RARE DISEASE
Primary orthostatic hypotension
Primary orthostatic hypotension
Primary orthostatic hypotension
Drug discovery
1
drug
With orphan designation
Overview
Primary orthostatic hypotension (OH) is a sustained blood pressure drop (≥20 mmHg systolic or ≥10 mmHg diastolic within 3 minutes of standing) caused by autonomic nervous system dysfunction. Symptoms include lightheadedness, syncope, and cognitive impairment, often linked to neurodegenerative disorders like Parkinson’s disease. Management prioritizes non-pharmacological interventions, with pharmacological options reserved for persistent symptoms [1][3][16].
Therapies
First-line: Discontinue offending medications (e.g., antihypertensives), increase fluid/salt intake, and apply physical maneuvers (leg crossing, abdominal binders) [3][8][18].
Pharmacotherapy: Midodrine (α₁-agonist) and droxidopa (norepinephrine precursor) are preferred; fludrocortisone (mineralocorticoid) or atomoxetine (norepinephrine reuptake inhibitor) for refractory cases [6][13][17].
Categories: rare neurological diseases
Research Papers
83 drug discovery papers about Primary orthostatic hypotension, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
83 drug discovery papers about Primary orthostatic hypotension, with 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-17 | SalT supplementation in Older adults with Orthostatic intolerance Disorders (STOOD) trial: a study protocol for a feasibility randomised controlled trial.
Orthostatic hypotension (OH) is a common cause of falls, and key source of morbidity and mortality due to injury (e.g. hip fracture). Current guidelines recommend increasing salt intake in patients with symptomatic orthostatic hypotension. However, the evidence underpinning this recommendation is poor, based primarily on small trials with very short-term follow-up (<8 weeks). High salt intake might improve quality of life and reduce the risk of falls, but might also increase the long-term risk of cardiovascular disease, in patients with OH. STOOD is a two-group, parallel, open-label, randomised controlled, single centre trial. Adults aged ≥65 years with symptomatic orthostatic hypotension, and estimated moderate salt intake (based on screening questions) will be eligible. Exclusion criteria include uncontrolled hypertension (>180/110 mmHg), heart failure (NYHA class III/IV, or ejection fraction < 30%), loop diuretic use, chronic kidney disease (eGFR < 30 ml/min/1.73m2), hyponatraemia (serum sodium < 125 mmol), evidence based clinician recommendation of high or low salt diet, and inability to provide informed consent. Participants will be randomised to receive salt supplementation of 5 g encapsulated sodium chloride per day (in addition to usual care) or usual care alone. The primary feasibility outcome will be recruitment and retention of the target sample size of 48 participants. The primary efficacy outcome is change in orthostatic hypotension questionnaire score from baseline to 6-month follow-up. A recommendation for long-term higher salt intake may have adverse cardiovascular consequences, which necessitates robust evidence of efficacy and identification of the optimal range of salt intake associated with the greatest reduction in falls risk and lowest cardiovascular risk. Our study will establish the feasibility and acceptability of evaluating the intervention (salt supplementation) in a single centre, and provide preliminary evidence of treatment effect of salt supplementation for management of orthostatic hypotension. ClinicalTrials.gov Identifier: NCT06188663. Registered on 17th December 2023.
2026-06-15 | Effect of midodrine on orthostatic intolerance after hip and knee arthroplasty: A randomized controlled trial (the MObILE study).
