The effect of long term use of Glibenclamide on serum and urinary sodium and potassium level in type 2 DM patients Iraqi J Pharm Sci, Vol.19(1) 2010 Effect of glibenclamide on sodium and potassium level 58 The Effect of Long Term use of Glibenclamide on Serum and Urinary Sodium and Potassium Level in Type 2 DM Patients Ali A. Ali* ,1 *Department of Clinical Pharmacy, College of Pharmacy, University of Baghdad, Baghdad, Iraq. Abstract Long-term use of sulfonylureas including chlorpropamide, is known to potentiate the antidiuretic action of arginine vasopressin (AVP), predisposing to hyponatremia.The present study was designed to evaluate the effect of long term use of glibenclamide on serum and urinary levels of sodium and potassium in Type 2 DM patients in Iraqi DM centers. Ninety eight patients with Type 2 DM who were maintained on different doses of glibenclamide for at least 1 year, attending the centre for Diabetes and Endocrinology in Al-Rusafa, Baghdad, were enrolled in the study, in addition to 15 normal healthy subjects. Patients were allocated into three groups according to the dose of glibenclamide that they received. Blood and urine samples were obtained for evaluation of sodium and potassium levels in these samples by flamephotometry. The results indicated that glibenclamide use resulted in significant elevation in serum levels of sodium and potassium compared to controls, while urinary excretion of these cations was not significantly changed. Stratification of patients according to the dose of glibenclamide revealed that this effect on sodium and potassium was not dose dependent. In conclusion, long term use of glibenclamide impairs normal values of Sodium and potassium independent of the administered dose. Key words: Glibenclamide, sodium, potassium. الخالصة ) غٍز اىَعخَذ عيى اُ دواء اىنيىربزوباٍاٌذ وهى ٍِ ٍدَىعت اىظيفىٍّو ٌىرٌا ٌظخخذً ىعالج ٍزضى اىظنزي ٍِ اىْىع اىثاًّ و ٌعخقذ اُ هذا اىذواء ٌعَو ٍباشزة عيى واىذي ٌظبب ّقص اىصىدٌىً االّظىىٍِ( وهى ٍعزوف بخحفٍشٓ ىعَو اىهزٍىُ اىَضاد ىيبىه فً هذا اىبحث ّىد دراطت حاثٍز دواء اىنيٍبٍْنالٍاٌذ وهى ٍِ ّفض ٍدَىعت اىنيىربزوباٍاٌذ )أي .ىيبىه ٍظخقبالث هزٍىُ اىَضاد طاعت فً اىَزضى 42اىَدَىع خاله ه اىبىاىظيفىٍّو ٌىرٌا(عيى حزمٍش اىصىدٌىً واىبىحاطٍىً فً اىذً )اىَصو( ومذىل فً وقذ 4009ٍِ عاًاىثاًّ وىغاٌت شهز ماّىُ 4002اىَصابٍِ بذاء اىظنزي اىْىع اىثاًّ وقذ اخزٌج هذا اىذراطت فً شهز اٌيىه هْاك ٍزٌض خارخً ٍِ ٍزمش اىغذد اىصٌ واىظنزي فً اىزصافت ببغذاد باىخعاوُ ٍع اىطبٍب االطخشاري 92شارك فً هذٓ اىذراطت حزمٍش اىصىدٌىً وقذ حٌ قٍاصطاعت فً اىَْشه( 42خاله اىَدَىع ىبىها) ىبىهشخص طيٌٍ وقذ اخذث عٍْاث ٍِ اىَصو وا 51و ٌؤثز بشنو ٍيحىظ عيى حزمٍش اىصىدٌىً اىنيٍبٍْنالٍاٌذواظهزث اىْخائح اُ قٍاص االىىاُ فً اىيهب واىبىحاطٍىً بىاططت خهاس 42اىَدَىع خاله ىبىهفً ا واىبىحاطٌٍ ذً ٍقارّت ٍع اىَدَىعت اىقٍاطٍت اٍا حاثٍزٓ عيى حزمٍش اىصىدٌىًواىبىحاطٍىً فً ٍصو اى ٍيحىظ. طاعت ىٌ ٌنِ بشنو Introduction Glibenclamide is a first line option for treating patients with type 2 diabetes mellitus (DM) who are not overweight or who can not take metformin (1) . It is mostly used when diet control and exercise have failed to achieve tight control of plasma glucose level; it also can be used alone or in combination with other hypoglycemic agents to provide better glycemic control (2) .Sodium is the important electrolyte in the extracellular space while potassium is the essential one in the intracellular space, this asymmetrical distribution of the electrolytes across the cell membrane requires the active exchange of both cations by the Na+/K+-ATPase . (3) Potassium is the principle electrolyte (cation) of intracellular fluid and the primary buffer within the cell itself. Ninety percent of potassium is contain in blood and bone. Damaged cells release potassium into the blood .(4) Using free flow micropuncture technique in rats, intravenous infusion of glibenclamide (3mg/hr) evoked a natriuresis and diuresis; while potassium excretion remained unchanged. It has been reported that glibenclamide impaires sodium reabsorption in one or more of the nephron segment that comprise the loop of Henle (5) .Moreover, other hypothesis indicates that the natriuretic effect of glibenclamide is a consequence of blockade of potassium channels in the apical membrane of the thick ascending part of Henle loop; or it may inhibited a small secretory potassium flux in the proximal tubule (6) .The present study was designed to evaluate the effect of long term use of different doses of glibenclamide on serum and urinary levels of sodium and potassium levels of Iraqi patients with type 2 DM. 1Corresponding author E- mail : aliaziz_1977@yahoo.com Received : 27/6/2009 Accepted : 9/3/ 2010 Iraqi J Pharm Sci, Vol.19(1) 2010 Effect of glibenclamide on sodium and potassium