Drug induced hypokalaemia in clinical practice

M Lam 林民，D V K Chao 周偉強

HK Pract 2001;23:502-505

Summary

Drug-induced hypokalaemia is common in clinical practice. Although all medical doctors know the possibility of this side effect when certain drugs are used, from time to time we still see patients with drug-induced hypokalaemia. It is important to have a high index of suspicion of this condition in order to diagnose hypo-kalaemia in our patients. Discussed in this article is a case of drug-induced hypokalaemia attributed to various drugs used in the same patient, together with the pathophysiology of potassium balance, mechanisms of various drugs that cause hypokalaemia and the consequences of hypokalaemia.

摘要

藥物引起的低鉀血症很常見。雖然醫生們對此副作用都有所了解，但是還是時有發生，問題的關鍵在於保持高度的警惕性以便及時診斷。本文報告了一位因使用多種藥物而引起低鉀血症的病例，討論鉀平衡的病理生理學，藥物引起低鉀血症的機制和後果。

Introduction

Hypokalaemia is one of the most common electrolyte disturbances encountered by doctors. It is found in over 20 percent of hospitalised patients.¹ This condition can cause malignant cardiac arrhythmia, and hypokalaemic paralysis which is a relatively uncommon but potentially life-threatening clinical syndrome.² Having the alertness and knowledge from the physician's perspective to suspect the presence of this condition and to give appropriate treatment is of paramount importance to our patients. Many drugs can cause hypokalaemia.³ Diuretics, especially loop diuretics, are the commonest culprit due to their common usage in clinical practice. A low serum potassium concentration has been found in 10 to 40 percent of patients treated with thiazide diuretics.⁴ In this article, we discuss a case of hypokalaemia in an elderly patient with multiple chronic illnesses being managed on multiple drugs including diuretic, beta-agonist and theophylline, all of which contribute to hypokalaemia.^3,5-10

Case report

A 77 years old gentleman with known history of hypertension, diabetes mellitus, chronic obstructive airway disease and impaired liver function with elevated alkaline phosphatase of liver origin and hypo-albuminaemia came back for follow up. He had been put on several medications for his chronic illnesses including glibenclamide, salbutamol, theophylline anhydrate, frusemide and potassium chloride. He had one episode of frusemide-induced hypokalaemia in September 1999, with potassium as low as 2.6mmol/L. This was treated with oral potassium replacement. He was found to have hypokalaemia again in February 2000 with a potassium level of 3.0mmol/L. Frusemide was stopped and he was given a potassium supplement. However, the patient resumed taking the loop diuretic again himself because of the recurrence of ankle oedema, the subsequent potassium level was found to be 2.6mmol/L and the concommitant urine potassium was 20mmol/L. Urea and creatinine were within their normal ranges. The patient remained asymptomatic throughout. His vital signs were stable and ECG revealed no cardiac arrhythmia. He was then admitted to the medical ward for potassium supplement and close monitoring. Oral potassium supplement was given and he was discharged 2 days after hospitalisation without any sequelae. His serum potassium was 3.6mmol/L on discharge.

Pathophysiology

Most of body's potassium (3,500mmol in an adult man) is intracellular. Potassium is the most abundant intracellular cation and is responsible for maintaining the resting membrane potentials of cells. Serum potassium levels are controlled by uptake of potassium into cells, renal excretion and extra-renal loss (e.g. gastrointestinal). Abnormalities of potassium concentration in plasma can result from changes in external potassium balance between intake and excretion, or internal balance between intracellular and extracellular potassium. Any disturbance of the homoeostasis of potassium can affect the functioning of cells in skeletal and myocardial muscle which, in turn, can cause muscular paralysis or cardiac arrhythmia if severe enough.

Discussion

As family physicians, we encounter lots of patients with a combination of chronic problems such as hypertension, heart failure, asthma and chronic obstructive airway disease. It is not uncommon that many of these patients are put on diuretics, beta-agonists and theophylline, all of which can contribute to hypokalaemia. It is important to bear in mind that hypokalaemia is usually asymptomatic. However, hypokalaemia does cause muscle weakness which can induce respiratory failure if advanced, and lethal cardiac arrhythmia including ventricular fibrillation,¹¹ especially in patients with cardiac ischaemia, heart failure, or left ventricular hypertrophy.^4,12 Hypokalaemia can be associated with ECG changes, namely: Flat T waves (occasionally inverted), prolonged PR, ST depression, and tall U waves. Apart from cardiac arrhythmia, hypokalaemia-related hypertension also contributes to increased morbidity and mortality,^13,14 though the mechanism is not completely clear. Hypokalaemia hyperpolarises skeletal muscle cells, impairing their ability to develop the depolarisation necessary for muscle contraction. It can also reduce blood flow to skeletal muscle, predisposing patients to rhabdomyolysis.¹³ Apart from the effects on heart and skeletal muscle, hypokalaemia worsens hyperglycaemia in diabetic patients by impairing both insulin release and end-organ sensitivity to insulin.^13,15,16 Without blood taking, one can never know what the serum potassium is.

