Overview
Primary (essential) hypertension accounts for ~90–95% of cases; secondary causes make up ~5–10% and include chronic kidney disease (CKD), primary hyperaldosteronism, renovascular disease (renal artery stenosis), phaeochromocytoma, obstructive sleep apnoea, coarctation of the aorta, Cushing syndrome, and medications (NSAIDs, oral contraceptive pill, decongestants, cocaine).
Hypertension is the “silent killer” — usually asymptomatic until end-organ damage has occurred. Key target organs are the heart (left ventricular hypertrophy, HFpEF, myocardial infarction), brain (stroke, lacunar infarcts, vascular dementia), kidney (hypertensive nephrosclerosis, CKD), retina (arteriovenous nipping, cotton-wool spots, papilloedema), and aorta (aneurysm, dissection).
Classification
| Category | Systolic (mmHg) | Diastolic (mmHg) | Action |
|---|---|---|---|
| Normal | <120 | <80 | Reassure; lifestyle advice |
| Elevated | 120–129 | <80 | Lifestyle modification; re-measure in 3–6 months |
| Stage 1 Hypertension | 130–139 | 80–89 | Lifestyle + consider pharmacotherapy (CVD risk ≥10%) |
| Stage 2 Hypertension | ≥140 | ≥90 | Pharmacotherapy + lifestyle modification |
| Hypertensive Urgency | >180 | >120 | No acute target-organ damage; oral agents; close follow-up within 24–48 h |
| Hypertensive Emergency | >180 | >120 | Acute end-organ damage (aortic dissection, STEMI, acute HF, hypertensive encephalopathy); IV therapy; ICU admission |
Pathophysiology
RAAS Axis
Reduced renal perfusion pressure activates juxtaglomerular (JG) cells to release renin. Renin cleaves angiotensinogen to angiotensin I (Ang I), which is then converted to angiotensin II (Ang II) by ACE in the pulmonary vasculature. Ang II acts on AT1R to cause:
- Direct vasoconstriction of arterioles → raised SVR
- Stimulation of adrenal zona glomerulosa → aldosterone → Na+/water retention (distal tubule, collecting duct)
- Endothelin-1 release → additional vasoconstriction and endothelial dysfunction
- Activation of NADPH oxidase → reactive oxygen species (ROS) → quench nitric oxide → reduced endothelium-dependent vasodilation
- TGF-β upregulation → vascular and cardiac fibrosis
Sympathetic stimulation of JG cells also drives renin release independently of renal perfusion, creating a positive feedback loop in obese patients and those with high central sympathetic outflow.
Sympathetic Nervous System
Increased central sympathetic outflow releases catecholamines (noradrenaline, adrenaline) acting via:
- α1-adrenoreceptors: peripheral vasoconstriction → raised SVR
- β1-adrenoreceptors: increased heart rate and contractility → raised cardiac output
Renal sympathetic nerves promote tubular Na+ reabsorption and renin release. In obesity, leptin acts centrally on hypothalamic nuclei to amplify sympathetic outflow, linking adiposity directly to hypertension. Obstructive sleep apnoea augments sympathetic activation through cyclic hypoxia and arousal responses.
