Mechanism of Action of Doxazosin

Introduction

Doxazosin is a selective α₁-adrenergic receptor blocker used primarily in the management of hypertension and benign prostatic hyperplasia (BPH). By targeting α₁ receptors in vascular smooth muscle and the lower urinary tract, doxazosin produces both vasodilatory and urodynamic benefits. It is a high-yield drug in pharmacology, cardiology, and urology examinations due to its receptor selectivity, long duration of action, and characteristic first-dose phenomenon.

Mechanism of Action (Step-wise)

Doxazosin exerts its effects by selectively blocking α₁-adrenergic receptors.

Step-wise mechanism:

1. α₁-Adrenergic Receptors
   α₁ receptors are located on:
   • Vascular smooth muscle
   • Prostate and bladder neck
   • Urethral smooth muscle
2. Selective α₁ Receptor Antagonism
   Doxazosin competitively blocks postsynaptic α₁-adrenergic receptors.
3. Inhibition of Sympathetic Vasoconstriction
   Blockade of α₁ receptors prevents norepinephrine-mediated vasoconstriction.
4. Vascular Smooth Muscle Relaxation
   Reduced intracellular calcium in vascular smooth muscle leads to vasodilation.
5. Reduction in Peripheral Vascular Resistance
   Systemic arterial vasodilation lowers blood pressure.
6. Relaxation of Prostatic and Bladder Neck Smooth Muscle
   α₁ blockade reduces urethral resistance.
7. Improved Urine Flow
   Decreased outlet obstruction improves symptoms of benign prostatic hyperplasia.
8. Overall Physiological Effects
   • Decreased blood pressure
   • Improved urinary flow
   • No significant reflex tachycardia (due to α₁ selectivity)

Pharmacokinetics

• Absorption: Well absorbed orally
• Bioavailability: High
• Distribution: Extensive tissue distribution; high protein binding
• Metabolism: Hepatic metabolism (CYP450 enzymes)
• Elimination: Biliary and fecal excretion
• Half-life: Long (16–22 hours)
• Dosing: Once daily

Clinical Uses

Doxazosin is used in cardiovascular and urologic disorders:

• Hypertension
• Benign prostatic hyperplasia (BPH)
• Patients with coexisting hypertension and BPH
• Adjunct therapy in resistant hypertension

It is not recommended as first-line monotherapy for hypertension.

Adverse Effects

Adverse effects are related to vasodilation and autonomic blockade:

• Cardiovascular:
  • Postural (orthostatic) hypotension
  • First-dose syncope
  • Dizziness
• Central:
  • Fatigue
  • Headache
• Others:
  • Nasal congestion
  • Peripheral edema

First-dose phenomenon:
Marked hypotension and syncope may occur after the initial dose or dose escalation.

Comparative Analysis (must include a table + explanation)

Comparison of α₁-Adrenergic Blockers

Explanation:
Doxazosin has a longer half-life than prazosin, allowing once-daily dosing and fewer blood pressure fluctuations. Tamsulosin is more uroselective and preferred when minimizing hypotensive effects.

MCQs (10–15)

1. Doxazosin blocks which receptor?
   a) β₁
   b) β₂
   c) α₁
   d) α₂

Answer: c) α₁

2. Doxazosin lowers blood pressure by:
   a) Reducing cardiac output
   b) Blocking renin release
   c) Decreasing peripheral vascular resistance
   d) Inhibiting sodium reabsorption

Answer: c) Decreasing peripheral vascular resistance

3. Doxazosin improves urinary flow in BPH by relaxing:
   a) Detrusor muscle
   b) Bladder epithelium
   c) Prostatic smooth muscle
   d) Renal pelvis

Answer: c) Prostatic smooth muscle

4. A characteristic adverse effect of doxazosin is:
   a) Bradycardia
   b) First-dose hypotension
   c) Hyperkalemia
   d) Reflex tachycardia

Answer: b) First-dose hypotension

5. Doxazosin is administered:
   a) Twice daily
   b) Three times daily
   c) Once daily
   d) Weekly

Answer: c) Once daily

6. Doxazosin differs from tamsulosin because it:
   a) Is α₁A selective
   b) Is used for hypertension
   c) Has no effect on BPH
   d) Has a short half-life

Answer: b) Is used for hypertension

7. Doxazosin causes minimal reflex tachycardia because it:
   a) Blocks β₁ receptors
   b) Is centrally acting
   c) Is α₁ selective
   d) Increases vagal tone

Answer: c) Is α₁ selective

8. Which condition benefits from both actions of doxazosin?
   a) Asthma
   b) Diabetes mellitus
   c) BPH with hypertension
   d) Heart failure

Answer: c) BPH with hypertension

9. Doxazosin is metabolized mainly in the:
   a) Kidney
   b) Heart
   c) Liver
   d) Lung

Answer: c) Liver

10. The most serious risk after the first dose of doxazosin is:
    a) Arrhythmia
    b) Syncope
    c) Hypoglycemia
    d) Bronchospasm

Answer: b) Syncope

FAQs (minimum 5)

1. What is the primary mechanism of doxazosin?
   Selective blockade of α₁-adrenergic receptors causing vasodilation and smooth muscle relaxation.
2. Why does doxazosin help in BPH?
   It relaxes prostatic and bladder neck smooth muscle, improving urine flow.
3. What is the first-dose phenomenon?
   Severe postural hypotension and syncope after the first dose.
4. Is doxazosin cardioselective?
   No, it is vasoselective via α₁ blockade.
5. Can doxazosin be used alone for hypertension?
   It is usually not first-line but may be used as add-on therapy.
6. Does doxazosin cause sexual dysfunction?
   It has a lower risk compared with other antihypertensives.

References

• Goodman & Gilman’s The Pharmacological Basis of Therapeutics
  https://accessmedicine.mhmedical.com
• Katzung BG. Basic and Clinical Pharmacology
  https://accessmedicine.mhmedical.com
• Tripathi KD. Essentials of Medical Pharmacology
  https://www.jaypeebrothers.com
• Harrison’s Principles of Internal Medicine
  https://accessmedicine.mhmedical.com

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