Secondary Hypertension

• Age at onset: < 30 yr or > 50 yr (systolic-diastolic hypertension [HTN])
• BP: > 180/110 mm Hg at diagnosis
• Significant target-organ damage at diagnosis
• Hemorrhages and exudates on retinal examination
• Renal insufficiency
• Left ventricular (LV) hypertrophy
• Poor response to appropriate three-drug therapy (which includes a diuretic)
• Accelerated or malignant HTN
• Sudden worsening of HTN at any age

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Differential Diagnosis

• Isolated clinic ("white-coat") HTN
• Secondary HTN

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Best Tests

Essential HTN

BP Measurement

• At least two clinic visits 1–2 mo apart (shorter period if initial BP is severely elevated) with two standardized readings at each visit averaging ≥ 140/90 mm Hg
• Patient self-measured BP ≥ 135/85 mm Hg
  • Elevated office BP with self-measured BP < 130/80 mm Hg identifies isolated clinic (white-coat) HTN
• Ambulatory BP monitoring to distinguish sustained HTN from isolated clinic (white-coat) HTN and to assess the following:
  • Hypotension
  • Episodic HTN
  • Masked HTN
  • Suspected autonomic dysfunction in patients with postural hypotension

Laboratory Tests

• Identify cardiovascular (CV) risk factors
  • Cholesterol (low-density lipoprotein [LDL] and high-density lipoprotein [HDL])
  • Triglycerides
  • Fasting blood glucose
• Identify target-organ injury
  • Chest x-ray
  • Electrocardiography (ECG)
  • Urinalysis
  • Serum creatinine or blood urea nitrogen (BUN)
  • Uric acid
• Potassium
• Sodium
• Hemoglobin
• Calcium
• Urinalysis
• If initial assessment suggests renal dysfunction, evaluate for chronic kidney disease by measuring 24-hour urinary protein excretion and estimating glomerular filtration rate (GFR):
  • GFR = (140 – age in yr) × (weight in kg) × 0.85 (if patient is female)/72 × serum creatinine (mg/dl)
  • Website for estimating GFR: www.hdcn.com/calcf/gfr.htm

Screening Tests for Secondary HTN (Sensitivity/Specificity)

Renovascular HTN

• Captopril radionuclide renal scan (75% sensitivity/85% specificity)
  • Advantage: no iodinated contrast exposure
  • Disadvantages: renal dysfunction impairs interpretation; may miss bilateral, accessory-, or branch-vessel disease
• Duplex ultrasonography (80%–90% sensitivity/80%–90% specificity)
  • Advantages: no iodinated contrast or radiation exposure; renal dysfunction does not impair interpretation; calculation of resistive index (RI) identifies subset of patients with renal dysfunction likely to benefit from intervention (RI < 0.80)
  • Disadvantages: failure to visualize both renal arteries (15%–20% of cases); may miss accessory- or branch-vessel disease
• Spiral computed tomographic (CT) angiography (86-100% sensitivity/94-100% specificity)
• Advantages: excellent images of renal arteries; can identify dissection, accessory vessels, and fibromuscular disease
• Disadvantages: considerable iodinated contrast load precludes use in presence of renal dysfunction; expensive
• Magnetic resonance angiography (85%–100% sensitivity/88%–100% specificity)
  • Advantages: no iodinated contrast or radiation exposure; renal dysfunction does not impair interpretation
  • Disadvantages: cost; may overstate degree of stenosis; claustrophobic patients may not tolerate test; risk of gadolinium-associated systemic fibrosis if GFR < 30 mL/min
• Renal angiography: gold standard
  • Advantages: identifies accessory- and branch-vessel disease; percutaneous interventions can be performed as part of study
  • Disadvantages: cost; iodinated contrast exposure; invasive (atheroemboli)

Primary Aldosteronism

• Screening: simultaneous measurement of plasma renin activity (PRA), and plasma aldosterone concentration (PAC) and calculation of ratio of PAC to PRA
• Screening positive if PAC-to-PRA >20
• Advantage: ratio is easy to obtain
• Disadvantages: many antihypertensive drugs can influence values of PRA and PAC and lead to false positive or false negative results; sensitivity and specificity of the ratio not established; many published cutpoints
• Confirmation: 24-hour urinary aldosterone, sodium, and PRA after 3 days of a 200 mEq sodium diet
• Diagnosis confirmed if U_Na > 200 mEq, U_aldo > 12 μg/24 hr, and PRA < 1.0 ng/mL/hr