Orthostatic intolerance (OI), characterized by dizziness and nausea during postural change, is common after hip and knee arthroplasty and can delay mobilization and discharge. Midodrine, an oral alpha-1 agonist, may reduce OI by improving vascular tone, but evidence in this setting is limited. A double-blind, randomized, placebo-controlled trial was performed in adults undergoing primary unilateral total hip or knee arthroplasty. Patients received oral midodrine hydrochloride 10 mg or placebo (four to five doses over 24-30 h). Mobilization included a standardized orthostatic challenge on postoperative days 0 and 1 with continuous beat-to-beat blood pressure monitoring. The primary outcome was OI during first mobilization on day 0. Secondary outcomes included OI on day 1, orthostatic hypotension, safety, hemodynamic responses, and length of stay. 170 patients were randomized; 159 were included in the modified intention-to-treat analysis. On day 0, OI occurred in 18% of patients receiving midodrine versus 33% receiving placebo (adjusted relative risk 0.56; p = 0.038). On day 1, OI occurred in 6% versus 15%, respectively (unadjusted relative risk 0.41; p = 0.064). Syncope occurred only in the placebo group (8%). Midodrine increased supine systolic and diastolic blood pressure at first mobilization and reduced symptom-defined OI, while the incidence of orthostatic hypotension defined by blood pressure thresholds did not differ between groups. Median length of stay was 2 days with midodrine versus 3 days with placebo. Adverse events were similar. Regular postoperative administration of midodrine 10 mg is well tolerated and reduces clinically relevant OI during early mobilization following hip and knee arthroplasty, potentially supporting safer and earlier recovery.
2026-04-08 | Efficacy and Safety of Intensive Blood Pressure Lowering on Cardiovascular Outcomes and Orthostatic Hypotension in Frail vs. Non-Frail Elderly Patients: A Systematic Review and Meta-Analysis
Background: The management of hypertension in the older adult population presents a complex clinical challenge, particularly regarding the balance between cardiovascular risk reduction and the provocation of adverse events such as orthostatic hypotension. Frailty status complicates this dynamic, creating uncertainty regarding the optimal blood pressure target. Methods: A systematic review and meta-analysis investigated the efficacy and safety of intensive versus standard blood pressure lowering in frail compared to non-frail older adults. Databases were systematically searched for randomized controlled trials and their secondary analyses reporting cardiovascular outcomes and orthostatic hypotension stratified by frailty. Data were extracted and synthesized using a random-effects model, calculating pooled risk ratios and standardized mean differences to assess primary cardiovascular events and safety outcomes. Results: Ten primary studies met the inclusion criteria. Intensive blood pressure lowering significantly reduced the incidence of major cardiovascular events in both non-frail and frail cohorts. Surprisingly, intensive treatment did not increase the risk of orthostatic hypotension in frail patients and was associated with a protective effect against orthostatic hypotension in specific subsets. The risk of bias was generally low across the included trials. Conclusion: Intensive blood pressure control provides substantial cardiovascular benefits for older adults, irrespective of baseline frailty status. Furthermore, the aggressive lowering of blood pressure does not exacerbate the risk of orthostatic hypotension, challenging previous clinical hesitations. These findings support the cautious but deliberate implementation of intensive targets in the geriatric population, monitored closely by comprehensive geriatric assessments.
2026-01-01 | Impact of COVID‑19 infection on subsequent prescriptions of autonomic dysfunction pharmacotherapy: a nationwide propensity‑score‑matched Cohort study in Japan
Autonomic dysfunction, including orthostatic hypotension and postural tachycardia syndrome, has emerged as a COVID-19 complication. This nationwide propensity score-matched cohort study investigated COVID-19’s impact on subsequent prescriptions of autonomic dysfunction in Japan. Using a claims database covering 16 million residents identified between 2020 and 2022, propensity-score matching (PSM) created comparable groups of COVID-19 patients and controls. PSM used age, sex, calendar month, comorbidities, and baseline medications, with nearest-neighbor 1:1 with replacement. The primary composite outcome was the first outpatient prescription of midodrine, fludrocortisone, amezinium methylsulfate, and droxidopa. Cox proportional hazards models yielded hazard ratios (HRs) with 95% confidence intervals (CIs). Effect modifications were examined by subgroups. Among 3,074,329 matched pairs, over a median follow-up of 8 months, 13011 composite outcome were observed, and COVID-19 infection was associated with a 36% relative increase in prescriptions (HR 1.36, 95%CI 1.32–1.41). The risk persisted beyond one year, with the strongest association observed for fludrocortisone (576 events, HR 1.71, 95%CI 1.44–2.02), although the frequency was the highest in midodrine prescription (7009 events, HR 1.28, 95%CI 1.22–1.34). Subgroup analysis revealed higher risks among older individuals, males, those with myocardial infarction, heart failure, and antihypertensive medications. COVID-19 infection is significantly associated with increased initiation of pharmacotherapy for autonomic dysfunction, with sustained risk beyond one year. These findings highlight the to manage autonomic dysfunction among COVID-19 survivors and informing clinical care and public health planning.
