Pharmacotherapy of Urinary Incontinence

Objectives

• Differentiate between the various types of urinary incontinence.
• Recognize the signs and symptoms of the different types of urinary incontinence in individual patients.
• Describe the pharmacological treatment options for urinary incontinence.
• Apply the clinical guidelines in the management of urinary incontinence.

Introduction

Urinary incontinence (UI) is a condition characterized by involuntary urination. It should be distinguished from over-active bladder (OAB), which is the increased urge to urinate that can lead to UI.

Epidemiology

• Women: Approximately 2x as prevalent as seen in men.
• Peak incidence occurs around menopause, with prevalence steadily increasing with age.
• Men: Less common – seen primarily in older age.
• In the non-institutionalized setting, more than 50% of elderly women and more than 25% of elderly men report urinary incontinence (UI).
• Up to 76% of nursing home residents irrespective of gender report having UI.

Physiology of the Bladder

• Bladder wall is surrounded by the detrusor muscle.
• Relaxation is controlled by the autonomic nervous system.
• To prevent incontinence, the urethral sphincter must maintain adequate closure to resist flow of urine.
• Internal sphincter: involuntary.
• External sphincter: voluntary and involuntary.

Detrusor

• Parasympathetic.
• Acetylcholine and muscarinic receptors.
• Involuntary and voluntary bladder contractions.
• Inappropriate stimulation causes involuntary contraction and urgency.

Bladder Neck and Internal Sphincter

• Sympathetic.
• Beta 3-adrenergic receptors.
• Stimulation relaxes detrusor muscle of the bladder, increases capacity.
• Alpha-adrenergic receptors.
• Stimulation tightens the internal bladder sphincter.

Etiology

• Urinary incontinence may occur from abnormalities (over-activity or under-activity) of urethra, bladder, or both.
• There are broad classifications/ types urinary incontinence:
  • Stress Urinary Incontinence (SUI).
  • Urge Urinary Incontinence (UUI).
  • Overflow Incontinence.
  • Mixed Incontinence.
  • Functional Incontinence.

Stress Urinary Incontinence (SUI)

• Incontinence during exertional exercise, coughing or sneezing.
• Episodic, small volume leakage.
• Increased intra-abdominal pressure forces urine through weakened sphincter.
• Risk factors:
  • Pregnancy.
  • Childbirth.
  • Menopause.
  • Obesity.
  • Age.
• Rare in men unless the sphincter is damaged by trauma or surgery.

Urge Urinary Incontinence (UUI)

• If bladder over-activity results in incontinence it is termed Urge Urinary Incontinence (UUI).
• Overactive bladder (OAB) could be a causative factor.
• Bladder (detrusor) over-activity, characterized by:
  • Urgency
  • Frequency
  • Nocturia
• Can occur in both men and women.
• Usually related to BPH in men.
• Idiopathic in women.

Overflow Incontinence

• Bladder always full and unable to empty.
• Seen mostly in men due to bladder outlet obstruction caused by BPH, prostate cancer, etc.
• Detrusor muscle may weaken and lose ability to voluntarily contract to initiate the urination process.
• Urine leaks past urethral sphincter.

Other Types of Urinary Incontinence

Functional Incontinence

• Not caused by bladder nor urethral problems.
• dementia, immobility, spinal cord injury, etc.

Mixed and Drug-Induced Incontinence

• Combination of bladder over-activity and urethral under-activity.
• Usually caused by drugs/medications.

Medications Affecting Urination

Diagnostic Criteria - UI

• Symptom analysis.
• Physical examination.
  • Prostate exam in males.
  • Direct observation of the urethral opening during straining/coughing.
• Laboratory analysis.
  • Urinalysis.
  • Post-void residual (PVR) volume.
• Urodynamic studies.
  • Uroflowmetry, Cystometry, etc.
• Other evaluations like checking for urological infections, trauma, etc.

Differences Between Common Types of UI

Guidelines for Management of Urinary Incontinence

• AUA 2024 guidelines for Overactive Bladder.
• AUA 2023 guidelines for Stress incontinence.
• AUA 2024 guidelines for incontinence secondary to prostate treatment.

Treatment Goals

• Restoration of continence.
• Reduction in the number of incontinence episodes.
• Prevent complications associated with UI (skin irritation, etc.).
• Minimize adverse effects related to treatment.
• Improve quality of life.

Pharmacologic Therapy

• Choice will depend on the specific type of incontinence.

Urge Urinary Incontinence (UUI)

• Anticholinergic drugs.
• β-3 receptor agonists.
• Onabotulinum A (Botox).

Stress Urinary Incontinence (SUI)

• Estrogens.
• α-adrenergic agonists.
• Duloxetine.

Pharmacological Management of UUI

• There is over-lap between the management UUI and OAB.
• Anticholinergic medications are first-line treatment for both.
• Beta3 agonists are also approved for treatment of OAB with UUI.
• Older agents like tricyclic antidepressants (TCA) are no longer favored due to their adverse effects.