Pheochromocytoma

• Plasma-free metanephrines (99% sensitivity/85–89% specificity)
• 24-hr total and fractionated urinary metanephrines (76–100% sensitivity/94–99% specificity)
• Use plasma test if degree of suspicion is high or familial syndrome is suspected
Cushing Syndrome
• 24-hr urinary free cortisol (95%–100% sensitivity/97%–100% specificity)
  • Diagnosis certain if 24-hour urinary free cortisol level > 3 times normal
  • Diagnosis excluded if level normal
  • Use low-dose dexamethasone suppression test if elevation < 3 times normal
Coarctation of the Aorta
• Chest x-ray; echocardiogram
• CT or magnetic resonance imaging (MRI) of the aorta
• Diagnostic findings on chest x-ray
  • "3" sign from dilation of aorta above and below the coarctation
  • Rib notching from collateral vessels

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Best Therapy*

Prehypertension

• Monitor BP annually
• Lifestyle adjustments to lower BP and CV risk and prevent progression to HTN
• In patients with heart disease, diabetes or renal disease, treat with lifestyle adjustments and antihypertensive drugs if systolic BP > 135 mm Hg or diastolic BP > 85 mm Hg (opinion-based recommendation)

Essential HTN: Risk Stratification and Initial Treatment in Hypertensive Patients by BP Stage (mm Hg)

• Prehypertension (120–139/80–89 mm Hg): lifestyle modification
• Stage 1 (140–159/90–99 mm Hg): lifestyle modification (up to 12 mo)
• Stage 2: (≥ 160/≥ 100): lifestyle modification + drug therapy

Risk Group B (≥ 1 CV Risk Factor, Not Including Diabetes; No Target-Organ Disease or Clinical Cardiovascular Disease)

• Prehypertension (120–139/80–89 mm Hg): lifestyle modification
• Stage 1 (140–159/90–99 mm Hg): lifestyle modification (up to 6 mo); consider adding drugs initially
• Stage 2: (≥ 160/≥ 100): lifestyle modification + drug therapy

Risk Group C (Target-Organ Disease or Clinical Cardiovascular Disease and/or Diabetes ± Other CV Risk Factors)

• Prehypertension (120–139/80–89 mm Hg)
  • Lifestyle modification
  • Drug therapy: use drugs if SBP > 135 mm Hg or if DBP > 85 mm Hg and patient has heart disease, chronic kidney disease, or diabetes (opinion-based recommendation)
• Stage 1 (140–159/90–99 mm Hg): lifestyle modification + drug therapy
• Stage 2: (≥ 160/≥ 100): lifestyle modification + drug therapy
• Treatment goals
  • Reduce risk of CV morbidity and mortality
  • Lower BP to < 140/90 mm Hg; lower to < 130/80 mm Hg in patients with heart disease, diabetes, renal disease (opinion-based recommendation); lower to < 140 mm Hg in older patients with isolated systolic HTN (evidence-based goal < 150 mm Hg)
• Coexisting cardiovascular disease (CVD) risk factors should be addressed
• Consider low-dose aspirin once BP is controlled
• Encourage self-measurement of BP

Treatment for Patients with Essential HTN

• Continue lifestyle modifications
• Start with lowest recommended dose of a once-daily drug
  • Combination drug therapy is appropriate if BP > 20/10 mm Hg above goal (caution in elderly and diabetics)
  • Thiazide diuretic + one of the following as second agent: beta blocker; angiotensin-converting enzyme (ACE) inhibitor; angiotensin receptor blocker; calcium antagonist; calcium antagonist-ACE inhibitor combination also effective; avoid ACE inhibitor-ARB combination
  • If no response or significant side effects at 2–4 wk, substitute another drug from a different class
  • If partial response at 2–4 wk and drug is well tolerated, increase dose of initial drug or add agent from a different class (diuretic if not chosen initially)
  • If not at goal BP in 2–4 more wk, continue titrating doses and adding agents from other classes at regular follow-up visits
  • If patient on three drugs and goal BP not reached, review considerations for resistant HTN; consider referral to HTN specialist

