medications for incontinence

by Diane K. Newman, RNC, MSN, CRNP, FAAN

Depending on either the symptoms or the result of a diagnostic evaluation, urinary incontinence (UI) and overactive bladder (OAB) may be treated with medication. Individuals whose overactive bladder (OAB) is secondary to excessive contractions of the bladder (detrusor) muscle (detrusor hyperreflexia) may be treated with drugs that reduce excessive bladder (detrusor) contractions. Other individuals who have an underactive detrusor muscle will require treatment with drugs that stimulate contractions in the detrusor muscle. If the primary symptoms in the individual result from excessive urethral sphincter contraction, drugs that relax the urethral sphincter may be indicated.

The attached Table is a list of common drugs used for UI. OAB with urge incontinence and detrusor hyperreflexia are the two most common causes of urinary incontinence that have been treated successfully by drug therapy.

Drugs used to treat these conditions affect the autonomic neuromuscular function of the bladder and detrusor muscle. Detrusor muscle instability may be treated with anticholinergics because of the drug’s ability to cause relaxation of the smooth muscle of the bladder. This treatment increases the volume that stimulates a detrusor contraction, while decreasing the strength of that contraction and the total bladder capacity. Currently there are many anticholinergic preparations available for the pharmacologic treatment of the OAB. In individuals with involuntary bladder contractions, anticholinergic agents will increase the volume to the first involuntary bladder contraction, decrease the amplitude of that contraction and increase bladder capacity. However, the drug will not change the "warning time" thus, drug therapy must always be combined with behavioral therapy to achieve optimal results in OAB (Wein, 1998).

One of the first antimuscarinic preparations developed was oxybutynin (Ditropan®), which was originally developed to treat gastrointestinal disorders. Oxybutynin is an anticholinergic and direct smooth muscle relaxant that is usually taken several times a day and is referred to as an immediate release drug. It blocks the contraction of the bladder by relaxing the bladder muscles. Although it is efficacious, the major drawback is it's adverse effects that are often severe enough to cause individuals to discontinue treatment. Of particular concern is bothersome "dry mouth," which occurs in 61% to 78% of individuals receiving generic oxybutynin. Attempts to minimize the side effects of oxybutynin have included intravesically -administered (directly into the bladder) doses in individuals with pre-existent or intermittent catheters, transdermal (skin) patches, and the development of a controlled-release delivery system incorporating the OROS osmotic drug delivery system in a new drug called Ditropan XL®. This new formulation of oxybutynin is taken once a day and its delivery system allows for the drug to be released over a 24-hour period (extended release). Research has shown that extended-release oxybutynin taken once daily has comparable efficacy to the immediate-release formulation (three times daily) at the same total daily dosage. The extended-release formulation has been associated with a significant reduction in "dry mouth" compared with the immediate-release formulation. Oxybutynin is also associated with gastrointestinal and central nervous system side effects.

Another new drug, tolterodine (Detrol®) has been introduced for the management of overactive bladder. Tolterodine is the first antimuscarinic to be developed specifically for overactive bladder, that has a low incidence of dry mouth. At the normal dosage of 2mg twice daily, tolterodine is well tolerated and effective in the management of all symptoms of overactive bladder, resulting in meaningful improvements for individuals. Tolterodine appears to lack many of the limitations of other antimuscarinic medications available for the treatment of overactive bladder. Studies show that fewer individuals taking tolterodine suffer from dry mouth and other gastrointestinal side effects when compared with oxybutynin at a therapeutically equivalent dosage (i.e. 5mg three times per day). A new extended release (ER) formulation of tolterodine, at a dosage of 4mg qd, provides significant improvements in the symptoms of overactive bladder in women and was 18 percent more effective than the immediate release formulation in a comparative study. Moreover, compared with the existing IR (immediate release) tablet formulation, tolterodine ER is significantly more effective in reducing incontinence episodes.

At this time, there are no studies that compare the efficacy and tolerability of Detrol LA® and Ditropan XL®. These are both extended release drugs.

Many clinicians have found that tricyclic antidepressants, particularly imipramine hydrochloride, are especially useful for facilitating urine storage, both by decreasing bladder contractility and by increasing outlet resistance. (Barrett) Imipramine, a tricyclic antidepressant, has a dual action when used to treat urinary incontinence. It decreases bladder contractions through its anticholinergic effects and increases urethral resistance to outflow through its alpha-agonist properties. It should be noted that imipramine is officially approved by the FDA for enuresis in children but not for adults. Side effects may include postural hypotension and cardiac conduction disturbances in older individuals. Older individuals with known cardiac conduction problems should avoid treatment with this category of drugs unless the benefits outweigh the risks.

