CASE 55

A 48-year-old Caucasian woman you have been treating for several years comes to your family medicine practice and seems embarrassed. She complains of urinating at least 10 times a day and 3 to 4 times at night and states it is interfering with her business and social life. She indicates her problem, which she says is “due to her getting older,” began about 2 years ago. She has tried several things to help, including drinking only one cup of coffee in the morning and total avoidance of liquid after 6 PM. She has begun wearing pads to avoid the embarrassment of leakage. She describes being in an important business meeting and having to get up and leave to go to the bathroom. She constantly worries about the location of the nearest bathroom and has avoided social events like her son’s soccer games, which are on an open field with no facilities. Upon further questioning she denies leakage with coughing, sneezing, or laughing. She denies any dysuria, hematuria, or feeling of incomplete voiding. She is monogamous without any prior history of sexually transmitted infections (STIs). You assure her the problem is not due to “getting old” and that there are treatable medical causes for the problem. Your physical examination is negative for STIs, vulvar or vaginal inflammation/infection/trauma, and cystocele. You order a urinalysis which comes back normal. You prescribe a trial of oxybutynin.

What are the causes of overactive bladder?

What is the mechanism of action of oxybutynin?

What are the different classes of agents used in the treatment of the different kinds of urinary incontinence?

ANSWERS TO CASE 55

Urinary Incontinence

Urge incontinence (see below for other forms of UI) is caused by contraction of the bladder such that urine passes the urethral sphincter at the wrong time.

Oxybutynin is an anticholinergic drug that blocks muscarinic cholinergic receptors. M3 cholinergic receptors are responsible for the direct activation of the detrusor muscle. Oxybutynin decreases frequency of symptoms, and delays initial desire to void.

CLINICAL CORRELATION

There are several types of urinary incontinence and they have different causes. Urge incontinence as described in this case is typified as urinating more than eight times a day accompanied by a sudden and intense urge to urinate, frequently followed by involuntary loss of urine. The detrusor muscle contracts well before the bladder has filled and may give a warning of only a few seconds before the bladder sphincter muscle relaxes. The fundamental problem seems to be neuromuscular in origin. Contraction of the detrusor muscle is mediated by M3 cholinergic receptors. Urge incontinence may be caused by urinary tract infections, bladder irritants, bowel disease, Parkinson disease, Alzheimer disease, stroke, or nervous system damage associated with multiple sclerosis. If there’s no known primary cause, urge incontinence is also called overactive bladder.

Stress urinary incontinence (SUI) occurs upon sneezing, laughing, coughing, or other maneuvers that increase intra-abdominal pressure in the presence of a weakened bladder sphincter. Urethral pressures, prolapse conditions, and congenital and acquired sphincteric dysfunction all contribute to SUI pathophysiology. In women, childbirth, pregnancy, and menopause can cause stress incontinence; in men, prostate removal is a cause.

Overflow incontinence is a frequent near-constant loss of urine caused by inability to void. This usually has an anatomical or neural cause that interferes with normal emptying of the bladder. Mixed incontinence refers to a combination of types. The most common type of urinary incontinence in older women is a mixture of urge and stress incontinence. Treatments include lifestyle and behavioral modifications, drugs, and surgery.

Often the detailed history and examination is sufficient to give a presumptive diagnosis; however, various testing may be needed to rule out other contributing or causative etiologies. On occasion diagnostic testing, radiographic testing, and laboratory testing may be required as well.

APPROACH TO:

Pharmacology of Agents that Act on the Urinary Tract

OBJECTIVES

1. List the drugs that are used in cases of urinary incontinence.

2. Describe the mechanism of action, route of administration, and adverse effects of these drugs.

DEFINITIONS

Urinary incontinence is the inability to control urine flow. It can be associated with decreased quality of life and social withdrawal. Elucidating the type of urinary incontinence guides management.

DISCUSSION

Urinary incontinence affects 10 to 70 percent of women depending somewhat on ethnicity, and prevalence increases with age. Annual medical costs are estimated at over $16 billion, which exceeds breast and ovarian cancer combined.

