Medications for the Management of Urinary Incontinence

Urinary incontinence refers to the involuntary leakage of urine. The condition is common in the elderly but can also affect younger adults. While urinary incontinence is thought to affect up to 10% of men and 38% of women in Australia, it is likely underdiagnosed and undertreated. Patients may be hesitant to report symptoms for a variety of reasons, such as embarrassment, a belief that incontinence is a normal part of ageing, or a lack of awareness of treatment options.

Urinary incontinence can be divided into categories based on the underlying cause. The most common types are:

• Stress urinary incontinence – related to weakness of the urethral sphincter and/or the pelvic floor. This results in the leakage of urine when intra-abdominal pressure increases, as can occur during sneezing, coughing, or physical exertion;
• Urge urinary incontinence – related to detrusor overactivity, which may be due to bladder irritation or loss of neurologic control;
• Mixed urinary incontinence – a combination of stress and urge incontinence;
• Overflow urinary incontinence – bladder outlet obstruction or impaired detrusor contractility can cause overdistension of the bladder, resulting in leakage. Benign prostatic hyperplasia (BPH) is a common cause of this in men. Other potential causes include spinal cord injuries, multiple sclerosis, diabetes, or external compression from pelvic organ prolapse or abdominal or pelvic masses;
• Functional urinary incontinence – the urinary system is functioning correctly, but another illness or disability is causing incontinence. For example, dementia or sedative medications can reduce the awareness of needing to go to the toilet. Alternatively, some disabilities can make it difficult for a person to get to the toilet and undress in time. Treatment of functional urinary incontinence typically focuses on improving functional status, reducing environmental barriers to toileting, and treating any modifiable causes of incontinence.

It is important that the cause of the incontinence is investigated as management differs depending upon the type of incontinence. Treatment may be conservative (e.g. behavioural therapies, pelvic floor exercises, weight loss), surgical, pharmacological, or a combination of modalities.

Anticholinergics and mirabegron are the main drugs used in the treatment of urinary urge incontinence. Botulinum toxin type A can be considered for certain patients who do not respond or do not tolerate anticholinergics. However, this is a more invasive option.

Anticholinergics

Anticholinergics are mainly used in the management of urinary urge incontinence. They work by reducing bladder muscle contractility and increasing bladder storage capacity. However, they can increase voiding dysfunction, causing urinary hesitancy and retention in some cases.

Medications in this class include:

• Darifenacin;
• Oxybutynin;
• Propantheline (rarely used);
• Solifenacin; and
• Tolterodine.

There are five subtypes of muscarinic receptors, with bladder contraction being primarily controlled by the M3 subtype. Oxybutynin, propantheline, and tolterodine are non-selective in that they exert effects in the bladder, as well as the gut and salivary glands. However, tolterodine has greater specificity for the bladder when compared to oxybutynin and may cause less dry mouth. Solifenacin and darifenacin are considered M3-selective agents and act mainly on the bladder. Selective agents may have a more favourable adverse effect profile, but can still be associated with anticholinergic adverse effects outside of the bladder.

The effectiveness of anticholinergics varies considerably between individuals. One review suggests that these medications are associated with an average of one fewer episode of incontinence per 48 hours compared to placebo. While this may not seem impressive, many of the studies included in this review did not utilise optimal clinical practice (i.e. concomitant bladder training) and most did not measure the effect on urinary urgency or quality of life.

Adverse effects

Adverse effects are typically dose-related but also depend upon patient factors, such as age and comorbidities. Particular caution is required in the elderly as they are more sensitive to the effects of anticholinergics and are more likely to be already taking medication with anticholinergic properties. The overall anticholinergic burden should be considered when using these medications in the elderly.

Anticholinergic adverse effects include urinary retention, dry mouth, constipation, dyspepsia, blurred vision, dry eyes, tachycardia, arrhythmia, dizziness, drowsiness, headache, hallucinations, confusion, and memory impairment. Oxybutynin is commonly associated with central effects, while these are unlikely with propantheline as it does not readily cross the blood-brain barrier. Dry mouth is also more likely with oral oxybutynin. Solifenacin may increase the QT interval, particularly in patients with known risk factors (e.g. history of QT prolongation, hypokalaemia).

Mirabegron

Mirabegron is used to treat urinary urgency, frequency, and incontinence in patients with overactive bladder (OAB) syndrome.

Mirabegron is an agonist at the beta₃-adrenoceptor. Studies demonstrate that relaxation of human bladder smooth muscle is largely mediated by the beta₃-adrenoceptor. Mirabegron relaxes the bladder, increases the amount of urine it can hold, and also improves bladder emptying.

Adverse effects

Mirabegron is generally well tolerated which is likely due to the limited expression of beta₃-adrenoceptors in other parts of the body. Mirabegron has very low intrinsic activity for beta₁ and beta₂-adrenoceptors which translates into little effect on the cardiovascular system. However, some beta₁ stimulation occurs with doses above 50mg. This may cause increased blood pressure and heart rate. Blood pressure should be monitored during treatment, and mirabegron should not be initiated in patients with severe uncontrolled hypertension.

