Hypokalemia

The normal concentration of potassium in the serum ranges between 3.5 and 5.0 mEq/l. A fall in the potassium levels below normal constitutes hypokalemia.¹Hypokalemia. Available at http://medical-dictionary.thefreedictionary.com/Potassium+depletion. Accessed on June 25, 2011.

Importance of potassium in the human body

Potassium is a very significant mineral in the body, playing important roles in both cellular and electrical function. Its functions can be described as follows:

• Regulation of water balance and acid-base balance in the blood and tissues, along with sodium. Potassium enters the cell more readily than does sodium and sets off the brief sodium-potassium exchange across the cell membranes. In the nerve cells, this sodium-potassium flux produces the electrical potential that is necessary for the conduction of nerve impulses. When potassium leaves the cell, it changes the membrane potential and allows the nerve impulse to progress. This electrical potential gradient, created by the “sodium-potassium pump,” facilitates smooth muscle contractions and regulates the heartbeat. In addition, the pump prevents the swelling of cells. If sodium is not pumped out, water accumulates within the cell causing it to swell and ultimately burst.²Haas EM. Role of Potassium in Maintaining Health. Available at http://www.hkpp.org/general/potassium_health.html. Accessed on June 25, 2011.
• Regulation of blood pressure: Potassium counters the effect of sodium and thus lowers blood pressure.³American Heart Association. Potassium and High Blood Pressure. Available at http://www.amhrt.org/HEARTORG/Conditions/HighBloodPressure/PreventionTreatmentofHighBloodPressure/Potassium-and-High-Blood-Pressure_UCM_303243_Article.jsp. Accessed on July 07, 2011.
• Role in cellular biochemical reactions and energy metabolism:²Haas EM. Role of Potassium in Maintaining Health. Available at http://www.hkpp.org/general/potassium_health.html. Accessed on June 25, 2011.
  • Participates in synthesis of protein from amino acids in the cell
  • Converts glucose to glycogen that can be stored in the liver for future energy
  • Important for normal growth and muscle building
• Role in waste removal by kidneys⁴Nuble C. Potassium and Its Benefits to the Human Body. Available at: http://ezinearticles.com/?Potassium-and-Its-Benefits-to-the- Human-Body&id=74138. Accessed on June 25, 2011.
• Significant role in promoting efficient cognitive functioning by providing oxygen to the brain⁴

Pathophysiology

Hypokalemia may result from conditions as varied as increased potassium excretion, deficient potassium intake, gastrointestinal losses and shift from extracellular to intracellular space.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.

• Increased potassium excretion. Increased excretion of potassium, especially coupled with poor intake, is the most common cause of hypokalemia. It is usually due to the use of diuretics or to hyperaldosteronism.
• Deficient potassium intake. This is an uncommon cause of hypokalemia, found in very elderly individuals who are unable to cook for themselves or have difficulty in chewing or swallowing. Patients receiving total parenteral nutrition (TPN) are also prone to hypokalemia if the potassium supplementation is inadequate for a prolonged period of time.
• Gastrointestinal losses. Diarrhea and vomiting are the common causes of gastrointestinal potassium loss. Vomiting causes volume depletion and metabolic alkalosis. These two processes are accompanied by increased renal potassium excretion. Volume depletion leads to secondary hyperaldosteronism, which, in turn, leads to enhanced cortical collecting tubule secretion of potassium in response to enhanced sodium reabsorption. Metabolic alkalosis also increases collecting tubule potassium secretion due to the decreased availability of hydrogen ions for secretion in response to sodium reabsorption.
• Shift from extracellular to intracellular space. This is also usually accompanied by increased excretion, leading to a potentiation of the hypokalemic effect of excessive loss. It is most commonly drug-induced; hence, it is important to review the patient’s drug record while treating the condition.⁶Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-458.

Clinical features

The clinical features of hypokalemia are non-specific and varied, and their severity depends on the degree of hypokalemia. Symptoms seldom occur unless the plasma K⁺ concentration falls below 3 mEq/L. They are:⁷Harrison’s Principles of Internal Medicine, 16th ed.

• Fatigue
• Myalgia
• Muscular weakness of the lower extremities
• More severe hypokalemia may lead to progressive weakness, hypoventilation (due to respiratory muscle involvement), and eventually complete paralysis
• Increased risk of rhabdomyolysis, due to impaired muscle metabolism and the blunted hyperemic response to exercise associated with profound K+ depletion
• Paralytic ileus, due to impairment of smooth-muscle function
• Symptoms of metabolic alkalosis, such as confusion (which may progress to stupor or coma), hand tremor, light-headedness, muscle twitching, nausea, vomiting, numbness or tingling in the face or extremities, prolonged muscle spasms (tetany)
• Symptoms of digitalis toxicity in patients taking digitalis. These symptoms include confusion, irregular pulse, loss of appetite, nausea, vomiting, diarrhea, palpitations, visual changes, impaired consciousness, decreased urine output, etc.

