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Harrison’s Manual of Medicine



Secondary Hypertension

DEFINITION   Chronic elevation in bp >140/90; etiology unknown in 90–95% of pts (“essential hypertension”). Always consider a secondary correctable form of hypertension, especially in pts under age 30 or those who become hypertensive after 55. Isolated systolic hypertension (systolic >160, diastolic <90) most common in elderly pts, due to reduced vascular compliance.
RENAL ARTERY STENOSIS   Due either to atherosclerosis (older men) or fibromuscular dysplasia (young women). Presents with sudden onset of hypertension, refractory to usual antihypertensive therapy. Abdominal bruit often audible; mild hypokalemia due to activation of the renin-angiotensin-aldosterone system may be present.
RENAL PARENCHYMAL DISEASE   Elevated serum creatinine and/or abnormal urinalysis, containing protein, cells, or casts.
COARCTATION OF AORTA   Presents in children or young adults; constriction is usually present in aorta at origin of left subclavian artery. Exam shows diminished, delayed femoral pulsations; late systolic murmur loudest over the midback. CXR shows indentation of the aorta at the level of the coarctation and rib notching (due to development of collateral arterial flow).
PHEOCHROMOCYTOMA   A catecholamine-secreting tumor, typically of the adrenal medulla, that presents as paroxysmal or sustained hypertension in young to middle-aged pts. Sudden episodes of headache, palpitations, and profuse diaphoresis are common. Associated findings include chronic weight loss, orthostatic hypotension, and impaired glucose tolerance. Pheochromocytomas may be localized to the bladder wall and may present with micturition- associated symptoms of catecholamine excess. Diagnosis is suggested by elevated urinary catecholamine metabolites in a 24-h urine collection (see below); the tumor is then localized by CT scan or angiography.
HYPERALDOSTERONISM   Due to aldosterone-secreting adenoma or bilateral adrenal hyperplasia. Should be suspected when hypokalemia is present in a hypertensive pt off diuretics (Chap. 172).
OTHER CAUSES   Oral contraceptive usage, Cushing’s and adrenogenital syndromes (Chap. 172), thyroid disease (Chap. 171), hyperparathyroidism (Chap. 176), and acromegaly (Chap. 169).

Approach to the Patient

Most pts are asymptomatic. Severe hypertension may lead to headache, epistaxis, or blurred vision.
Clues to Specific Forms of Secondary Hypertension   Use of birth control pills or glucocorticoids; paroxysms of headache, sweating, or tachycardia (pheochromocytoma); history of renal disease or abdominal traumas (renal hypertension).
Physical Examination
Measure bp with appropriate-sized cuff (large cuff for large arm). Measure bp in both arms as well as a leg (to evaluate for coarctation). Signs of hypertension include retinal arteriolar changes (narrowing/nicking); left ventricular lift, loud A2, S4. Clues to secondary forms of hypertension include cushingoid appearance, thyromegaly, abdominal bruit (renal artery stenosis), delayed femoral pulses (coarctation of aorta).
Laboratory Workup
Screening Tests for Secondary Hypertension   Should be carried out on all pts with documented hypertension: (1) serum creatinine, BUN, and urinalysis (renal parenchymal disease); (2) serum K measured off diuretics (hypokalemia prompts workup for hyperaldosteronism or renal artery stenosis); (3) CXR (rib notching or indentation of distal aortic arch in coarctation of the aorta); (4) ECG (LV hypertrophy suggests chronicity of hypertension); (5) other useful screening blood tests include CBC, glucose, cholesterol, triglycerides, calcium, uric acid.
Further Workup   Indicated for specific diagnoses if screening tests are abnormal or bp is refractory to antihypertensive therapy: (1) renal artery stenosis: magnetic resonance angiography, captopril renogram, renal duplex ultrasound, digital subtraction angiography, renal arteriography, and measurement of renal vein renin; (2) Cushing’s syndrome: dexamethasone suppression test (Chap. 172); (3) pheochromocytoma: 24-h urine collection for catecholamines, metanephrines, and vanillylmandelic acid; (4) primary hyperaldosteronism: depressed plasma renin activity and hypersecretion of aldosterone, both of which fail to change with volume expansion; (5) renal parenchymal disease (Chap. 137, Chap. 138, Chap. 139, Chap. 140, Chap. 141, Chap. 142, Chap. 143, Chap. 144, Chap. 145, Chap. 146 and Chap. 147).

