Alpha blockers

Introduction

Alpha blockers, also known as alpha-adrenergic antagonists, are a class of medications that inhibit the stimulation of alpha-adrenergic receptors located on vascular smooth muscle, bladder neck, prostate, and other tissues. By blocking these receptors, alpha blockers prevent the binding of norepinephrine and epinephrine, thereby reducing smooth muscle contraction and vascular resistance.

Clinically, these agents are widely used in the management of hypertension, benign prostatic hyperplasia (BPH), pheochromocytoma, and certain vascular disorders such as Raynaud’s disease. Their pharmacological significance lies in their ability to improve urinary outflow in men with prostate enlargement and to decrease systemic vascular resistance in hypertensive patients.

---

Mechanism of Action

Alpha blockers act by selectively or non-selectively antagonizing alpha-adrenergic receptors:

• Alpha-1 receptors are predominantly found in vascular smooth muscle, the prostate, bladder neck, and urethra. Blocking these receptors causes vasodilation and relaxation of urinary tract muscles, leading to reduced blood pressure and improved urinary flow.

• Alpha-2 receptors are primarily located in presynaptic adrenergic nerve terminals and regulate norepinephrine release. Blocking them may increase norepinephrine release, leading to reflex tachycardia and heightened sympathetic activity.

Thus, alpha-1 selective blockers are preferred for hypertension and BPH due to fewer reflex cardiovascular effects compared to non-selective alpha blockers.

---

Classification of Alpha Blockers

1. Non-selective alpha-adrenergic antagonists (alpha-1 and alpha-2 blockers)

   • Examples: Phenoxybenzamine, Phentolamine

   • Clinical use: pheochromocytoma, hypertensive crises, extravasation management.

2. Selective alpha-1 blockers

   • Examples: Prazosin, Doxazosin, Terazosin, Alfuzosin, Tamsulosin, Silodosin

   • Clinical use: hypertension, benign prostatic hyperplasia (BPH).

3. Selective alpha-2 blockers (rarely used therapeutically)

   • Example: Yohimbine

   • Clinical use: previously for erectile dysfunction; rarely used now.

---

Therapeutic Uses

1. Hypertension

   • Alpha-1 blockers decrease peripheral vascular resistance, lowering blood pressure.

   • Usually prescribed when patients are intolerant to first-line antihypertensives (ACE inhibitors, ARBs, calcium channel blockers, diuretics).

2. Benign Prostatic Hyperplasia (BPH)

   • Relaxation of smooth muscle in the bladder neck and prostate improves urine flow, reduces hesitancy, and decreases nocturia.

   • Tamsulosin and silodosin are preferred due to higher selectivity for alpha-1A receptors in the prostate.

3. Pheochromocytoma

   • Non-selective alpha blockers (phenoxybenzamine, phentolamine) are used to control hypertension before surgical removal of catecholamine-secreting tumors.

4. Raynaud’s Disease and Peripheral Vascular Disorders

   • Vasodilation helps alleviate symptoms of digital ischemia.

5. Other Investigational/Off-label Uses

   • PTSD-related nightmares (prazosin).

   • Urinary retention caused by bladder outlet obstruction.

---

Common Alpha Blockers: Generic Names and Doses

1. Prazosin

• Indications: Hypertension, BPH, PTSD-associated nightmares.

• Usual Dose:

  • Hypertension: Start with 1 mg orally 2–3 times daily, titrated up to 20 mg/day.

  • BPH: 0.5–1 mg initially, titrated to 1–5 mg two or three times daily.

  • PTSD: Start at 1 mg at bedtime, titrate gradually (up to 10 mg/day).

2. Doxazosin

• Indications: Hypertension, BPH.

• Usual Dose:

  • Hypertension: 1 mg once daily, titrated to 4–8 mg daily.

  • BPH: 1 mg once daily, titrated up to 8 mg daily.

3. Terazosin

• Indications: Hypertension, BPH.

• Usual Dose:

  • Hypertension: Start with 1 mg at bedtime, increased gradually up to 20 mg/day.

  • BPH: 1 mg at bedtime, titrated to 10 mg daily.

4. Alfuzosin

• Indication: BPH.

• Usual Dose: 10 mg once daily after the same meal.