Most symptoms (including complex ventricular arrhythmias) do not occur unless the potassium level is less than 3mmol/L. Skeletal muscle weakness can be seen when the potassium level has fallen to around 2.5mmol/L. Levels of less than 2mmol/L can precipitate rhabdomyolysis and conduction abnormalities, which may appear as a U-wave.

A potassium level of 3mmol/L seems safe, but one cannot guarantee that the level will not keep decreasing if proper treatment is not given and the primary cause not eliminated.

Potassium is completely filtered at the glomerulus and over 90% of the filtered potassium is reabsorbed in the proximal tubule and the loop of Henle, further reabsorption being achieved in the distal tubule and collecting duct. Renal excretion of potassium is determined by tubular secretion into the cortical collecting ducts (CCD), and the following are the main factors enhancing potassium secretion at CCD:

1. Increased sodium delivery and rate of flow of filtrate into the CCD.
2. Increased aldosterone secretion.
3. High plasma potassium concentration.
4. Alkalosis.
5. Presence of non-resorbable anion such as bicarbonate and ketone bodies in the CCD.

Frusemide, being a loop diuretic, blocks the chloride-associated sodium reabsorption, thus increasing delivery of sodium to the collecting tubules, where its reabsorption creates a favourable electrochemical gradient for potassium secretion.³ Beta-2 adrenoceptor agonists bind to beta-2 adrenergic receptors on the muscle and liver cell membrane, activating the sodium-potassium-ATPase pump through the cyclic AMP pathway to effect intracellular transfer of potassium and thus hypokalaemia. Beta-2 agonists also increase plasma insulin which may further contribute to the hypokalaemic effect.⁷ Theophylline stimulates the release of sympathetic amines and may also increase sodium-potassium-ATPase activity by inhibiting cellular phosphodiesterase.³ Thyrotoxic periodic paralysis has occurred quite frequently in male Asian patients and so thyrotoxicosis should be suspected in male hypokalaemic patients with or without paralysis in Hong Kong.

Hypokalaemia can be caused by either redistribution or potassium loss, and the cause is usually obvious from history. Investigation is directed to distinguish gastrointestinal loss from renal loss by measuring the urinary excretion of potassium which is high in the case of renal loss. Treatment of hypokalaemia should always aim at identifying the primary cause and giving appropriate treatment. In most cases, withdrawal of oral diuretic and starting potassium supplements is usually good enough. Oral potassium supplement is safer, because potassium enters the circulation more slowly³ and so the risk of iatrogenic hyperkalaemia can be minimised. Intravenous potassium is given in such conditions as cardiac arrhythmia, muscle weakness or severe diabetic ketoacidosis when the potassium level is less than 2.5mmol/L or when the patient is unable to take oral potassium by mouth. Rate of infusion of potassium should not exceed 20mmol/hour unless there is muscle paralysis or malignant ventricular arrhythmia. Ideally, potassium chloride should be mixed with normal saline since dextrose solution may aggravate hypokalaemia by insulin-mediated movement of potassium into cells. Serum potassium is checked every 3-6 hours if intravenous potassium is being administered. Occasionally hypokalaemia may be refractory to potassium replacement, which may be due to magnesium deficiency that makes potassium correction more difficult. Concomitant magnesium repletion can prevent this problem. Patient education has always been one of the most important part of our management. Patients should be well informed why certain drugs are stopped and the potential risks if they keep taking them.

Conclusion

Hypokalaemia is common in clinical practice. Despite the time constraint in our busy daily practice, a high index of suspicion for possible hypokalaemia should be maintained to avoid unnecessary morbidity and mortality arising from the electrolyte disturbance. There is no rigid guideline as to when the renal function should be checked in patients taking drugs that can cause electrolyte disturbance, but it is quite logical to check the electrolytes 2 to 4 weeks after starting the drugs. What is more important is that the electrolytes should be checked periodically, say half-yearly, as it is quite common to discover hypokalaemia in patients whose initial potassium levels are normal.