Drug Therapy of Essential Hypertension
Goal is to control hypertension with minimal side effects using a single drug if possible. First-line agents include ACE inhibitors, calcium antagonists, beta blockers, diuretics, and a-adrenergic receptor blockers.
Beta Blockers (Table 124-1)   Particularly effective in young pts with “hyperkinetic” circulation. Begin with low dosage (e.g., atenolol 25 mg qd). Relative contraindications: bronchospasm, CHF, AV block, bradycardia, and “brittle” insulin-dependent diabetes.

Table 124-1 Beta Blockers

ACE Inhibitors (Table 124-2)   Well tolerated with low frequency of side effects. May be used as monotherapy or in combination with beta blockers, calcium antagonists, or diuretics. Side effects are uncommon and include rash, angioedema, proteinuria, or leukopenia, particularly in pts with elevated serum creatinine. A nonproductive cough may develop in the course of therapy, requiring an alternative regimen. Note that renal function may deteriorate as a result of ACE inhibitors in pts with bilateral renal artery stenosis.

Table 124-2 ACE Inhibitors

Potassium supplements and potassium-sparing diuretics should be used cautiously with ACE inhibitors to prevent hyperkalemia. If pt is intravascularly volume depleted, hold diuretics for 2–3 d prior to initiation of ACE inhibitor, which should then be administered at very low dosage (e.g., captopril 6.25 mg bid).
For pts who do not tolerate ACE inhibitors because of cough or angioedema, consider angiotensin receptor antagonists (Table 124-3) instead.

Table 124-3 Angiotensin II Receptor Antagonists

Calcium Antagonists (Table 124-4)   Direct arteriolar vasodilators; all have negative inotropic effects (particularly verapamil) and should be used cautiously if LV dysfunction is present. Verapamil, and to a lesser extent diltiazem, can result in bradycardia and AV block so combination with beta blockers is generally avoided. Use sustained-release formulations, as short- acting dihydropyridine calcium channel blockers may increase incidence of coronary events.

Table 124-4 Calcium Channel Antagonists

Diuretics (Table 17-1)   Thiazides preferred over loop diuretics because of longer duration of action; however, the latter are more potent when GFR < 25 mL/min. Major side effects include hypokalemia, hyperglycemia, and hyperuricemia, which can be minimized by using low dosage (e.g., hydrochlorothiazide 12.5–50 mg qd). Diuretics are particularly effective in elderly and black pts. Prevention of hypokalemia is especially important in pts on digitalis glycosides.
If bp proves refractory to drug therapy, work up for secondary forms of hypertension, especially renal artery stenosis and pheochromocytoma (see HPIM-15, Table 246-6, p. 1424) for detailed list of antihypertensives).
Special Circumstances
Pregnancy   Safest antihypertensives include methyldopa (250–1000 mg PO bid-tid) and hydralazine (10–150 mg PO bid-tid). Calcium channel blockers also appear to be safe in pregnancy. Beta blockers need to be used cautiously—fetal hypoglycemia and low birth weights have been reported. ACE inhibitors and angiotensin receptor antagonists are contraindicated in pregnancy.
Renal Failure   Standard thiazide diuretics may not be effective. Consider metolazone, furosemide, or bumetanide, alone or in combination.
Malignant Hypertension   Diastolic bp > 120 mmHg is a medical emergency. Immediate therapy is mandatory if there is evidence of cardiac decompensation (CHF, angina), encephalopathy (headache, seizures, visual disturbances), or deteriorating renal function. Drugs to treat hypertensive crisis are listed in Table 124-5. Replace with PO antihypertensive as pt becomes asymptomatic and diastolic bp improves.

Table 124-5 Treatment of Malignant Hypertension and Hypertensive Crisis


For a more detailed discussion, see Williams GH: Approach to the Patient with Hypertension, Chap. 35, p. 211, and Hypertensive Vascular Disease, Chap. 246, p. 1414, in HPIM-15.


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