Continuing Education Activity

Doxazosin is a medication used to manage and treat benign prostatic hyperplasia, hypertension, ureteral stones, and PTSD-associated nightmares. It is a quinazoline derivative that acts as a competitive alpha1-antagonist. This activity describes the indications, action, and contraindications for doxazosin as a valuable agent in treating and managing benign prostatic hyperplasia, hypertension, ureteral stones, and PTSD-associated nightmares. This activity will highlight the mechanism of action, adverse event profile, and other key factors pertinent to healthcare providers.

Objectives:

• Identify the mechanism of action of doxazosin.
• Describe the potential adverse effects that can accompany therapy with doxazosin.
• Review disease-related concerns for which a provider must exercise caution when prescribing doxazosin.
• Summarize some interprofessional team strategies for improving care coordination and communication to advance and improve outcomes using doxazosin.

Indications

FDA approved Indications

• Benign Prostatic Hyperplasia
  • Doxazosin is an alpha1 antagonist that is FDA approved to treat the signs and symptoms of benign prostatic hyperplasia (BPH) or lower urinary tract symptoms (LUTS). In the USA, alpha1 antagonists are the most commonly used treatment for the signs and symptoms of BPH.[1] Though drug therapy for the management of symptoms BPH or LUTS may not be as effective as surgery, it may be sufficient for symptom management and avoid the more serious adverse effects of surgery.[2]
  • There is also an extended-release formulation of doxazosin. It utilizes the gastrointestinal therapeutic system (GITS). It is FDA-approved for the treatment of BPH and LUTS but does not have approval for the treatment of hypertension. One benefit of the extended-release formulation is stable drug concentrations throughout the day and decreased incidence of orthostatic hypotension/syncope. 

• Hypertension (immediate release only)
  • The immediate-release formulation can a second-line agent for the management of hypertension in patients with concomitant BPH.[3] If combination therapy is needed to achieve blood pressure control, the recommendation is to combine it with a diuretic for optimal effectiveness.[4] There is a sentiment that doxazosin can be used as monotherapy for hypertension in a patient with LUTS or BPH; however, the American Urologic Society states that monotherapy with doxazosin is not optimal and hypertension should have separate management.

Non-FDA Approved Indications

• Ureteral Stones
  • The use of alpha1-antagonists, including doxazosin, for the treatment of ureteral calculi is recommended by US and European guidelines. Tamsulosin has the most evidence, but doxazosin has demonstrated efficacy in the expulsion of ureteral calculi less than 10 mm as medical therapy alone or in combination with shockwave lithotripsy.[5]

• PTSD Associated Nightmares
  • Like prazosin, doxazosin has an off-label use for the treatment of PTSD-associated nightmares. There have been numerous small studies and case reports that have shown that doxazosin is effective in treating PTSD-related nightmares.[6][7][8][9]
  • The benefits of doxazosin over prazosin are a longer half-life and a gastrointestinal therapeutic availability system (in the extended-release form), allowing for a more gradual absorption of the drug, thereby reducing the peak to trough concentration ratio. This characteristic permits higher initial doses without the risk of hypotension. Extended-release doxazosin dosing initially starts at 4 mg daily.[10][11]

Mechanism of Action

Doxazosin is a quinazoline derivative that acts as a competitive alpha1-antagonist at the post-synaptic receptor.

In Hypertension

• Doxazosin competitively inhibits post-synaptic alpha1-adrenergic receptors causing vasodilation of arterioles and veins, which results in decreased total peripheral resistance and blood pressure. 

In Benign Prostatic Hyperplasia

• Symptoms of BPH are caused by mechanical or dynamic obstruction of urine flow through the urethra. Mechanical obstruction is mostly due to prostate size. Dynamic obstruction is associated with an increase in smooth muscle tone at the neck of the bladder and the prostate. Doxazosin works by blocking alpha1 receptors, thereby decreasing urethral resistance and improving urine flow.[12]

Administration

Formulations

• Tablet, Oral: 
  • 1 mg, 2 mg, 4 mg 

• Tablet, Oral, as mesylate: 
  • 8 mg 

• Tablet Extended-Release 24 Hour, Oral: 
  • 4 mg, 8 mg 
  • As with all extended-release formulations, this formulation should not be crushed to pass through a nasogastric, orogastric, or PEG tube. 

