Medication Induced Hypokalaemia

Hypokalaemia

Hypokalaemia is one of the most commonly encountered fluid and electrolyte abnormalities in clinical medicine. It can be an asymptomatic finding, identified only on routine electrolyte screening, or it can be associated with symptoms ranging from mild weakness to sudden death.¹Weiner D, Wingo CS. Hypokalemia-Consequences, Causes, and Correction. J Am SocNephrol. 1997; 8(7):1179-88.

Hypokalaemia is defined as a serum potassium concentration of less than 3.5 mEq/L. Hypokalaemia is categorised as mild (serum potassium, greater than 3 to 3.5 mEq/L), moderate (serum potassium, 2.5 to 3 mEq/L), or severe (serum potassium, less than 2.5 mEq/L).The signs and symptoms of hypokalaemia are described in Table 1.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

Hypokalaemia results either when there is a total body potassium deficit, or when serum potassium is shifted into the intracellular compartment. Hypomagnesemia, which is present in more than 50% of cases of clinically significant hypokalaemia, contributes to the development of hypokalaemia by reducing the intracellular potassium concentration and promoting renal potassium wasting.

When concomitant hypokalaemia and hypomagnese-mia exist, the magnesium deficiency should be corrected first; otherwise, full repletion of the potassium deficit is difficult to achieve.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

Causes of Hypokalaemia

Hypokalaemia results from abnormal losses, trans-cellular shifts, or insufficient intake (Table 2). Abnormal losses are most common. Because the kidney can significantly lower potassium excretion in response to decreased intake, insufficient intake is rarely the sole cause of Hypokalaemia, but it often contributes to hypokalaemia in hospitalised patients.³Viera AJ, Wouk N. Potassium Disorders: Hypokalemia and Hyperkalemia. Am Fam Physician. 2015;92(6):487-495.

Medication Induced Hypokalaemia

Medications cause hypokalaemia through a variety of mechanisms, including intracellular potassium shifting, increased renal loss, and/or stool loss. Table 3 highlights selected medications associated with hypokalaemia.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

Epidemiology

The occurrence of hypokalaemia is strongly dependent on the patient population. In otherwise healthy adults not receiving any medications, less than 1% will develop hypokalaemia. Most cases of hypokalaemia occur in the setting of specific disease states. Patients receiving diuretics are at the highest risk. Thiazide diuretics are more likely to cause hypokalaemia than loop or osmotic diuretics. Individuals with secondary hyperaldosteronism, whether due to congestive heart failure, hepatic insufficiency, or nephrotic syndrome, constitute a second group at high risk. Those patients with diseases that alter renal potassium conservation through interaction with salt delivery to the cortical collecting duct (CCD) are also at high risk for hypokalaemia.¹Weiner D, Wingo CS. Hypokalemia-Consequences, Causes, and Correction. J Am SocNephrol. 1997; 8(7):1179-88.

Diagnosis

The cause of hypokalaemia is often apparent from the history. Measurements of BP and urinary potassium excretion, and assessment of acid-base balance are often helpful when the cause is not apparent.⁴. Kabadi U. Evaluation of hypokalemia [Internet]. 2017 [updated 2016 Oct 24; cited 2017 Oct 24]. Available from: http://us.bp.api.bmj.com/best practice/ monograph/59/diagnosis/step-by-step.html

The diagnostic approach to the patient with hypoka-laemia is shown in Figure 1.⁵.Assadi F. Diagnosis of Hypokalemia A Problem-Solving Approach to Clinical Cases. Iranian Journal of Kidney Diseases. 2008; 2(3):115-122

First, assess the urinary potassium excretion to differentiate between gastrointestinal and urinary losses as the major contributor. It is not necessary to obtain a 24 hour urine potassium excretion; the same information can be obtained by urine potassium creatinine (K/C) ratio in random urine sample. A spot urine K/C ratio less than 1.5 suggests poor intake, a shift into the intracellular space or gastrointestinal loss.⁵.Assadi F. Diagnosis of Hypokalemia A Problem-Solving Approach to Clinical Cases. Iranian Journal of Kidney Diseases. 2008; 2(3):115-122

Second, use acid-base and blood pressure status to help in the differential diagnosis. In a patient with a urine K/C ratio less than 1, who denies diarrhoea, consider laxative abuse in the presence of hyperchloremic metabolic acidosis, surreptitious vomiting, or diuretic abuse in the presence of metabolic alkalosis. In patient with a urine K/C ratio of 1.5 or higher, consider 2 categories based upon the presence or absence of hypertension.⁵.Assadi F. Diagnosis of Hypokalemia A Problem-Solving Approach to Clinical Cases. Iranian Journal of Kidney Diseases. 2008; 2(3):115-122

