Medication Summary
The goal of therapy is to improve the symptoms of frequency, nocturia, urgency, and urge incontinence. Pharmacologic treatment options include anticholinergics, antispasmodic agents, tricyclic antidepressants (TCAs), and beta-3-adrenergic receptor agonists.
In patients with stress incontinence, alpha agonist treatment results in contraction of the internal urethral sphincter and increases the urethral resistance to urinary flow. Sympathomimetic drugs, estrogen, and tricyclic agents increase bladder outlet resistance to improve symptoms of stress urinary incontinence.
Pharmacologic therapy for stress incontinence and an overactive bladder may be most effective when combined with a pelvic exercise regimen. The 3 main categories of drugs used to treat urge incontinence include anticholinergic drugs, antispasmodics, and TCAs.
When a single drug treatment does not work, a combination therapy such as oxybutynin (Ditropan) and imipramine (Tofranil) may be used. Although their mechanism of action differs, oxybutynin and imipramine work together to improve urge incontinence.
Oxybutynin causes direct smooth muscle relaxation of the urinary bladder and has local anesthetic properties. Imipramine has a direct inhibitory and local anesthetic effect on the bladder smooth muscle, similar to oxybutynin; however, imipramine also increases the bladder outlet resistance at the level of the bladder neck. Thus, the combination of these drugs produces a synergistic effect to relax the unstable bladder and to hold in urine and prevent urge incontinence. Potential anticholinergic adverse effects may be additive because both drugs have similar adverse reactions.
Beta-3 adrenergic receptor agonists (eg, mirabegron, vibegron) cause relaxation of the detrusor muscle and increased bladder capacity. These agents are indicated for overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency.
Alpha-Adrenergic Agonists
Class Summary
The bladder neck contains a high concentration of receptors that are sensitive to alpha-agonists. Alpha-agonists increase bladder outlet resistance by contracting the bladder neck. These agents are beneficial in the treatment of mild to moderately severe stress incontinence in women.
Midodrine
The active metabolite of midodrine, desglymidodrine, is an alpha1-agonist that may increase bladder outlet resistance.
Pseudoephedrine hydrochloride (Sudafed, Genaphed, SudoGest)
Pseudoephedrine helps stress incontinence. The subjective improvement and cure rates are similar to that of phenylpropanolamine, which was recalled from the US market. Pseudoephedrine stimulates vasoconstriction by directly activating alpha-adrenergic receptors.
Anticholinergic Agents
Class Summary
These agents represent first-line medicinal therapy in women with urge incontinence. These agents are useful in treating urinary incontinence associated with urinary frequency, urgency, and nocturnal enuresis.
Anticholinergic agents inhibit the binding of acetylcholine to the cholinergic receptor, thereby suppressing involuntary bladder contraction of any etiology. In addition, they increase the urine volume at which first involuntary bladder contraction occurs, decrease the amplitude of the involuntary bladder contraction, and may increase bladder capacity.
All anticholinergic drugs have a similar performance profile and toxicity. Potential adverse effects of all anticholinergic agents include blurred vision, dry mouth, heart palpitations, drowsiness, and facial flushing. When anticholinergic drugs are used in excess, the bladder may go into acute urinary retention.
All drugs with anticholinergic effects or side effects are contraindicated if patients have documented narrow-angle glaucoma. Wide-angle glaucoma is not a contraindication to their use.
Other contraindications to anticholinergic use are urinary retention, bowel obstruction, ulcerative colitis, myasthenia gravis, and severe heart diseases. Because of the potential for drowsiness—especially when combined with alcohol, sedatives, or hypnotic drugs—these agents may impair the patient's ability to perform hazardous activities, such as driving or operating heavy machinery.
Dicyclomine hydrochloride (Bentyl)
An anticholinergic agent with smooth muscle relaxant properties, dicyclomine blocks the action of acetylcholine at parasympathetic sites in secretory glands and smooth muscle.
Darifenacin (Enablex)
Darifenacin is an extended-release product eliciting competitive muscarinic receptor antagonistic activity. It reduces bladder smooth muscle contractions. Darifenacin has high affinity for M3 receptors involved in bladder and GI smooth muscle contraction, saliva production, and iris sphincter function. It is indicated for overactive bladder with symptoms of urge incontinence, urgency, and frequency. Swallow whole; do not chew, divide, or crush.
Solifenacin succinate (VESIcare)
Solifenacin elicits competitive muscarinic receptor antagonist activity, which results in anticholinergic effects and inhibition of bladder smooth muscle contraction. This agent is indicated for overactive bladder with symptoms of urgency, frequency, and urge incontinence. It must be swallowed whole; do not crush or chew.
