Midodrine
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Harrison's Principles of Internal Medicine, Twenty First Edition
Page 12488
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midodrine side effects contraindications pharmacology
Harrison's Principles of Internal Medicine, Twenty First Edition
Page 12488
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Midodrine
Mechanism of Action
Midodrine is a directly acting α₁-adrenergic receptor agonist (prodrug converted to its active metabolite desglymidodrine). Crucially, it does not cross the blood-brain barrier, so its vasopressor effects are purely peripheral — it increases arterial and venous tone, raising blood pressure without significant CNS effects (Harrison's, p. 12488).
Primary Indications
| Indication | Notes |
|---|---|
| Neurogenic orthostatic hypotension (OH) | First-line pharmacologic agent; used in autonomic neuropathy, MSA, PAF, PD |
| Vasovagal/reflex syncope | Adjunctive in refractory cases |
| POTS (postural orthostatic tachycardia syndrome) | Off-label; improves venous return |
| Dialysis-associated hypotension | Off-label; used intradialytically |
| Hepatorenal syndrome | Off-label adjunct with albumin and octreotide |
Dosing
- Standard: 5–10 mg orally three times daily (TID)
- Decremental dosing (preferred by some patients):
- 15 mg on awakening
- 10 mg at midday
- 5 mg in the afternoon
- Last dose: Must be taken no later than 6:00 PM to avoid nocturnal supine hypertension (Harrison's, p. 12488)
- Onset: ~1 hour; duration of action: 2–4 hours
Side Effects
| Side Effect | Details |
|---|---|
| Supine hypertension | Most clinically significant; dose-dependent |
| Pruritus / piloerection | Due to peripheral α₁ stimulation of piloerector muscles |
| Urinary retention | α₁ stimulation of bladder neck/sphincter |
| Bradycardia | Reflex response to increased BP |
| Paresthesias, scalp tingling | Common |
Contraindications
- Severe organic heart disease
- Acute renal failure / urinary retention
- Pheochromocytoma
- Thyrotoxicosis
- Persistent/excessive supine hypertension
- Use with caution in patients with diabetes or visual problems (may exacerbate)
Comparison with Other Agents for Neurogenic OH
| Drug | Mechanism | Key Advantage | Key Drawback |
|---|---|---|---|
| Midodrine | Direct α₁ agonist | Proven, titratable | Supine HTN, frequent dosing |
| Droxidopa | NE prodrug | Effective in PAF, PD, MSA | Costly |
| Fludrocortisone | Mineralocorticoid | Volume expansion | Worsens supine HTN, fluid retention |
| Pyridostigmine | AChE inhibitor | Minimal supine HTN effect | Modest BP benefit |
(Harrison's, p. 12488)
Key Clinical Pearls
- Patients should be upright or seated when taking midodrine — do not take while supine or recumbent
- Monitor supine blood pressure regularly; a reasonable threshold is to hold if supine BP >180 mmHg systolic
- Elevating the head of bed (10–20°) at night reduces supine hypertension risk
- In hepatic failure/HRS, used in the classic triplet: midodrine + octreotide + albumin infusion
- FDA approved for symptomatic orthostatic hypotension; many other uses are off-label
octreotide
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octreotide side effects contraindications pharmacology somatostatin analog
Harrison's Principles of Internal Medicine, Twenty First Edition
Page 2582
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Octreotide
Mechanism of Action
Octreotide is a synthetic octapeptide analog of somatostatin (natural somatostatin has a half-life of ~2 minutes; octreotide's is ~90–120 minutes). It binds primarily to somatostatin receptors 2 and 5 (SSTR2, SSTR5), mediating:
- Inhibition of GH, IGF-1, glucagon, insulin, gastrin, secretin, VIP, and other gut hormones
- Splanchnic vasoconstriction (reduces portal venous pressure)
- Reduced GI secretion and motility
- Antiproliferative effects on neuroendocrine tumor cells
Formulations
| Formulation | Route | Half-life / Duration | Use |
|---|---|---|---|
| Octreotide acetate (short-acting) | SC or IV | ~90–120 min | Acute conditions, titration |
| Octreotide LAR (long-acting release) | IM (monthly) | ~23–30 days | Chronic maintenance |
Indications & Dosing
1. Acromegaly
- Short-acting: 50–100 mcg SC TID (titrated up to 500 mcg TID)
- LAR: 20 mg IM q4 weeks (titrate to 10–40 mg)
2. Carcinoid Syndrome / Neuroendocrine Tumors (NETs)
- Short-acting: 100–600 mcg/day SC in 2–4 divided doses
- LAR: 20–30 mg IM q4 weeks
- Short-acting formulation still used for breakthrough symptoms and perioperatively around surgery or PRRT (Neuroendocrine Neoplasms, p. 67)
3. Variceal Hemorrhage (acute upper GI bleeding)
- 50 mcg IV bolus, then 25–50 mcg/hour continuous IV infusion for 3–5 days
- Mechanism: splanchnic vasoconstriction → reduced portal pressure
4. VIPoma / Zollinger-Ellison / Other Secretory Tumors
- 200–300 mcg/day SC in divided doses; titrate to symptom control
5. Hepatorenal Syndrome (HRS)
- Used as part of the midodrine + octreotide + albumin triplet
- 100–200 mcg SC TID (or IV infusion in ICU settings)
6. Other (off-label)
- Refractory diarrhea (e.g., dumping syndrome, short bowel syndrome)
- Chylothorax / chylous ascites
- Insulinoma, glucagonoma
- Thyroid storm (adjunctive)
Side Effects
| Category | Effects |
|---|---|
| GI (early, usually transient) | Nausea, abdominal cramps, bloating, loose stools — up to 1/3 of patients in first 1–2 months, typically subsides (Harrison's, p. 2582) |
| Pancreatic insufficiency | Fat malabsorption with prolonged use; treat with pancreatic enzyme supplements |
| Glucose dysregulation | Mild hyperglycemia (inhibits insulin) OR hypoglycemia (inhibits glucagon counter-regulation) |
| Cholelithiasis | Significant long-term risk — impaired gallbladder contractility → delayed emptying → gallstones; consider prophylactic cholecystectomy if surgery planned (Harrison's, p. 2582) |
| Bradycardia / conduction abnormalities | QT prolongation rare; sinus bradycardia more common |
| Hypothyroidism | With prolonged use |
| Injection site reactions | Pain, induration (SC route) |
Contraindications / Cautions
- No absolute contraindications in acute settings
- Use with caution in:
- Diabetes — unpredictable glucose effects
- Cholelithiasis — risk of worsening
- Renal/hepatic impairment — dose reduction may be needed (LAR especially)
- Patients on cyclosporine (reduced absorption)
Key Clinical Pearls
- In variceal bleeding, combine with endoscopic therapy (band ligation or sclerotherapy) — octreotide alone is insufficient
- For carcinoid crisis (life-threatening flushing/hypotension perioperatively), IV octreotide is the treatment of choice
- Somatostatin receptor scintigraphy (Octreoscan) exploits the same receptor binding for imaging NETs — high SSTR2 expression predicts better response to octreotide therapy
- LAR requires 4–6 weeks to reach steady state; always overlap with short-acting SC doses initially when transitioning
- Gallbladder ultrasound at baseline and periodically during long-term therapy is recommended
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