alpha-1 antagonist

**Mechanism:** α1 receptors are Gq-coupled (↑PLC → ↑IP3/DAG → ↑intracellular Ca²⁺ → smooth muscle contraction). Antagonists block norepinephrine/epinephrine-mediated contraction → arterial and venous vasodilation (↓TPR, ↓BP) and relaxation of smooth muscle in the prostate, prostatic capsule, and bladder neck (↓urethral resistance, improved urine flow).

**Classification:** - *Selective α1 blockers:* prazosin, terazosin, doxazosin (non-subtype-selective; quinazoline derivatives; used for HTN and BPH). Tamsulosin, silodosin (α1A/α1D-selective, more prostate-specific, so less hypotension; used for BPH only). Alfuzosin (uroselective). - *Nonselective α blockers:* phenoxybenzamine (irreversible, noncompetitive, long-acting) and phentolamine (reversible, competitive). Used in pheochromocytoma (give BEFORE β-blocker to avoid unopposed α stimulation and hypertensive crisis), and phentolamine for hypertensive emergencies from catecholamine excess (e.g., MAOi tyramine crisis, clonidine withdrawal) and for reversing extravasation of vasopressors or local anesthetic with epinephrine. - *α1 + other:* labetalol and carvedilol (nonselective β + α1 blockade). - *Others with α1 blockade:* many antipsychotics (e.g., chlorpromazine, quetiapine, risperidone), TCAs, and trazodone cause orthostatic hypotension through α1 antagonism.

**Clinical uses:** - BPH (↓ symptoms quickly, but don't shrink prostate; 5-α-reductase inhibitors shrink prostate over months). - Hypertension (no longer first-line; ALLHAT showed doxazosin had more heart failure than chlorthalidone). Useful in resistant HTN or HTN with BPH. - Pheochromocytoma (preoperative control). - PTSD-associated nightmares (prazosin; lipophilic, crosses the BBB). - Medical expulsive therapy for distal ureteral stones (tamsulosin). - Raynaud phenomenon, cocaine-induced hypertension/vasoconstriction (alternatives).

**Adverse effects:** - First-dose syncope / orthostatic hypotension (start at bedtime, low dose, titrate). - Reflex tachycardia (less with selective blockers, since presynaptic α2 is spared and NE release remains regulated). - Dizziness, headache, nasal congestion, peripheral edema, retrograde ejaculation (esp. silodosin/tamsulosin). - Intraoperative floppy iris syndrome (IFIS) with tamsulosin during cataract surgery (ask about use before ophthalmic surgery). - Additive hypotension with PDE-5 inhibitors (sildenafil), so use caution/low doses. - Phenoxybenzamine: also can cause marked hypotension, miosis, and inhibited ejaculation.

**Associated physiologic effects (high-yield):** - With nonselective α blockade (e.g., phentolamine) in the setting of epinephrine, "epinephrine reversal" occurs: unmasked β2 vasodilation causes a net ↓ in BP (pressor response is converted to depressor response). - Pupil: α1 blockade → miosis (dilator pupillae relaxation). - Urinary: ↓ sympathetic tone to bladder neck/prostate → ↑ flow, ↓ obstructive symptoms. - Does not affect lipid profile adversely (may slightly ↓ LDL/↑ HDL).

**Mnemonic:** Alpha-1 blockers end in "-osin" (prazosin, doxazosin, terazosin, tamsulosin, alfuzosin, silodosin). "Zosin for the prostate and pressure; the first dose will make you flop."

**Related Step 1 comparisons:** - α2 agonists (clonidine, methyldopa) ↓ central sympathetic outflow; α2 antagonists (mirtazapine, yohimbine) ↑ NE release. - α1 agonists (phenylephrine) ↑ BP with reflex bradycardia; used for nasal decongestion and mydriasis.