Drug-Induced Urinary Incontinence

US Pharm. 2014;39(8):24-29.

ABSTRACT: Urinary incontinence affects both men and women, and especially the elderly. The Agency for Health Care Policy and Research identified four types of urinary incontinence: stress, urge, mixed, and overflow. Pharmacologic agents including oral estrogens, alpha-blockers, sedative-hypnotics, antidepressants, antipsychotics, ACE inhibitors, loop diuretics, nonsteroidal anti-inflammatory drugs, and calcium channel blockers have been implicated to some degree in the onset or exacerbation of urinary incontinence. The pharmacist should consider urinary incontinence–inducing drugs when reviewing patient profiles.

In healthy humans, voiding occurs at intervals several times a day, even though the kidneys produce urine continuously. This means that the bladder must store urine for several hours, a feature that requires the musculature of the bladder-outflow tract to contract to generate resistance. Disturbances of this storage function of the bladder lead to urinary incontinence. A number of factors may be responsible, including disease and adverse effects of medical treatment.¹

A number of medications have been proposed as possible causes of drug-induced urinary incontinence, including alpha₁-adrenoceptor antagonists, antipsychotics, benzodiazepines, antidepressants, and drugs used for hormone replacement therapy.¹ Since drugs are frequently metabolized and excreted in the urine, the lower urinary tract is particularly vulnerable to adverse effects. Furthermore, carcinogens or inflammatory agents in the urine are in close proximity to the epithelium for prolonged periods when they are stored in the bladder. The drugs may cause stress incontinence, urge incontinence, or overflow incontinence.²

This article discusses the different types of incontinence, their causes, and the possible mechanisms underlying incontinence resulting from medications.

Epidemiology

The prevalence of urinary incontinence increases with age, with an overall prevalence of 38% in women and 17% in men. In women, the prevalence is about 12.5% in those aged 60 to 64 years and rises to about 20.9% in those aged ≥85 years. Furthermore, a higher prevalence has been noted in non-Hispanic white women (41%) compared with non-Hispanic black (20%) and Mexican-American women (36%).³ In a similar study, the prevalence of weekly incontinence was highest among Hispanic women, followed by white, black, and Asian-American women.⁴

In men, the prevalence increases with age, from 11% in those aged 60 to 64 years to 31% in those aged ≥85 years. The rate of incontinence in black men is similar to that for black women, but in white and Mexican-American men, the rate is 2.5 times lower than in women of the same ethnicity.³

Urinary incontinence may be underreported, owing to the embarrassing nature of the condition.

Types of Incontinence

According to the clinical practice guidelines issued by the Agency for Health Care Policy and Research (now called Agency for Healthcare Research and Quality), there are four types of incontinence: stress, urge, mixed, and overflow. Other guidelines identify functional incontinence as a fifth type.^5-8 TABLE 1 describes the various types of incontinence in more detail, along with the usual approaches used in the management of each.^5-10

Mechanisms of Urinary Continence

In healthy individuals, the urinary bladder senses the volume of urine by means of distention. Distention of the bladder excites afferent A-delta fibers (and C fibers, in a pathologic condition) that relay information to the pontine storage center in the brain. The brain, in turn, triggers efferent impulses to enhance urine storage through activation of the sympathetic innervation of the lower urinary tract (hypogastric nerve). These impulses also activate the somatic, pudendal, and sacral nerves.¹

The hypogastric nerves release norepinephrine to stimulate beta₃-adrenoceptors in the detrusor and alpha₁-adrenoceptors in the bladder neck and proximal urethra. The role of beta₃-adrenoceptors is to mediate smooth-muscle relaxation and increase bladder compliance, whereas that of alpha₁-adrenoceptors is to mediate smooth-muscle contraction and increase bladder outlet resistance.¹ The somatic, pudendal, and sacral nerves release acetylcholine to act on nicotinic receptors in the striated muscle in the distal urethra and pelvic floor, which contract to increase bladder outlet resistance.¹

Efferent sympathetic outflow and somatic outflow are stopped when afferent signaling to the brain exceeds a certain threshold. At this point, the parasympathetic outflow is activated via pelvic nerves. These nerves release acetylcholine, which then acts on muscarinic receptors in detrusor smooth-muscle cells to cause contraction. A number of transmitters, including dopamine and serotonin, and endorphins are involved in this process.¹

Pharmacologic Agents That Cause Urinary Incontinence

A variety of drugs have been implicated in urinary incontinence, and attempts have been made to determine the mechanism responsible based upon current understanding of the processes involved in continence and the transmitters that play a role. Each of the processes described previously can be manipulated by pharmacologic agents to cause one or more types of incontinence.

The drugs commonly pinpointed in urinary incontinence include anticholinergics, alpha-adrenergic agonists, alpha-antagonists, diuretics, calcium channel blockers, sedative-hypnotics, ACE inhibitors, and antiparkinsonian medications. Depending upon the mode of action, the effect may be direct or indirect and can lead to any of the types of incontinence. Taking these factors into account, it is important to consider a patient’s drug therapy as a cause of incontinence, particularly in new-onset incontinence patients and in elderly patients, in whom polypharmacy is common.^11,12

On the other hand, a pharmacologic agent or any other factor that results in chronic urinary retention can lead to a rise in intravesical pressure and a resultant trickling loss of urine. In this way, drugs that cause urinary retention can indirectly lead to overflow incontinence.²