The differential diagnosis rests upon the measurement of aldosterone and renin levels, response to spironolactone and amiloride, diuretic screen in urine, measurement of plasma cortisol level and the ratio of urinary cortisol to cortisone, and genetic testing (11 – α – hydroxylase and 17 – α – hydroxylase deficiencies). Hypomagnesemia can cause hypokalaemia. However, hypomagnesemia is not associated with an acid-base disturbance.⁵.Assadi F. Diagnosis of Hypokalemia A Problem-Solving Approach to Clinical Cases. Iranian Journal of Kidney Diseases. 2008; 2(3):115-122

TTKG in differential diagnosis of hypokalaemia

For hypokalaemic patients, the transtubular potassium gradient (TTKG) is used to gauge renal potassium secretion by the cortical collecting duct, indirectly assessing mineralocorticoid bioactivity.⁶Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008 Mar;19(3):424-6.   It helps to differentiate between renal and non-renal causes of hypokalaemia.⁷Nurko S. Hypokalemia and Hyperkalemia. Available from: http://www. clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/ hypokalemia-and-hyperkalemia/ [Accessed on 4th January 2017].

TTKG determines the potassium gradient between the urine and blood in the distal nephron and is calculated as

Where Osmblood and Osmurine are plasma osmo-lalities; [K + ] urine/[ K + ] blood is the urine-to-plasma K + concentration ratio that measures the gradient for K + secretion.⁶Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008 Mar;19(3):424-6.  ⁷Nurko S. Hypokalemia and Hyperkalemia. Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/ hypokalemia-and-hyperkalemia/ [Accessed on 4th January 2017].

TTKG in normal individuals is about 6 to 8. In hypokalaemia a TTKG of >10 suggest excessive renal potassium loss, while a TTKG of <2 suggest non-renal losses. TTKG value of 5-7 suggests aldosterone deficiency or resistance.⁷Nurko S. Hypokalemia and Hyperkalemia. Available from: http://www. clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/ hypokalemia-and-hyperkalemia/ [Accessed on 4th January 2017].

According to a study conducted by Joo KW et al., TTKG is useful in the pathophysiological differential diagnosis of hypokalaemia.⁸Joo KW , Chang SH, Lee JG, et al. Transtubular potassium concentration gradient (TTKG) and urine ammonium in differential diagnosis of hypokalemia. J Nephrol. 2000 Mar-Apr;13(2):120-5

Treatment

Treatment for hypokalaemia focuses on restoring a normal potassium balance, preventing serious complications, and removing or treating the underlying causes. The management strategies for treating hypokalaemia vary depending on the severity of the imbalance (Table 4).²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

Most cases of mild-to-moderate hypokalaemia may be corrected with oral potassium supplements. Potassium chloride (KCl) is the most common salt used for repletion. Potassium acetate is a preferred agent in patients with hypokalaemia and metabolic acidosis. Administration of potassium phosphate should be considered in patients with hypokalaemia and hypophosphataemia.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

Patients who have severe hypokalaemia or who cannot take oral supplements require intravenous (IV) potassium replacement therapy. IV potassium must be administered with caution to prevent serious complications, including potentially fatal cardiac arrhythmias. All infusions should be diluted and mixed thoroughly in adequate amounts of fluid; use premixed potassium solutions when possible. To prevent or reduce toxic effects, IV infusion concentrations should not exceed 40 mEq/L and should be infused at a rate of 10 mEq per hour or less.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

A patient taking a thiazide or loop diuretic may be switched to a potassium sparing agent like spironolactone, eplerenone, triamterene or amiloride to prevent excessive urinary potassium loss.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

After the serum potassium level returns to normal, a sustained release oral potassium supplement may be required with daily dosages ranging from 20 mEq to 80 mEq. Patients may also need to increase their dietary intake of potassium rich foods, such as dried fruits (e.g., dates, prunes, figs), nuts, avocados, bran cereals, spinach, potatoes, kiwi, and bananas.²Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.

Careful monitoring during treatment is essential because supplemental potassium is a common cause of hyperkalaemia in hospitalised patients. The risk of rebound hyperkalaemia is higher when treating redistributive hypokalaemia.³Viera AJ, Wouk N. Potassium Disorders: Hypokalemia and Hyperkalemia. Am Fam Physician. 2015;92(6):487-495.

General Guidelines for Potassium Replacement in Clinical Practice⁹Cohn JN et al. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000; 160(16):2429-2436.

• Dietary consumption of potassium rich foods should be supplemented with potassium replacement therapy. Often, increasing dietary potassium intake is not completely effective in replacing the potassium loss associated with chloride depletion because dietary potassium is almost entirely coupled with phosphate, rather than with chloride.
• Potassium replacement is recommended for individuals who are sensitive to sodium or who are unable or unwilling to reduce salt intake; it is especially effective in reducing blood pressure in such persons.
• Potassium replacement is recommended for individuals who are subject to nausea, vomiting, diarrhoea, bulimia, or diuretic/laxative abuse. Potassium chloride has been shown to be the most effective means of replacing acute potassium loss.
• Potassium supplements are best administered orally in a moderate dosage over a period of days to weeks to achieve the full repletion of potassium.
• Although laboratory measurement of serum potassium is convenient, it is not always an accurate indicator of total body potassium. Measurement of 24 hour urinary potassium excretion is appropriate for patients who are at high risk (e.g., those with CHF).
• Patient adherence to potassium supplementation may be increased with compliance enhancing regimens. Microencapsulated formulations have no unpleasant taste and are associated with a relatively low incidence of gastrointestinal side effects.
• Potassium supplementation regimens should be as uncomplicated as possible to help optimise long-term compliance.
• A dosage of 20 mmol/d of potassium in oral form is generally sufficient for the prevention of hypokalaemia, and 40 to 100 mmol/d sufficient for its treatment.

