Thiazides: do they kill?
Peter Gross and
Catrin Palm
Nephrology, Medizinische Klinik III, Universitätsklinikum C.G. Carus, Dresden, Germany
Correspondence and offprint requests to: Peter Gross, Nephrology, MK III, Universitätsklinikum C.G. Carus, Fetscherstr. 74, D-01307 Dresden, Germany. Email: peter.gross{at}mailbox.tu-dresden.de
Keywords: aquaporin-2; hyponatraemia; thiazides
 |
Introduction
|
---|
In 2000 and 2002 after the ALLHAT-study had been published [1,2] there was a paradigm shift in the use of thiazides. ALLHAT was a study of cardiovascular endpoints in relation to different antihypertensive treatments in 33 357 hypertensive patients observed over an average of 4.9 years. The study [1,2] found no differences between the three treatment groups [diuretics in the form of chlorthalidone vs calcium antagonists (amlodipine) vs ACEI (lisinopril)]. Consequently, after ALLHAT, it was emphasized that thiazides ought to be an integral part of the hypertensive patient's prescription sooner or laterand health policy makers clearly favoured sooner over later because of their low cost. Indeed, the sale of thiazide-like agents has more than doubled between 2001 and 2004 in Germany alone. In the meantime, quite a few articles have dealt with the pros and cons of thiazides [3], when prescribed on such an extended basis. However, there appears to be yet another important side-effect of thiazides that is frequently missedeven though it may kill patients. This will be discussed herein.
 |
Why is the lady comatose?
|
---|
The clinical manifestation to be discussed is almost always stereotype: an elderly lady will have been admitted to hospital a short while ago in an unexplained comatose state. The major discernible abnormality detected in the ICU will be severe hyponatraemia (110116 mmol/l) associated with mild hypokalaemia (3.03.4 mmol/l). The constellation of laboratory results will not quite fit that of classical SIADH (with euvolaemia) nor that of hypovolaemic hyponatraemia. Euvolaemia is usually characterized by low or below normal levels of uric acid, urea and creatinine in the absence of major hyperglycaemia; there will be normal blood pressure and no signs of dehydration. Hypovolaemia, in contrast, would show mildly elevated plasma concentrations of urea, creatinine and uric acid; low blood pressure and clinical signs of volume loss; absence of edema. The patients with thiazide-induced hyponatraemia seem to be in between such euvolaemia and hypovolaemia. Meanwhile in the ICU it will usually take about 48 h of more or less heated discussions with the house staff about the best mode and particularly about the rate of corrective treatment of the hyponatraemia, plus discontinuation of thiazides (if they are a known prescription at that time), fluid restriction and possibly other measures (such as infusions of normal or hypertonic saline) until the serum sodium rises towards near normal levels, making the patient more awake and communicative. It will then be revealed that thiazides had been prescribed for the first time about 14 weeks earlier, usually for hypertension and sometimes for congestive cardiac failure. Occasionally, one will find a neighbour who had noticed the patient often drinking a lot of fluids.
 |
Thiazide-hyponatraemia: do they die?
|
---|
Thiazide-induced hyponatraemia is fully reversible once the diuretic is stopped. Re-exposure is very likely to produce the same consequences should it be enacted. A seminal report on seven index patients with thiazide-hyponatraemia by Ashraf et al. [4] appeared in 1981, almost 25 years ago. All seven patients were elderly ladies who had first been started on thiazides on average <16 days before severe hyponatraemia (105±6 mmol/l) ensued. The serum creatinine was normal in all and urinary sodium excretion rate was somewhat high (on average 100 mmol/l). Plasma ADH was low, but measurable. The patients in the report [4] suffered from CNS changes such as generalized seizures, stupor, coma, death or permanent paralysissupposedly all related to the associated brain edema and its consequences. Subsequent reports have confirmed all essential features of this syndrome, including the preferential occurrence in elderly women, the associated hypokalaemia and the preceding polydipsia [58]. The causative agents were not limited to hydrochlorothiazide (HCTZ) per se but metolazone, indapamide, and combinations of HCTZ with amiloride or with triamterene have also been incriminated. Chow et al. [9] analysed 223 cases of thiazide-hyponatraemia in their hospital: they were able to identify old age, low body weight and low serum potassium concentrations as specific risk factors.
 |
What is wrong with summer?
|
---|
Why does the syndrome preferentially occur in summer? For instance we observed over the last 4 years in our own (university) hospital that the daily incidence of all hyponatraemias increased by 100200% in a hot summer (P. Gross, unpublished observations).
Hyponatraemia is usually the result of relative water overload. To generate body water overload a reduced renal water excretion is necessary and this is usually related to failure to suppress ADH. In that situation, drinking (hypotonic) fluid will make the problem worse. In hot summers most people drink many more hypotonic fluids than normal. The system works like a bath tub. The water level in the tub rises too high (hyponatraemia) if the outflow is too narrow (renal antidiuresis from too much ADH), which will be made a lot worse if there happens to be an increased inflow (thirst and increased drinking in summertime).