Hyoscyamine (Cystospaz®) and hyoscyamine sulfate (levsin, cystospaz-M) are reported to have about the same anti-cholinergic actions and side effects as other drugs of this classification. Flavoxate (Urispas®) has a direct spasmolytic as well as anticholinergic effect on smooth muscle. Research has not demonstrated the efficacy of these drugs.

Another used drug is propantheline (Pro-Banthine®), which has antimuscarinic and ganglionic-blocking effects. Even in young individuals, the drug has a high incidence of side effects and it must be used with caution in the individual with glaucoma, coronary artery disease, or prostatism. Elderly individuals are especially prone to confusion, agitation, and orthostatic hypotension with propantheline. When using this medication, post-void urine residuals should be monitored to avoid urinary retention.

Bethanechol (Duvoid®, Myotonachol®, Urecholine®) is a cholinergic drug that is used to treat bladder (detrusor) underactivity in those individuals with incomplete bladder emptying. This drug is contraindicated in individuals with asthma, bradycardia and Parkinson's disease. Its side effects include sweating and excessive salivation which are often considered intolerable. All anticholinergic agents are contraindicated in individuals with documented narrow-angle glaucoma.

In individuals with stress incontinence, pharmacologic therapy should be focused on using agents that increase bladder outlet resistance through their actions on the bladder neck and base, and on the proximal urethra. Sympathomimetic drugs with alpha-adrenergic agonist actions are the agents of choice. The two most commonly used sympathomimetic agents were phenylpropanolamine (PPA), which was found in agents such as Ornade and Sudafed. Both of these medications are OTC drugs that are commonly used as decongestants. Phenylpropanolamine is believed to stimulate alpha-adrenergic receptors and increase bladder outlet resistance. Side effects of this class of drug include tachycardia, elevated blood pressure, stomach cramping, nervousness, respiratory difficulty and dizziness. Because of these side effects, the FDA recommended that phenylpropanolamine be removed from all OTC products. Therefore these drugs are no longer available for stress UI.

Another group of medications for women that have recently received more positive attention are hormones (estrogens). Estrogen therapy has the potential to treat urge and mixed UI and OAB symptomatology in postmenopausal women. Although there are multiple mechanisms by which estrogen might favorably affect lower urinary tract function, opinion is divided as to whether low dose local (topical) therapy or systemic therapy can, per se, ameliorate irritative lower urinary tract symptoms in the post menopausal female (Cardozo, 1997.)

Estrogens can restore the integrity of the urethral mucosa and thus, increase resistance to outflow. Estrogens are either used systemically or topically. The following side effects have been reported: endometrial cancer, fluid retention, depression, nausea, vomiting, elevated blood pressure, gallstones, and cardiovascular effects such as stroke and myocardial infarction. A cyclic topical application is preferred because of its decreased side effect. Local administration is felt to be more effective for reducing frequency of recurrent UTIs and other urogenital symptoms than oral therapy. Estrogen supports colonization of the vaginal vault by lactobacilli. Lactobacilli produce lactic acid, which keeps vaginal pH low thus preventing the growth of bacteria, e.g. Escherichia (E Coli). The change in pH is felt to change the entire urogenital environment leading to UTIs, pelvic organ prolapse, UI and OAB. Studies have shown that estrogen therapy provides significant protection from UTIs. (Cardozo, Bachmann, McClish, et al., 1998) It is believed that when there is a vaginal response to estrogen there will be a similar response in urethra and bladder mucosa. (Carson, Choiken, Haney, Staskin, 2000) In elderly women with diagnosed atrophic vaginitis who reside in nursing homes or in their own homes, a low dose of conjugated vaginal estrogen cream applied to urogenital tissues either intravaginally or externally for 6 weeks was found to be effective in reducing vaginal pH. (Maloney & Olsen, 2001) Local application of estrogen may also prevent recurrent UTIs especially in women with recurrent infections (Maloney, 1998). It is also felt that lower systemic absorption of estrogen results from intravaginal administration compared with oral administration.

The traditional form of local estrogen therapy is an estrogen vaginal cream. A fingertip’s worth of estradiol cream weighs about 1 g., which equals 0.1 mg of estradiol. This form of topical application as vaginal cream must be measured by user and may be difficult to insert. The cream can leave a residue on the vulva and undergarments, and necessitate deferring sex.

