The most common causes of secondary hypertension are primary aldosteronism and

renal artery stenosis, chronic kidney disease, and obstructive sleep apnea

clinical clues : Otherwise unexplained hypokalemia is the major clue to the presence of
primary hyperaldosteronism. However, more than 50 percent of patients with proven
primary hyperaldosteronism are normokalemic at presentation. Chronic kidney
disease Diuretics should be pushed until the blood pressure goal is reached or the
patient has attained "dry weight," which, in the presence of persistent hypertension, is
defined as the weight at which further fluid loss leads to either symptoms (fatigue,
orthostatic hypotension) or decreased tissue perfusion as evidenced by an otherwise
unexplained elevation in the blood urea nitrogen and/or serum creatinine concentration.

Laboratory evaluation serum electrolytes, glucose, and creatinine as well as a

urinalysis with estimation of proteinuria (eg, urine albumin-to-creatinine
ratio).Screening for primary aldosteronism with a paired morning measurement of the
plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to determine
whether the patient has an elevated or high-normal PAC, suppressed PRA, and elevated
PAC/PRA ratio.

a 24-hour urine collection should be obtained on the patient's usual diet for
determination of sodium excretion, creatinine clearance, and aldosterone excretion.
Urinary sodium excretion permits estimation of dietary sodium intake unless the patient
has been recently (within the past two weeks) started on a diuretic or there has been a
recent dose increase.

Patients with resistant hypertension should be evaluated for pheochromocytoma

The pharmacologic treatment of resistant hypertension, by definition, involves

combinations of three or more drugs, including a diuretic. Persistent volume expansion
(typically not sufficient to produce edema) contributes to resistant hypertension, even
among patients who have been on conventional doses of thiazide diuretics. Diuretics
should be titrated until the blood pressure goal or the maximum recommended dose has
been reached or the patient has signs suggestive of overdiuresis such as fatigue,
orthostatic hypotension, or decreased tissue perfusion In patients with little renal
impairment, chlorthalidone and indapamide are preferred over hydrochlorothiazide for
the treatment of resistant hypertension Chlorthalidone and indapamide have a more
potent antihypertensive effect than HCTZ. Begin chlorthalidone at 12.5 mg daily with
subsequent titration up to 25 mg daily or, rarely, higher. Among patients with an
estimated glomerular filtration rate of less than 30 mL/min per 1.73 m2, thiazide
diuretics are less effective, and loop diuretics, such as furosemide, torsemide, or
bumetanide, may be necessary for effective volume control. At a given diuretic dose in
stable hypertensive patients, urinary sodium and potassium loss only occur in the first
10 to 14 days of therapy. Thereafter, the patient is in a steady state, in which the
extracellular fluid volume is reduced but stable, and the serum potassium is stable at a
level that is usually lower than baseline

Spironolactone, eplerenone, and amiloride provide significant antihypertensive benefit

when added to existing multiple-drug regimens in patients with resistant hypertension.
This effect may reflect, at least in part, significantly higher plasma aldosterone levels in
patients with resistant hypertension compared with individuals who have normal blood
pressure or controlled hypertension on one or two medications. However,
spironolactone, which has been most widely studied, can also lower the blood pressure
in patients with resistant hypertension who have normal plasma and urine aldosterone

CHOICE OF REGIMEN
 sequentially combine agents with different mechanisms of action. The triple
combination of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin
receptor blocker (ARB), a long-acting dihydropyridine calcium channel blocker (usually
amlodipine), and a long-acting thiazide diuretic (preferably chlorthalidone or
indapamide) is often effective and generally well tolerated. Among patients with
uncontrolled hypertension who are already being treated with such a three-drug regimen
at maximum recommended and tolerated doses, we add spironolactone. begin
spironolactone at 12.5 mg/day before titrating to 25 and, if necessary, 50 mg/day. The
risk of adverse effects such as gynecomastia, breast tenderness, and erectile dysfunction
increases with higher doses. We generally do not increase the spironolactone dose
above 50 mg daily in the absence of proven primary aldosteronism. The more specific
aldosterone blocker, eplerenone, is now generic and does not induce the side effects
seen with spironolactone

If the patient is still hypertensive, additional medications are added sequentially.

Possible agents that may be used include vasodilating beta blockers (labetalol,
carvedilol, bisoprolol, or nebivolol), centrally acting agents (clonidine or guanfacine),
and direct vasodilators (hydralazine or minoxidil). If beta blockers are used, a
vasodilating beta blocker, such as labetalol, carvedilol or nebivolol, may provide more
antihypertensive benefit with fewer side effects compared to traditional beta blockers,
particularly when high doses are used . Centrally acting agents may be effective, but
adverse effects are common. Direct vasodilators hydralazine or minoxidil are reserved
for patients who remain hypertensive despite the above approach. Fluid retention and
tachycardia are common side effects. Minoxidil also causes hirsutism, which may be a
particular problem in women that may require switching to hydralazine.

EXPERIMENTAL THERAPIES Catheter-based radiofrequency ablation of renal

sympathetic nerves The utility of catheter-based radiofrequency ablation of renal
sympathetic nerves (also known as renal denervation) has not been established in
patients with resistant hypertension.

Electrical stimulation of carotid sinus baroreceptors Electrical stimulation of the

carotid sinus baroreflex system, or baroreflex activation therapy (BAT), may decrease
blood pressure in patients with resistant hypertension.

Patients with resistant hypertension are more likely to have target-organ damage and
are at greater risk of stroke, myocardial infarction, heart failure, and/or chronic kidney
disease compared with patients who have more easily controlled hypertension. The high
cardiovascular risk is attributable in part to long-standing, poorly controlled
hypertension [57] and to the coexistence of other cardiovascular risk factors, including
left ventricular hypertrophy, obesity, diabetes, hyperlipidemia, chronic kidney disease,
and obstructive sleep apnea.