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.
Resistant hypertension is defined as systolic blood pressure 130 mmHg or greater and/or diastolic blood pressure 80 greater despite the use of three or more antihypertensive medications of different classes at maximal tolerated doses.
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 renin state, driven by inappropriate renin 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.
The definition of resistant hypertension is uncontrolled blood pressure despite the use of three different medication classes typically a calcium channel blocker, renin-angiotensin system inhibitor, and diuretic.
TRH may be attributable to volume overload, obstructive sleep, apnea, renovascular disease, inappropriate and renin-independent aldosterone excess without over primary aldosteronism, obesity, and chronic kidney disease diseases are common among patients with resistant hypertension.
Non-steroidal anti-inflammatory drugs, some antidepressants, and illicit drugs are associated with poor blood pressure control.
Medications and substances increasing blood pressure:
Drugs or substances associated with mineralcorticoid excess or renin angiotensin system activation include: glucocorticoids, glycyrrhizin (licorice), ketoconazole, itraconazole, abiraterone acetate, synthetic estrogens combined with progesterone.
Drugs or substances with direct vasopressor properties include immunosuppressive agents – cyclosporine, tacrolimus, and calcineurin inhibitors, EPO, drugs targeting vascular endothelia growth, factor, including monoclonal antibodies, and tyrosine kinase inhibitors, and PARP inhibitors.
Drugs with substances activating the sympathetic nervous system, including illicit drugs of abuse, such as cocaine and amphetamines, epinephrine, or phenylephrine, ephedrine, antidepressants, appetite suppressants and modafinal.
Drugs substances with various mechanisms of action include antiretroviral drugs, non-steroidal anti-inflammatory drugs, Briton kinase inhibitors, teraflunomide, and alcohol.
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.
Management of resistant hypertension includes lifestyle modifications with adherence to a low sodium diet, reducing or avoiding alcohol, moderate intensity exercise of 150 minutes per week or greater of regular, moderate intensity aerobic exercise, and greater than two days a week of resistance exercise, and weight loss.
The use of combinations of pills, intensifying diuretic therapy by using preferably chlorthalidone, the addition of a mineral corticoid receptor antagonists are recommended along with other therapeutic options of beta blockers, Alpha1 adrenergic blockers, cetrally acting antihypertensive agents, non-dihydropyridine calcium channel blockers, direct vasodilators, or dual endothelin receptor antagonists
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.