Renal Na+ Retention (Guyton Model)
Guyton’s whole-body model argues that sustained hypertension ultimately requires impaired renal pressure natriuresis — a rightward shift in the pressure–natriuresis curve. Primary renal Na+ retention (from whatever cause) leads to volume expansion, raised cardiac output, and autoregulatory increase in SVR. Over months, the kidney resets its operating point at higher pressure. Monogenic forms illustrate discrete molecular mechanisms:
- Liddle syndrome: ENaC gain-of-function → constitutive Na+ reabsorption in collecting duct → severe early-onset hypertension, hypokalaemia, low aldosterone
- Gordon syndrome (PHA2): WNK4/SPAK kinase mutations → upregulation of NCC in distal tubule → salt-sensitive hypertension with hyperkalaemia
Endothelial Dysfunction
Nitric oxide (NO) produced by eNOS in endothelial cells maintains vasodilation and inhibits platelet aggregation, smooth muscle proliferation, and leukocyte adhesion. In hypertension, ROS generated by NADPH oxidase and xanthine oxidase quench NO, reducing its bioavailability. Simultaneously, endothelin-1 (ET-1) and thromboxane A2 promote vasoconstriction and inflammation. The net result is:
- Increased vascular smooth muscle tone → raised SVR
- Vascular remodelling (inward eutrophic remodelling: reduced lumen diameter, increased wall:lumen ratio)
- Increased arterial stiffness → raised pulse wave velocity → isolated systolic hypertension in elderly patients (wide pulse pressure)
- ICAM-1/VCAM-1 upregulation → atherosclerosis initiation
End-Organ Damage
| Organ / Target | Mechanism & Lesion | Clinical Consequence |
|---|---|---|
| Heart — LVH | Concentric hypertrophy: sustained pressure overload → sarcomere addition in parallel → increased wall thickness, normal/small cavity; TGF-β and Ang II drive interstitial fibrosis | Diastolic dysfunction (HFpEF); arrhythmia (AF, VT); sudden cardiac death; increased MI risk |
| Coronary artery disease | Endothelial dysfunction, LDL oxidation, and shear stress accelerate atherosclerotic plaque development; LVH increases O2 demand | Angina, MI; HTN is an independent cardiovascular risk factor |
| Stroke | Large-vessel: atherosclerosis of carotid/intracerebral arteries → embolic or thrombotic infarct; Small-vessel: lipohyalinosis of penetrating arteries → lacunar infarcts; haemorrhagic: rupture of Charcot–Bouchard micro-aneurysms | Motor, sensory, cognitive deficits; most powerful modifiable risk factor for stroke globally |
| Hypertensive nephrosclerosis | Afferent arteriolar hyalinosis and fibrosis → reduced glomerular filtration → focal segmental glomerulosclerosis; loss of pressure autoregulation in black patients (APOL1 risk variants) | Proteinuria, CKD progression; HTN+CKD form a vicious amplifying cycle (CKD worsens HTN) |
| Retinopathy | Grade I: arteriolar narrowing; Grade II: AV nipping (copper/silver wiring); Grade III: flame haemorrhages, cotton-wool spots; Grade IV: papilloedema (malignant HTN) | Visual loss (Grade III–IV); retinal changes predict CVD risk; fundoscopy provides non-invasive vascular assessment |
| Aorta | Chronic pressure load → elastin fragmentation, smooth muscle hypertrophy, medial degeneration → aneurysm; acute intimal tear → dissection | Aortic aneurysm (AAA in abdominal, ascending aortic in Marfan/bicuspid); type A/B dissection |
Treatment
Lifestyle Modifications (First Line)
- DASH diet: Dietary Approaches to Stop Hypertension — low Na+ (<2.3 g/day, ideally <1.5 g/day), high fruits and vegetables, low-fat dairy, reduced saturated fat; reduces BP by ~11/3 mmHg in trials
- Weight loss: ~1 mmHg SBP reduction per 1 kg weight loss in overweight patients
- Aerobic exercise: 90–150 min/week moderate-intensity → ~5–8 mmHg SBP reduction
- Alcohol limitation: ≤1 drink/day (women), ≤2 drinks/day (men)
- Smoking cessation: reduces overall CVD risk; each cigarette causes acute BP spike via catecholamines
Pharmacological Agents