Hyoscyamine sulfate (Levsin/SL, Levsin, Levsinex, Cystospaz-M, Levbid)
Hyoscyamine blocks the action of acetylcholine at parasympathetic sites in smooth muscle, secretory glands, and the CNS, which in turn has antispasmodic effects. Hyoscyamine is absorbed well by the GI tract. Food does not affect absorption of this drug. Hyoscyamine is available in sublingual form (Levsin SL, Symax SL), conventional tablets (Levsin), and extended-release tablets (Levbid).
Propantheline (Pro-Banthine)
A prototypical anticholinergic agent, propantheline blocks action of acetylcholine at postganglionic parasympathetic receptor sites.
Tolterodine (Detrol and Detrol LA)
Competitive muscarinic receptor antagonist for overactive bladder. However, it differs from other anticholinergic types in that it has selectivity for urinary bladder over salivary glands. Exhibits a high specificity for muscarinic receptors, has minimal activity or affinity for other neurotransmitter receptors and other potential targets such as calcium channels. In clinical studies, the mean decrease in urge incontinence episodes was 50% and the mean decrease in urinary frequency was 17%. The mean decrease in urge incontinence episodes per wk was 53% for Detrol LA 4 mg qd.
Trospium (Sanctura)
Quaternary ammonium compound that elicits antispasmodic and antimuscarinic effects. Antagonizes acetylcholine effect on muscarinic receptors. Parasympathetic effect reduces smooth muscle tone in the bladder. Indicated to treat symptoms of overactive bladder (eg, urinary incontinence, urgency, frequency).
Fesoterodine (Toviaz)
Competitive muscarinic receptor antagonist. Antagonistic effect results in decreased bladder smooth muscle contractions. Indicated for symptoms of overactive bladder (eg, urinary urge incontinence, urgency, and frequency). Available as 4- or 8-mg extended-release tab.
Antispasmodic Drugs
Class Summary
These agents relax the smooth muscles of the urinary bladder. By exerting a direct spasmolytic action on the smooth muscle of the bladder, these medications have been reported to increase bladder capacity and effectively decrease or eliminate urge incontinence.
The adverse effect profile of antispasmodic drugs is similar to that of anticholinergic agents. These drugs may impair the ability to perform activities requiring mental alertness and physical coordination. Drinking alcohol and using sedatives in combination with these antispasmodic drugs is contraindicated.
In 2001, Appell et al reported the results of the Overactive Bladder: Judging Effective Control and Treatment (OBJECT) trial. This was a large double-blind, multicenter, prospective, randomized controlled study that compared the efficacy and tolerability of oxybutynin (Ditropan XL) (n = 160) with that of tolterodine (Detrol) (n = 170) in men and women with symptoms of overactive bladder. The study concluded that oxybutynin 10 mg was statistically superior to tolterodine 2 mg bid in terms of efficacy. However, both drugs had similar adverse-effect profiles. [69]
Oxybutynin chloride (Ditropan IR, Ditropan XL, Gelnique)
Both the immediate-release and the extended-release forms of oxybutynin have both an anticholinergic and a direct smooth muscle relaxant effect on the urinary bladder. In addition, oxybutynin provides a local anesthetic effect on the irritable bladder.
The human detrusor has M2 and M3 muscarinic receptors. The M3 receptor mediates contractile response of human detrusor. Oxybutynin has greater affinity for the M3 receptor. Urodynamic studies have shown oxybutynin increases bladder size, decreases frequency of symptoms, and delays initial desire to void.
Ditropan XL has an innovative drug delivery system: oral osmotic delivery system (OROS). The Ditropan XL tablet has a bilayer core that contains a drug layer and a "push layer" that contains osmotic components. The outer tablet is composed of a semipermeable membrane with a precision laser-drilled hole that allows the drug to be released at a constant rate.
When the drug is ingested, the aqueous environment in the gastrointestinal tract causes water to enter the tablet via semipermeable membrane at a constant rate. The introduction of water inside the tablet liquefies drug and causes the push layer to swell osmotically. As the push layer swells, it forces the drug suspension out the hole at a constant rate over a 24-h period.
Ditropan XL achieves steady-state levels over a 24-h period. It avoids first pass metabolism in liver and upper gastrointestinal tract to avoid cytochrome P450 enzymes. It has excellent efficacy, with minimal adverse effects.
Flavoxate (Urispas)
Flavoxate is used for symptomatic relief of dysuria, urgency, nocturia, and incontinence, as may occur in cystitis, prostatitis, urethritis, and urethrocystitis/urethrotrigonitis. It exerts a direct relaxant effect on smooth muscles via phosphodiesterase inhibition. It provides relief for a variety of smooth muscle spasms.