Class

Pharmacologic treatment depends on the type of urinary incontinence. Conservative management of urge incontinence includes behavioral techniques and lifestyle changes. Behavioral techniques include pelvic floor muscle training (PFMT, Kegel exercises), vaginal devices, and bladder training; lifestyle modifications include weight management; reducing alcohol consumption, smoking, and caffeine; and liquid intake reduction. A mainstay of pharmacologic management is anticholinergic therapy. The bladder contraction is controlled mostly by M2 and M3 muscarinic cholinergic receptors, and the direct contraction of the detrusor muscle via M3 receptors is most important. First-line agents include oxybutynin and tolterodine, and if these are ineffective solifenacin, trospium, darifenacin, fesoterodine, and tropantheline may be used. Oxybutynin has some specificity for M3 cholinergic receptors but also blocks M2 and M1, all of which are present in the bladder. Tricyclic antidepressants such as imipramine can be used if anticholinergics fail. A combination of tricyclics in conjunction with oxybutynin may be used cautiously for a synergistic effect.

Tolterodine, solifenacin, arifenacin, and fesoterodine are “second-generation” antimuscarinics with reduced central nervous system penetration and have better selectivity for the M3 subclass of acetylcholine receptors, resulting in improved tolerability. Tolterodine is better tolerated than oxybutynin with less moderate-to-severe dry mouth and fewer dropouts because of medication side effects but is not as effective.

Solifenacin in another antimuscarinic that has proven effective in patients with urge incontinence who have not responded to tolterodine or oxybutynin. It has a long elimination half-life that permits once-a-day dosing.

For stress incontinence caused by urethral sphincter insufficiency, the first-line pharmacologic therapy is pseudoephedrine, if there are no contraindications. Tricyclics such as amitriptyline or imipramine can be useful in mild or moderate cases. Although the cure rates are low, subjective improvement rates are moderate. This is also useful in patients who are considered a high surgical risk. Estrogen can be used as an adjunct in postmenopausal women with stress incontinence. There are many surgical procedures that have been developed for urinary incontinence. Most act to support the function of the urinary sphincter.

Structure

Oxybutynin is a tertiary amine. It supplied as a mixture of the (R)- and (S)- enantiomers; the (S)-enantiomer has little anticholinergic activity.

Adverse Effects

Common adverse effects associated with oxybutynin and other antimuscarinic anticholinergics include dry mouth, difficulty in urination, constipation, blurred vision, drowsiness, and dizziness. Anticholinergics have also been known to induce delirium. Dry mouth may be particularly severe especially with oxybutynin; one estimate is that 25 to 50 percent of patients who begin oxybutynin treatment may have to stop because of dry mouth. N-Desethyloxybutynin is an active metabolite of oxybutynin that is thought to be responsible for much of the adverse effects of the drug.

Administration

Oxybutynin is available as an oral, transdermal, or topical agent.

COMPREHENSION QUESTIONS

55.1 The most frequent adverse effect seen with anticholinergic drugs used to treat urge incontinence is

A. Anxiety

B. Dry mouth

C. Sweating

D. Elevated blood pressure

55.2 A female patient complains of urinary leakage when she coughs or sneezes. This has not improved after 2 months of pelvic floor training including Kegel exercises, and a trial of tolterodine. Her blood pressure is 160/100 mm Hg. Which of the following would be optimal to add on to her therapy?

A. Oxybutynin

B. Pseudoephedrine

C. Amytriptyline

D. Desmopressin

ANSWERS

55.1 B. Common side effects of antimuscarinic drugs are dry mouth, blurred vision, fatique, and dizziness. Antimuscarinic drugs also reduce sweating; this increases the risk of overheating and heat stroke.

55.2 C. Pharmacologic treatment of stress incontinence includes sympathomimetics such as pseudoepedrine, which would be contraindicated here because of the hypertension. A combination of a tricyclic like amitriptyline and an anticholinergic appears to provide a synergistic effect that can work in refractory cases.

PHARMACOLOGY PEARLS

Assessing the type of urinary incontinence is critical to select the correct course of treatment.

Use of anticholinergics have modest but important benefits to the quality of life, but discontinuation of drugs is high.

REFERENCES

Shamliyan T, Wyman JF, Ramakrishnan R, Sainfort F, Kane RL. Benefits and harms of pharmacologic treatment for urinary incontinence in women: a systematic review. Ann Intern Med 2012;156(12):861–74.

Madhuvrata P, Cody JD, Ellis G, Herbison GP, Hay-Smith EJ. Which anticholinergic drug for overactive bladder symptoms in adults. Cochrane Database Syst Rev 2012, Jan 18;1:CD005429.

Hartmann KE, McPheeters ML, Biller DH, Ward RM, McKoy JN, Jerome RN, Micucci SR, Meints L, Fisher JA, Scott TA, Slaughter JC, Blume JD. Treatment of overactive bladder in women. Evid Rep Technol Assess 2009;187:1–120.