| Drug Class | Mechanism | Preferred Indications | Key Trials / Notes |
|---|---|---|---|
| Thiazide/thiazide-like diuretics (chlorthalidone, indapamide; HCTZ second choice) |
Inhibit NCC in distal convoluted tubule → Na+/water loss → reduced plasma volume and CO; long-term: vasodilation | First-line; isolated systolic HTN in elderly; salt-sensitive HTN; Afro-Caribbean patients | ALLHAT (2002): chlorthalidone superior to doxazosin, lisinopril, amlodipine for primary outcomes; chlorthalidone and indapamide preferred over HCTZ for 24 h BP control |
| ACE inhibitors (enalapril, ramipril, lisinopril, perindopril) |
Block ACE → reduced Ang II → vasodilation + reduced aldosterone + reduced Na+ retention; preserve bradykinin → NO/prostacyclin release | First-line; CKD with proteinuria; diabetic nephropathy; HFrEF; post-MI LV dysfunction | HOPE (ramipril); PROGRESS (perindopril + indapamide for stroke prevention); SOLVD (enalapril in HFrEF). Cough in 5–20% (bradykinin); angioedema 0.1–0.5%; contraindicated in pregnancy; monitor K+/creatinine |
| ARBs (losartan, valsartan, irbesartan, candesartan, olmesartan) |
Block AT1R → same downstream effects as ACE-I without bradykinin accumulation | Same as ACE-I; preferred if ACE-I cough; CKD; HFrEF (if ACE-I intolerant) | ONTARGET (telmisartan non-inferior to ramipril); LIFE (losartan better than atenolol for stroke prevention); do not combine with ACE-I (ONTARGET: excess renal adverse events) |
| Calcium channel blockers (amlodipine, felodipine — DHP; diltiazem, verapamil — non-DHP) |
DHP: block L-type Ca2+ channels in vascular smooth muscle → vasodilation, minimal negative inotropy; non-DHP: also slow AV node | Isolated systolic HTN; elderly patients; Afro-Caribbean patients; angina (non-DHP or DHP); HTN + AF (diltiazem/verapamil) | CAMELOT (amlodipine); VALUE (valsartan vs. amlodipine): amlodipine provided faster BP lowering and reduced MI; ankle oedema common (DHP); avoid non-DHP + beta-blocker (heart block risk) |
| Beta-blockers (atenolol, bisoprolol, metoprolol, carvedilol, nebivolol) |
Block β1-AR → reduced heart rate and cardiac output; also reduce renin secretion; carvedilol/nebivolol have vasodilatory properties | HTN + HFrEF; HTN + post-MI; HTN + angina; HTN + tachyarrhythmia; pregnancy (labetalol) | LIFE and ASCOT: atenolol less effective than ARBs/CCBs for stroke prevention; not preferred as monotherapy in uncomplicated HTN; avoid abrupt withdrawal |
| Mineralocorticoid receptor antagonists (MRA) (spironolactone, eplerenone) |
Block aldosterone receptor → reduced Na+ reabsorption (collecting duct) → volume reduction + antifibrotic effects | Primary hyperaldosteronism; resistant hypertension; HFrEF (RALES/EMPHASIS-HF doses) | PATHWAY-2 trial (Williams 2015): spironolactone best 4th agent in resistant HTN; monitor K+ (risk of hyperkalaemia, especially with ACE-I/ARB + CKD); spironolactone causes gynaecomastia → switch to eplerenone |
| Alpha-blockers (doxazosin) |
Block α1-AR → vasodilation; no metabolic adverse effects | Add-on in resistant HTN; HTN + BPH; ALLHAT showed inferior to chlorthalidone for HF prevention | Postural hypotension on first dose; useful in selected patients |
| Others | Hydralazine: direct vasodilator (NO-mediated); methyldopa: central α2-agonist → reduced sympathetic outflow; clonidine: central α2-agonist | Hydralazine/labetalol/methyldopa: hypertension in pregnancy; clonidine: add-on therapy | Hydralazine can cause drug-induced lupus at high doses; methyldopa: preferred in pregnancy; clonidine: avoid abrupt withdrawal (rebound hypertension) |
Resistant Hypertension
Defined as BP >130/80 mmHg despite adherence to three antihypertensive agents at optimal doses, including a diuretic. Before labelling resistant HTN, exclude: white-coat effect (confirm with ABPM), medication non-adherence, secondary causes (primary hyperaldosteronism, renovascular disease), and drug interactions (NSAIDs antagonise antihypertensives).
