivery to these regions of the . Thiazides and loop diuretics have contrasting well- For personal use only. described effects on Ca2+ renal handling; thiazides reduce distal nephron: all of carbonic anhydrase inhibitors, osmotic urinary Ca2+ excretion by a large percentage and are diuretics, loop diuretics, and thiazides and related agents indicated for the treatment of nephrolithiasis with promote K+ secretion by inhibiting Na+ reabsorption in their increased urinary Ca2+ excretion, whereas loop diuretics site of action and increasing Na+ delivery to the collecting increase Ca2+ loss and are used to treat hypercalcaemia. duct [4,5,7,8]. The second factor is diuretic-induced volume . Carbonic anhydrase inhibitors typically increase renal - depletion, which stimulates the renin–angiotensin system HCO3 excretion resulting in metabolic acidosis, especially in elderly patients. Potassium-sparing diuretics can also (RAS) resulting, among others, in secondary hyperaldoster- induce metabolic acidosis. Mild metabolic alkalosis onism; aldosterone stimulates Na+ reabsorption and, there- + develops commonly during thiazide or loop diuretic fore, K secretion in the collecting duct [4,5,7,8]. With the treatment but is usually without important consequences. exception of carbonic anhydrase inhibitors, all the above Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Sydney - This box summarises key points contained in the article. agents induce Cl depletion which independently promotes + urinary K loss [9], whereas loop and thiazide diuretics pro- mote Mg2+ depletion which also induce kaliuresis, through + unknown mechanisms [3,10]. Further, as K loss is also a In the renal tubules, reabsorption of NaCl is driven by the function of dietary NaCl, when NaCl intake is high, distal electrochemical Na+ gradient generated by the Na+-K+- delivery of Na+ remains also high and K+ secretion is pro- ATPase pump of the basolateral membrane, which is present moted [5]. Finally, the risk of hypokalaemia would be greater in practically all tubular epithelial cells; however, the Na+ in patients with low total body potassium, as in many elderly transport pathways of the luminal tubular membrane, as well patients [11]. as the amount of Na+ reabsorbed, differ between the various Several studies on the prevalence and severity of hypoka- segments of the nephron [3]. With the exception of osmotic laemia in patients receiving diuretics suggest that they differ agents, all other diuretics act by interfering with a specific between the various diuretic classes and that they are dose- transport system of the luminal membrane; in fact, the most related. Long-acting agents, such as chlorthalidone, produce common classification