alpha-2 antagonist

**Receptor physiology** - α2 receptors are Gi-coupled (↓adenylyl cyclase → ↓cAMP). Presynaptic α2 autoreceptors on noradrenergic terminals provide negative feedback on NE release. Presynaptic α2 heteroreceptors on serotonergic neurons similarly inhibit 5-HT release. - Also found in pancreatic β cells (inhibit insulin release), platelets (promote aggregation), and CNS brainstem (↓sympathetic outflow). - Antagonism → blocks the negative feedback → ↑NE (and 5-HT) release → ↑sympathetic tone (↑HR, ↑BP, anxiety, tremor, mydriasis possible).

**Key drugs** 1. **Mirtazapine** (atypical antidepressant; "NaSSA" = noradrenergic and specific serotonergic antidepressant) - α2 antagonist (↑NE and 5-HT release) plus potent 5-HT2A, 5-HT2C, 5-HT3 and H1 antagonism. - H1 blockade → sedation and weight gain; 5-HT2C blockade → ↑appetite/weight gain; 5-HT2A/5-HT3 blockade → less sexual dysfunction and less nausea/GI upset than SSRIs. - Use: MDD, especially with insomnia, anorexia/weight loss (e.g., elderly, cancer, HIV patients); also used off label for nausea and sleep. - Adverse effects: sedation, weight gain, ↑cholesterol/triglycerides, dry mouth, constipation; rare agranulocytosis (check CBC if fever/infection signs). Less sexual dysfunction than SSRIs. 2. **Mianserin**: similar tetracyclic (not US-available). 3. **Yohimbine**: selective α2 antagonist (from yohimbe bark). Historically used for erectile dysfunction; can cause anxiety, hypertension, tachycardia, tremor. Used experimentally to provoke panic/PTSD symptoms. 4. **Phentolamine** and **phenoxybenzamine**: nonselective α blockers (α1 > α2 effects). Reflex tachycardia is amplified partly because α2 blockade removes presynaptic inhibition, increasing NE release. Used in pheochromocytoma (phenoxybenzamine, irreversible) and for hypertensive emergencies from catecholamine excess/extravasation (phentolamine). 5. Others: atipamezole (veterinary reversal of dexmedetomidine); some antipsychotics (e.g., clozapine, risperidone, asenapine) have α2 antagonism contributing to side effect/efficacy profiles.

**Contrast with α2 agonists** - Clonidine, guanfacine, methyldopa (via α-methylnorepinephrine), dexmedetomidine, tizanidine, brimonidine: ↓NE release/sympathetic outflow → ↓BP, sedation, analgesia, ↓IOP. Clonidine withdrawal causes rebound hypertension; α2 antagonists would have the opposite effect (↑sympathetic outflow).

**Boards pearls** - "Depressed patient with insomnia and poor appetite" → mirtazapine. - Mirtazapine + sedation/weight gain; avoid in obesity/metabolic syndrome patients when possible. - Mirtazapine can be combined with an SSRI/SNRI (“California rocket fuel” = venlafaxine + mirtazapine) for refractory depression. - Serotonin syndrome risk is lower but not zero when combined with other serotonergic agents. - Remember: α2 blockade of pancreatic β cells ↑insulin release (opposite of α2 agonism which ↓insulin). - Receptor mnemonic: α1 = Q (Gq, "qiss" – vasoconstriction); α2 = I (Gi, "sIs"); β1, β2 = S (Gs).