Botulinum toxin type A

Botulinum toxins may be used in the management of urinary incontinence related to neurological illness (e.g. multiple sclerosis or spinal cord injury) or OAB. Botulinum toxin can be administered by intradetrusor injection. This therapy reduces detrusor contractility by blocking the release of acetylcholine into the neuromuscular junction.

Clinical improvement may occur within two weeks of administration. Re-dosing may be considered when the effects have diminished, but there should be at least three months between doses. In clinical studies, the median duration between injections for OAB was around six months.

Adverse effects

Adverse effects include urinary tract infection (UTI), urinary retention, dysuria, and haematuria. The patient must not have a UTI at the time of administration. The manufacturer recommends prophylactic antibiotics to be given one to three days before treatment, on the day of treatment, and for up to three days after treatment.

There is a lack of data regarding the intradetrusor injection of botulinum toxin in patients taking antiplatelet or anticoagulant medications. These patients were either excluded from initial trials or ceased their anticoagulant or antiplatelet a week prior to the procedure. A recently published retrospective review suggests that continuing anticoagulants and antiplatelet medicines may be safe during therapy with intradetrusor botulinum toxin. However, the manufacturer recommends that antiplatelet therapy be discontinued at least three days before injection.

Selective alpha antagonists

Selective alpha antagonists may be used to manage urge incontinence, overflow incontinence, and other symptoms associated with BPH. These medications block alpha₁ receptors, relaxing the muscles of the prostate and urethra. This results in increased urinary flow rate and reduced obstruction.

Medications in this class are:

• Alfuzosin;
• Prazosin;
• Silodosin; and
• Tamsulosin.

These medications can improve urinary symptoms within 48 hours, with the full effect seen in four to six weeks. The efficacy of selective alpha antagonists does not appear to be dependent upon the prostate size.

Common adverse effects include first-dose hypotension, orthostatic hypotension, and dizziness. These are all more common with prazosin and may be minimised by starting with a low dose. Other common adverse effects with this medication class are nasal congestion, urinary urgency, headache, weakness, and fatigue.

5-alpha reductase inhibitors

These medications inhibit 5-alpha reductase, an enzyme responsible for converting testosterone to dihydrotestosterone (a potent stimulant of prostate growth). Inhibition of this enzyme can alleviate lower urinary tract symptoms associated with BPH. It may take six months or more to notice an improvement in symptoms following the initiation of a 5-alpha reductase inhibitor. Efficacy is dependent on prostate size, and men with larger prostates are likely to respond better.

Examples include dutasteride and finasteride. Dutasteride is also available in a fixed-dose combination with the selective alpha-blocker, tamsulosin.

Common adverse effects of this class include fatigue, loss of libido, erectile dysfunction, and ejaculation disorder.

Estrogens

Topical estrogen can be used in perimenopausal or postmenopausal women with urge incontinence and vaginal atrophy due to genitourinary syndrome of menopause (GSM). Options include creams and pessaries.

Systemic estrogen is not recommended for urinary incontinence, as the evidence suggests that this may worsen the issue.

Tricyclic antidepressants

Tricyclic antidepressants reduce bladder contractility and increase urethral resistance. Amitriptyline and imipramine are approved for the treatment of nocturnal enuresis.

The side effect profile of this class limits their usefulness for the treatment of incontinence. Common side effects include sedation, dry mouth, orthostatic hypotension, and confusion. They can also affect cardiac conduction and are rarely associated with hepatitis and blood dyscrasias.

Drugs contributing to incontinence

There are many medications that have been implicated in causing or exacerbating urinary incontinence, including:

• ACE inhibitors and angiotensin receptor blockers – blocking the renin-angiotensin system reduces detrusor overactivity and urethral sphincter tone. Therefore, these medications can worsen stress incontinence but may improve urge incontinence;
• Alpha-antagonists – while these agents may be used to treat urinary symptoms related to BPH, they can cause incontinence due to reduced bladder outlet resistance;
• Anticholinergics – while these medicines are often used to treat urge incontinence, they can indirectly cause overflow incontinence due to urinary retention;
• Antipsychotics – many antipsychotics are associated with urinary incontinence, including chlorpromazine, thioridazine, trifluoperazine, and haloperidol;
• Calcium channel blockers – inhibit bladder contractions and may cause overflow incontinence due to urinary retention;
• Diuretics – may cause frequency, urgency and incontinence due to increased urine production. This is particularly evident with loop diuretics such as furosemide; and
• Sedative-hypnotics – can contribute to functional incontinence.

Summary

Drug treatment for urinary incontinence typically has only modest benefits and may be limited by adverse effects. Anticholinergics are commonly used, although mirabegron is a newer option that may be better tolerated.

A summary of commonly used medications is shown in Table 1.

Table 1. Overview of medications for urinary incontinence