It is estimated that in the United States, approximately 10% of persons with hypertension, have treatment resistant hypertension (10-12 million) defined as elevated blood pressure, despite concurrent use of at least three antihypertensive, drugs of different classes, including a diuretic.
Inappropriately elevated aldosterone production relative to patient sodium levels is a key driver of resistant hypertension, and hypertension mediated organ damage.
In many cases, resistant hypertension is a salt retaining, low rennin state, driven by inappropriate rennin independent aldosterone secretion.
Excess aldosterone drives sodium and water retention, along with fibrosis, inflammation, and vascular injury amplifying the risk beyond blood pressure elevation.
Mineralcorticoid receptor antagonist counter these effects but they use is constrained by hyperkalemia, reduced safety and efficacy in advanced kidney disease, and sex hormone related side effects.
Mineralcorticoid receptor antagonists also trigger a compensatory increase in aldosterone with downstream consequences.
Resistant hypertension is associated with heightened cardiovascular risk and increased healthcare use and expenditures.
Defined as the inability to control office blood pressure despite optimal therapy with at least 3 antihypertensive drugs at full dosages.
The definition of resistant hypertension is uncontrolled blood pressure despite the use of three different medication classes typically a calcium channel blocker, rein-angiotensin system inhibitor, and diuretic.
TRH may be attributable to volume overload, obstructive, sleep, apnea, and renovascular disease.
TRH may occur with hormonal dysregulation related hyperparathyroidism, thyroid disease, pheochromocytoma, paraganglioma, reninoma, undiagnosed, primary aldosteronism, and hypercortisolism.
Patients with treatment related resistant hypertension are often prescribed at least four anti-hypertensive agents with the goal of systolic blood pressures of less than 130 mmHg and diastolic blood pressures of 80 mmHg or less.
Treatment resistant hypertension is associated with high cardiovascular risk and renal adverse events.
The pathophysiology of resistant hypertension involves inappropriate and renin independent, aldosterone excess, sympathetic, endothelium – 1, and vasopressin over activity, impaired nattruretic peptide system activity, and impaired endothelial function.
These factors contribute to volume and sodium overload, increases in arterial stiffness, and kidney fibrosis.
Excess dietary sodium intake causes low plasma renin activity and promotes volume overload, which diminishes the effectiveness of renin-angiotension system blockers and increases the requirement for diuretics at higher doses or in combination to achieve adequate natriuresis.
Low potassium dietary intake may also contribute to elevated blood pressure by increasing sodium retention by the kidneys and increase vascular tone.
Obstructive sleep apnea may independently increase blood pressure through sympathetic overdrive, renin-angiotensin, aldosterone system activation, and the fuel dysfunction possible fluid retention.
Current guidelines, recommend the addition of spironolactone, a mineralocorticoid receptor antagonist as a fourth line agent.
It is suggested that treatment resistant hypertension is associated with autonomous aldosterone production.
Many patients with TRH have salt sensitive hypertension, in which increase sodium intake results in increase blood pressure through sodium and water retention.
This process occurs due to the activation of the sympathetic nervous system impairing the suppression of the renin-angiotensin-aldosterone system with consequent increase in aldosterone levels.
Increased aldosterone increases sodium reabsorption and passive water absorption across the distal tubule of the nephron contributing to hypertension.
Mineralcorticoid receptor antagonists can block the mineralcorticoid receptor mediated pathophysiological effects of aldosterone, but are underused because of dose dependent adverse effects.
Mineralcorticoid receptor antagonists induce dose related counter regulatory increases in renin and circulating aldosterone levels that may stimulate mineralcorticoid receptor independent effects of aldosterone.
Spironolactone is effective in treating treatment resistant hypertension,and is the first line agent for resistant hypertension, being the fourth anti-hypertensive medication.
Amiloride is also considered a first line agent for treating treatment resistant hypertension.
Among adults with hypertension, bedtime administration of anti-hypertensive medications did not reduce cardiovascular risk compared to taking medication in the morning:Administration time does not affect the risks and benefits of blood pressure lowering medication and should be guided by patient preferences.
The addition of a single subcutaneous dose of zilebesiran added to indapamide, amlopidine, or olmesartan therapy showed significant additional reductions in 24 hour mean ambulatory and office systolic pressure at three months.
Surgical sympathectomy was an effective treatment for some patients, but profound orthostatic hypotension has made the procedure obsolete.
Patients with treatment resistant hypertension should be evaluated for poor adherence to lifestyle in antihypertensive medications, and for the use of drugs that interfere with antihypertensive drug effectiveness, such as nonsteroidal anti-inflammatory agents, oral contraceptives, hormone therapy, or glucocorticoids.
Patients with resistant hypertension should be screened for secondary hypertension and assess target organ damage.
Baxtrostat directly inhibits aldosterone synthase which catalyzes the final three steps in aldosterone biosynthesis.
Baxtrostat is a highly selected, potent aldosterone synthase inhibitor with a plasma half life of approximately 30 hours, allowing for once daily administration and has shown treatment of uncontrolled resistant hypertension in addition to background therapy results and significantly lower systolic blood pressures at 12 weeks and than placebo.
Lorundrostat an aldosterone synthesis inhibitor significantly reduces blood pressure in patients with resistant hypertension.