A 52-year-old man with depression and comorbid hypertension is started on an antidepressant. After 3 weeks, he reports improved mood but develops severe orthostatic hypotension and syncope. Which feature best distinguishes the likely drug (TCA) from an SNRI in this clinical context?

Question

Accepted Answer

B. α-Adrenergic receptor antagonism causing vasodilation and orthostatic hypotension. ## Orthostatic Hypotension: TCA vs SNRI

### Mechanism of Orthostatic Hypotension in TCAs

Tricyclic antidepressants cause orthostatic hypotension through **α₁-adrenergic receptor antagonism**, a property that SNRIs do not possess. This is a cardinal distinguishing feature with major clinical implications.

### Pharmacological Basis

**Key Point:** TCAs block α₁-adrenergic receptors on vascular smooth muscle, preventing norepinephrine-mediated vasoconstriction. When the patient changes position (supine to upright), compensatory vasoconstriction fails, leading to a sudden drop in blood pressure and syncope.

**High-Yield:** SNRIs (venlafaxine, duloxetine) inhibit the *reuptake* of norepinephrine, increasing synaptic norepinephrine concentration. This leads to **increased sympathetic tone**, which typically raises blood pressure rather than lowering it. SNRIs rarely cause orthostatic hypotension; they may instead cause hypertension, especially at higher doses.

### Comparative Mechanism Table

| Mechanism | TCAs | SNRIs |
|-----------|------|-------|
| **α₁-adrenergic blockade** | Yes (prominent) | No |
| **Orthostatic hypotension risk** | High (especially amitriptyline, imipramine) | Low |
| **Hypertension risk** | Low | Moderate to high (dose-dependent) |
| **Norepinephrine effect** | Blocked reuptake + α-blockade (net ↓ BP) | Blocked reuptake (net ↑ sympathetic tone) |
| **Syncope in elderly** | Common; major safety concern | Rare |

**Clinical Pearl:** In this 52-year-old man with pre-existing hypertension, a TCA was a poor choice because of orthostatic hypotension risk. An SNRI would have been safer, as it would not lower blood pressure and might even elevate it slightly—requiring monitoring but not causing syncope.

**Mnemonic:** **CAST** = Cardiovascular Adverse effects of TCAs: **C**ardiac conduction delay, **A**ntiarrhythmic (paradoxically), **S**yncope (orthostatic), **T**achycardia (anticholinergic).

[cite:Harrison 21e Ch 397]

Answer

A. Direct vasodilation of cerebral blood vessels reducing cerebral perfusion

Answer

C. Inhibition of norepinephrine reuptake leading to increased sympathetic tone and hypertension

Answer

D. Blockade of β-adrenergic receptors causing bradycardia and reduced cardiac output

A 52-year-old man with depression and comorbid hypertension is started on an antidepressant. After 3 weeks, he reports improved mood but develops severe orthostatic hypotension and syncope. Which feature best distinguishes the likely drug (TCA) from an SNRI in this clinical context?

Explanation

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