Pharmacology · Cardiovascular

Understanding Hypertension

Definition, pathophysiology, and the hemodynamic framework for drug selection

The ACC/AHA 2017 guidelines lowered the hypertension threshold to 130/80 mm Hg (Stage 1), departing from the previous 140/90 threshold still used by ESH/ESC — recognizing that cardiovascular risk rises continuously with blood pressure, not in a step-function at an arbitrary number; hypertensive crisis above 180/120 requires immediate evaluation for end-organ damage.
Blood pressure equals cardiac output multiplied by total peripheral resistance — this equation is the direct basis for rational drug selection: every antihypertensive reduces one or both variables, and understanding which mechanism is dominant in a given patient guides which class to choose first.
The RAAS cascade (low renal perfusion → renin → angiotensin I → angiotensin II via ACE → vasoconstriction, aldosterone release, SNS activation, cardiac remodeling) is the dominant neurohormonal pathway targeted by ACE inhibitors, ARBs, aldosterone antagonists, and beta-blockers (which reduce renin release via beta-1 blockade).
Sustained hypertension injures multiple organ systems simultaneously: left ventricular hypertrophy and HFpEF (cardiac), stroke and hypertensive encephalopathy (cerebrovascular), hypertensive nephrosclerosis and progressive CKD (renal), and aortic aneurysm, peripheral arterial disease, and hypertensive retinopathy (vascular/ophthalmologic).
Agents reducing cardiac output include beta-blockers (heart rate, contractility, renin) and diuretics (preload); agents reducing total peripheral resistance include calcium channel blockers, ACE inhibitors/ARBs, alpha-1 blockers, and direct vasodilators; combined alpha-beta blockers (labetalol, carvedilol) and centrally acting agents (clonidine, methyldopa) reduce both.

Blood Pressure Classification (ACC/AHA 2017)

Diagnostic Thresholds

Blood Pressure Categories

Category	Systolic (mm Hg)	Diastolic (mm Hg)	Status
Normal	Below 120	Below 80	Normal
Elevated	120–129	Below 80	Watch
Stage 1 Hypertension	130–139	80–89	Stage 1
Stage 2 Hypertension	140 or above	90 or above	Stage 2
Hypertensive Crisis	Above 180	and/or above 120	Emergency

Renin-Angiotensin-Aldosterone System Pathway

Stimulus

Low Renal Perfusion

or low sodium delivery; beta-1 stimulation

→

Kidney

Renin Released

from juxtaglomerular cells

→

Liver Product

Angiotensinogen

cleaved to Angiotensin I

→

Lung (ACE)

Angiotensin II

angiotensin converting enzyme cleaves angiotensin I

→

AT1 Receptor Effects

Vasoconstriction + Aldosterone + SNS + Remodeling

raises BP, retains sodium

Pharmacological Targets

Where Drugs Act on RAAS

Angiotensin converting enzyme inhibitors: block angiotensin converting enzyme, prevent angiotensin II formation
Angiotensin receptor blockers: block angiotensin II type 1 receptor directly
Aldosterone antagonists (spironolactone, eplerenone): block mineralocorticoid receptor in collecting duct
Beta-blockers: reduce renin release via beta-1 blockade

Sympathetic Nervous System

SNS Contributions to Hypertension

Increased heart rate and contractility: raises cardiac output
Arteriolar vasoconstriction: raises total peripheral resistance
Renal sodium retention via tubular alpha-adrenoceptors
Renin release stimulation via beta-1 receptors
Feed-forward loop with renin-angiotensin-aldosterone system

Target Organ Damage

Cardiac

Heart

Left ventricular hypertrophy
Heart failure with preserved ejection fraction
Coronary artery disease
Atrial fibrillation

Cerebrovascular

Brain

Ischemic and hemorrhagic stroke
Lacunar infarcts
Hypertensive encephalopathy
Cognitive impairment

Renal

Kidney

Hypertensive nephrosclerosis
Progressive chronic kidney disease
Microalbuminuria (early marker)
Reciprocal: kidney disease worsens hypertension

Other

Vessels & Eyes

Hypertensive retinopathy
Aortic aneurysm and dissection
Peripheral arterial disease
Endothelial dysfunction (systemic)

Hemodynamic Drug Class Map

BP = Cardiac Output × Total Peripheral Resistance

Drug Classes by Hemodynamic Target

Target

Reduce Cardiac Output

Beta-blockers

Reduce heart rate, contractility, renin

Diuretics

Reduce preload via natriuresis

Target

Reduce Total Peripheral Resistance

Calcium channel blockers

Arteriolar vasodilation

Angiotensin converting enzyme inhibitors / Angiotensin receptor blockers

Block renin-angiotensin-aldosterone system vasoconstriction

Alpha-1 blockers

Block sympathetic vasoconstriction

Direct vasodilators

Hydralazine, minoxidil — arteriolar relaxation

Target

Reduce Both

Combined alpha-beta blockers

Labetalol, carvedilol — cardiac output and peripheral resistance

Centrally acting agents

Clonidine, methyldopa — reduce sympathetic outflow

Suggested References

Author / Organization	Title	Source
Katzung BG, ed.	Basic and Clinical Pharmacology. 15th ed.	McGraw-Hill; 2021
Brunton LL, Knollmann BC, eds.	Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed.	McGraw-Hill; 2023
Whelton PK, Carey RM, Aronow WS, et al.	2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults	J Am Coll Cardiol. 2018;71(19):e127–e248
Mancia G, Kreutz R, Brunstrom M, et al.	2023 ESH guidelines for the management of arterial hypertension	J Hypertens. 2023;41(12):1874–2071
NCD Risk Factor Collaboration	Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019	Lancet. 2021;398(10304):957–980
Oparil S, Acelajado MC, Bakris GL, et al.	Hypertension	Nat Rev Dis Primers. 2018;4:18014
Guyton AC	Blood pressure control — special role of the kidneys and body fluids	Science. 1991;252(5014):1813–1816
Carey RM, Muntner P, Bosworth HB, Whelton PK	Prevention and control of hypertension: JACC health promotion series	J Am Coll Cardiol. 2018;72(11):1278–1293
Schmieder RE	End organ damage in hypertension	Dtsch Arztebl Int. 2010;107(49):866–873
Williams B, Mancia G, Spiering W, et al.	2018 ESC/ESH guidelines for the management of arterial hypertension	Eur Heart J. 2018;39(33):3021–3104
Pimenta E, Calhoun DA	Primary aldosteronism: diagnosis and treatment	J Clin Hypertens. 2006;8(12):887–893