On physical examination, tachycardia or tachypnea may be found occasionally due to respiratory muscle weakness. Blood pressure may be raised because of primary hyperaldosteronism, renal artery stenosis, licorice ingestion, or the more unusual forms of genetically transmitted hypertensive syndromes such as congenital adrenal hyperplasia, glucocorticoid remediable hypertension, or Liddle syndrome. In addition, there may be muscle weakness and flaccid paralysis; deep-tendon reflexes may be depressed or absent.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.

Clinical effects of hypokalemia

Effects of hypokalemia can vary from mild to severe. If not treated in time, it can have serious consequences, which may be life-threatening.

• Cardiac effects: The most lethal consequence of hypokalemia is cardiac arrhythmias. ECG reveals U waves >1 mm in height; T waves in the same lead; ST segment depression; T wave flattening, followed by inversion.⁸Hypokalemia. Available at http://www.ccspublishing.com/journals2a/hypokalemia.htm. Accessed on June 25, 2011.  Hypokalemia can also cause hypertension.⁹What Does Potassium do for the Body? Available at http://www.tech-faq.com/what-does-potassium-do-for-the-body.html. Accessed on June 25, 2011.
• Musculoskeletal effects: The initial symptom of K+ depletion is muscle weakness, which can lead to paralysis, which can involve the respiratory muscles if severe.⁸Hypokalemia. Available at http://www.ccspublishing.com/journals2a/hypokalemia.htm. Accessed on June 25, 2011.
• Gastrointestinal effects: Nausea, vomiting, constipation⁸Hypokalemia. Available at http://www.ccspublishing.com/journals2a/hypokalemia.htm. Accessed on June 25, 2011.
• Renal effects: Mild polyuria and impairment of kidney’s ability to concentrate urine. If combined with hyperaldosteronism, hypokalemia can cause renal cystic disease.¹⁰Effects of Hypokalemia (Low Potassium). Available at http://www.buzzle.com/articles/effects-of-hypokalemia-low-potassium. html. Accessed on June 25, 2011.
• Hepatic effects: Hepatic encephalopathy or aggravation of its symptoms.10
• CNS effects: Memory loss, seizures

Drug-induced hypokalemia

Diuretics

Diuretic therapy is the most common cause of hypokalemia. Loop diuretics like frusemide and torsemide prevent the reabsorption of sodium and chloride ions at the loop of Henle in the kidney. Thiazide diuretics like hydrochlorothiazide also prevent sodium and chloride reabsorption in the distal convoluted tubule.

Both these types of diuretics cause increased amounts of sodium and water to pass through the collecting tubules. This, in turn, causes a reflex secretion of potassium into the urine by increased aldosterone secretion. Also, volume depletion due to increased urine output as a result of the diuretic causes further increased secretion of aldosterone, which further increases the secretion of potassium into the collecting duct and into the urine (this is an effect of aldosterone action trying to maintain volume in the cardiovascular system). Thus, there is a two-way method of potassium loss through the urine which then causes hypokalemia.¹¹Why do diuretics cause hypokalemia? Available at http://answers.yahoo.com/question/index?qid=20090509005839AAO7Ygh. Accessed on June 25, 2011.

⁶Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-458.

Digitalis

Hypokalemia potentiates the effects of digitalis. Digitalis induces arrhythmias by changing the ion concentrations in the myocardial cells or changing the transcellular ion gradient. Both diuretic-induced hypokalemia and digitalis inhibit the membrane-Na+K+ATPase activity, leading to a fall in the intracellular potassium concentration. This may explain how cardiac arrhythmias occur during digitalis treatment and during severe hypokalemia, and also explain why myocardial sensitivity for digitalis increases in the presence of hypokalemia. The myocardial uptake of digitalis, however, is markedly increased at low extracellular potassium concentration and this may explain the interaction between digitalis and hypokalemia. Not only are the myocardial digoxin kinetics changed during hypokalemia but the renal excretion rate of digoxin is also markedly reduced, leading to increased serum digoxin concentration and thereby the risk of digitalis intoxication.¹²Steiness E. Diuretics, digitalis and arrhythmias. Acta Med Scand Suppl. 1981;647:75-8.

Salbutamol

Salbutamol can also induce hyperglycemia and hypokalemia. Both these effects occur due to stimulation of ß₂-receptors, which activate the Na+K+ATPase, thereby driving potassium into the cells.¹³Risks of salbutamol use. Available at http://www.ch.ic.ac.uk/local/projects/mohataren/Files/risks.htm. Accessed on June 25, 2011.   These effects occur with oral as well as inhaled salbutamol.¹⁴Nagdeote AN, Pawade YR. The effect of oral salbutamol on the metabolism of electrolytes in asthmatic children. Journal of Clinical and Diagnostic Research. 2011;5(2):176-178.   In high doses, salbutamol can cause so much stimulation that a significant amount of potassium is shifted into the intracellular space, causing hypokalemia.¹⁵How does salbutamol cause hypokalemia? Available at http://answers.yahoo.com/question/index?qid=20091005054329AAf75o C. Accessed on June 25, 2011.

