Doxazosin

1. Drug Name

• Generic Name: Doxazosin

• Brand Names: Cardura, Cardura XL, Doxadura

2. Drug Classification

• Class: Alpha-1 Adrenergic Blocker

• Subclass: Antihypertensive, BPH treatment agent

3. Mechanism of Action

Doxazosin is a selective alpha-1 adrenergic antagonist that works by blocking the alpha-1 receptors on smooth muscle in the vasculature and the prostate. Its primary effects are:

• Vasodilation: By blocking the alpha-1 receptors on the smooth muscle of blood vessels, doxazosin causes vasodilation, reducing peripheral vascular resistance and lowering blood pressure. This effect makes it useful in the treatment of hypertension.

• Prostatic Smooth Muscle Relaxation: Doxazosin also blocks alpha-1 receptors in the smooth muscle of the prostate and bladder neck. This leads to relaxation of the smooth muscles, improving urine flow and reducing symptoms of benign prostatic hyperplasia (BPH), such as frequent urination, difficulty urinating, and incomplete bladder emptying.

• Improved Urine Flow in BPH: Doxazosin is especially effective in reducing symptoms related to the bladder outlet obstruction caused by BPH, such as nocturia and urinary retention.

4. Pharmacokinetics

• Absorption: Doxazosin is well absorbed after oral administration. The bioavailability is about 60-70%. The peak plasma concentration occurs approximately 2-3 hours after oral administration for the immediate-release form, and 6-12 hours for the extended-release form.

• Distribution: The volume of distribution (Vd) of doxazosin is approximately 1.8 L/kg. It is 98% protein-bound, primarily to albumin.

• Metabolism: Doxazosin is extensively metabolized in the liver via the cytochrome P450 enzymes (mainly CYP3A4) to inactive metabolites, which are then excreted in the urine.

• Excretion: The half-life (t½) of doxazosin is approximately 22 hours for the immediate-release formulation, allowing for once-daily dosing. The drug is primarily excreted in the urine (about 63%), with the rest excreted in the feces.

• Special Considerations:

  • Renal Impairment: Dose adjustments are generally not required in patients with mild-to-moderate renal impairment, although caution is recommended.

  • Hepatic Impairment: In patients with hepatic impairment, the clearance of doxazosin may be reduced, and dose adjustments may be necessary. It should be used with caution in patients with liver dysfunction.

5. Indications

• Primary Indications:

  • Hypertension: Doxazosin is used to treat hypertension, either as monotherapy or in combination with other antihypertensive agents such as diuretics, ACE inhibitors, or calcium channel blockers.

  • Benign Prostatic Hyperplasia (BPH): Doxazosin is commonly used to treat symptoms of BPH, such as difficulty urinating, urinary retention, and nocturia.

• Off-Label Uses:

  • Post-Traumatic Stress Disorder (PTSD): Occasionally used for the management of nightmares in PTSD, though this is not a standard indication.

  • Raynaud's Phenomenon: Some off-label use in vasospastic disorders, although not first-line.

• Special Populations:

  • Elderly: Doxazosin is commonly prescribed to elderly patients for hypertension and BPH, but close monitoring is recommended, particularly during dose initiation, due to the risk of hypotension.

  • Pediatrics: Doxazosin is not generally used in pediatric populations due to limited safety data.

6. Dosage and Administration

• Adult Dosing:

  • Hypertension: The initial dose of doxazosin for hypertension is typically 1 mg once daily. The dose may be gradually titrated to 2-8 mg once daily depending on the response, with a maximum recommended dose of 16 mg/day.

  • Benign Prostatic Hyperplasia (BPH): The usual starting dose is 1 mg once daily, which can be increased to 2-4 mg once daily based on the patient’s response. The maximum recommended dose for BPH is 8 mg/day.

• Renal Impairment: No significant dose adjustments are required in patients with mild-to-moderate renal impairment. However, use caution in those with severe renal dysfunction.

• Hepatic Impairment: In patients with hepatic impairment, the clearance of doxazosin may be decreased, and a lower starting dose should be considered.

• Administration: Doxazosin can be taken with or without food, but it should be taken consistently the same way (either always with food or always without) to avoid variability in absorption. The extended-release formulation should be swallowed whole and not crushed or chewed.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity: Known hypersensitivity to doxazosin or any component of the formulation.

  • Severe Hepatic Impairment: Doxazosin should not be used in patients with severe liver dysfunction due to reduced metabolism and increased risk of adverse effects.

