What are the treatment options for a patient with orthostatic hypotension, including medications such as midodrine (alpha-1 adrenergic receptor agonist) and fludrocortisone (mineralocorticoid)?

Treatment of Orthostatic Hypotension

Initial Management Strategy

Begin with non-pharmacologic interventions for all patients, and add pharmacologic therapy only when these measures fail to adequately control symptoms—the goal is minimizing postural symptoms and improving function, not achieving arbitrary blood pressure targets. 1

Non-Pharmacologic Interventions (First-Line for All Patients)

Before initiating medications, implement these evidence-based strategies:

Medication Review and Discontinuation:

• Discontinue or switch medications that worsen orthostatic hypotension rather than simply reducing doses—drug-induced autonomic failure is the most frequent cause of orthostatic hypotension 1
• Priority medications to discontinue: diuretics, vasodilators, alpha-1 blockers (doxazosin, prazosin, terazosin), centrally acting agents (clonidine, methyldopa), and avoid combining multiple vasodilating agents 1

Fluid and Salt Management:

• Increase fluid intake to 2-3 liters daily 1
• Increase salt intake to 6-9 grams daily (unless contraindicated by heart failure) 1

Physical Countermeasures:

• Teach leg crossing, squatting, stooping, and muscle tensing during symptomatic episodes—particularly effective in patients under 60 years with prodromal symptoms 1
• Use waist-high compression stockings (30-40 mmHg) and abdominal binders to reduce venous pooling 1

Lifestyle Modifications:

• Elevate head of bed by 10 degrees during sleep to prevent nocturnal polyuria and ameliorate supine hypertension 1
• Eat smaller, more frequent meals to reduce postprandial hypotension 1
• Acute water ingestion of ≥480 mL provides temporary relief with peak effect at 30 minutes 1
• Encourage physical activity to avoid deconditioning 1

---

Pharmacologic Treatment (When Non-Pharmacologic Measures Fail)

First-Line Medications

Midodrine is the preferred first-line agent with the strongest evidence base among pressor agents, supported by three randomized placebo-controlled trials. 1, 2

Midodrine Dosing and Administration:

• Start at 2.5-5 mg three times daily 1
• Titrate up to 10 mg three times daily based on response (maximum studied dose 20 mg three times daily) 1, 3
• Critical timing: Last dose must be taken at least 3-4 hours before bedtime (not later than 6 PM) to prevent supine hypertension during sleep 1, 3
• Increases standing systolic BP by 15-30 mmHg for 2-3 hours 1, 3
• FDA-approved specifically for symptomatic orthostatic hypotension 3

Midodrine Mechanism:

• Alpha-1 adrenergic agonist (via active metabolite desglymidodrine) producing arteriolar constriction and venoconstriction 4, 3
• Does not stimulate cardiac beta-receptors 3
• Poorly crosses blood-brain barrier, minimizing central effects 3

Midodrine Monitoring and Adverse Effects:

• Monitor for supine hypertension (occurs in up to 25% of patients)—measure both supine and standing BP at each visit 1, 4
• Watch for reflex bradycardia due to baroreceptor activation from increased peripheral vascular resistance 4, 3
• Other side effects: pilomotor reactions, urinary retention, gastrointestinal symptoms, headache 4, 2
• Use cautiously with cardiac glycosides (may enhance bradycardia or AV block) and avoid with MAO inhibitors 3
• Start at 2.5 mg in renal impairment as desglymidodrine is renally eliminated 3

---

Alternative First-Line Options

Fludrocortisone:

• Start at 0.05-0.1 mg once daily, titrate to 0.1-0.3 mg daily (maximum 1.0 mg daily) 1
• Acts through sodium retention and vessel wall effects, increasing plasma volume 1
• Contraindications: Active heart failure, severe cardiac dysfunction, pre-existing supine hypertension, severe renal disease 1
• Monitor for: supine hypertension, hypokalemia, congestive heart failure, peripheral edema 1
• Check electrolytes periodically due to mineralocorticoid effects causing potassium wasting 1
• Evidence quality is limited (very low-certainty evidence from small, short-term trials) 1