Antitubercular drugs

Drugs used in the treatment of multidrug-resistant tuberculosis (MDR-TB), particularly capreomycin, often cause electrolyte disturbances, like hypokalemia and hypomagnesemia. These adverse effects pose a great challenge to clinicians because of the paucity of presenting symptoms and potential morbidity associated with this disorder. Several mechanisms are responsible for the occurrence of electrolyte disturbance in patients treated for MDR-TB. One of them is that antituberculous agents cause diarrhea and vomiting, resulting in GI electrolyte loss. There is also evidence that the use of aminoglycosides and capreomycin induces secondary hyperaldosteronism, leading to urinary loss of potassium and magnesium.^16-18Darr M, Hamburger S, Ellerbeck E. Acid-base and electrolyte abnormalities due to capreomycin. South Med J 1982;75,627-628
Holmes A, Hesling C, Wilson T. Capreomycin-induced electrolyte abnormalities. Thorax 1970;25,608-611
Holmes A, Hesling C, Wilson T. Drug-induced secondary hyperaldosteronism in patients with pulmonary tuberculosis. Q J Med 1970;154,299-315    Moreover, the role of magnesium as a co-factor in the ATP-dependent mechanism for active transport of sodium and potassium across the cell membrane leads to further potassium loss as a consequence of resultant intracellular magnesium deficiency. As shown by Shin et al,¹⁹Shin S, Furin J, Alcántara F, Hyson A, Joseph K, Sánchez E, Rich M. Hypokalemia among patients receiving treatment for multidrugresistant tuberculosis. Chest. 2004 Mar;125(3):974-80.   use of capreomycin and low initial body weight were associated with an increased likelihood of developing hypokalemia.

Corticosteroids

Corticosteroids can produce hypokalemia and other electrolyte disturbances via mineralocorticoid effects, the degree of which depends upon the agent and route of administration. However, large systemic doses

of any corticosteroid can demonstrate these effects, particularly if given for long periods.²⁰Drug interactions between Accuretic and prednisone. Available at: http://www.drugs.com/drug-interactions/accuretic-withprednisone-1266-1275-1936-0.html. Accessed on June 25, 2011. Examples of corticosteroids with a potassium-lowering effect include fludrocortisone and hydrocortisone. They cause hypokalemia only in very high doses. On the other hand, corticosteroids like methylprednisolone and dexamethasone have little or no effect on potassium levels. Also, inhaled and topically applied corticosteroids do not affect potassium levels.²¹Corticosteroids: A cause of low potassium (hypokalemia)? Available at http://www.riversideonline.com/health_reference/Questions-Answers/AN01385.cfm. Accessed on June 25, 2011.

Acetazolamide

Acetazolamide is a diuretic that can enhance the effect of other diuretics, such as thiazides, when used concurrently. Since thiazides are known to cause hypokalemia, this effect can also be potentiated by acetazolamide, especially when the latter is used in high doses.²²Acetazolamide Drug Interactions. Available at http://www.hkpp.org/physicians/dr_acetazolamide.html. Accessed on June 25, 2011.

Treatment

The goals of treating hypokalemia are:⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.

• To minimize the potassium losses
• To replenish the potassium stores
• To evaluate potential toxicities
• To determine the cause so as to prevent recurrences

Minimizing potassium losses

• Treat diarrhea or vomiting.
• Use H₂ blockers to decrease nasogastric suction losses
• Control hyperglycemia if glycosuria is present

