Pharmacology · Cardiovascular

Diagnosis, Evaluation & Secondary Causes

Blood pressure phenotypes, pharmacological implications of secondary causes, and treatment thresholds

A single elevated reading never establishes hypertension — diagnosis requires averaging at least two readings on at least two separate visits using correct technique, with both arms measured at the first visit because a between-arm difference greater than 15 mm Hg warrants vascular evaluation for subclavian stenosis or coarctation.
Comparing office against out-of-office measurement defines four phenotypes that office readings alone cannot distinguish: white coat hypertension (15 to 30%) risks premature treatment, while masked hypertension (10 to 15%) carries the same cardiovascular risk as sustained hypertension and is missed entirely without ambulatory or home monitoring.
The evaluation of a newly diagnosed patient is pharmacologically driven — a systematic medication review (NSAIDs, oral contraceptives, decongestants, calcineurin inhibitors, stimulants, erythropoietin), a targeted physical examination, and baseline creatinine, potassium, urinalysis, and lipids together determine which drug classes are safe before any agent is started.
Secondary hypertension accounts for 5 to 10 percent of all cases but 30 to 40 percent of resistant hypertension, and two contraindication rules dominate: alpha blockade must precede beta blockade in pheochromocytoma and cocaine-associated crisis, and ACE inhibitors and ARBs are contraindicated in bilateral renal artery stenosis where angiotensin II is sustaining glomerular filtration through efferent arteriolar constriction.
Treatment thresholds and targets — pharmacotherapy for all Stage 2 patients, for Stage 1 when 10-year cardiovascular risk reaches 10 percent or established cardiovascular disease, chronic kidney disease, or diabetes is present, aiming below 130/80 — form the framework against which every drug class in the following modules is evaluated.

Abbreviations: BP = blood pressure · CV = cardiovascular · CVD = cardiovascular disease · HTN = hypertension · RAAS = renin-angiotensin-aldosterone system · ACE = angiotensin converting enzyme · ARB = angiotensin receptor blocker · MRA = mineralocorticoid receptor antagonist · NSAID = nonsteroidal anti-inflammatory drug · CKD = chronic kidney disease · DASH = Dietary Approaches to Stop Hypertension · ACC/AHA = American College of Cardiology / American Heart Association · KDIGO = Kidney Disease: Improving Global Outcomes

The Four Blood Pressure Phenotypes

Office vs Out-of-Office Measurement

Why Out-of-Office Measurement Changes the Diagnosis

Phenotype	Office BP	Out-of-Office BP	Prevalence	Action
Normotension	Normal	Normal	—	No treatment
White Coat Hypertension	Elevated	Normal	15–30%	Avoid premature treatment — monitor
Masked Hypertension	Normal	Elevated	10–15%	Same CV risk as sustained HTN — treat
Sustained Hypertension	Elevated	Elevated	—	Confirmed — treat per stage and risk

Clinical Evaluation — Findings That Change Drug Selection

Systematic Review Before Diagnosis

Medication History

NSAIDs, estrogen-containing oral contraceptives, decongestants
Calcineurin inhibitors, stimulants, erythropoietin
Drug-induced elevation is common and easily missed without a systematic review
Exclude before labeling hypertension as primary

Directed Physical Examination

Signs With Pharmacological Consequences

Renal artery bruit → renovascular hypertension; determines RAAS inhibitor safety
Fundoscopic changes → grade retinopathy; indicates treatment urgency
Central adiposity and striae → Cushing syndrome
Between-arm difference above 15 mm Hg → subclavian stenosis or coarctation

Baseline Before Drugs Are Started

Laboratory Evaluation

Serum creatinine: kidney function governs class choice and dosing
Potassium: critical for diuretic and RAAS inhibitor safety
Urinalysis: proteinuria directs ACE inhibitor or ARB first-line
Lipid panel: contributes to 10-year cardiovascular risk estimate

Secondary Causes — Key Pharmacological Rules

Pheochromocytoma / Cocaine

Alpha Before Beta — Critical Rule

Never give beta-blocker first in pheochromocytoma: removes beta-2 vasodilation, leaves alpha-1 vasoconstriction unopposed → hypertensive crisis
Start alpha blocker (phenoxybenzamine or doxazosin) 10–14 days before surgery
Add beta-blocker for rate control only after alpha blockade confirmed
Same rule applies to cocaine-associated hypertension: use phentolamine or benzodiazepines, not beta-blockers