Lifestyle Modification

• Weight reduction if overweight
• Reduce sodium intake to ≤ 100 mmol/day: 2.4 g sodium, 6 g salt
• Increase aerobic exercise: 30–45 min/day
• Limit alcohol intake to ≤ 1 oz/day
• Maintain adequate intake of potassium: 90 mmol/day
• Eat a diet rich in fruits, vegetables, and low-fat dairy products but reduced in saturated and total fat
• Discontinue tobacco use (reduce CVD risk)

Pharmacologic Therapy

• Thiazide diuretics are initial drugs of choice for most patients with uncomplicated HTN
• Common comorbid conditions may dictate choice
• Long-acting agents preferable because compliance and consistency of BP control are superior with once-a-day dosing
• When monotherapy is unsuccessful, add second agent of a different class
• Initiate treatment with combination therapy (two drugs) if BP > 20/10 mm Hg above goal (caution in elderly and diabetics)
• Include a diuretic appropriate for level of renal function
• Refractory/resistant HTN: consider the following: noncompliance, interfering substances, inappropriate regimens, office (white-coat) HTN, secondary HTN

Diuretics

• General side effects of diuretics: hyponatremia; hypokalemia; hypomagnesemia; hyperglycemia; hypercalcemia (decrease in urinary calcium excretion); hyperuricemia; increase in triglycerides and cholesterol; decrease in lithium excretion
• Contraindications: diuretics should be avoided in pregnancy and in patients with gout
• Hydrochlorothiazide (HCTZ)
  • First choice in uncomplicated HTN and isolated systolic HTN
  • Initial dose: 12.5 mg/day; range: 12.5–50 mg/day
• Chlorthalidone
  • First choice in uncomplicated HTN and isolated systolic HTN
  • Initial dose: 12.5 mg/day; range: 12.5–25 mg/day
• Indapamide
  • Use in presence of renal insufficiency
  • Initial dose: 1.25 mg/day; range: 1.25–5.0 mg/day
• Metolazone
  • Use in presence of renal insufficiency
  • Initial dose: 1.25 mg/day; range: 1.25–5.0 mg/day
• Furosemide
• Alternate diuretic in renal insufficiency
• Side effects: same as other diuretics but increases urinary calcium excretion
• Initial dose: 20 mg/day; range: 20–320 mg/day
• Short-acting: requires twice-daily dosing schedule
• Bumetanide
• Alternate diuretic in renal insufficiency
• Side effects: same as other diuretics but increases urinary calcium excretion
• Initial dose: 0.5 mg/day; range: 0.5–5.0 mg/day
• Ethacrynic acid
  • Alternate diuretic in renal insufficiency or sulfa-based diuretic allergy
  • Only non-sulfa-based diuretic
  • Side effects: same as other diuretics but increases urinary calcium excretion
  • Initial dose: 25 mg/day; range: 25–100 mg/day
• Torsemide
  • Alternate diuretic in renal insufficiency
  • Long-acting loop diuretic
  • Side effects: same as other diuretics but increases urinary calcium excretion
  • Initial dose: 5 mg/day; range: 5–20 mg/day
• Spironolactone (also available combined with HCTZ)
  • Potassium sparing
  • Aldosterone antagonist
  • Avoid in renal insufficiency
  • Specific side effects: hyperkalemia, hyponatremia, painful gynecomastia, menstrual irregularities
  • Initial dose: 25 mg/day; range 25–100 mg/day
• Eplerenone
  • Potassium sparing
  • Aldosterone antagonist
  • Fewer antiandrogen side effects than spironolactone
  • Avoid in renal insufficiency
  • Specific side effects: hyperkalemia, hyponatremia
  • Reduce dose by half if patient is on verapamil
  • Initial dose: 50 mg/day; range: 50–100 mg/day
• Triamterene (also available combined with HCTZ)
  • Potassium sparing
  • Usually used for prevention of diuretic-induced hypokalemia
  • Specific side effects: hyperkalemia, nephrolithiasis
  • Initial dose: 50 mg/day; range: 50–150 mg/day
• Amiloride (also available combined with HCTZ)
  • Potassium sparing
  • Usually used for prevention of diuretic-induced hypokalemia
  • Specific side effect: hyperkalemia
  • Initial dose: 5 mg/day; range: 5–10 mg/day

Calcium Antagonists (Alternative First-Line Drugs)

