How does Trazodone (triazolopyridine antidepressant) cause orthostatic hypotension?

Trazodone and Orthostatic Hypotension: Mechanism

Trazodone causes orthostatic hypotension primarily through antagonism of alpha-1 adrenergic receptors, which impairs the normal vasoconstrictor response needed to maintain blood pressure when standing. 1

Pharmacological Mechanism

Alpha-1 Adrenergic Receptor Blockade is the primary mechanism by which trazodone induces orthostatic hypotension:

• Trazodone antagonizes α1A-adrenergic receptors with a binding affinity (Ki) of 153 nM, which directly impairs peripheral vasoconstriction 1
• This alpha-1 blockade prevents the compensatory arterial and venous constriction normally required to maintain blood pressure during postural changes 1, 2
• The FDA drug label explicitly states that "trazodone antagonizes alpha 1-adrenergic receptors, a property which may be associated with postural hypotension" 1

Additional Contributing Mechanisms

Beyond alpha-1 blockade, trazodone's complex receptor profile contributes to hypotensive effects:

• Serotonergic effects: Trazodone acts as both a serotonin reuptake inhibitor (Ki = 367 nM) and 5-HT2A receptor antagonist (Ki = 35.6 nM), which may modulate vascular tone 1
• Multiple receptor antagonism: The drug also blocks 5-HT2B, 5-HT2C, and α2C receptors, creating a cumulative effect on cardiovascular regulation 1
• Partial agonism at 5-HT1A receptors (Ki = 118 nM) may further influence autonomic cardiovascular control 1

Clinical Evidence and Risk Profile

The orthostatic hypotension risk is clinically significant and well-documented:

• In a 2025 study of hypertensive adults ≥75 years, trazodone users showed a systolic BP drop of 23.8 mmHg immediately upon standing versus 14.3 mmHg in non-users (p = 0.037), and diastolic BP drop of 8.9 mmHg versus 1.6 mmHg (p = 0.004) 3
• Trazodone users had a 58.3% incidence of syncope and falls compared to 21.2% in non-users (p = 0.001) 3
• The FDA warns that "hypotension, including orthostatic hypotension and syncope has been reported in patients receiving trazodone hydrochloride" 1

High-Risk Populations

Elderly patients face substantially elevated risk:

• Orthostatic hypotension occurs more frequently in elderly patients, particularly those with pre-existing heart disease 4, 2
• The 2015 American Academy of Sleep Medicine guidelines specifically note that trazodone is "associated with significant risks, including priapism, orthostatic hypotension, and cardiac arrhythmias" in older adults 5
• Lower office diastolic BP (71.8 vs 80.1 mmHg) was observed in elderly trazodone users 3

Critical Clinical Warnings

Concomitant antihypertensive use requires dose adjustment:

• The FDA label states that "concomitant use with an antihypertensive may require a reduction in the dose of the antihypertensive drug" 1
• Multiple guidelines identify medications, including trazodone, as common causes of orthostatic hypotension that should be discontinued or modified as first-line management 6

Cardiovascular monitoring is essential:

• Patients with cardiac disease should be closely monitored, as trazodone may cause cardiac arrhythmias in addition to hypotension 1
• The drug should be avoided during the initial recovery phase of myocardial infarction 1

Practical Implications

The mechanism explains why trazodone, despite being widely used off-label as a hypnotic at low doses (25-100 mg), still carries substantial orthostatic hypotension risk even at these lower doses—the alpha-1 blockade occurs independently of dose-dependent antidepressant effects 4, 2. This is particularly problematic given that trazodone is often prescribed to elderly patients specifically because it is perceived as safer than benzodiazepines, yet the orthostatic hypotension risk may actually increase fall risk in this vulnerable population 3, 7.