5. Tamsulosin

• Indication: BPH (high selectivity for alpha-1A receptors).

• Usual Dose: 0.4 mg once daily, may increase to 0.8 mg daily.

6. Silodosin

• Indication: BPH.

• Usual Dose: 8 mg once daily with food. (For renal impairment: 4 mg once daily).

7. Phenoxybenzamine (non-selective, irreversible)

• Indication: Pheochromocytoma.

• Usual Dose: 10 mg orally twice daily, titrated up to 40–100 mg/day in divided doses.

8. Phentolamine (non-selective, reversible)

• Indications: Hypertensive emergencies due to pheochromocytoma, extravasation management.

• Usual Dose:

  • Hypertensive crisis: 5 mg IV bolus, repeat if needed.

  • Extravasation: 5–10 mg in 10 mL saline injected locally.

9. Yohimbine (selective alpha-2 antagonist, rarely used)

• Indication: Erectile dysfunction (historical use).

• Usual Dose: 5–10 mg orally three times daily.

---

Contraindications

• History of orthostatic hypotension

• Severe hepatic or renal impairment (dose adjustments may be required)

• Known hypersensitivity to the drug

• Concomitant PDE-5 inhibitors with certain alpha blockers (e.g., tamsulosin + sildenafil) may cause profound hypotension

---

Side Effects

1. Cardiovascular: Orthostatic hypotension, reflex tachycardia, palpitations, syncope.

2. Neurological: Dizziness, fatigue, headache, drowsiness.

3. Genitourinary: Ejaculatory dysfunction (notably with tamsulosin, silodosin).

4. Gastrointestinal: Nausea, diarrhea, abdominal pain.

5. Rare but serious: Priapism (rarely reported with tamsulosin, prazosin).

---

Precautions

• First-dose effect: Prazosin and similar drugs can cause marked hypotension and syncope after the first dose. Start with the lowest possible dose at bedtime.

• Elderly patients: Higher risk of falls due to dizziness and orthostatic hypotension.

• Combination therapy: Caution when used with beta-blockers, diuretics, or PDE-5 inhibitors (sildenafil, tadalafil).

• Liver and kidney disease: Dose adjustment may be required for alfuzosin, silodosin, and doxazosin.

---

Drug Interactions

1. PDE-5 inhibitors (sildenafil, tadalafil, vardenafil):

   • Risk of profound hypotension when combined with alpha-1 blockers.

   • If combination is necessary, stagger administration and start at lowest doses.

2. Antihypertensives (beta-blockers, diuretics, ACE inhibitors, ARBs, CCBs):

   • Additive hypotensive effects.

3. NSAIDs:

   • May reduce antihypertensive efficacy of alpha blockers.

4. CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, clarithromycin):

   • Increase plasma levels of alfuzosin, tamsulosin, and silodosin.

5. Alcohol:

   • Increases risk of dizziness and orthostatic hypotension.

---

Clinical Considerations

• Choice of Agent:

  • For hypertension: Long-acting agents such as doxazosin and terazosin are preferred.

  • For BPH: Uroselective drugs like tamsulosin, alfuzosin, and silodosin are superior due to reduced systemic hypotension.

  • For pheochromocytoma: Non-selective alpha blockers such as phenoxybenzamine and phentolamine are essential.

• Monitoring Parameters:

  • Blood pressure (especially postural changes).

  • Symptoms of urinary obstruction improvement.

  • Adverse effects such as dizziness, syncope, or abnormal ejaculation.

• Patient Counseling:

  • Take the first dose at bedtime to minimize risk of fainting.

  • Stand up slowly from sitting or lying positions.

  • Report prolonged or painful erections.

  • Avoid driving or operating heavy machinery until drug effects are known.

---

Emerging Trends and Research

Recent studies have investigated alpha blockers beyond traditional uses:

• Prazosin in PTSD: Shows significant benefit in reducing trauma-related nightmares, improving sleep quality, and reducing hyperarousal symptoms.

• Potential role in chronic kidney disease: Alpha blockers may improve renal perfusion and reduce proteinuria.

• Combination therapy: Increasingly combined with 5-alpha-reductase inhibitors (e.g., dutasteride, finasteride) in managing BPH for improved long-term outcomes.