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
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
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).
- 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.
- Rimmer JM, Horn JF, Gennari FJ. Hyperkalemia as a complication of drug therapy. Arch Intern Med 1987;147:867-9.
- Schweda F, Kurtz A. Cellular mechanism of rennin release. Acta Physiol Scand 2004;181:383-90.
LC, Macpherson DS. Hyperkalemia in outpatients using
angiotensin-converting enzyme inhibitors. How much should we worry?
Arch Intern Med 1998;158:26-32.
- Guyton AC, Hall JE eds. Unit V: The Body Fluids and Kidneys. In: Textbook of Medical Physiology. 11th Edition. Elsevier. Philadelphia, PA. 2005.
- Leiberman M, Marks AD eds. Mark's Basic Medical Biochemistry A Clinical Approach. 3rd Ed. Lippincott Williams & Wilkins. Philadelphia, PA. 2009.
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.
- Garty H. Mechanisms of aldosterone action in tight epithelia. J Membr Biol 1986;90:193-205.
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.
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.
BF. Managing hyperkalemia caused by inhibitors of the
renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-92.
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.
Investigators. Effects of an angiotensin-converting-enzyme inhibitor,
ramipril, on cardiovascular events in high-risk patients. N Engl J Med
- Pongpaew C, Songkhla RN, Kozam RL. Hyperkalemic cardiac arrhythmia secondary to spironolactone. Chest 1973;63:1023-5.