Prazosin

Indications

• FDA-approved only for hypertension in adults; every psychiatric use of prazosin described below is off-label.
• Used off-label for PTSD-related nightmares and sleep disruption, the best-studied psychiatric application of the drug.
• The American Academy of Sleep Medicine position paper states prazosin may be used for PTSD-associated nightmares, a conditional recommendation.
• Trial results conflict: earlier studies in active-duty soldiers were positive while the 2018 multicenter veteran trial found no benefit over placebo.
• Used off-label for daytime PTSD hyperarousal with a small added morning or afternoon dose in patients who respond at night.
• Occasionally used off-label for alcohol use disorder craving and for benign prostatic hyperplasia symptoms, where other alpha blockers are preferred.

Mechanism of action

• Selectively blocks postsynaptic alpha-1 adrenergic receptors, causing arterial and venous dilation and lowering blood pressure.
• It is lipophilic and crosses the blood-brain barrier, unlike some peripheral alpha-1 blockers, which allows a central effect on sleep.
• Central alpha-1 blockade is thought to dampen noradrenergic activity during rapid eye movement sleep, reducing nightmare intensity.
• Prazosin does not sedate directly; improved sleep continuity comes from suppressing nocturnal noradrenergic surges rather than hypnosis.
• Peripheral alpha-1 blockade also relaxes bladder neck and prostatic smooth muscle, explaining urinary effects and the floppy iris syndrome.

Pharmacokinetics

• Tmax is 1-3 hours after oral dosing, so bedtime dosing places the peak effect during the first half of the sleep period.
• Elimination half-life is 2-3 hours, while the antihypertensive effect lasts 6-10 hours, which supports a second daytime dose if needed.
• Extensively metabolized in the liver by demethylation and conjugation, with excretion mainly in bile and feces rather than urine.
• Protein binding is high at about 97 percent, and bioavailability ranges widely between 43 and 82 percent across individuals.
• The short half-life means nightmares typically return within a night or two of stopping, which patients should be told in advance.

Dosing

• PTSD nightmares off-label: start 1 mg PO at bedtime, warning the patient about first-dose hypotension and syncope.
• Increase every 3 to 7 days as tolerated through 2, 4, 6, and 10 mg; typical effective doses are 6-15 mg at bedtime in men.
• Women often respond at lower doses, with mean effective doses near 7-10 mg compared with about 13-15 mg in men.
• For daytime hyperarousal, add 1-2 mg in the morning or afternoon only after the bedtime dose is established and tolerated.
• Hypertension labeling: 1 mg two or three times daily, increased slowly, with usual maintenance doses of 6-15 mg/day divided.
• Taper rather than stop abruptly after prolonged higher doses, and restart at 1 mg if a patient has missed several days.

Adverse effects

• Dizziness in about 10 percent, headache, drowsiness, fatigue, and palpitations are the most common effects at initiation.
• First-dose phenomenon of marked orthostatic hypotension and syncope occurs within 30 to 90 minutes, which is why the first dose is at bedtime.
• Nasal congestion, dry mouth, and urinary frequency are common and occasionally lead to discontinuation despite benefit for nightmares.
• Priapism is rare but requires emergency urologic care, and patients should be told explicitly to seek help for prolonged erection.
• Intraoperative floppy iris syndrome can complicate cataract surgery, so any ophthalmologist should be told the patient takes prazosin.
• Rebound nightmares or sleep disruption occur within one or two nights of stopping because of the short half-life.

Monitoring

• Check blood pressure and orthostatic vitals at baseline, after the first dose is established, and after each titration step.
• Ask directly about dizziness on standing, near-syncope, and falls, particularly in older adults and patients on other antihypertensives.
• Track nightmare frequency and intensity with a nightmare diary or the CAPS-5 recurrent distressing dreams item rather than global impressions.
• Reassess dose adequacy at 4 weeks, since undertreatment at 1-2 mg is the most common reason prazosin appears to fail.
• Screen for daytime hyperarousal separately, since bedtime-only dosing leaves daytime symptoms untreated.

Interactions

• Additive hypotension with other antihypertensives, nitrates, and particularly with phosphodiesterase-5 inhibitors such as sildenafil and tadalafil.
• Beta-blockers and calcium channel blockers increase the risk and severity of the first-dose orthostatic reaction.
• Alcohol and other sedatives worsen orthostatic symptoms and increase fall risk when taken near the bedtime dose.
• Nonsteroidal anti-inflammatory drugs and sympathomimetics blunt the antihypertensive effect and can reduce clinical benefit.
• No significant CYP-mediated interactions are established, which makes prazosin easy to combine with most psychotropic regimens.

Special populations

• Pregnancy: limited human data; prazosin has been used for hypertension and pheochromocytoma in pregnancy when clearly needed.
• Lactation: small amounts appear in human milk, so monitor the infant for sedation and poor feeding if breastfeeding continues.
• Pediatric: safety and effectiveness are not established, though small studies describe use for pediatric PTSD nightmares off-label.
• Geriatric: begin at 1 mg, titrate slowly, and weigh fall and fracture risk against nightmare relief in frail patients.
• Renal impairment: no formal adjustment is required, but patients with severe impairment often respond to lower doses.

Clinical pearls

• First dose is always 1 mg at bedtime; the first-dose syncope reaction is real and preventable.
• Most prazosin failures are underdosing; men often need 10-15 mg at night to stop nightmares.
• Warn about floppy iris syndrome before cataract surgery and priapism as an emergency.