Add spironolactone 25–50 mg as the fourth agent (PATHWAY-2 trial). Renal denervation (second-generation trials SPYRAL-OFF-MED and RADIANCE-HTN SOLO) shows ~5 mmHg SBP reduction vs. sham; approved adjunctive procedure in some guidelines for persistent resistant HTN.
Hypertensive Emergencies
| Emergency | Features | Target & Agent |
|---|---|---|
| Hypertensive encephalopathy / PRES | Confusion, vomiting, visual disturbance, seizures; MRI: posterior reversible leukoencephalopathy (PRES pattern); papilloedema; breakthrough of cerebrovascular autoregulation | Reduce MAP by 25% in 1 h; IV labetalol or IV nicardipine; avoid sodium nitroprusside (cyanide risk with prolonged use) |
| Aortic dissection (Type A & B) | Sudden tearing chest/back pain, pulse deficits, aortic regurgitation; CT aortogram | Target SBP 100–120 mmHg within 20 min; IV esmolol (HR <60 bpm first) + sodium nitroprusside; Type A: emergency surgery |
| Acute decompensated heart failure | Pulmonary oedema, orthopnoea, hypoxia; elevated filling pressures; often precipitated by severe HTN reducing LV afterload tolerance | IV loop diuretics (furosemide); IV nitrates (GTN, sodium nitroprusside) to reduce preload/afterload; consider CPAP/NIV |
| Eclampsia / pre-eclampsia | Pregnancy >20 weeks; BP ≥160/110 + seizures, proteinuria, thrombocytopaenia, elevated LFTs | IV MgSO4 for seizure prophylaxis and treatment; IV labetalol or hydralazine for BP; definitive: delivery |
| Hypertensive emergency + STEMI | Acute coronary syndrome with severely elevated BP; HTN worsens myocardial O2 demand | IV nitrates; primary PCI; beta-blockers after haemodynamic stabilisation; avoid excessive BP reduction pre-PCI |
Connections
- RAAS axisAngiotensin II — central pressor hormone; AT1R-mediated vasoconstriction, aldosterone release, Na+ retention, fibrosis, and oxidative stress all contribute to sustained hypertension
- systemCardiovascular System — heart and vasculature are both drivers and targets of hypertension; pressure load remodels both
- target organKidney — Guyton model: renal pressure natriuresis is the ultimate long-term BP controller; hypertensive nephrosclerosis creates a positive feedback loop with CKD
- treatmentACE Inhibitors — first-line agents; interrupt RAAS; reduce cardiovascular mortality, stroke, and progression of CKD
- treatmentARBs — AT1R antagonism; same indications as ACE-I; preferred if cough develops on ACE-I
- complicationHeart Failure — LVH → HFpEF; years of pressure overload → decompensated HFrEF; HTN is leading modifiable cause of HF globally
- vascular basisArterial Wall — vascular remodelling, reduced compliance, pulse wave velocity elevation, and elastin fragmentation underlie isolated systolic HTN and aortic disease
References
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. J Am Coll Cardiol. 2018;71(19):e127–e248. doi:10.1016/j.jacc.2017.11.006
- 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. doi:10.1093/eurheartj/ehy339
- ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288(23):2981–2997. doi:10.1001/jama.288.23.2981
- Carey RM, Whelton PK; 2017 ACC/AHA Hypertension Guideline Writing Committee. Prevention, Detection, Evaluation, and Management of High Blood Pressure: Synopsis of the 2017 American College of Cardiology/American Heart Association Hypertension Guideline. Ann Intern Med. 2018;168(5):351–358. doi:10.7326/M17-3203