Pharmacologic therapy of UI Francesco Cappellano, MD, FEBU Head of Urology and Neurourology Clinic Pelvic Care Centre Harley Street Hospital – Abu Dhabi ( UAE)

Introduction Medication may have some benefit in stress and urge urinary incontinence. These agents are not uniformly effective, and adverse effects may limit their long-term use Alpha-adrenergic agonists Anticholinergic agents Antispasmodic drugs Tricyclic antidepressants Estrogen Alpha-adrenergic blockers Botulinum toxin

Stress incontinence In patients with stress incontinence, alpha agonist treatment results in contraction of the internal urethral sphincter increasing resistance Sympathomimetic drugs, estrogen, and tricyclic agents increase bladder outlet resistance as well Pharmacologic therapy for stress incontinence and an overactive bladder is most effective when combined with a pelvic exercise regimen.

OAB The goal of therapy is to improve the symptoms of frequency, nocturia, urgency, and urge incontinence. Treatment options include anticholinergics, antispasmodic agents, and tricyclic antidepressants (TCAs) When a single drug treatment does not work, a combination therapy such as oxybutynin and 1 or 2 more drugs may be used. Although their mechanism of action differs, oxybutynin and other drugs work together to improve urge incontinence

Alpha-adrenergic agonists Alpha agonists, such as midodrine or pseudoephedrine, may improve symptoms of mild stress incontinence by increasing intrinsic urethral tone The subjective improvement and cure rates with pseudoephedrine resulted in few cures or dryness (0-14%) but provided subjective improvement in 20-60% of women. In adults, dosing is 60 mg qid, or 120 mg bid with the extended-release form

Tricyclic antidepressants TCAs have historically been used to treat major depression, but their pharmacological effects also make these drugs good choices for mixed incontinence, nocturia, and nocturnal enuresis Also been used in the treatment of stress incontinence. They possess both a central and peripheral anticholinergic effect, as well as being alpha-adrenergic agonists and central sedatives

Imipramine (Tofranil) is the most widely used tricyclic for urologic indications. Alpha-adrenergic effect on the bladder neck, an antispasmodic effect on the detrusor muscle, and a local anesthetic effect on the bladder mucosa Adult dosing is 10-50 mg 1 to 3 times daily, with a range of 25-100 mg qd The combination of imipramine and oxybutynin (Ditropan) produces a synergistic effect

Amitriptyline (Elavil) is a tricyclic antidepressant with sedative properties that increases circulating levels of norepinephrine It is extremely effective in decreasing symptoms of urinary frequency It restores serotonin levels and helps break cycle of pelvic floor muscle spasms. Adult dosing is 10 mg qd; titrate if necessary by 10 mg/wk until a maximum dose of 150 mg Central effects, such as sedation and tremor, may be troublesome to some patients

Duloxetine Is the first drug developed and marketed specifically for stress urinary incontinence Increases pudendal motor nerve output via increased levels of serotonin and norepinephrine in the pudendal motor nucleus of the sacral spinal segments It enhances urethral closure through neuromodulation of the external urethral sphincter. Schuessler, 2006

Clinical results A multicenter, double-blind, randomized, placebo-controlled study in 2,758 women with predominant stress incontinence found that after 6 weeks, the decrease in weekly incontinence episode frequency was significantly greater with duloxetine compared with placebo (-50 vs -29.9%). In an uncontrolled, open-label, 72-week extension of the study in 2,290 patients, 21.5% of patients discontinued the drug because of adverse effects. However, the efficacy of duloxetine was maintained in those women who remained on therapy Cardozo 2010

Anticholinergic agents Anticholinergic agents inhibit the binding of acetylcholine to the cholinergic receptor, thereby suppressing involuntary bladder contraction. They increase the urine volume at which first involuntary bladder contraction occurs, decrease the amplitude of the involuntary bladder contraction, increase bladder capacity

Anticholinergic agents Typical anticholinergic adverse effects can be expected, including dry mouth, constipation, dry eyes, blurred vision, orthostatic hypotension, and increased heart rate. These agents should be avoided by patients with heart disease and closed-angle glaucoma.

Oxybutynin (Ditropan XL), which has both antimuscarinic and antispasmodic effects, reduces incontinence episodes by 83-90%. The total continence rate has been reported to be 41-50%. Mean reduction in urinary frequency was 23%. In clinical trials, only 1% stopped taking the drug because of dry mouth and less than 1% stopped taking it due to CNS adverse effects.

Tolterodine (Detrol) is a potent antimuscarinic agent for treating detrusor overactivity. In animal models, the drug has shown selectivity for the urinary tract over the salivary glands. Well in clinical trials, showing comparable efficacy to oxybutynin with lower discontinuance rates. The dosage range is 1-2 mg twice daily. In clinical studies, the mean decrease in urge incontinence episodes was 50% and the mean decrease in urinary frequency was 17%.