2025-12-22 | Droxidopa in Critical Care: A Systematic Review of an Emerging Off-Label Practice.
Prolonged use of intravenous (IV) vasopressors in critically ill patients is associated with significant complications. Droxidopa, a norepinephrine precursor approved for neurogenic orthostatic hypotension, has gained interest as an off-label agent for facilitating vasopressor weaning in ICU settings. This systematic review aimed to evaluate the efficacy and safety of droxidopa for vasopressor weaning in ICU patients. A systematic review was conducted following PRISMA guidelines. Databases searched included PubMed, Embase, Cochrane, and Web of Science through April 2025. Eligible studies reporting primary clinical data on droxidopa use in ICU patients were included. Outcomes included time to IV vasopressor discontinuation, duration of droxidopa use, ICU length of stay (LOS), and ICU mortality, and results were narratively synthesized. The risk of bias was assessed using the ROBINS-I and the JBI checklists. Seven studies involving 161 ICU patients were included. Five studies reported time to vasopressor discontinuation, ranging from 29 to 120 h. The duration of droxidopa use ranged from 87 to 192 h. Two studies reported ICU LOS, ranging from 18 to 44 days. ICU mortality was inconsistently reported. These findings are primarily drawn from small, retrospective studies and should be interpreted cautiously. Findings suggest that droxidopa may effectively facilitate vasopressor weaning in critically ill patients. However, variations in dosing, patient selection, and outcome reporting limit generalizability. Evidence is drawn primarily from small, retrospective studies, some available only as abstracts. Available evidence on droxidopa for vasopressor weaning in ICU patients remains limited and heterogeneous, with very low certainty. Further research is warranted. No funding was received for this review, and the review was not prospectively registered.
small molecules
2026-07-17 | SalT supplementation in Older adults with Orthostatic intolerance Disorders (STOOD) trial: a study protocol for a feasibility randomised controlled trial.
Orthostatic hypotension (OH) is a common cause of falls, and key source of morbidity and mortality due to injury (e.g. hip fracture). Current guidelines recommend increasing salt intake in patients with symptomatic orthostatic hypotension. However, the evidence underpinning this recommendation is poor, based primarily on small trials with very short-term follow-up (<8 weeks). High salt intake might improve quality of life and reduce the risk of falls, but might also increase the long-term risk of cardiovascular disease, in patients with OH. STOOD is a two-group, parallel, open-label, randomised controlled, single centre trial. Adults aged ≥65 years with symptomatic orthostatic hypotension, and estimated moderate salt intake (based on screening questions) will be eligible. Exclusion criteria include uncontrolled hypertension (>180/110 mmHg), heart failure (NYHA class III/IV, or ejection fraction < 30%), loop diuretic use, chronic kidney disease (eGFR < 30 ml/min/1.73m2), hyponatraemia (serum sodium < 125 mmol), evidence based clinician recommendation of high or low salt diet, and inability to provide informed consent. Participants will be randomised to receive salt supplementation of 5 g encapsulated sodium chloride per day (in addition to usual care) or usual care alone. The primary feasibility outcome will be recruitment and retention of the target sample size of 48 participants. The primary efficacy outcome is change in orthostatic hypotension questionnaire score from baseline to 6-month follow-up. A recommendation for long-term higher salt intake may have adverse cardiovascular consequences, which necessitates robust evidence of efficacy and identification of the optimal range of salt intake associated with the greatest reduction in falls risk and lowest cardiovascular risk. Our study will establish the feasibility and acceptability of evaluating the intervention (salt supplementation) in a single centre, and provide preliminary evidence of treatment effect of salt supplementation for management of orthostatic hypotension. ClinicalTrials.gov Identifier: NCT06188663. Registered on 17th December 2023.
