Refractory hypertension (RfHTN) is

hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...

, a high

blood pressure Blood pressure (BP) is the pressure of Circulatory system, circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term ...

, that remains uncontrolled on maximal or near-maximal therapy, that includes the use of ≥5 antihypertensive agents of different classes. Agents used include a long-acting thiazide-like diuretic (such as chlorthalidone) and

spironolactone Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema, fluid build-up due to hepatic cirrhosis, liver disease or kidney disease. It is also used to reduce risk o ...

. Refractory hypertension is typically associated with increased sympathetic nervous system activity. The phenotype of refractory hypertension was first proposed in a retrospective analysis of patients referred to the University of Alabama at Birmingham Hypertension Clinic whose blood pressure could not be controlled on any antihypertensive regimen. Observational studies suggest that RfHTN is rare, affecting <5% of patients.

Apparent versus true

The term apparent refractory hypertension, as opposed to true refractory hypertension is used by investigators to refer to patients with resistant hypertension based on the number of prescribed medications, without accounting for common causes of pseudo-resistance, ie, inaccurate blood pressure measurements, nonadherence, undertreatment, or white-coat effects. These phenomena are well understood in resistant hypertension, but not in refractory hypertension. The white-coat effect is reportedly much more prevalent in RfHTN than in resistant hypertension, but the other causes of apparent resistant hypertension remain unstudied in refractory hypertension. Specifically, none of the studies of refractory hypertension has reported adherence based on measurement of drug or drug metabolite levels in serum or

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

Cause

Transthoracic impedance cardiography, combined with assessment of

arterial stiffness Arterial stiffness occurs as a consequence of biological aging, arteriosclerosis and genetic disorders, such as Marfan, Williams, and Ehlers-Danlos syndromes. Inflammation plays a major role in arteriosclerosis and arterial stiffness. Incre ...

, suggests that status angiotensus may not be secondary to persistent excess fluid retention, but instead is likely neurogenic in pathogenesis, and attributable to heightened sympathetic outflow.

Risk factors

Risk factors for RfHTN overlap with those for resistant hypertension including Black race,

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

, and

chronic kidney disease Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...

. However, patients with refractory hypertension tend to be younger and more often women than those with resistant hypertension.

Treatment

By definition, refractory hypertension cannot be effectively treated. RfHTN does not respond to

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...

calcium channel blocker Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...

ACE An ace is a playing card, die or domino with a single pip. In the standard French deck, an ace has a single suit symbol (a heart, diamond, spade, or a club) located in the middle of the card, sometimes large and decorated, especially in the ...

, or

renin Renin ( etymology and pronunciation), also known as an angiotensinogenase, is an aspartic protease protein and enzyme secreted by the kidneys that participates in the body's renin-angiotensin-aldosterone system (RAAS)—also known as the reni ...

inhibitors; endothelium receptor blockers;

Angiotensin II Angiotensin is a peptide hormone that causes vasoconstriction and an increase in blood pressure. It is part of the renin–angiotensin system, which regulates blood pressure. Angiotensin also stimulates the release of aldosterone from the ...

Adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

Aldosterone Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...

, or

Alpha-2 adrenergic receptor The alpha-2 (α2) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the Gi alpha subunit, Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-adrenergic, α2A-, ...

agonists; or

Vasodilators Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wal ...

Terminology

The term resistant hypertension has been used since the early 1960s to identify patients with difficult-to-treat hypertension. In 2008, the

American Heart Association The American Heart Association (AHA) is a nonprofit organization in the United States that funds cardiovascular medical research, educates consumers on healthy living and fosters appropriate Heart, cardiac care in an effort to reduce disability ...

defined resistant hypertension as blood pressure uncontrolled with 3 medications, but controlled with ≥4 medications. The lack of a similar codified definition of refractory hypertension has led to some discrepancy in terminology. Status angiotensus and refractory hypertensive state are usually used as synonyms for refractory hypertension and RfHTN, however sometimes they can describe a sudden acute hypertensive crisis arising from refractory hypertension.

References

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