Anticholinergic Drugs

• Oxybutynin (Ditropan).
• Tolterodine (Detrol).
• Fesoterodine (Toviaz).
• Trospium chloride (Sanctura).
• Solifenacin (Vesicare).
• Darifenacin (Enablex).

Anticholinergic Drugs

• Mechanism of Action: Antagonize muscarinic M3 receptors causing relaxation of detrusor muscle.

• Restore continence in only 15% of patients.

• Reduce incontinence episodes by 0.5 – 1 per day.

• All considered equally effective.

• Trial of at least 4 weeks – efficacy and tolerability may improve with time.

• Anticholinergic side effects are the primary limitation.

• Immediate Release (IR) agents have high rates of dry mouth, constipation, dyspepsia, dry eyes, cognitive impairment, tachycardia, and urinary retention.

• Dry mouth is especially bothersome and can lead to dental caries, swallowing difficulties. Gum or saliva substitutes may be helpful.

• All are contraindicated in uncontrolled narrow-angle glaucoma.

• Extended-release (ER) formulations cause less dry mouth and other anticholinergic effects, but cannot be crushed or chewed. Cannot by used if patient unable to swallow tablets whole.

• Oxybutynin TDS (transdermal) an option for patients who cannot take oral medications. Dermal adverse effects.

Key Features of Anticholinergics

Beta-3 Receptor Agonists

• Mirabegron (Myrbetriq), Vibegron (Gemtesa).
• Causes detrusor muscle relaxation via agonism of β-3 receptors in the bladder.
• First line therapy for Overactive Bladder (OAB).Not specifically for UUI.
• Similar efficacy to anticholinergic drugs.
• Better adverse effect profile.
• Hypertension is most common adverse effect.

Key Features of Beta-3 Receptor Agonists

Onabotulinumtoxin A (Botox)

• Third-line treatment for patient's refractory to 1st and 2nd line treatments. Injections into the detrusor muscle to inhibit the release of acetylcholine.
• Dose: Onabotulinumtoxin A 100 units as 5-unit injections across 20 sites (intra-detrusor). Repeat no sooner than 12 weeks from previous administration.
• Contraindications: Infection at injection site, UTI, urinary retention.
• Side effects: UTI, urinary retention, dysuria.
• Boxed warning: Botulinum toxin products may spread from the area of injection to produce symptoms consistent with botulinum toxin effects; swallowing and breathing difficulties can be life-threatening.

Stress Incontinence (SI)

• Pelvic floor muscle exercises/rehabilitation (PMFR) are the most efficacious treatment for SUI. Drug therapy may be added to PMFR to increase efficacy.
• α-adrenergic agonists:
  • SUI may be exacerbated by drugs with α-adrenergic antagonism.
  • α-adrenergic agonists, although once used to treat SUI, are generally no longer recommended due to lack of efficacy and serious adverse effects: hypertension, tachyarrhythmias, dry mouth, headache.
  • Contraindications – hypertension, tachyarrhythmias, CAD, MI.

Estrogens

• Trophic effect on urethral epithelium and collagenous tissue, enhanced local circulation, increased numbers/sensitivity of α-adrenergic receptors.
• Systemic therapy is not recommended due to adverse effects: mastodynia, uterine bleeding, thromboembolism, cancers. Topical products preferred.

Duloxetine

• Serotonin-Norepinephrine Reuptake Inhibitor (SNRI).
• Enhances serotonergic and adrenergic tone which is involved in control of urethral smooth muscle and the internal urinary sphincter.
• Studies show improvement in incontinence episode frequency, number of micturition/day & quality of life compared to placebo.
• Modest benefit and intolerability issues limit use to cases of comorbidities (depression, anxiety, fibromyalgia, etc.).
• High rates of discontinuation due to adverse effects: nausea, headache, insomnia, dry mouth, dizziness, fatigue, somnolence or insomnia.

Overflow Incontinence

• Treatment aimed at managing underlying cause: BPH or prostate cancer, other bladder outlet obstruction (e.g. stone).
• α-adrenergic antagonist may be beneficial to relax the bladder sphincter.
• Catheters may be used in patients not responding to treatment.

Non-Pharmacological Treatment

• Exercises:
  • Pelvic floor muscle exercises.
  • Vaginal weight training.
• Devices:
  • Pessaries – support bladder neck, relieve prolapse.
  • Urethral compression device.
  • External collection device.
• Behavioral modification.
  • Timed voiding.
• Absorbent products.
• Behavioral modification can be used in conjunction with pharmacologic treatment.

Surgery

Stress Urinary Incontinence

• Pubovaginal slings.
• Tension-free vaginal slings.

Urge Urinary Incontinence

• Implantable nerve stimulation devices.