In this episode of Hospital Medicine Unplugged, we dive into evidence-based, hospital-focused management of resistant hypertension—a condition affecting up to 1 in 5 hypertensive adults and carrying ≥50% higher risk of MI, stroke, ESKD, and cardiovascular death. We start by drawing the line between true resistant hypertension (BP above goal despite 3 complementary agents including a diuretic, or controlled BP on ≥4 meds) and the look-alikes: refractory HTN (uncontrolled on ≥5 agents including an MRA) and malignant HTN (acute end-organ damage). In the hospital, we must separate chronic resistant HTN from acutely uncontrolled BP driven by pain, anxiety, missed meds, volume shifts, or acute illness. Our first task: rule out pseudoresistance. That means fixing measurement errors, restarting home meds, identifying nonadherence, assessing pain and volume status, and removing BP-raising drugs—NSAIDs, steroids, sympathomimetics, calcineurin inhibitors, erythropoietin, excess IV fluids, and more. We emphasize the ACC/AHA message: 20% of hypertensive adults regularly take interfering medications, and up to 41% of hospitalized patients miss home antihypertensives. Next, we confirm true resistance with out-of-office BP—home BP or, ideally, ABPM, since white-coat resistant HTN carries far lower long-term cardiovascular risk than true resistance. If the numbers hold, we move into systematic secondary evaluation: primary aldosteronism, OSA, renal parenchymal disease, renovascular disease, and medication-induced hypertension. Treatment opens with the guideline-backed triple therapy backbone:• ACE-I/ARB + long-acting CCB + thiazide-like diuretic (chlorthalidone/indapamide preferred).• Below eGFR 40–45: switch thiazides to loop diuretics, typically q12h dosing. Then we deploy the fourth-line star: spironolactone 25–50 mg, the most effective agent based on RCTs and network meta-analyses, cutting 24-hour SBP by ~7–9 mm Hg. But since 4–40% cannot tolerate spironolactone, we cover alternatives:• Amiloride (10–20 mg)—equally effective in trials• Eplerenone—better tolerated hormonally, less potent BP reduction• Consider finerenone in CKD with albuminuria (role in resistant HTN still emerging) For fifth-line therapy, we reserve beta-blockers, alpha-blockers, clonidine, and direct vasodilators—but hydralazine/minoxidil must be paired with a β-blocker + loop diuretic to blunt reflex tachycardia and fluid retention. We also break down renal denervation, which offers modest (~3–5 mm Hg) 24-hour SBP reduction but lacks long-term CVD outcome data. Aprocitentan, FDA-approved in 2025, adds another option, though edema (9–18%) limits use in volume-sensitive patients. CKD deserves its own playbook: resistant HTN is twice as common in CKD, thiazides lose power as GFR falls, and aldosterone excess plus sympathetic activation fuel volume-driven hypertension. We outline strategies including loop diuretics, cautious low-dose MRAs with potassium binders, and the evolving role of nonsteroidal MRAs. Throughout, we reinforce that intensive BP control matters. For resistant HTN, pooled SPRINT/ACCORD analyses show similar benefit from a systolic target <120 mm Hg—when tolerated—cutting major CV events and mortality. We close with a hospital-ready framework:• Fix pseudoresistance first—measurement, meds, volume, pain, interfering agents• Confirm with out-of-office BP• Screen systematically for secondary causes• Build the ACE/ARB + CCB + potent diuretic foundation• Add spironolactone, or amiloride/ eplerenone when needed• Use advanced agents and devices selectively• Individualize BP targets while avoiding overcorrection of asymptomatic inpatient BP spikes Volume control, aldosterone blockade, clean med lists, and accurate BP data—that’s how you turn apparent chaos into controlled, evidence-based management of resistant hypertension in the hospital.