Potassium disorders — the drugs that cause them and the drugs that correct them

Potassium is mainly intracellular: the Na⁺/K⁺-ATPase keeps about 140 mEq/L inside cells against 4 to 5 mEq/L outside, so the serum level is an unreliable guide to total body stores. Alkalemia, insulin and β-adrenergic stimulation move potassium into cells; metabolic acidosis, cell injury and insulin deficiency move it out.

The kidney sets the balance. About 80 to 90% of potassium intake leaves in the urine, and the kidney does not conserve potassium well. In the collecting duct, sodium entering principal cells through ENaC makes the lumen negative, and potassium is secreted through ROMK channels. Aldosterone, acting on mineralocorticoid receptors in those cells, increases ENaC and Na-K ATPase, so potassium is secreted into the urine.

Loop and thiazide diuretics deliver more sodium to the collecting duct and activate the renin–angiotensin–aldosterone system. Aldosterone-driven sodium reabsorption makes the lumen negative and traps potassium and H⁺ there, so hypokalemia comes with a metabolic alkalosis; it is more common with loops. Thiazides also lower distal calcium delivery, which stimulates ENaC and adds to potassium secretion.

Insulin and inhaled β-adrenergic agonists cause hypokalemia by increasing uptake into cells, and chronic corticosteroid therapy, laxative abuse and sodium polystyrene sulfonate (which raises potassium loss in stool) are other drug causes. Low magnesium makes hypokalemia worse: it inhibits ROMK, increasing urinary potassium loss, so potassium replacement alone may fail.

The danger is the heart. Hypokalemia flattens the T wave, then depresses the ST segment and brings a U wave; severe hypokalemia can cause torsades de pointes and ventricular tachycardia. Digoxin competes with potassium at the Na⁺/K⁺-ATPase, so diuretic-induced hypokalemia leaves digoxin unopposed — loops carry the greatest digoxin-toxicity risk among diuretics.

ACE inhibitors and ARBs remove the angiotensin II that drives aldosterone secretion, and without aldosterone less potassium is secreted. Potassium-sparing diuretics act at the same final step: amiloride and triamterene block ENaC directly, and spironolactone and eplerenone block the mineralocorticoid receptor, suppressing the aldosterone-induced proteins that raise ENaC activity. Less ENaC activity means less potassium and H⁺ secretion, so hyperkalemia comes with a hyperchloremic metabolic acidosis.

The risk climbs when these drugs are combined or the kidney is weak. Hyperkalemia is more likely with impaired renal function, proteinuria and diabetes, and with ACE inhibitors, ARBs and NSAIDs taken together with a potassium-sparing agent. Dual renin–angiotensin system blockade is avoided for this reason. Amiloride is excreted unchanged by the kidney and can accumulate in renal dysfunction, and IV potassium chloride can cause life-threatening hyperkalemia in renal insufficiency.

Other drugs release potassium from cells: β-blockers, succinylcholine and calcineurin inhibitors, among others. Digoxin, potassium penicillin and total parenteral nutrition are also listed medication sources.

Hypokalemia. Replace magnesium first when it is low, because magnesium repletion makes potassium repletion possible. Concentrated potassium chloride must be diluted — direct injection may be instantaneously fatal — and IV repletion is preferred with dysrhythmias, digitalis toxicity or cardiac ischemia. It is given in saline rather than dextrose, because dextrose stimulates insulin and drives potassium into cells. When the loss is iatrogenic renal wasting, a potassium-sparing diuretic is added; ENaC blockers are used to correct hypokalemia caused by other diuretics.

Hyperkalemia. Calcium is given first when the ECG has changed: it stabilizes cardiac membranes but does not lower potassium. Insulin (with glucose unless the patient is hyperglycemic) and β2 agonists such as albuterol then shift potassium into cells, and bicarbonate may help in metabolic acidosis. Removal follows: gastrointestinal cation exchangers — whose onset is delayed, so they are not emergency treatment — and hemodialysis, the definitive treatment in end-stage kidney disease.