Hypertensive Crisis: Emergency Therapy

• Hospitalize patient in intensive care unit
• Begin parenteral therapy to lower mean BP by 20% in the first hour (DBP should be reduced to 100–110 mm Hg)
• If patient stable, reduce BP further over the next 24 hr; oral therapy can be started, and parenteral therapy gradually discontinued
• Monitor patient for evidence of worsening cerebral, renal, or cardiac function
• Once the patient is stabilized, evaluate for causes of secondary HTN

Parenteral Therapy for Hypertensive Crisis

• Sodium nitroprusside
• General drug of choice
• Produces direct arteriolar and venous dilation
• Immediate onset and offset
• Side effects: metabolic acidosis, nausea, vomiting, agitation, psychosis, tremor (monitor thiocyanate levels)
• Dose: 0.25–10.0 μg/kg/min IV infusion
• Labetalol
• Combination alpha/beta blocker
• Onset 5–10 min, offset 3–6 hr
• Useful in most settings, especially postoperative state, hypertensive crisis of pregnancy
• Avoid in acute heart failure
• Take beta-blocker precautions
• Side effects: scalp tingling, vomiting, heart block, orthostatic hypotension
• Dose: repetitive IV boluses of 20–80 mg q. 10 min or constant infusion of 0.5–2.0 mg/min
• Glyceryl trinitrate
• Produces direct arteriolar and venous dilation
• Onset 5–10 min, offset 3–5 min
• Especially useful in acute coronary ischemia, congestive heart failure
• Tolerance with prolonged infusion
• Side effects: headache, flushing, nausea, methemoglobinemia
• Dose: 5–100 μg/min IV infusion
• Esmolol
• Cardioselective beta blocker
• Onset 1–2 min, offset 10–20 min
• Especially useful in postoperative state, aortic dissection, ischemic heart disease
• Take beta-blocker precautions
• Side effects: bradycardia, nausea
• Dose: 50–300 μg/kg/min IV
• Hydralazine
• Causes direct arteriolar vasodilation
• Onset 10–20 min, offset 3–8 hr
• Used primarily for hypertensive crisis of pregnancy
• Avoid in acute myocardial infarction, angina, aortic dissection
• Side effects: headache, flushing, nausea, vomiting, tachycardia, angina
• Dose: 10–20 mg IV bolus
• Enalapril
• ACE inhibitor
• Onset 15 min, offset 6 hr
• Especially useful in acute heart failure in postoperative state
• Lower doses in renal disease
• Side effects: precipitous decline in BP (high-renin states), acute renal failure (presence of renal vascular disease)
• Dose: 1.25–5 mg IV bolus, q. 6 hr
• Nicardipine
• DHP calcium antagonist
• Onset 5–10 min, offset 1–4 hr
• Especially useful in postoperative state
• Avoid in acute heart failure
• Side effects: headache, nausea, flushing, phlebitis
• Dose: 5–15 mg/hr IV infusion
• Clevidipine
• DHP calcium antagonist
• Onset 5–10 min, offset 10–15 min
• Useful in emergency department and postoperative state
• Side effects: tachycardia, atrial fibrillation, headache, nausea, hypotension, acute kidney injury
• Dose: 1–32 mg/hr IV infusion
• Fenoldopam
• Dopamine (DA1) agonist
• Onset 5 min, offset 30–60 min
• Especially useful in patients with impaired renal function
• Side effects: nausea, vomiting, headache, flushing
• Dose: 0.1–1.6 μg/kg/min IV infusion
• Phentolamine
• Alpha blocker
• Onset instantaneous, offset 3–10 min
• Drug of choice for pheochromocytoma crisis
• Side effects: flushing, tachycardia
• Dose: 5–15 mg IV bolus
• Trimethaphan
• Ganglionic blocker
• Onset 1–5 min, offset 10 min
• Tachyphylaxis common with prolonged infusion
• Side effects: urinary retention, paralytic ileus, dry mouth, blurred vision, orthostatic hypotension
• Dose: 0.5–15 mg/min IV infusion

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Best References

Chobanian AV, et al. Hypertension 2003;42:1206. [PMID 14656957]

European Society of Hypertension–European Society of Cardiology Guidelines Committee. J Hypertens 2003;21:1011. [PMID 12777938]

Mancia G, et al. J Hypertens 2009;27:212.