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Drugs for overactive bladder

by Diane K. Newman, DNP, FAAN, BCB-PMD

Medications for overactive bladder and urinary incontinence can be effective treatments.

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Depending on either the symptoms of urinary  incontinence or the result of a diagnostic evaluation, various medications will be used for treatment. 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 table below shows a list of common drugs used for urinary incontinence. Overactive bladder 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 overactive bladder. 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 overactive bladder (Wein, 1998).

Antimuscarinic drugs for overactive bladder

Oxybutynin (Ditropan®)
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.

Tolterodine (Detrol®)
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 urinary 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.

Tricyclic Antidepressants
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.

Medications for stress incontinence

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.

Estrogens for stress incontinence

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 urinary incontinence and overactive bladder 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, urinary incontinence and overactive bladder. 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.

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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 urinary incontinence and overactive bladder. They are*:

  • Darifenacin – is a drug for  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.overactive bladder
  • Oxybutynin – transdermal (Oxytrol) – is a drug for overactive bladder 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 urinary incontinence 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 overactive bladder that may have a reduced potential for side effects such as somnolence.

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

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

References

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Cardozo, L, Bachmann, G, McClish, D, et al., (1998) Meta-analysis of estrogen therapy in the management of urogenital atrophy in post-menopausal women: second report of the Hormones and Urogenital Therapy Committee, Obstetrics and Gynecology. 92(4 pt 2): 722-727.

Cardozo L. (1997) Discussion: The effect of estrogens. Urology. 50 (6A suppl):85.

Carson, CC, Chaikin, D, Haney, AF, Staskin, DR, (2000) Urogenital Consequences of Estrogen Deficiency. Contemporary Urology. Nov. Supplement: 3-12.

Casper, F., Petri, E. and the Vaginal Ring Study Group (1999) "Local Treatment of Urogenital Atrophy with an Estradiol-Releasing Vaginal Ring: A Comparative and a Placebo-Controlled Multicenter Study Int Urogynecol J , 10:171-176.

Lackner, TE. (2000) Pharmacologic management of urinary incontinence. Annals of Long-Term Care 8(2):29-37.

Maloney, C, Oliver, ML, (2001) Effect of Local Conjugated Estrogens on Vaginal pH in Elderly Women. J Am Med Dir Assoc. March/April. 2:51-55

Maloney, C. (1998) Hormone replacement therapy in female nursing home residents with recurrent urinary tract infection. Annals of Long-Term Care 6(3):77-82.

Mouritisen, L., Frialoney C. (1997) Estrogen in urinary incontinence treatment: an anatomic and physiologic approach. Urologic Nursing 17(3): 88-91.

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Newman, DK. (1998) Controversies in Incontinence. The Clinical Letter for Nurse Practitioners, 2(6), November/December: 1-8.

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Additional References

Abrams, P., Freeman, R., Anderstrom, C., Mattiasson, A. (1998) Tolterodine, a new anti-muscarinic agent: as effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol ;81:801–810.

Abrams, P., Wein, AJ, eds. The overactive bladder: From basic science to clinical management.Urology. 1997;50(6 suppl):1-3.

Abrams, P., Koury, S., Wein, A. International Consultation on Incontinence Plymouth, UK: Health Publications, Ltd., 1999.

Anderson RU, Mobley, D., Blank., et al. Once daily controlled versus immediate-release oxybutynin chloride for urge urinary incontinence. OROS® Oxybutynin Study Group. J Urol 1999;161:1809–1812.

Appell, Sand, P., Dmochowski, R. et al for the OBJECT Study Group. Prospective randomized controlled trial of extended-release oxybutynin chloride and tolterodine tartrate in the treatment of overactive bladder. Mayo Clin Prac.2001;76:358-363.

Chancellor, M., Freedman, S., Mitcheson, D., Antoci, A., Primus, G., Wein, A. Tolterodine, an effective and well tolerated treatment for urge incontinence and other overactive bladder symptoms. Clin Drug Invest 2000;19:83–91.

Chancellor, MB, Appell, RA, Sathyan, G., Gupta, SK. A comparison of the effects on saliva output of oxybutynin chloride and tolterodine tartrate. Clin Ther 2001;23:753-760.

Davila, GW., Daugherty, CA, Sanders, SW for the Transdermal Oxybutynin Study Group. A Short-term multicenter, randomized double blind dose titration study of the efficacy and anticholinergic side effects of transdermal compared to immediate release oral oxybutynin treatment of patients with urge urinary incontinence. J of Urology 2001;166:140-145.

Hampel, C., Wienhold, D., Benken, N., et al. Definition of overactive bladder and epidemiology of urinary incontinence. Urology. 1997;50(6A suppl):4-14.

Hu, TW., Wagner, TH. Economic considerations in overactive bladder. Am J of Managed Care 2000., 6(11):S591-598.

Katz, IR, Sands, LP., Bilker, W., DiFillippo, S., Boyce, A., D’Angelo, K. Identification of medications that cause cognitive impairment in older people: the case of oxybutynin chloride. J Am Geriatr Soc 1998;46:8–13.

Kobelt G. Kirchberger, I and Malone-Lee, J., Quality of life aspects of the overactive bladder and the effect of treatment with tolterodine. BJU International 1999, 83, 583-90.

Milsom, I., Abrams, P., Cardozo, L., Roberts, RG., Thuroff, J., Wein, AJ., How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU International. 2001. 87:760-766.

Newman, DK. The Urinary Incontinence Sourcebook, 2nd Ed., 1999, Lowell House, California

Nilvebrant, L. The mechanism of action of tolterodine. Rev Contemp Pharmacother 2000;11:13–27.

Payne, CK. Epidemiology, pathophysiology and evaluation of urinary incontinence and overactive bladder. Urology. 1998a;51(2A suppl):3-10.

Thom, D. Diagnosis of a hidden disorder. The Practice Journal for Primary Care Physicians. A Supplement to Patient Care. Winter 2000;6–14.

Versi, E, Appell, R., Mobley, D., Patton, W., Saltzstein, D., Ditropan XL Study Group. Dry mouth with conventional and controlled-release oxybutynin in urinary incontinence. Obstet Gynecol 2000;95:718–721.

Wein, AJ, et al. Overactive bladder survey. Evaluates the extent of symptoms in family doctor setting. Fam Urol 2000;V:7–8.

Wein, AJ. Pharmacological agents for the treatment of urinary incontinence due to overactive bladder. Exp Opin Invest Drugs 2001;10(1):65-83.

Yarker, E, et al. Oxybutynin: a review of its pharmacodynamics and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging 1995;6:243–262.

Posted October 2001
Last Updated July 2009

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