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The Mechanism for ACE inhibitor (e.g., fosinopril, lisinopril, ramipril) Induced Hyperkalemia

Summary:

  • ACE inhibitors are a well established class of medications used for the treatment of hypertension, heart failure, and renal protection in patients with diabetes that has been associated with altered electrolytes, specifically hyperkalemia.
  • ACE inhibitors inhibit the peripheral conversion of angiotensin I to angiotensin II by inhibiting the enzyme ACE, thereby decreasing the availability of ATII, which can then stimulate the production and secretion of aldosterone from the adrenal cortex (specifically the zona glomerulosa).
  • Aldosterone exerts its effect by increasing the gene expression and availability of the following biologic processes:  First is in the Na+ ion permease enzyme, which will allow for a greater number of sodium ions to cross from the lumen to the inside of the renal tubular cell.   Next, is in Na+/K+ATPase on the peritubular side of the renal tubular cell to transfer the increased cytosolic Na+levels into the peritubular fluid, which ultimately causes a lowering in the intracellular electronegativity.  Lastly is an increase in citrate synthase activity within the mitochondria for the purpose of increasing the number of ATP available to fuel the increase in Na+/K+ATPase activity. 
  • The overall risk for ACE inhibitor associated hyperkalemia is generally low in normal patients, but it is increased in patients who have chronic kidney disease, use K+ sparing diuretics, use K+ supplements or use K+ containing salt substitutes. 

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Content Editor:
Donald S. Nuzum, PharmD, BCACP, BC-ADM, CDE, CPP
Last Reviewed:
October 2015

Explanation

  • Angiotensin converting enzyme (ACE) inhibitors are a well established class of medications that are used in the treatment of many conditions including, hypertension, congestive heart failure, and renal protection in patients with diabetes, to name a few.  Regardless of the indication, the risk of increasing serum potassium (K+) levels (i.e., hyperkalemia as defined by a serum K+ > 5.0 mEq/L) is a well known side effect.  In fact, ACE inhibitor induced hyperkalemia has been associated with 10 to 38% of hospital admissions, 10% of which develop it within 1 year of initiation.1-3 

    Normally, renin is released from the juxtaglomerular cells in response to a change in afferent perfusion pressure within the glomerulus of the kidney.  Renin is also normally secreted in response to low sodium concentrations in the renal tubular filtrate at the macula densa. Lastly, an increases in renin occurs with an increase in sympathetic activity.4,5  Renin facilitates the conversion of angiotensinogen to angiotensin I (ATI).  The ATI can then be converted to angiotensin II (ATII) by ACE, which is found in the endothelial cells lining the lung.  It is at this point that ATII will go to the adrenal gland (specifically in the zona glomerulosa of the adrenal cortex) and bind to AT receptors.  This binding will cause an increase in aldosterone synthesis by promoting the movement of cholesterol into the mitochondria where it is converted to pregnenolone.5  Through a series of reactions, pregnenolone is then converted to corticosterone, which is then metabolized to aldosterone by aldosterone synthase.5-7 

    The newly formed aldosterone will then travel to the distal renal convoluted tubule, where it will ultimately increase the reabsorption of sodium (Na+) and water at the expense of K+ for the purpose of increasing plasma volume and blood pressure.5  Aldosterone brings about this effect by increasing the gene expression and availability of several enzymes.  The first of these is the Na+ ion permease enzyme, which will allow for a greater number of sodium ions to cross from the lumen to the inside of the renal tubular cell.   Next is Na+/K+ATPase on the peritubular side of the renal tubular cell which acts to transfer the increased cytosolic Na+ into the peritubular fluid resulting in a lowering of the intracellular electronegativity.  Lastly, there is an increase in citrate synthase activity within the mitochondria for the purpose of increasing the number of ATP available to fuel the increase in Na+/K+ATPase activity on the peritubular side of the renal tubular cell.8-10  Pharmacologically, ACE inhibitors prevent the conversion of ATI to ATII thereby decreasing the production and release of aldosterone from the adrenal cortex.11  This results in an overall reduction in the reabsorption of Na+ and water and allows for the retention of potassium.11 

    This clinically relevant adverse effect is most likely to occur in patients who have chronic kidney disease, have a comorbid condition that increases their risk for electrolyte abnormalities, use K+ sparing diuretics, use K+supplements or use K+ containing salt substitutes.11,12  Overall, the discontinuation rate for ACE inhibitors evaluated in clinical trials is very low or not related to changes in serum K+ levels.13   The greatest concern in patients who develop hyperkalemia is the increased risk for malignant ventricular arrhythmias that can lead to death.14  It is for this reason that all patients with hyperkalemia should have en ECG performed, even if they are not symptomatic (i.e. experiencing positive systemic symptoms that include ECG changes, such as peaked T-waves).

    References:

    1. Acker CG, Johnson JP, Palevsky PM et al.  Hyperkalemia in hospitalized patients: causes, adequacy of treatment, and results of an attempt to improve physician compliance with published guidelines.  Arch Intern Med  1998;158:917-24.  
    2. Rimmer JM, Horn JF, Gennari FJ.  Hyperkalemia as a complication of drug therapy.  Arch Intern Med  1987;147:867-9.  
    3. Schweda F, Kurtz A.  Cellular mechanism of rennin release.  Acta Physiol Scand  2004;181:383-90. 
    4. Reardon LC, Macpherson DS.  Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors.  How much should we worry?  Arch Intern Med  1998;158:26-32.  
    5. Guyton AC, Hall JE eds. Unit V: The Body Fluids and Kidneys.  In: Textbook of Medical Physiology. 11th Edition.  Elsevier. Philadelphia, PA. 2005.
    6. Leiberman M, Marks AD eds.  Mark's Basic Medical Biochemistry A Clinical Approach.  3rd Ed.  Lippincott Williams & Wilkins. Philadelphia, PA. 2009.
    7. Pratt JH, Rothrock JK, Dominguez JH.  Evidence that angiotensin-II and potassium collaborate to increase cytosolic calcium and stimulate the secretion of aldosterone.  Endocrinology  1989;125:2463-9.  
    8. Garty H.  Mechanisms of aldosterone action in tight epithelia.  J Membr Biol  1986;90:193-205.  
    9. Verrey F, Schaerer E, Zoerkler P et al.  Regulation by aldosterone of Na+,K+-ATPase mRNAs, protein synthesis, and sodium transport in cultured kidney cells.  J Cell Biol  1987;104:1231-7.  
    10. Laplace JR, Husted RF, Stokes JB.  Cellular responses to steroids in the enhancement of Na+ transport by rat collecting duct cells in culture.  Difference between glucocorticoid and mineralocorticoid hormones.  J Clin Invest  1992;90:1370-8.  
    11. Palmer BF.  Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system.  N Engl J Med  2004;351:585-92.  
    12. Ray K, Dorman S, Watson R.  Severe hyperkalaemia due to the concomitant use of salt substitutes and ACE inhibitors in hypertension: a potentially life threatening interaction.  J Hum Hypertens  1999;13:717-20.  
    13. HOPE Investigators.  Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.  N Engl J Med  2000; 342:145-153.  
    14. Pongpaew C, Songkhla RN, Kozam RL.  Hyperkalemic cardiac arrhythmia secondary to spironolactone.  Chest  1973;63:1023-5.

MESH Terms & Keywords

  • ACE, Angiotensin Converting Enzyme, ACE Inhibitor, Potassium, Hyperkalemia, Lisinopril, Fosinopril, Ramipril, Altace, Perindopril, Quinapril, Trandolapril