2026-06-15 | Effect of midodrine on orthostatic intolerance after hip and knee arthroplasty: A randomized controlled trial (the MObILE study).
Orthostatic intolerance (OI), characterized by dizziness and nausea during postural change, is common after hip and knee arthroplasty and can delay mobilization and discharge. Midodrine, an oral alpha-1 agonist, may reduce OI by improving vascular tone, but evidence in this setting is limited. A double-blind, randomized, placebo-controlled trial was performed in adults undergoing primary unilateral total hip or knee arthroplasty. Patients received oral midodrine hydrochloride 10 mg or placebo (four to five doses over 24-30 h). Mobilization included a standardized orthostatic challenge on postoperative days 0 and 1 with continuous beat-to-beat blood pressure monitoring. The primary outcome was OI during first mobilization on day 0. Secondary outcomes included OI on day 1, orthostatic hypotension, safety, hemodynamic responses, and length of stay. 170 patients were randomized; 159 were included in the modified intention-to-treat analysis. On day 0, OI occurred in 18% of patients receiving midodrine versus 33% receiving placebo (adjusted relative risk 0.56; p = 0.038). On day 1, OI occurred in 6% versus 15%, respectively (unadjusted relative risk 0.41; p = 0.064). Syncope occurred only in the placebo group (8%). Midodrine increased supine systolic and diastolic blood pressure at first mobilization and reduced symptom-defined OI, while the incidence of orthostatic hypotension defined by blood pressure thresholds did not differ between groups. Median length of stay was 2 days with midodrine versus 3 days with placebo. Adverse events were similar. Regular postoperative administration of midodrine 10 mg is well tolerated and reduces clinically relevant OI during early mobilization following hip and knee arthroplasty, potentially supporting safer and earlier recovery.
2026-04-08 | Efficacy and Safety of Intensive Blood Pressure Lowering on Cardiovascular Outcomes and Orthostatic Hypotension in Frail vs. Non-Frail Elderly Patients: A Systematic Review and Meta-Analysis
Background: The management of hypertension in the older adult population presents a complex clinical challenge, particularly regarding the balance between cardiovascular risk reduction and the provocation of adverse events such as orthostatic hypotension. Frailty status complicates this dynamic, creating uncertainty regarding the optimal blood pressure target. Methods: A systematic review and meta-analysis investigated the efficacy and safety of intensive versus standard blood pressure lowering in frail compared to non-frail older adults. Databases were systematically searched for randomized controlled trials and their secondary analyses reporting cardiovascular outcomes and orthostatic hypotension stratified by frailty. Data were extracted and synthesized using a random-effects model, calculating pooled risk ratios and standardized mean differences to assess primary cardiovascular events and safety outcomes. Results: Ten primary studies met the inclusion criteria. Intensive blood pressure lowering significantly reduced the incidence of major cardiovascular events in both non-frail and frail cohorts. Surprisingly, intensive treatment did not increase the risk of orthostatic hypotension in frail patients and was associated with a protective effect against orthostatic hypotension in specific subsets. The risk of bias was generally low across the included trials. Conclusion: Intensive blood pressure control provides substantial cardiovascular benefits for older adults, irrespective of baseline frailty status. Furthermore, the aggressive lowering of blood pressure does not exacerbate the risk of orthostatic hypotension, challenging previous clinical hesitations. These findings support the cautious but deliberate implementation of intensive targets in the geriatric population, monitored closely by comprehensive geriatric assessments.