level 59 Subjects and methods Ninety eight patients (54 female and 44 males) with type 2 diabetes mellitus, were referred to the specialized center for Endocrinology and Diabetes, Baghdad during the period from September 2008 to January 2009 were enrolled in the study; their age range was 52.26 ± 8.65 years and diagnosed to have type 2 DM for at least five years( Average duration of type 2 DM 5.5 ± 0.4 years) and maintained on glibenclamide 5 mg , 10 mg or 15 mg at least 1 year with adequate glycemic control (Average fasting blood sugar = 6.0 ± 0.94 mmole/L) and no detectable secondary complications .All patients were inflamed about the nature of the study and their signed consents were obtained before participation. Additionally, 15 healthy subjects with comparable age to that of patients were utilized as control. After overnight fasting, venous blood samples were obtained from all subjects without using tournique to avoid leakage of cellular potassium, and serum was prepared for evaluation of serum levels of sodium and potassium using flamephotometer (The flamephotometer used is FP 20 seac from Seag Radim company-Italy). Moreover, 24 hours urine sample was collected for evaluation urinary excretion of sodium and potassium using flamephotometry. For 24 hours urine collection, we instructed the patients to void at 8 AM and discard the specimen. Then collect all urine including the final specimen voided at the end of the 24-hour collection period (i.e, 8 AM the next morning) (7). For evaluation of the effect of glibenclamide on serum and urinary levels of sodium and potassium, all patients data were compared with those of controls; Meanwhile ,for the evaluation of the effect of glibenclamide dose ,patients were classified in three groups, those who are treated with 5 mg/day(n=56), those treated with 10 mg/day(n=29) and those treated with 15 mg/day(n=13). All data were expressed as mean ± standard deviation; un-paired students t-test between patients and control and ANOVA test was performed for evaluation of differences between groups and p-values < 0.05 were considered significant. Flame photometry based on atomic emission method for the routine detection of metal salts, principally Na, K, Li, Ca and Ba. Quantitative analysis of these species is performed by measuring the flame emission of solution containing the metal salts.Solution is aspirated into the flame. The hot flame evaporates the solvent, atomizes the metal, and excites a valence electron to an upper state. Optical filters are used to select the emission wavelength monitored for the analyte species. Comparison of emission intensities of unknowns to either that of standard solutions, or to those of an internal standard, allows quantitative analysis of the analyte metal in the sample solution .(8, 9) Results In the present study, table 1 shows that serum sodium concentration in total number of patients is significantly different (P<0.05) compared to that in control group. Table 1 also shows that both urine sodium and potassium concentrations in total number of patients are not-significantly different (P>0.05) compared to that in control group. In table 2, the average urinary excretion of sodium and potassium was not significantly different (P>0.05) among patients who were using different doses of glibenclamide. Table 1 : Effect of glibenclamide on serum and urinary levels of sodium and potassium in type 2 patients. Parameter Control subjects (n=15) DM patients treated with glibenclamide (n=98) Serum sodium (meq/L) 139.95 ± 3.859 142.29 ± 6.67* Serum potassium (meq/L) 4.13 ± 0.56 4.71 ± 0.663* Urine sodium (meq/L) 103.14±26.25 100.64 ± 48.8 Urine potassium (meq/L) 62.02±33.2 51.76 ± 25.12 Values were expressed as mean ± SD; n= number of subjects; * = significantly different from control (p< 0.05). Iraqi J Pharm Sci, Vol.19(1) 2010 Effect of glibenclamide on sodium and potassium level 60 Table 2: Effect of 5 mg /day , 10 mg/day and 15 mg/day Glibenclamide on serum and urinary sodium and potassium levels in type 2 DM patients. parameter Patients treated with 5 mg /day glibenclamide N=56 Patients treated with 10 mg /day glibenclamide N=29 Patients treated with 15 mg /day glibenclamide N=13 Serum sodium ( meq/L) 142.3 ± 4.5 a 142.7 ± 7.8 a 141.53±4.33 a Serum potassium ( meq/L) 4.746 ± 0.659 a 4.648 ± 0.748 a 4.73 ± 0.496 a Urine sodium ( meq/L) 109.08 ± 52.28 a 96.4 ±41.58 a 73.75 ± 46.89 a Urine potassium (meq / L) 55.39 ± 21.59 a 41.85 ±24.77 a 54.75 ± 35.964 a Values were expressed as mean ± SD; n= number of subjects; values with identical superscripts (a ) were considered non significantly different (P>0.05) (ANOVA). Discussion Systemic administration of glibenclamide