Indeed, excessive drinking has been noted in reports of thiazide-hyponatraemia. Given this baseline fact it is more than likely that high temperatures in hot summer lead to increased thirst and fluid intake and further worsening of hyponatraemia. This then appears to be the chain of events linking hot summer to coma (in thiazide users, that is), although admittedly this aspect has never been studied in a systematic fashion.
 |
Any new kids on the block?
|
---|
So what is the point of thiazide-hyponatraemia at this particular point in time? Is there anything new?
Clinicallyas mentioned beforewhen prescribing thiazides more frequently, as is now widely observed, we must direct more awareness to the hyponatraemic risk occurring in elderly thin ladies; we ought to measure their serum sodium concentration perhaps 2 and 8 weeks after the start of a thiazide to protect them from the occasional severe symptomatic hyponatraemia.
A new publication has very recently indicated a potential explanation forhitherto unexplainedthiazide-hyponatraemia [10]. In this paper, Kim et al. [10] present evidence obtained in rats to show that thiazides may upregulate aquaporin-2 in the collecting duct. The authors suggest that by this mechanism the common practice of using thiazides to improve nephrogenic diabetes insipidus may also be explained. To be sure, many issues remain to be explained, including the mechanism of this effect of thiazides in the collecting duct (principal) cell, any potential effects of sex hormones on the upregulation of aquaporin-2 after thiazide, the apparent lack of feedback of aquaporin-2 upregulation on ADH-secretion and the dysregulated thirst in thiazide-hyponatraemia. However, a new starting point has been set and further observations will undoubtedly follow.
The imminent introduction of oral V1/V2 vasopressin antagonists into clinical practice scheduled for early 2006 (Conivaptan of Astellas) will soon make the treatment of thiazide-hyponatraemia more specific and hopefully easier. These agents promise to allow better fine-tuning of the treatment of any hyponatraemia especially when severe.
 |
Conclusions
|
---|
After ALLHAT, there has been a widespread surge in the use of thiazides primarily for the treatment of hypertension, but also of congestive cardiac failure. Several important side-effects of thiazides such as hypokalaemia and arrhythmias, hyperglycaemia and hyperuricaemia triggering acute attacks of gout are well known; in contrast, thiazide-hyponatraemia is usually missed. It is not extremely rare, it manifests in the first 4 weeks after the start of thiazides, it affects primarily elderly thin women, it manifests a severe symptomatic hyponatraemia (comatose state; 110116 mmol/l) and the laboratory constellation is somewhat reminiscent of that in SIADH, however, associated with mild hypokalaemia. The best mode of treatment is discontinuation of thiazides (if known), fluid restriction to <1 l/day all fluids included and other measures (infusions of isotonic or hypertonic saline) to increase the serum sodium concentration at a rate of <0.5 mmol/l/h. The best present explanation of thiazide-hyponatraemia is thiazide-induced overexpression of aquaporin-2 in the collecting duct in susceptible individuals. The causes of this particular susceptibility remain to be elucidated. The literature has described patients that have died from thiazide-hyponatraemia.
Conflict of interest statement. None declared.
 |
References
|
---|
- Davis BR, Cutler JA, Gordon D et al. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlortalidone. JAMA 2000; 283: 19671975[Abstract/Free Full Text]
- Wright JT, Davis BR, Furberg CD et al. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretics. JAMA 2002; 288: 29812997[Abstract/Free Full Text]
- Morganti A. Should a diuretic always be the first choice in patients with essential hypertension? The case for no. J Am Soc Nephrol 2005; 16: S70S73[Abstract/Free Full Text]
- Ashraf N, Locksley R, Arieff AI. Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients. Am J Med 1981; 70: 11631168[CrossRef][ISI][Medline]
- Booker JA. Severe symptomatic hyponatremia in elderly outpatients: the role of thiazide therapy and stress. J Am Geriatr Soc 1984; 32: 108113[ISI][Medline]
- Oles KS, Denham JW. Hyponatremia induced by thiazide-like diuretics in the elderly. South Med J 1984; 77: 13141315[ISI][Medline]
- Sonnenblick M, Algur N, Rosin A. Thiazide-induced hyponatremia and vasopressin release. Ann Int Med 1989; 110: 751[Medline]
- Friedman E, Shadel M, Halkin H, Farfel Z. Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis. Ann Int Med 1989; 110: 2430[ISI][Medline]
- Chow KM, Szeto CC, Wong TYH, Leung CB, Li PKT. Risk factors for thiazide-induced hyponatremia. Q J Med 2003; 96: 911917[ISI]
- Kim GH, Lee JW, Oh YK et al. Antidiuretic effect of hydrochlorothiazide in lithium-induced nephrogenic diabetes insipidus is associated with upregulation of aquaporin-2, Na-Cl co-transporter, and epithelial sodium channel. J Am Soc Nephrol 2004; 15: 28362843[Abstract/Free Full Text]