Droxidopa:

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

---

Combination Therapy for Non-Responders

For patients inadequately controlled on monotherapy, combine midodrine with fludrocortisone—they work through complementary mechanisms (alpha-1 adrenergic stimulation vs. sodium retention). 1

• Midodrine's alpha-1 agonism provides immediate vascular effects 1
• Fludrocortisone's volume expansion provides sustained benefit 1
• When combining, intensify monitoring for supine hypertension 1

---

Second-Line and Refractory Options

Pyridostigmine (for refractory cases):

• Particularly beneficial in elderly patients with refractory orthostatic hypotension who have not responded to other treatments 1
• Key advantage: Does not worsen supine hypertension, making it preferred when supine hypertension is a concern 1
• Dose: 60 mg orally three times daily (maximum 600 mg daily) 1
• Mechanism: Acetylcholinesterase inhibitor enhancing ganglionic sympathetic transmission 1
• Side effects: Nausea, vomiting, abdominal cramping, sweating, salivation, urinary incontinence (generally manageable) 1
• Class IIa recommendation from ACC/AHA/HRS guidelines for neurogenic orthostatic hypotension refractory to other treatments 1

Other Agents (Limited Evidence):

• Atomoxetine: Emerging evidence shows promise, especially in central autonomic failure 5, 6
• Erythropoietin: Consider for patients with anemia and severe autonomic neuropathy 1
• Desmopressin: May correct nocturnal polyuria and morning orthostatic hypotension 1

---

Special Populations and Considerations

Patients with Concurrent Hypertension and Orthostatic Hypotension:

• Use long-acting dihydropyridine calcium channel blockers or RAS inhibitors as first-line antihypertensive therapy 1
• Switch (don't just reduce dose) BP-lowering medications that worsen orthostatic hypotension 1
• Asymptomatic orthostatic hypotension during treatment should not trigger automatic down-titration—intensive BP lowering may actually reduce orthostatic hypotension risk by improving baroreflex function 1

Elderly Patients (≥85 years) with Frailty:

• Defer blood pressure-lowering treatment until BP >140/90 mmHg 1
• Target "as low as reasonably achievable" (ALARA principle) rather than strict 130/80 mmHg 1
• Pyridostigmine preferred in this population due to favorable side effect profile 1

Diabetic Patients:

• Assess for cardiovascular autonomic neuropathy 1
• Consider α-lipoic acid for painful diabetic neuropathy (potentially beneficial for autonomic function) 1
• Use midodrine or fludrocortisone with caution—monitor for worsening glycemic control and visual problems (fludrocortisone can increase intraocular pressure) 3

Hemodialysis Patients:

• Midodrine 5-10 mg orally 30 minutes before initiating hemodialysis effectively prevents intradialytic hypotension 4
• Midodrine is effectively cleared during dialysis (half-life reduced to 1.4 hours) 4
• Lower dialysate temperature to 34-35°C and use bicarbonate-containing dialysate as adjunctive measures 4

---

Monitoring Protocol

Initial Assessment:

• Measure BP after 5 minutes lying/sitting, then at 1 and 3 minutes after standing 1
• Document both supine and standing BP to establish baseline 1
• Assess renal and hepatic function before initiating therapy 3

Follow-Up:

• Reassess within 1-2 weeks after medication changes 1
• Measure both supine and standing BP at each visit 1
• Monitor for supine hypertension (most important limiting factor with pressor agents) 1
• Check electrolytes periodically if using fludrocortisone 1
• Monitor orthostatic vital signs at each follow-up visit 1

---

Critical Pitfalls to Avoid

• Do not simply reduce the dose of offending medications—switch to alternative therapy 1
• Do not administer midodrine after 6 PM 1
• Do not use fludrocortisone in patients with heart failure or supine hypertension 1
• Do not combine multiple vasodilating agents without careful monitoring 1
• Do not overlook volume depletion as a contributing factor 1
• Do not target normotension—the goal is symptom relief and functional improvement 1, 3
• Do not continue midodrine unless patients report significant symptomatic improvement 3