Replenishing potassium stores

• Every 1 mEq/L decrease in serum potassium creates a potassium deficit of approximately 200-400 mEq and patients with plasma levels under 3.0 mEq/L often require more than 600 mEq of potassium to correct the deficit.⁷Harrison’s Principles of Internal Medicine, 16th ed. Therefore, the plasma potassium concentration should be monitored frequently when assessing the response to treatment.
• The ready absorption of oral potassium allows the administration of relatively large doses safely because oral potassium enters the circulation more slowly, avoiding the risk of hyperkalemia.⁶Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-458.
• The drug of choice is potassium chloride, as it promotes more rapid correction of hypokalemia and metabolic alkalosis.⁷Harrison’s Principles of Internal Medicine, 16th ed. The oral preparation of potassium chloride available in the market contains 40 mEq of potassium in 30 ml.
• Intravenous potassium is less well tolerated because it can be highly irritating to veins and can be given only in relatively small doses, generally 10 mEq/h.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.  Moreover, the risk of hyperkalemia is greatest with the administration of intravenous potassium; hence,this route should be avoided as far as possible.⁶Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-458.
• Oral and parenteral potassium can be used safely concurrently.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.
• Ongoing potassium losses should be taken into consideration by measuring the volume and potassium concentration of body fluid losses.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.
• In severe hypokalemia, glucose-containing parenteral fluids should be avoided so as to prevent an insulin-induced shift of potassium into the cells.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.
• In presence of acidosis, the potassium level should be corrected first to prevent an alkali-induced shift of potassium into the cells.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.
• Magnesium should be replenished if low.⁵Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.
• Treatment should be tailored to the individual patient. For example, if diuretics cannot be discontinued due to an underlying disorder such as congestive heart failure, oral potassium supplements can be given. Typically, 40 to 100 mEq of supplemental potassium chloride is needed each day to maintain serum potassium concentrations near or within the normal range in patients receiving diuretics.⁶Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-458.

Monitoring for toxicity of hypokalemia

Hypokalemia is most detrimental to the heart. The patient should be monitored for evidence of cardiac arrhythmias.

References

1. Hypokalemia. Available at http://medical-dictionary.thefreedictionary.com/Potassium+depletion. Accessed on June 25, 2011.
2. Haas EM. Role of Potassium in Maintaining Health. Available at http://www.hkpp.org/general/potassium_health.html. Accessed on June 25, 2011.
3. American Heart Association. Potassium and High Blood Pressure. Available at http://www.amhrt.org/HEARTORG/Conditions/ HighBloodPressure/PreventionTreatmentofHighBloodPressure/Potassium-and-High-Blood-Pressure_UCM_303243_Article.jsp. Accessed on July 07, 2011.
4. Nuble C. Potassium and Its Benefits to the Human Body. Available at: http://ezinearticles.com/?Potassium-and-Its-Benefits-to-the- Human-Body&id=74138. Accessed on June 25, 2011.
5. Lederer E. Hypokalemia. Available at http://emedicine.medscape.com/article/242008-overview#showall. Accessed on June 25, 2011.
6. Gennari FJ. Hypokalemia. N Engl J Med 1998;339:451-458.
7. Harrison’s Principles of Internal Medicine, 16th ed.
8. Hypokalemia. Available at http://www.ccspublishing.com/journals2a/hypokalemia.htm. Accessed on June 25, 2011.
9. What Does Potassium do for the Body? Available at http://www.tech-faq.com/what-does-potassium-do-for-the-body.html. Accessed on June 25, 2011.
10. Effects of Hypokalemia (Low Potassium). Available at http://www.buzzle.com/articles/effects-of-hypokalemia-low-potassium. html. Accessed on June 25, 2011.
11. Why do diuretics cause hypokalemia? Available at http://answers.yahoo.com/question/index?qid=20090509005839AAO7Ygh. Accessed on June 25, 2011.
12. Steiness E. Diuretics, digitalis and arrhythmias. Acta Med Scand Suppl. 1981;647:75-8.
13. Risks of salbutamol use. Available at http://www.ch.ic.ac.uk/local/projects/mohataren/Files/risks.htm. Accessed on June 25, 2011.
14. Nagdeote AN, Pawade YR. The effect of oral salbutamol on the metabolism of electrolytes in asthmatic children. Journal of Clinical and Diagnostic Research. 2011;5(2):176-178.
15. How does salbutamol cause hypokalemia? Available at http://answers.yahoo.com/question/index?qid=20091005054329AAf75o C. Accessed on June 25, 2011.
16. Darr M, Hamburger S, Ellerbeck E. Acid-base and electrolyte abnormalities due to capreomycin. South Med J 1982;75,627-628
17. Holmes A, Hesling C, Wilson T. Capreomycin-induced electrolyte abnormalities. Thorax 1970;25,608-611
18. Holmes A, Hesling C, Wilson T. Drug-induced secondary hyperaldosteronism in patients with pulmonary tuberculosis. Q J Med 1970;154,299-315
19. Shin S, Furin J, Alcántara F, Hyson A, Joseph K, Sánchez E, Rich M. Hypokalemia among patients receiving treatment for multidrugresistant tuberculosis. Chest. 2004 Mar;125(3):974-80.
20. Drug interactions between Accuretic and prednisone. Available at: http://www.drugs.com/drug-interactions/accuretic-withprednisone-1266-1275-1936-0.html. Accessed on June 25, 2011.
21. Corticosteroids: A cause of low potassium (hypokalemia)? Available at http://www.riversideonline.com/health_reference/Questions-Answers/AN01385.cfm. Accessed on June 25, 2011.
22. Acetazolamide Drug Interactions. Available at http://www.hkpp.org/physicians/dr_acetazolamide.html. Accessed on June 25, 2011.