There are two relatively new low-dose Estrogen drug delivery systems: an estrodial vaginal ring (Estring®) and vaginal tablets (Vagifem®). The ring is soft, slightly opaque, and flexible. It is inserted into the upper part of the vagina as a contraceptive diaphragm would be. The ring releases a steady, low dose of estrogen that is absorbed into the vaginal tissues over a period of three months. The estrodial release rate is determined through the silicone ring and remains constant at 7.5 mg/24 hours for a period of 90 days. (Caspar, Petri, et.al. 1999) It normally takes 2 to 3 weeks after insertion to feel the full effects of the ring. Estradiol vaginal tablets are small white film coated, hydrophilic tablets containing 25 mg of estradiol. The tablet is contained in a disposable single-use applicator used for insertion of the tablet into the vagina. A gel layer forms when the tablet comes in contact with the vagina. The estradiol is released from this gel layer. The advantages to topical versus oral HRT are that there are beneficial effects on vaginal and urinary symptoms and mucosal appearance without provoking withdrawal bleeding from the endometrium.

There are several new medications currently in development for UI and OAB. They are*:

Darifenacin – is a drug for OAB that is a muscarinic antagonist that is selective for the smooth muscle of the bladder and may not affect the salivary glands thus may not cause the side effect of dry mouth.
Oxybutynin – transdermal (Oxytrol) – is a drug for OAB that is convenient once a day administration using a skin patch. It is felt that this form of drug delivery may decrease common side effects seen with other drugs taken orally.
Duloxetine – is a drug for stress UI that stimulates the release of nerve transmitters from the pudendal nerve in the pelvis causing the urethral sphincter to contract thus preventing urine leakage.
Trospium chloride is an anticholinergic drug for the treatment of OAB that may have a reduced potential for side effects such as somnolence.

* These drugs have not yet been approved by the FDA for use in the United States.

Table: Drug Therapy for Urinary Incontinence

Conjugated Estrogens(Premarin) Estradiol vaginal cream (Estrace) Estradiol vaginal tablets (Vagifem)	Hormone replacement therapy restores the integrity of the urethral mucosa and increases resistance to outflow. It is felt that estrogens may restore urethral mucosal coaptation and increase vascularity & tone.	Topical conjugated estrogens: 0.3 to 1.25 mg/day topically @ hr. Apply for 3 wk on and 1 wk off. Oral Estradiol: 500 µ to 2 mg continuously or cyclicly Insert 2 to 4 g (marked on applicator or 1 fingertip) dose for 10 days 1 g twice a week Insert 25 mg tab every day x 2 weeks, then 1 tab twice weekly.	Endometrial cancer, fluid retention, depression, nausea, vomiting, elevated blood pressure, gallstones and cardiovascular effects./td>	May benefit individuals with stress UI and mixed UI. Women with a uterus need oppositional therapy with progesterone when oral estrogens are prescribed. Contraindicated in individuals with known or suspected breast or uterine cancer. Women already taking oral hormones may benefit from topical application.
Tolterodine tartrate (Detrol, Detrol LA)	Anticholinergic agent that inhibits cholinergic muscarinic receptors in the bladder	2 mg twice a day 4 mg daily (LA) In Special populations –1 mg twice a day 2 mg daily (LA)	Dry mouth, dyspepsia, headache, constipation and xeropthalmia	Indicated for individuals with an overactive bladder with symptoms of urinary frequency, urgency, or urge UI. May cause urinary retention.
Oxybutynin (Ditropan, Ditropan XL)	Anticholinergic agent that blocks bladder contraction by relaxing the bladder muscles	5 mg twice or three times a day 5 mg daily (Ditropan XL) In Special populations 2.5 – 5 mg twice a day Titrate: Increase by 2.5 mg increments every 1 – 2 days as needed	Dry mouth, blurred vision, constipation, increased intraocular pressure, delirium or confusion, cardiac disturbances	May cause urinary retention. Sometimes useful at bedtime in individuals with nocturia and nocturnal enuresis.
Imipramine (Tofranil) (can be effective in both stress and urge UI)	Tricyclic anti-depressant and anticholinergic that decreases bladder contractions and increases urethral resistance to outflow	10 mg to 25 mg three times a day (but usually given at bedtime)	Postural hypotension, Cardiac conduction disturbances	FDA has approved for enuresis in children but not in adults
Propantheline (Probanthine)	Tertiary amine that is a smooth muscle relaxant	15 mg to 30 mg every 4 to 6 hrs	Confusion, agitation & orthostatic hypotension	High incidence of side effects, especially in the elderly. Use with caution in individuals with glaucoma, CAD or prostatism

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Posted October 2001