Renovascular Hypertension

RAAS Inhibitor Contraindication

Bilateral renal artery stenosis: angiotensin II maintains glomerular filtration via efferent arteriolar constriction
ACE inhibitors and ARBs remove this compensatory mechanism → acute kidney injury
Use calcium channel blockers, diuretics, or centrally acting agents instead
Clue: acute kidney injury shortly after starting ACE inhibitor or ARB in refractory hypertension

Primary Aldosteronism

Mineralocorticoid Receptor Antagonists

Autonomous aldosterone secretion: sodium retention, potassium wasting, renin suppression
Spironolactone: first-line medical therapy; non-selective (anti-androgenic side effects)
Eplerenone: selective MRA; preferred when gynecomastia or sexual dysfunction is a concern
Avoid thiazides: worsen existing hypokalemia

Drug-Induced Hypertension

Common Offenders & Mechanisms

NSAIDs: prostaglandin inhibition → sodium retention; blunt diuretics and RAAS inhibitors
Oral contraceptives: estrogen → angiotensinogen ↑ → RAAS activation
Calcineurin inhibitors: renal vasoconstriction; use amlodipine (avoid diltiazem/verapamil — raise drug levels)
Sympathomimetics: alpha-1 agonism → vasoconstriction

Treatment Thresholds & Blood Pressure Targets

When to Start and What to Aim For

Evidence-Based Treatment Framework

BP Stage	When to Start Pharmacotherapy	Target	Key Evidence
Stage 1 (130–139/80–89)	10-year CV risk ≥10%, or established CVD / CKD / diabetes; otherwise lifestyle first	Below 130/80	ACC/AHA 2017
Stage 2 (≥140/90)	All patients; combination therapy if ≥160/100	Below 130/80	SPRINT (2015)
Diabetes	All patients with Stage 1 or 2	Below 130/80	ACCORD (2010)
Chronic kidney disease with proteinuria	All patients; ACE inhibitor or ARB first-line	Below 130/80	KDIGO 2021

Lifestyle Modifications — Quantified BP Reductions

DASH diet: −11 mm Hg systolic · Sodium restriction (<2.3 g/day): −5 to 6 mm Hg · Aerobic exercise: −5 to 8 mm Hg · Weight loss (per kg): −1 mm Hg · Additive with pharmacotherapy at all stages

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
Stergiou GS, Palatini P, Parati G, et al.	2021 European Society of Hypertension practice guidelines for office and out-of-office blood pressure measurement	J Hypertens. 2021;39(7):1293–1302
Lenders JW, Duh QY, Eisenhofer G, et al.	Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline	J Clin Endocrinol Metab. 2014;99(6):1915–1942
Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group	KDIGO 2021 clinical practice guideline for the management of blood pressure in chronic kidney disease	Kidney Int. 2021;99(3S):S1–S87
ASTRAL Investigators; Wheatley K, Ives N, Gray R, et al.	Revascularization versus medical therapy for renal-artery stenosis (ASTRAL)	N Engl J Med. 2009;361(20):1953–1962
Cooper CJ, Murphy TP, Cutlip DE, et al.	Stenting and medical therapy for atherosclerotic renal-artery stenosis (CORAL)	N Engl J Med. 2014;370(1):13–22
Funder JW, Carey RM, Mantero F, et al.	The management of primary aldosteronism: case detection, diagnosis, and treatment — an Endocrine Society clinical practice guideline	J Clin Endocrinol Metab. 2016;101(5):1889–1916
Drager LF, Togeiro SM, Polotsky VY, Lorenzi-Filho G	Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome	J Am Coll Cardiol. 2013;62(7):569–576
Appel LJ, Moore TJ, Obarzanek E, et al.	A clinical trial of the effects of dietary patterns on blood pressure (DASH trial)	N Engl J Med. 1997;336(16):1117–1124
SPRINT Research Group; Wright JT Jr, Williamson JD, Whelton PK, et al.	A randomized trial of intensive versus standard blood-pressure control	N Engl J Med. 2015;373(22):2103–2116
ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al.	Effects of intensive blood-pressure control in type 2 diabetes mellitus	N Engl J Med. 2010;362(17):1575–1585
Jamerson K, Weber MA, Bakris GL, et al.	Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients (ACCOMPLISH)	N Engl J Med. 2008;359(23):2417–2428
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
Nieman LK, Biller BM, Findling JW, et al.	The diagnosis of Cushing syndrome: an Endocrine Society clinical practice guideline	J Clin Endocrinol Metab. 2008;93(5):1526–1540
Calhoun DA, Jones D, Textor S, et al.	Resistant hypertension: diagnosis, evaluation, and treatment — a scientific statement from the American Heart Association	Hypertension. 2008;51(6):1403–1419