2026-01-01 | Impact of COVID‑19 infection on subsequent prescriptions of autonomic dysfunction pharmacotherapy: a nationwide propensity‑score‑matched Cohort study in Japan
Autonomic dysfunction, including orthostatic hypotension and postural tachycardia syndrome, has emerged as a COVID-19 complication. This nationwide propensity score-matched cohort study investigated COVID-19’s impact on subsequent prescriptions of autonomic dysfunction in Japan. Using a claims database covering 16 million residents identified between 2020 and 2022, propensity-score matching (PSM) created comparable groups of COVID-19 patients and controls. PSM used age, sex, calendar month, comorbidities, and baseline medications, with nearest-neighbor 1:1 with replacement. The primary composite outcome was the first outpatient prescription of midodrine, fludrocortisone, amezinium methylsulfate, and droxidopa. Cox proportional hazards models yielded hazard ratios (HRs) with 95% confidence intervals (CIs). Effect modifications were examined by subgroups. Among 3,074,329 matched pairs, over a median follow-up of 8 months, 13011 composite outcome were observed, and COVID-19 infection was associated with a 36% relative increase in prescriptions (HR 1.36, 95%CI 1.32–1.41). The risk persisted beyond one year, with the strongest association observed for fludrocortisone (576 events, HR 1.71, 95%CI 1.44–2.02), although the frequency was the highest in midodrine prescription (7009 events, HR 1.28, 95%CI 1.22–1.34). Subgroup analysis revealed higher risks among older individuals, males, those with myocardial infarction, heart failure, and antihypertensive medications. COVID-19 infection is significantly associated with increased initiation of pharmacotherapy for autonomic dysfunction, with sustained risk beyond one year. These findings highlight the to manage autonomic dysfunction among COVID-19 survivors and informing clinical care and public health planning.
2025-12-22 | Droxidopa in Critical Care: A Systematic Review of an Emerging Off-Label Practice.
Prolonged use of intravenous (IV) vasopressors in critically ill patients is associated with significant complications. Droxidopa, a norepinephrine precursor approved for neurogenic orthostatic hypotension, has gained interest as an off-label agent for facilitating vasopressor weaning in ICU settings. This systematic review aimed to evaluate the efficacy and safety of droxidopa for vasopressor weaning in ICU patients. A systematic review was conducted following PRISMA guidelines. Databases searched included PubMed, Embase, Cochrane, and Web of Science through April 2025. Eligible studies reporting primary clinical data on droxidopa use in ICU patients were included. Outcomes included time to IV vasopressor discontinuation, duration of droxidopa use, ICU length of stay (LOS), and ICU mortality, and results were narratively synthesized. The risk of bias was assessed using the ROBINS-I and the JBI checklists. Seven studies involving 161 ICU patients were included. Five studies reported time to vasopressor discontinuation, ranging from 29 to 120 h. The duration of droxidopa use ranged from 87 to 192 h. Two studies reported ICU LOS, ranging from 18 to 44 days. ICU mortality was inconsistently reported. These findings are primarily drawn from small, retrospective studies and should be interpreted cautiously. Findings suggest that droxidopa may effectively facilitate vasopressor weaning in critically ill patients. However, variations in dosing, patient selection, and outcome reporting limit generalizability. Evidence is drawn primarily from small, retrospective studies, some available only as abstracts. Available evidence on droxidopa for vasopressor weaning in ICU patients remains limited and heterogeneous, with very low certainty. Further research is warranted. No funding was received for this review, and the review was not prospectively registered.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
1 orphan drug designation for Primary orthostatic hypotension, including 1 approved therapy.
1 orphan drug designation for Primary orthostatic hypotension, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Midodrine HCl [Amatine] | small molecules | FDA | Approved | Takeda Development Center Americas, Inc. |
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