• Relative Contraindications:

  • Orthostatic Hypotension: Patients who are prone to hypotension, especially following dose initiation or dose increases, should be monitored closely.

  • Severe Renal Impairment: Caution is advised in patients with severe renal impairment, as the drug is excreted via the kidneys.

8. Warnings and Precautions

• Orthostatic Hypotension: Doxazosin can cause a significant first-dose effect, leading to orthostatic hypotension. It is important to start therapy at a low dose and increase gradually. Patients should be advised to take the first dose at bedtime to reduce the risk of dizziness or fainting.

• Syncope: There is a risk of syncope or fainting, particularly during the initial dose titration or if the patient is volume-depleted. Patients should be monitored closely during the initial weeks of treatment.

• Priapism: Although rare, doxazosin can cause priapism (a prolonged, painful erection). If this occurs, medical intervention is required immediately.

• Surgical Considerations: Doxazosin may cause intraoperative floppy iris syndrome (IFIS) during cataract surgery, which should be communicated to the surgeon beforehand.

9. Adverse Effects

• Common Adverse Effects:

  • Dizziness (especially upon standing)

  • Fatigue

  • Headache

  • Nasal congestion

  • Palpitations

• Less Common but Clinically Significant Side Effects:

  • Orthostatic Hypotension: Especially after the first dose or dose adjustments.

  • Syncope: Episodes of fainting may occur, particularly with increased doses or in volume-depleted patients.

• Rare/Serious Adverse Reactions:

  • Priapism: A prolonged, painful erection, which requires emergency medical attention.

  • Liver Toxicity: Liver enzyme elevations are possible; monitor liver function in patients with pre-existing liver conditions.

10. Drug Interactions

• Major Drug Interactions:

  • Phosphodiesterase Type 5 Inhibitors (e.g., sildenafil, tadalafil): Co-administration with doxazosin may increase the risk of severe hypotension, and caution is required when using this combination.

  • Other Antihypertensive Agents: When used with other antihypertensive medications, there is an enhanced hypotensive effect. Careful monitoring of blood pressure is essential.

• Food-Drug Interactions: Doxazosin can be taken with or without food, but the timing of food intake should be consistent to avoid variations in drug absorption.

11. Clinical Pharmacology

• Pharmacodynamics: Doxazosin is a potent and selective alpha-1 receptor blocker. By inhibiting alpha-1 receptors, it causes smooth muscle relaxation in both vascular tissues and the prostate, leading to a reduction in blood pressure and improvement in urinary flow.

• Additional Effects: It has minimal effects on heart rate and does not significantly affect renal function or glucose metabolism in the therapeutic range.

12. Special Populations

• Pregnancy: Category C. Doxazosin should only be used in pregnancy if the benefits justify the potential risks to the fetus. There is limited data on its use in pregnant women.

• Lactation: It is not known whether doxazosin is excreted in breast milk. Caution is advised when administering the drug to breastfeeding mothers.

• Pediatrics: Doxazosin is generally not recommended for use in pediatric patients due to limited safety and efficacy data.

• Geriatrics: Elderly patients are more susceptible to the hypotensive effects of doxazosin, particularly during the first dose. Careful titration and monitoring are necessary.

13. Therapeutic Uses

• Hypertension: Doxazosin is used in the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents like ACE inhibitors, diuretics, or beta-blockers.

• Benign Prostatic Hyperplasia (BPH): It is one of the first-line treatments for BPH, helping to alleviate symptoms like urinary frequency, urgency, and weak stream.

14. Monitoring and Follow-Up

• Blood Pressure: Regular monitoring is essential for ensuring adequate control of hypertension, particularly during the initial weeks of therapy and when adjusting doses.

• Urinary Symptoms: In BPH patients, monitor urinary symptoms to assess improvement in flow and frequency.

15. Overdose Management

• Symptoms of Overdose: Overdose may present with severe hypotension, tachycardia, dizziness, and syncope.

• Treatment: Overdose treatment includes intravenous fluids, vasopressors (if needed), and close monitoring. Activated charcoal may be administered if the overdose occurred within the last hour.

16. Patient Counseling Information

• Key Points:

  • Take doxazosin at the same time each day, preferably at bedtime.

  • Avoid sudden position changes (e.g., standing up quickly) to minimize the risk of dizziness.

  • Notify your doctor if you experience persistent dizziness, fainting, or painful erections.

• Seek Immediate Medical Attention: Seek immediate medical attention if you experience a prolonged erection (priapism), severe dizziness, or any signs of liver problems, such as yellowing of the skin or eyes.