Alpha Adrenergic Blockers

Alpha adrenergic blockers antagonise alpha-1 receptors (or both alpha-1 and alpha-2), lowering vascular tone and prostatic smooth muscle tone. They treat benign prostatic hyperplasia, hypertension and catecholamine excess in phaeochromocytoma, and are used to prevent or treat the effects of sympathomimetic overdose and extravasation.

Classification. Non-selective irreversible: phenoxybenzamine. Non-selective reversible: phentolamine. Alpha-1 selective: prazosin, doxazosin, terazosin, alfuzosin, tamsulosin, silodosin and indoramin. Alpha-2 antagonists: yohimbine, with mirtazapine and mianserin having antagonistic action.

Uroselectivity. Tamsulosin favours alpha-1A and alpha-1D receptors and silodosin is most selective for alpha-1A, so both affect blood pressure less than the vascular-active agents (prazosin, doxazosin, terazosin).

Mechanism. Blockade of alpha-1 receptors relaxes arterial and venous smooth muscle, lowering blood pressure and preload, and relaxes the prostate, bladder neck and urethra, improving urinary flow. Blockade of presynaptic alpha-2 receptors raises noradrenaline release, causing reflex tachycardia.

Pharmacokinetics. Prazosin is short acting (half-life 2 to 3 hours). Doxazosin and terazosin act for 24 hours. Phenoxybenzamine alkylates receptors covalently, so effect lasts 24 to 48 hours until new receptors are made. Tamsulosin and alfuzosin are CYP3A4 substrates.

Effects. Postural hypotension, reflex tachycardia, nasal congestion, miosis, ejaculatory dysfunction, and improved urine flow rate by about 2 to 3 mL/second.

• Phenoxybenzamine: preoperative control in phaeochromocytoma; irreversible blockade gives smooth but long lasting effect.
• Phentolamine: intravenous for hypertensive crisis from catecholamines, phaeochromocytoma and extravasation.
• Prazosin: hypertension, Raynaud phenomenon, and used for nightmares in post-traumatic stress disorder with mixed evidence.
• Doxazosin, terazosin: benign prostatic hyperplasia and hypertension.
• Tamsulosin, silodosin, alfuzosin: benign prostatic hyperplasia, with fewer blood pressure effects.
• Indoramin: hypertension and prostatic symptoms; sedation is common.

• Benign prostatic hyperplasia: tamsulosin 400 micrograms daily after the same meal each day, alfuzosin prolonged release 10 mg daily after a meal, silodosin 8 mg daily with food, doxazosin 1 mg daily increased to 2 to 4 mg (maximum 8 mg). Onset is within days. Combined with a 5-alpha reductase inhibitor in large prostates.
• Acute urinary retention: start an alpha blocker for 2 to 3 days before an attempt to remove the catheter, which raises the chance of voiding.
• Phaeochromocytoma: phenoxybenzamine 10 mg twice daily, increased every other day to 20 to 40 mg 2 to 3 times daily, for at least 7 to 14 days before surgery, aiming for mild postural hypotension and blood pressure under 130/80 mmHg supine. Doxazosin is an alternative. Add a beta blocker only after adequate alpha blockade, because unopposed alpha stimulation can cause hypertensive crisis. Phentolamine 5 mg intravenously for crisis.
• Hypertension: doxazosin 1 mg daily increased to a maximum of 16 mg, or prazosin 0.5 mg 2 to 3 times daily increased to a maximum of 20 mg daily. Not first line. Doxazosin as monotherapy was linked with more heart failure than a thiazide-like diuretic. Use as add-on in resistant hypertension.
• Extravasation of vasopressors: phentolamine 5 to 10 mg in 10 mL of 0.9% sodium chloride infiltrated into the site as soon as possible.
• Ureteric stones: tamsulosin 400 micrograms daily to aid passage is contested, with benefit mainly for larger distal stones.
• Selection: use a uroselective agent for urinary symptoms in men on antihypertensives or with postural symptoms.

Contraindications. History of micturition syncope or postural hypotension. Silodosin contraindicated with creatinine clearance under 30 mL/min and in severe hepatic impairment. Alfuzosin is not advised in severe hepatic impairment or with QT prolongation.

Adverse effects. First-dose hypotension and syncope, dizziness, headache, fatigue, nasal congestion, peripheral oedema, retrograde ejaculation (highest with silodosin and tamsulosin), and rarely priapism. Intraoperative floppy iris syndrome occurs in cataract surgery, especially with tamsulosin; tell the ophthalmologist, but stopping beforehand does not reliably prevent it.

First-dose precautions. Start at a low dose at night, with lying down advised after the first dose and each increase. Prazosin test dose 0.5 mg.

Interactions. Phosphodiesterase 5 inhibitors can cause symptomatic hypotension; start sildenafil at 25 mg or lower and separate doses. Other antihypertensives, alcohol and anaesthetics add to hypotension. Strong CYP3A4 inhibitors raise tamsulosin and alfuzosin levels. Labetalol has a mild alpha effect and adds to hypotension.

Monitoring. Blood pressure supine and standing, symptom score and urine flow in prostatic disease, and for phenoxybenzamine nasal symptoms and heart rate.

Special groups. Older adults: higher fall risk, so start low. Pregnancy: phenoxybenzamine or doxazosin is used for phaeochromocytoma under specialist care. Hepatic impairment: reduce prazosin and doxazosin doses. Renal impairment: tamsulosin is not advised with creatinine clearance under 10 mL/min.