Hypertension Pathophysiology & Drug Mechanisms

Renin cleaves angiotensinogen to angiotensin I, converted by ACE to angiotensin II. Ang II causes potent vasoconstriction, aldosterone release, sympathetic activation, and vascular remodeling. ACEi, ARBs, MRAs, and direct renin inhibitors all target this pathway.

Increased sympathetic tone raises BP through increased heart rate and cardiac output (beta-1), vasoconstriction (alpha-1), renin release, and renal sodium reabsorption. Beta-blockers, alpha-blockers, and central agents target different nodes of this pathway.

The endothelium regulates vascular tone via nitric oxide (NO) from eNOS. Hypertension reduces NO bioavailability through oxidative stress, inflammation, and shear stress dysregulation — impaired vasodilation, increased platelet aggregation, and vascular remodeling. CCBs and ACEi/ARBs (via kinin pathway) address this pathway.

The kidney regulates BP through pressure-natriuresis. In HTN this set-point is reset — higher BP is required to achieve normal natriuresis. Overactive RAAS/aldosterone, SNS activation, and intrinsic tubular abnormalities drive chronic volume expansion. Thiazides, loop diuretics, and MRAs target different tubular segments.

With aging, arterial elastin degrades and collagen crosslinks accumulate, increasing aortic stiffness. Stiff vessels reflect pulse waves earlier, augmenting systolic pressure while reducing diastolic pressure — widening pulse pressure. Isolated systolic hypertension is the dominant HTN phenotype in adults over 60.

First-line antihypertensive agents are selected based on mechanism, compelling indications, and contraindications. The 2025 AHA/ACC guideline recommends ACEi/ARB, dihydropyridine CCB, and thiazide-type diuretics as first-line. Combination therapy (SPC) is preferred over sequential monotherapy for most patients requiring more than one agent.