What is the appropriate treatment approach for orthostatic hypotension?

Treatment of Orthostatic Hypotension

Begin with non-pharmacological interventions and medication review; if symptoms persist despite these measures, initiate midodrine as first-line pharmacological therapy, with fludrocortisone as an alternative or add-on agent for refractory cases. 1

Initial Evaluation and Reversible Causes

• Confirm the diagnosis by measuring blood pressure after 5 minutes of lying or sitting, then at 1 and 3 minutes after standing; orthostatic hypotension is defined as a drop of ≥20 mmHg systolic or ≥10 mmHg diastolic 1, 2
• Immediately discontinue or switch offending medications rather than simply reducing doses, as drug-induced autonomic failure is the most frequent cause of orthostatic hypotension 1
• High-priority medications to discontinue include:
  • Alpha-1 blockers (doxazosin, prazosin, terazosin, tamsulosin) 1, 3
  • Diuretics causing volume depletion 1, 3
  • Centrally-acting antihypertensives (clonidine, methyldopa) 1, 3
  • Vasodilators (hydralazine, minoxidil) 1, 3
  • Psychotropic medications 1
• Assess for volume depletion, blood loss, or dehydration as reversible contributors 1, 4

Non-Pharmacological Management (First-Line for All Patients)

• Increase fluid intake to 2-3 liters daily unless contraindicated by heart failure 1, 2
• Increase salt consumption to 6-9 grams daily if not contraindicated 1, 2
• Teach physical counter-maneuvers including leg crossing, squatting, stooping, and muscle tensing during symptomatic episodes—particularly effective in patients under 60 years with prodromal symptoms 1, 2
• Use compression garments: waist-high compression stockings (30-40 mmHg) and abdominal binders to reduce venous pooling 1
• Elevate the head of the bed by 10 degrees during sleep to prevent nocturnal polyuria, maintain favorable fluid distribution, and ameliorate nocturnal hypertension 1
• Recommend smaller, more frequent meals to reduce post-prandial hypotension 1
• Encourage physical activity and exercise to avoid deconditioning, which worsens orthostatic intolerance 1
• Advise acute water ingestion of ≥480 mL for temporary relief, with peak effect occurring 30 minutes after consumption 1
• Teach gradual staged movements with postural changes, avoiding rapid standing 1, 2

Pharmacological Management (When Non-Pharmacological Measures Fail)

First-Line Agent: Midodrine

Midodrine has the strongest evidence base among pressor agents, with three randomized placebo-controlled trials demonstrating efficacy and FDA approval for symptomatic orthostatic hypotension. 1, 5

• Dosing: Start at 2.5-5 mg three times daily, with the first dose taken before arising 1, 2
• Timing: The last dose must be taken at least 3-4 hours before bedtime (not after 6 PM) to prevent supine hypertension during sleep 1, 2
• Mechanism: Alpha-1 adrenergic agonist that increases standing systolic BP by 15-30 mmHg for 2-3 hours through arteriolar and venous constriction 1
• Titration: Can be individually tailored up to 10 mg two to four times daily based on response 1
• Hepatic impairment: Initiate at the lower end of the dosing range (2.5 mg three times daily) in patients with liver disease 1

Alternative First-Line Agent: Fludrocortisone

• Dosing: Start at 0.05-0.1 mg once daily, titrate to 0.1-0.3 mg daily based on individual response 1, 2
• Mechanism: Mineralocorticoid that acts through sodium retention and vessel wall effects, increasing plasma volume 1
• Monitoring requirements:
  • Check for supine hypertension (most important limiting factor) 1
  • Monitor electrolytes periodically for hypokalemia due to mineralocorticoid effects 1
  • Watch for congestive heart failure and peripheral edema 1
• Contraindications: Active heart failure, significant cardiac dysfunction, severe renal disease where sodium retention would be harmful, and pre-existing supine hypertension 1

Combination Therapy for Inadequate Response

For patients who do not achieve adequate symptom control with monotherapy, combine midodrine with fludrocortisone, as they act via complementary mechanisms (vascular constriction plus sodium retention). 1

• Start midodrine first, then add fludrocortisone if insufficient response 1
• Monitor closely for supine hypertension, hypokalemia, heart failure, and peripheral edema 1

Additional Pharmacological Options

Droxidopa:

• FDA-approved for neurogenic orthostatic hypotension, particularly effective in Parkinson's disease, pure autonomic failure, and multiple system atrophy 1
• May reduce falls in these populations 1

Pyridostigmine:

• Beneficial for refractory orthostatic hypotension in elderly patients who have not responded to other treatments 1
• Preferred when supine hypertension is a concern because it does not worsen supine BP 1
• Dosing: 60 mg orally three times daily, maximum 600 mg daily 1
• Mechanism: Acetylcholinesterase inhibitor that enhances ganglionic sympathetic transmission 1
• Does not cause fluid retention, making it safer in patients with underlying cardiac dysfunction 1
• Common side effects: nausea, vomiting, abdominal cramping, sweating, salivation, urinary incontinence 1

Treatment Goals and Monitoring

The therapeutic goal is minimizing postural symptoms and improving functional capacity, NOT restoring normotension. 1, 2

• Balance the benefits of increasing standing blood pressure against the risk of worsening supine hypertension 1
• Measure blood pressure in supine, sitting, and standing positions at follow-up visits 1, 2
• Reassess patients within 1-2 weeks after medication changes 1
• Continue midodrine only for patients who report significant symptomatic improvement 5
• Monitor for supine hypertension (BP >200 mmHg systolic), which can cause end-organ damage 1, 5

Special Populations

Diabetic patients with orthostatic hypotension:

• Assess for cardiovascular autonomic neuropathy (CAN) in patients aged >50 years using cardiac autonomic reflex tests 1
• CAN is a Level A evidence risk marker for all-cause mortality 1
• Consider α-lipoic acid for potential benefits on autonomic function 1, 2
• Cardioselective β-blockers without intrinsic sympathomimetic activity (metoprolol, nebivolol, bisoprolol) can treat resting tachycardia associated with autonomic neuropathy 2

Patients with concurrent hypertension and orthostatic hypotension:

• Consider long-acting dihydropyridine calcium channel blockers or RAS inhibitors as first-line antihypertensive therapy 1, 3
• These agents have minimal impact on orthostatic blood pressure 3
• Avoid beta-blockers unless compelling indications exist 1, 3

Elderly/frail patients (≥85 years):

• Defer blood pressure-lowering treatment until BP >140/90 mmHg in those with moderate-to-severe frailty or limited life expectancy 1
• If antihypertensive therapy is needed, prefer long-acting dihydropyridine CCBs or RAS inhibitors 1, 3
• Asymptomatic orthostatic hypotension during treatment should not trigger automatic down-titration 1

Critical Pitfalls to Avoid

• Do not simply reduce the dose of offending medications—switch to alternative therapy instead 1
• Do not administer midodrine after 6 PM to prevent nocturnal supine hypertension 1
• Do not use fludrocortisone in patients with heart failure or supine hypertension 1
• Do not combine multiple vasodilating agents (ACE inhibitors + calcium channel blockers + diuretics) without careful monitoring 1
• Do not overlook volume depletion as a contributing factor 1
• Do not withhold treatment based on age alone unless diastolic BP is lowered to 55-60 mmHg 1