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#163 How low can the potassium and sodium go with commonly prescribed blood pressure medications?

What is the risk of electrolyte disturbances with diuretics and ACE Inhibitors and when should we check?

Moderate hyponatremia (Na <130 mmol/L) and hypokalemia (<3.2 mmol/L) each occur in ~4% of thiazide users, and hyperkalemia (>5.4 mmol/L) occurs in 4% of ACE inhibitor (and angiotensin receptor blocker) users. Limited evidence suggests checking electrolytes in the first 2-4 weeks after starting, and again after increasing doses of these agents, and at least annually thereafter.  

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  • Large hypertension Randomized Controlled Trials (RCTs) reporting sodium (Na) and Potassium (K). 
    • ALLHAT sub-study1 of 19,731 patients with normal baseline potassiumResults for chlorthalidone (12.5-25 mg) or lisinopril (10-40mg) or amlodipine (2.5-10 mg). At one year: 
      • K <3.2 mmol/L: Chlorthalidone 3.5%, lisinopril 0.2%, amlodipine 0.3%. 
      • K >5.4mmol/L: Chlorthalidone 1.2%, lisinopril 3.6%, amlodipine 1.9%. 
      • 8% of ALLHAT chlorthalidone users were on potassium supplements at five years.2 
    • SHEP:3 4,736 patients on chlorthalidone (12.5-25mg) or placebo. At any time in 4.5 years:  
      • K <3.2 mmol/L: Chlorthalidone 3.9%, placebo 0.8%. 
      • Na < 130 mmol/L: Chlorthalidone 4.1%, placebo 1.3%. 
    • Other large diuretic RCTs:  
      • HYVET4 (indapamide vs placebo): Excluded patients with abnormal potassium. 
        • Compared to placebo, K was 0.05 mmol/L lower with indapamide at two years. 
        • Na not reported. 
      • ANBP25 (enalapril vs hydrochlorothiazide): Electrolyte results not reported. 
    • Chlorthalidone 12.5-25 mg decreases potassium on average by  ~0.2-0.4 mmol/L6-8 about 0.1-0.2 mmol/L more than the same dose of hydrochlorothiazide.7 
    • Angiotensin receptor blockers (ARBs) have similar hyperkalemia rates as ACE inhibitors.9 
  • Diuretics are first line agents for uncomplicated hypertensive patients10 with additional advantage of low cost.11 
  • Limited evidence suggests that thiazide induced hypokalemia or hyponatremia may occur within the first days to weeks of therapy,12,13 but can also develop years later.14  
  • Hypokalemia and hyponatremia risk factors: Women>men,1,15 increasing age,15,16 and diuretic dose.15,16 
    • Most patients with mild hypokalemia are asymptomatic, but symptoms can include weakness, myalgias, and cardiac arrhythmias.17  
    • Moderate-to-severe hyponatremia (Na <130) may produce lethargy, dizziness, nausea, and confusion.18 
  • Combining diuretics with ACE19 or using potassium-sparing diuretics (like amiloride)20 may help maintain normokalemia.  

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  • Michael R Kolber BSc MD CCFP MSc
  • Ricky D. Turgeon BSc(Pharm) ACPR PharmD

1. Alderman MH, Piller LB, Ford CE, et al. Hypertension. 2012; 59:926-33.

2. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002; 288:2981-97.

3. SHEP Cooperative Research Group. JAMA. 1991; 265:3255-64.

4. Beckett NS, Peters R, Fletcher AE, et al. N Engl J Med. 2008; 358:1887-98.

5. Wing LMH, Reid CM, Ryan P, et al. N Engl J Med. 2003; 348:583-92.

6. Savage PJ, Pressel SL, Curb D, et al. Arch Intern Med. 1998; 158:741-51.

7. Ernst ME, Carter BL, Zheng S, et al. Am J Hypertens. 2010; 23:440-6.

8. Dorsch MP, Gillespie BW, Erickson SR, et al. Hypertension. 2011; 57:689-94.

9. The ONTARGET Investigators. N Engl J Med. 2008; 358:1547-59.

10. Daskalopoulou SS, Rabi DM, Zarnke KB, et al. Can J Cardiol. 2015; 31:549-68.

11. Kolber MR, Nickonchuk T, Lee J, et al. Price Comparison of Commonly Prescribed Pharmaceuticals in Alberta 2016. Available at: Last accessed March 9, 2016.

12. Maronde RF, Milgrom M, Vlachaki ND, et al. JAMA. 1983; 249:237-41.

13. Barber J, McKeever TM, McDowell SE, et al. Br J Clin Pharmacol. 2015; 79(4):566-77.

14. Leung AA, Wright A, Pazo V, et al. Am J Med. 2011; 124:1064-72.

15. Sharabi Y, Illan R, Kamari Y, et al. J Hum Hypertens. 2002; 16:631-5.

16. Clayton JA. Rodgers S, Blakey J, et al. Br J Clin Pharmacol. 2006; 61:87-95.

17. Gennari FJ. N Engl J Med. 1998; 339(7):451-8.

18. Hwang KS, Kim G-H. Electrolyte Blood Press. 2010; 8:51-7.

19. Weber MA, Bakris GL, Jamerson K, et al. J Am Coll Cardiol. 2010; 56:77-85.

20. Brown MJ, Williams B, Morant SV, et al. Lancet Diabetes Endocrinol. 2016; 4:136-47.

Authors do not have any conflicts to disclose.