Tricyclic Antidepressants
Class Summary
Historically, these drugs were used to treat major depression; however, TCAs have an additional use in the treatment of bladder dysfunction. They function to increase norepinephrine and serotonin levels. In addition, they exhibit an anticholinergic and direct muscle relaxant effect on the urinary bladder. Due to their black box warnings, the use of TCAs are often avoided.
Imipramine hydrochloride (Tofranil)
A typical TCA, imipramine facilitates urine storage by decreasing bladder contractility and increasing outlet resistance. It has an alpha-adrenergic effect on the bladder neck and an antispasmodic effect on the detrusor muscle. Imipramine also has a local anesthetic effect on bladder mucosa.
Amitriptyline hydrochloride (Elavil)
A TCA with sedative properties, amitriptyline increases the circulating levels of norepinephrine and serotonin by blocking their reuptake at nerve endings. It ineffective for use in urge incontinence but is extremely effective in decreasing symptoms of urinary frequency in women with pelvic floor muscle dysfunction. Amitriptyline restores serotonin levels and helps break the cycle of pelvic floor muscle spasms. It is well tolerated and effective in the majority of women with urinary frequency.
Beta3 Agonists
Class Summary
Cause relaxation of the detrusor smooth muscle of the urinary bladder and increased bladder capacity.
Mirabegron (Myrbetriq)
Indicated for overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency
Vibegron (Gemtesa)
Indicated for adults with OAB who have symptoms of urge urinary incontinence, urgency, and urinary frequency.
Estrogens
Class Summary
Conjugated estrogens increase the tone of urethral muscle by up-regulating the alpha-adrenergic receptors in the surrounding area, and they enhance alpha-adrenergic contractile response to strengthen the pelvic muscles, which is important in urethral support (ie, prevents urethral hypermobility). Mucosal turgor of periurethral tissue from proper nourishment enhances urethral mucosal coaptation.
The result is an improved mucosal seal effect, which is important in urethral function (ie, it prevents intrinsic sphincter deficiency). Estrogen supplementation appears to be the most effective in postmenopausal women with mild-to-moderate incontinence. Both types of stress incontinence improve with estrogen fortification. There is also evidence however, estrogen use can exacerbate incontinence.
Conjugated estrogen (Premarin)
Conjugated estrogen may be used as an adjunctive pharmacologic agent for postmenopausal women with stress or mixed incontinence. Oral or vaginal form of estrogen may be used. The usual oral dose is 0.3-1.25 mg taken daily in a cyclic regimen.
When oral estrogens are needed, prescribe 0.625-mg pills. To prevent overstimulation of the uterus, conjugate estrogen is taken once a day for 21 consecutive days, followed by 7 days without the drug (eg, 3 wk on and 1 wk off). This regimen is repeated as necessary and tapered or discontinued at 3- to 6-month intervals.
Conjugated estrogen vaginal cream is available in a package with a plastic applicator and a tube that contains 42.5 grams of conjugated estrogens. Each gram contains 0.625 mg of conjugated estrogens. When vaginal cream is used, 2-4 g (0.5-1 applicator) of the cream may be administered intravaginally daily in the usual cyclic regimen.
Estrogen cream is readily absorbed through the skin and mucous membranes. When this cream is used for treatment of atrophic vaginitis, it may be placed intravaginally or applied topically around the vaginal tissues.
When estrogen is used long term in women with an intact uterus, the addition of progestin therapy is recommended to prevent endometrial hyperplasia. Medroxyprogesterone 2.5-10 mg/d is needed for 10-13 days to provide maximum maturation of endometrium and to eliminate any hyperplastic changes. Medroxyprogesterone may be administered continuously or intermittently.
Treatment with estrogen derivatives results in few cures (0-14%) but may cause subjective improvement in 29-66% of women. Limited evidence suggests that oral or vaginal estrogen therapy may benefit some women with stress and mixed urinary incontinence. Other potential beneficial effects of estrogen use include decreased bone loss and resolution of hot flashes during menopause.
Routinely prescribing conjugated estrogens to premenopausal women is not recommended. Use this medication in postmenopausal women who are incontinent and who have had a hysterectomy. For postmenopausal women with an intact uterus, cautiously recommend a short-term low-dose of conjugated estrogen and monitor frequently.
Antidepressants, Serotonin/Norepinephrine Reuptake Inhibitors
Class Summary
Some agents in this class may improve stress incontinence
Duloxetine (Cymbalta)
Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake. Its antidepressive action is theorized to be due to serotonergic and noradrenergic potentiation in the CNS.