OBJECT study In the Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial, extended-release oxybutynin 10 mg was statistically superior to tolterodine 2 mg bid in controlling urge incontinence, total incontinence, and micturition frequency. Both drugs had similar adverse-effect profiles. OBJECT was a large double-blind, multicenter, prospective, randomized controlled study in 276 women and 56 men with symptoms of overactive bladder. Appel RA 2001

Trospium (Sanctura) is a quaternary ammonium compound that elicits antispasmodic and antimuscarinic effects It acts by antagonizing acetylcholine effect on muscarinic receptors. The typical dose is 20 mg bid at least 1 h before meals. The dose is reduced to 20 mg in patients with renal insufficiency and elderly individuals (>75 y). Mild anticholinergic effects (eg, dry mouth, constipation, dry eyes, blurred vision) may occur.

Solifenacin (VESIcare) is a competitive muscarinic receptor antagonist that causes anticholinergic effects and inhibits bladder smooth muscle contraction. The initial dose is 5 mg, which may be increased to 10 mg/d Precautions include renal or hepatic impairment (do not exceed 5 mg with CrCl < 30 mL/min or moderate hepatic impairment [Child-Pugh class B]), controlled narrow-angle glaucoma, history of prolonged QT interval, bladder outflow obstruction, or decreased GI motility

Antispasmodic drugs These agents relax the smooth muscles of the urinary bladder. Increase bladder capacity and effectively decrease or eliminate urge incontinence The adverse effect profile of antispasmodic drugs is similar to that of anticholinergic agents. May impair the ability to perform activities requiring mental alertness and physical coordination. Drinking alcohol and using sedatives in combination is contraindicated

Flavoxate ( URISPAS) is used for symptomatic relief of dysuria, urgency, nocturia, and incontinence, as may occur in cystitis, prostatitis, urethritis, and urethrocystitis. It exerts a direct relaxant effect on smooth muscles via phosphodiesterase inhibition. Relief for a variety of smooth muscle spasms. The usual dosage is 100-200 mg 3-4 times per day.

Dicyclomine ( MERBENTYL) is a smooth muscle relaxant that has been used most commonly to treat irritable bowel syndrome. Moderate efficacy has been reported with a dosage of 10-20 mg taken orally 3 times daily. Adverse effects mostly are anticholinergic.

Beta-adrenergic agonists

Estrogen Estrogen therapy may have several positive effects in patients with stress incontinence who are estrogen deficient. Estrogen may increase the density of alpha-receptors in the urethra. In addition, the vascularity of the urethral mucosa is increased and the coaptive abilities of the urethral mucosa may be augmented A number of small studies show oral estrogen therapy to be of no clinical benefit to women with stress incontinence or detrusor overactivity Only few cured (0-14%) but subjective improvement in 29-66% of women

Botulinum toxin A neurotoxin produced by Clostridium botulinum, onabotulinumtoxinA (Botox) prevents acetylcholine release from presynaptic membrane In August 2011, was approved by FDA for urinary incontinence in patients with neurologic conditions who have overactive bladder In January 2013, the FDA expanded the approved use of onabotulinumtoxinA to treat adults with overactive bladder who cannot use or do not adequately respond to anticholinergic drugs

The ABC trial (Anticholinergic therapy vs onabotulinum toxinA for urgency incontinence) shed some light on the utility of 100 units of onabotulinum toxinA in the setting of overactive bladder. The data have shown comparable efficacy of 100 units of onabotulinum toxinA to anticholinergic medications with reduced systemic side effects in the onabotulinum toxinA-injected group Yet higher rates of retention and urinary tract infections

Intravesical pharmacotherapy Capsaicin, the main pungent ingredient of hot peppers, has been evaluated for the treatment of detrusor overactivity and neurogenic detrusor overactivity. The proposed mechanism is through desensitization of capsaicin-sensitive unmyelinated afferents. Neuronal damage through osmotic swelling also may occur. Improvement rates of 40-100% have been reported. Observation has ranged from 1-60 months. In the largest of these series, 44% of patients with neurogenic detrusor overactivity secondary to multiple sclerosis were dry.

Lidocaine, 1%, is administered intravesically 5-15 minutes before capsaicin is administered. Approximately 50-100 mL of 1-2 mmol capsaicin is mixed in 30% ethanol with saline. The solution is left in the bladder for approximately 30 minutes Adverse effects can include transient worsening of irritative symptoms or incontinence, perineal pain, a burning sensation, hematuria, and UTI Administration of capsaicin is best accomplished under general anesthesia In one small study, some patients who failed capsaicin therapy responded to resiniferatoxin.

Intravesical oxybutynin has been used in patients who are nonresponsive or have severe adverse effects. The medication is self-administered following clean catheterization. Tissue and plasma concentration of the drug are higher after intravesical administration than after oral administration. Despite higher plasma levels, adverse effects appear to be minimal. A hepatic metabolite may be responsible for many of the adverse effects observed after oral administration.