inhibits sodium reabsorption in the loop of Henle (6) ; this extra-pancreatic effect of glibenclamide reveal natriuretic activity (10) ,which is attributed to elevation of functional sodium delivery to the distal tubules. Moreover ,glibenclamide impairs sodium reabsorption in one or more of the nephron segments that comprise the loop of Henle (5) .In the present study, long term use of glibenclamide by DM patients resulted in significant elevation in serum levels of sodium and potassium (table 1) ;this effect may be attributed to enhancement of free water excretion induced by glibenclamide in patients with DM (11) .In clinical practice, administration of 5 mg single oral dose of glibenclamide in patients with type 2 DM did not essentially affect sodium and potassium excretion (12) .Several agents belong to sulfonylureas group ,including glibenclamide, have diuretic action in well hydrated normal subjects (11) , and glibenclamide enhances water excretion in patient with diabetes insipidus (13,14) , and diabetes mellitus (11) .In this respect, the reported elevation in serum levels of sodium and potassium (in the present study),without affecting urinary levels, may be explained on the bases of improper hydration status of enrolled patients, especially when associated with excessive of water excretion. The data presented in table 2 indicated that there is no dose-related effect for glibenclamide on sodium and potassium homeostasis; this observation may indicate that the reported elevation in serum levels of the cation is beyond the pharmacodynamic activity of glibenclamide .Moreover, the limitation of patients' sample, duration of follow up multifactorial pathophysiology may have potential interference in this respect. Accordingly, larger patients sample with proper selection criteria could be a proper approach for clear definition of the problems. Conclusion In this study we conclude that glibenclamide dose not satisfy syndrome of inappropriate antidiuretic hormone secretion (SIADH) criteria because no hyponatremia occure (SIADH criteria are hyponatremia and urinary sodium concentration >20mmol/L) (15, 16) .Also we conclude that long-term use of different doses of glibenclamide in type 2 DM may impaire sodium and potassium homeostasis unrelated to the administered dose. Acknowledgments I would like to thank Dr.Khalid Ibraheem , specialist of endocrinology, centre of diabetes and endocrinology in Al-Rusafa-Baghdad . Also I am grateful to the staff of quality control department - central laboratories /Baghdad. References 1. Hensen J; Haenelt M; Gross P. Water retention after oral chlorpropamide is associated with an increase in renal papillary arginine vasopressin receptor.Eur.J Endocrinolo 1995 Apr;132(4): 459-64. 2. WHO Model list of Essential Medicines, 15th edition, Word Health Organization, p.21.Retrieved on 2007-11-19. 3. Thomas L: Water balance and fluid compartments; Sodium, Clinical lab diagnostics, 1st edition, 1998, vol.1, 289. 4. Frances Fischbach, Potassium, A manual of laboratories and diagnostic test, sixth edition, 2000, chapter 6, 349. 5. Baily M.A and S.J. Walter: Renal effects of Glibenclamide: A micropuncture study: The journal of pharmacology and experimental thrapeutics; may 1998, vol.285, issue 2,464-467. Iraqi J Pharm Sci, Vol.19(1) 2010 Effect of glibenclamide on sodium and potassium level 61 6. Bailey M.A., Shirley D.G., Stocking CJ. Jonathan M. Slater, Stephen J. Walter . The natriuretic effect of glibenclamide:evidence for a non-luminal site of action. European Journal of physiology. Vol.444, Number 6/ September, 2002, 777-784. 7. Harrington JT and Cohen JJ," Measurement of Urinary Electrolytes- Indications and Limitations", N Engl J Med, 1975,293(24):1241-3. 8. Sawyer, Heineman, Beebe, Chemistry Experiments for Instrumental Methods, Wiley, New York, 1984. 9. D. C. Harris Quantitative Chemical Analysis 4th Ed., W. H. Freeman and Company, New York 1995 Chapter 21. 10. Clark MA, Humphrey SJ ,Smith MP, Ludens JH. Unique natriuretic properties of the ATP-sensitive K1 channel-blocker glyburide in conscious rats. J Pharmacol Exp Ther 1993; 165:933-937. 11. Moses AM, Howantiz J, Miller M. Diuretic action of three sulfonylurea drugs. Ann Intern Med 1973,78:541— 544,. 12. 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Schweiz Med Wschr, 1991; 121; 1271-82. http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Ylitalo%20P%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Oksala%20H%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=Search&Term=%22Pitk%C3%A4j%C3%A4rvi%20T%22%5BAuthor%5D&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus javascript:AL_get(this,%20'jour',%20'Arzneimittelforschung.');