Alpha-Adrenergic Blockers
Class Summary
These agents have been used to decrease bladder overactivity. They have shown some success in patients who have decentralized or autonomous bladders as the result of myelodysplasia, spinal cord injury, or radical pelvic surgery.
Phenoxybenzamine (Dibenzyline)
This agent decreases bladder contractions through long-lasting, noncompetitive, alpha-adrenergic blockade of postganglionic synapses at smooth muscle and exocrine glands.
Prazosin (Minipress)
Prazosin decreases internal sphincter tone and can improve the flow of urine, improving emptying of bladder. Although doses greater than 20 mg/d usually do not increase efficacy, a few patients may benefit from dose as high as 40 mg/d. If an increase in dose is needed, give first dose of each increment at bedtime to reduce syncopal episodes.
Botulinum Toxins
Class Summary
Intradetrusor injections with botulinum toxin are a novel treatment modality that has been shown to decrease episodes of urinary leakage in patients who have failed pharmacological therapy.
OnabotulinumtoxinA (BOTOX)
Neurotoxin from Clostridium botulinum; prevents ACh release from presynaptic membrane. Indicated for urinary incontinence in patients with neurologic conditions (eg, spinal cord injury, multiple sclerosis) in adults who have an inadequate response to or are intolerant of an anticholinergic medication.
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Urinary incontinence. Normal findings on urodynamic study of a 35-year-old white man. During the filling cystometrogram (CMG), there is absence of uninhibited detrusor contractions. Bladder compliance is normal. His maximum bladder capacity is 435 mL. During the pressure-flow study, his maximum flow rate (Qmax) is 25 mL/s and detrusor pressure at maximum flow rate (Pdet Qmax) is 50 cm H2O. The uroflow pattern is without abnormality, producing a bell-shaped curve without any abdominal straining. He voids to completion, and the postvoid residual urine is negligible.
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Urinary incontinence. Urodynamic study revealing detrusor instability in a 75-year-old man with urge incontinence. Note the presence of multiple uninhibited detrusor contractions (phasic contractions) that is generating 40- to 75-cm H2O pressure during the filling cystometrogram (CMG). He also has small bladder capacity (81 mL), which is indicative of poorly compliant bladder.
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Urinary incontinence. Urodynamic study revealing detrusor hyperreflexia in a 22-year-old woman with multiple sclerosis. Note the presence of multiple phasic contractions (uninhibited detrusor contractions) generating as much as 100 cm H2O pressure.
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Urinary incontinence. Urodynamic recording of bladder outlet obstruction due to benign prostatic hyperplasia (BPH) in a 55-year-old man. Note that during a pressure-flow study, his maximum flow rate (Qmax) is only 6 mL/s and detrusor pressure at maximum flow rate (Pdet Qmax) is very high at 101 cm H2O. He also has a small bladder capacity (50 mL) due to chronic bladder outlet obstruction. His flow curve is flat and "bread-loaf" in pattern, which is consistent with infravesical obstruction.
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Urinary incontinence. Urodynamic study revealing detrusor sphincter dyssynergia in a 35-year-old woman with C5 spinal cord injury. Note the absence of uninhibited detrusor contractions during the filling cystometrogram (CMG). Typically, patients with cervical cord lesions manifest detrusor hyperreflexia. However, this patient is taking Ditropan XL. Thus, phasic contractions are suppressed. During the pressure-flow study, note the increase in amplitude of the electromyogram (EMG) coincident with detrusor contraction and voiding. Her uroflow rate is low (1 mL/s), detrusor pressure is high (42 cm H2O), and the EMG recording is elevated.
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Urinary incontinence. Video-urodynamic study illustrating type III stress urinary incontinence (intrinsic sphincter deficiency [ISD]) in a 65-year-old woman. Static cystogram reveals obvious contrast leakage via the urethra during Valsalva maneuver. Urodynamic study records abdominal leak point pressure (ALPP) of 55 cm H2O, consistent with ISD.
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A cystoscopic view of the bladder mucosa reveals shallow ulcerations and petechial hemorrhages, which are findings consistent with interstitial cystitis.
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A cotton swab angle greater than 30° denotes urethral hypermobility. Figure 1 shows that the cotton swab at rest is zero with respect to the floor. Figure 2 shows that the cotton swab at stress is 45° with respect to the floor.
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A squirt of urine is observed at the peak of an increase in intra-abdominal pressure in a supine patient
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This photo illustrates a variety of pelvic organ prolapses, including grade-IV cystocele, uterine descensus, enterocele, and rectocele alone or in combination. In situations where a significant prolapse (eg, uterus, bladder) has occurred, evaluate for possible ureteral obstruction at the level of the pelvic inlet.