Dosing

• Benign Prostatic Hyperplasia
  • Oral Immediate Release: Initiate at 1 mg once daily. The dose may be titrated up at 1- to 2-week intervals up to a maximum dose of 8 mg once daily. This titration should take place by doubling the dose while monitoring for response and tolerability. 
  • Oral Extended Release: Initiate at 4 mg once daily. The dose may be titrated up at 3- to 4-week intervals up to a maximum dose of 8 mg once daily. The clinician should titrate by doubling the dose while monitoring for response and tolerability. 
  • The reinitiation of Therapy: If therapy discontinues for several days, reinitiate therapy at the initial dose and titrate according to the initial dose regimen.

• Hypertension
  • Oral Immediate Release: Initiate at 1 mg once daily. The dose may be titrated up to 16 mg once daily; this should occur while monitoring for response and tolerability.

Adverse Effects

Dose-related Adverse Effects

• Orthostatic hypotension/syncope can occur, especially when combined with another antihypertensive, nitrates, or a PDE-5 inhibitor. 
  • These adverse effects occur most commonly after the initial dose or following the reinitiation of therapy; this requires patients to follow a multistep titration regimen to avoid syncope. 

Common Adverse Effects

• Dizziness
• Fatigue
• Headache
• Weakness
• Tachycardia
• Upper respiratory tract infection
• Edema
• Rhinitis
• Dyspnea
• Allergic reactions

In a research study, researchers randomly assigned a total of 3,047 men were randomly assigned to groups of a placebo, doxazosin, or combination therapy with finasteride. Adverse effects of orthostatic hypotension and dizziness occurred significantly more in the groups taking doxazosin and combination treatment compared to the placebo group. Rates of adverse effects were reported to peak at year one during a mean duration of 4.5 years of treatment.[13]

Contraindications

Contraindications for the use of doxazosin are:

• Hypersensitivity to doxazosin or other quinazolines.
• Pregnancy
  • Doxazosin is Pregnancy Category C, meaning that there is no adequate data on the safety of doxazosin in pregnant women. 

Monitoring

Effective therapy with doxazosin for its various indications requires titration based upon response and tolerability. Open communication between patients and providers is crucial for successful treatment. Patients should receive education on the different common side effects of doxazosin, and the provider should conduct a thorough review of other medications for possible interactions, paying particular attention to other antihypertensives, nitrates, and PDE-5 inhibitors. 

Toxicity

Reports with overdosage and toxicity with the alpha-1 antagonists, including doxazosin, remain very limited in the literature. There is a report of one case of acute doxazosin overdose in 2005.[14] The study found that the patient presented to the emergency department (ED) with drowsiness, decreased blood pressure, and reflex tachycardia but did not have orthostatic hypotension or any other abnormalities. This patient was able to fully awaken with supportive therapy in 8 hours and was discharged 48 hours after admission to the ED. Although there are limited works of literature for the toxicity of doxazosin, it appears to have low acute toxicity.

Enhancing Healthcare Team Outcomes

Doxazosin may not be a drug that providers find themselves prescribing daily. However, it has a few key contexts where it proves to be a valuable tool for health care workers in the treatment of BPH, hypertension, ureteral stones, and PTSD-associated nightmares. Doxazosin is a medication that requires titration to an effective dose and tolerance. As such, interprofessional healthcare teams need to monitor patients closely upon the initiation and titration of therapy, starting with the prescribing clinician. The extended-release formulation of doxazosin has the benefit of once-daily dosing and more stable serum concentrations. Nurses can serve as the initial point of contact for patient questions and provide initial counseling on using the drug, dosing, and what to watch for regarding possible adverse reactions. This dosing regimen reduces the incidence of orthostatic hypotension and various other adverse effects. Because doxazosin has many drug-drug interactions, it may be helpful for a pharmacist to review the different medications that a patient is on before initiating therapy. These examples of interprofessional teamwork show how such an approach can lead to improved patient outcomes with doxazosin. [Level 5]