How do B2 (beta-2) adrenergic agonists, such as salbutamol (albuterol), cause hypokalemia?

Mechanism of Beta-2 Adrenergic Agonist-Induced Hypokalemia

Beta-2 adrenergic agonists cause hypokalemia primarily by stimulating the Na+/K+ ATPase pump in skeletal muscle cells, which shifts potassium from the extracellular to the intracellular compartment without affecting total body potassium. 1

Physiological Mechanism

• Beta-2 adrenergic agonists bind to beta-2 receptors on skeletal muscle cell membranes, activating a signaling cascade that involves cAMP (cyclic adenosine monophosphate) 1
• The activated cAMP pathway stimulates the Na+/K+ ATPase pump, which actively transports potassium ions into cells while moving sodium ions outward 1
• This mechanism is independent of insulin, aldosterone, or renal excretion of potassium 1
• The potassium shift is primarily into skeletal muscle cells, which contain the highest concentration of beta-2 receptors 2

Clinical Significance and Magnitude

• Multiple studies document a decrease in serum potassium concentration after the use of short-acting beta-2 agonists 2
• The average decrease in serum potassium is approximately 0.5 mmol/L (0.54 mmol/L in one study and 0.52 mmol/L in another) 2
• In clinical practice, the hypokalemic effect begins within 15-30 minutes after administration and can last between 4-6 hours 3, 4
• More severe hypokalemia (below 2.5 mmol/L) can occur when beta-2 agonists are combined with other medications like theophylline 5

Factors Affecting Severity of Hypokalemia

• Dose-dependent response: Higher doses of beta-2 agonists cause more pronounced hypokalemia 6
• Route of administration: Intravenous administration typically causes more significant hypokalemia than inhaled administration 2
• Concomitant medications: Non-potassium-sparing diuretics can worsen beta-agonist-induced hypokalemia 7
• Theophylline potentiates the hypokalemic effect of beta-2 agonists when used in combination 5
• Pre-existing conditions: Patients with underlying electrolyte abnormalities or cardiac disease may be more susceptible to clinically significant hypokalemia 7

Clinical Applications and Therapeutic Use

• The hypokalemic effect of beta-2 agonists is utilized therapeutically in the treatment of hyperkalemia 3, 4
• Nebulized albuterol (10-20 mg over 15 minutes) is recommended as part of the treatment algorithm for hyperkalemia 3
• The hypokalemic effect correlates with bronchodilation in asthmatic patients, suggesting a common underlying mechanism 8

Potential Complications

• Cardiac arrhythmias may occur due to hypokalemia, especially in patients with pre-existing heart disease 7
• ECG changes associated with hypokalemia include T-wave flattening, ST-segment depression, and U-wave prominence 9
• The hypokalemic effect is transient, and rebound hyperkalemia can occur after 2 hours if no other potassium-lowering interventions are implemented 3, 4
• Patients receiving non-potassium-sparing diuretics are at higher risk for clinically significant hypokalemia when treated with beta-2 agonists 7

Clinical Management Considerations

• Monitor serum potassium levels in patients receiving high doses or frequent administration of beta-2 agonists 7
• Consider potassium supplementation in symptomatic patients or those with significant ECG changes 9
• Use caution when administering beta-2 agonists to patients with cardiovascular disorders, especially those with arrhythmias or coronary insufficiency 7
• Be aware of potential drug interactions, particularly with non-potassium-sparing diuretics and digoxin 7