Conclusion

Hypokalaemia is a common electrolyte disorder caused by changes in potassium intake, altered excretion, or transcellular shifts. Diuretic use and gastrointestinal losses are common causes of hypokalaemia.In the absence of early detection and treatment, hypokalaemia can cause serious complications that could be life-threatening.Therefore, a first priority is determining the need for urgent treatment through a combination of history, physical examination, laboratory, and electrocardiography findings. Hypokalaemia is treated with oral or intravenous potassium. It is important to consider potential causes of transcellular shifts because patients are at increased risk of rebound potassium disturbances.

Key Points

• Serum potassium concentration does not accurately reflect total body potassium deficits. Even mild hypokalaemia may be associated with significant deficits and require correction over several days, especially in the setting of ongoing losses.¹⁰.Asmar A, Mohandas R, Wingo CS. A Physiologic-Based Approach to the Treatment of a Patient With Hypokalemia. Am J Kidney Dis. 2012; 60(3): 492-497.
• The oral route is the preferred mode of potassium replacement therapy in hypokalaemia. Intrave-nous therapy should be reserved for those with malfunctioning gut, neurological symptoms, cardiac arrhythmias, digitalis toxicity, and recent or ongoing cardiac ischaemia.¹⁰.Asmar A, Mohandas R, Wingo CS. A Physiologic-Based Approach to the Treatment of a Patient With Hypokalemia. Am J Kidney Dis. 2012; 60(3): 492-497.
• The preferred salt for replacement therapy of hypokalaemia is potassium chloride as most causes of hypokalaemia are accompanied by metabolic alkalosis and require chloride repletion.¹⁰.Asmar A, Mohandas R, Wingo CS. A Physiologic-Based Approach to the Treatment of a Patient With Hypokalemia. Am J Kidney Dis. 2012; 60(3): 492-497.
• Though serum potassium concentration and symptoms might be dramatic in hypokalaemia from cellular shifts, total body stores are normal and careful monitoring during potassium replacement is necessary to prevent hyperkalaemia.¹⁰.Asmar A, Mohandas R, Wingo CS. A Physiologic-Based Approach to the Treatment of a Patient With Hypokalemia. Am J Kidney Dis. 2012; 60(3): 492-497.
• Many patients with potassium depletion, especially those on loop diuretics, may also have magnesium deficiency, which will lead to refractory hypokalaemia unless identified and treated early.¹⁰.Asmar A, Mohandas R, Wingo CS. A Physiologic-Based Approach to the Treatment of a Patient With Hypokalemia. Am J Kidney Dis. 2012; 60(3): 492-497.

References

1. Weiner D, Wingo CS. Hypokalemia-Consequences, Causes, and Correction. J Am SocNephrol. 1997; 8(7):1179-88.
2. Veltri KT, Mason C. Medication-Induced Hypokalemia. Pharmacovigilance Forum. 2015; 40(3):185-190.
3. Viera AJ, Wouk N. Potassium Disorders: Hypokalemia and Hyperkalemia. Am Fam Physician. 2015;92(6):487-495.
4. Kabadi U. Evaluation of hypokalemia [Internet]. 2017 [updated 2016 Oct 24; cited 2017 Oct 24]. Available from: http://us.bp.api.bmj.com/best practice/monograph/59/diagnosis/step-by-step.html
5. Assadi F. Diagnosis of Hypokalemia A Problem-Solving Approach to Clinical Cases. Iranian Journal of Kidney Diseases. 2008; 2(3):115-122.
6. Choi MJ, Ziyadeh FN. The utility of the transtubular potassium gradient in the evaluation of hyperkalemia. J Am Soc Nephrol. 2008 Mar;19(3):424-6.
7. Nurko S. Hypokalemia and Hyperkalemia. Available from: http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/hypokalemia-and-hyperkalemia/ [Accessed on 4th January 2017].
8. Joo KW , Chang SH, Lee JG, et al. Transtubular potassium concentration gradient (TTKG) and urine ammonium in differential diagnosis of hypokalemia. J Nephrol. 2000 Mar-Apr;13(2):120-5.
9. Cohn JN et al. New Guidelines for Potassium Replacement in Clinical Practice. Arch Intern Med. 2000; 160(16):2429-2436.
10. Asmar A, Mohandas R, Wingo CS. A Physiologic-Based Approach to the Treatment of a Patient With Hypokalemia. Am J Kidney Dis. 2012; 60(3): 492-497.