Which medication class is most appropriate as first-line therapy for uncomplicated primary hypertension?

Thiazide-type diuretics are recommended as first-line therapy for uncomplicated primary (essential) hypertension by major guidelines including JNC 8 and the American College of Cardiology/American Heart Association. They reduce blood pressure by promoting sodium and water excretion, decreasing plasma volume and cardiac output. They have a strong evidence base showing reduction in cardiovascular morbidity and mortality and are cost-effective. Combining an ACE inhibitor with an angiotensin receptor blocker (ARB) is contraindicated because dual renin-angiotensin-aldosterone system blockade significantly increases the risk of hyperkalemia, hypotension, and acute kidney injury without additional cardiovascular benefit. A combination of an ACE inhibitor with a calcium channel blocker can be appropriate in certain situations, such as when a diuretic is not tolerated, but it is not the primary first-line choice for uncomplicated hypertension. Alpha-1 blockers are generally reserved for specific populations, such as men with concurrent benign prostatic hyperplasia, because they have not demonstrated the same mortality benefit as thiazides in large outcomes trials. Therefore, the thiazide-type diuretic stands alone as the most appropriate initial pharmacological choice for uncomplicated primary hypertension.