Alpha-Adrenergic Antagonists: As described earlier, the stimulation of alpha₁-adrenoceptors by norepinephrine leads to increased bladder outlet resistance. It has been shown that alpha₁-adrenoceptors influence lower urinary tract function not only through a direct effect on smooth muscle, but also at the level of the spinal cord ganglia and nerve terminals. In this way, they mediate sympathetic, parasympathetic, and somatic outflows to the bladder, bladder neck, prostate, and external urethral sphincter.¹³ Blocking these receptors with such agents as prazosin, doxazosin, and terazosin would therefore lead to reduced bladder outlet resistance and, accordingly, to incontinence.² One study found that the use of alpha-blockers increased the risk of urinary incontinence in older African American and white women nearly fivefold.¹⁴ Another study showed that almost half of female subjects taking an alpha-blocker reported urinary incontinence.¹⁵ Phenoxybenzamine, a nonselective, irreversible alpha-adrenoceptor antagonist, has been associated with stress urinary incontinence.¹

It is useful to note that many antidepressants and antipsychotics exhibit considerable alpha₁-adrenoceptor antagonist activity.¹

Alpha-Adrenergic Agonists: Alpha-adrenergic agonists such as clonidine and methyldopa mimic the action of norepinephrine at receptors. In this way they may contract the bladder neck, causing urinary retention and thus overflow urinary incontinence.^2,16-18

Antipsychotics: A number of antipsychotics have been associated with urinary incontinence, including chlorpromazine, thioridazine, chlorprothixene, thiothixene, trifluoperazine, fluphenazine (including enanthate and decanoate), haloperidol, and pimozide.^19-24 Incontinence occurs over a broad range of antipsychotic dosages. Additionally, whereas some patients experience urinary incontinence within hours of initiating antipsychotic therapy, others do not experience incontinence for weeks after initiation. In most cases, the incontinence remits spontaneously upon discontinuation of the antipsychotic. Typical antipsychotics are primarily dopamine antagonists and lead to stress urinary incontinence, whereas atypical antipsychotics are antagonists at serotonin receptors.²⁴ Antipsychotics also cause incontinence by one or more of the following mechanisms: alpha-adrenergic blockade, dopamine blockade, and cholinergic actions on the bladder.²⁵ Owing to these complex drug-receptor interactions, a generalized description of how antipsychotics cause urinary incontinence cannot be given.¹

If it is not possible to discontinue the antipsychotic, urinary incontinence caused by antipsychotics can be managed with a variety of pharmacologic agents. Desmopressin is perhaps the most effective, but also the most expensive, therapeutic agent available for this use. Other agents include pseudoephedrine, oxybutynin, benztropine, trihexyphenidyl, and dopamine agonists.²⁵

Antidepressants: There are a number of classes of antidepressants, all with varying pharmacologic properties. This makes it difficult to generalize the underlying mechanisms that lead to urinary incontinence as a result of antidepressant use. However, all antidepressants result in urinary retention and, eventually, in overflow incontinence. Most antidepressants are inhibitors of norepinephrine and/or serotonin uptake. Some also act as antagonists at adrenergic, cholinergic, or histaminergic receptors at therapeutic doses.¹

Diuretics: The purpose of a diuretic is to increase the formation of urine by the kidneys. As a result, diuretics increase urinary frequency and may cause urinary urgency and incontinence by overwhelming the patient’s bladder capacity. One study reported a link between diuretics and/or conditions associated with their use and urinary incontinence in community-dwelling women.²⁶ In another study, the use of a loop diuretic with an alpha-blocker almost doubled the risk of urinary incontinence versus alpha-blockers alone, but no increased risk was noted when thiazide diuretics or potassium-sparing diuretics were added to the alpha-blockers.²⁷

Calcium Channel Blockers: Calcium channel blockers decrease smooth-muscle contractility in the bladder. This causes urinary retention and, accordingly, leads to overflow incontinence.¹⁰

Sedative-Hypnotics: Sedative-hypnotics result in immobility secondary to sedation that leads to functional incontinence.¹⁰ Furthermore, benzodiazepines can cause relaxation of striated muscle because of their effects on gamma-aminobutyric acid type A receptors in the central nervous system.^1,28

ACE Inhibitors and Angiotensin Receptor Blockers: The renin-angiotensin system exists specifically in the bladder and the urethra. Blocking angiotensin receptors with ACE inhibitors or angiotensin receptor blockers decreases both detrusor overactivity and urethral sphincter tone, leading to reduced urge incontinence and increased stress urinary incontinence.²⁹ Furthermore, ACE inhibitors can result in a chronic dry cough that can cause stress incontinence. This was demonstrated in a female patient with cystocele who was receiving enalapril. The patient developed a dry cough and stress incontinence, which ceased within 3 weeks of discontinuing the ACE inhibitor.

Estrogens: One study showed that oral and transdermal estrogen, with or without progestin, increased the risk of urinary incontinence by 45% to 60% in community-dwelling elderly women.¹⁴ A summary of randomized, controlled trials also showed that the use of oral estrogen increased the risk of urinary incontinence by 50% to 80%.³⁰

Hydroxychloroquine: Hydroxychloroquine has recently been identified as an agent that can induce urinary incontinence. There is currently only one report supporting this finding. In this report, a 71-year-old female patient developed urinary incontinence as an adverse reaction to hydroxychloroquine administered at therapeutic doses to treat rheumatoid arthritis. Urinary incontinence remitted with drug withdrawal and reappeared when the drug was readministered.³¹

Conclusion

A variety of drugs have been associated with urinary incontinence. This may be due to direct incontinence or overflow incontinence secondary to urinary retention. When reviewing patient profiles, pharmacists should take into consideration the use of oral estrogens, alpha-blockers, sedative-hypnotics, antidepressants, antipsychotics, ACE inhibitors, loop diuretics, nonsteroidal anti-inflammatory drugs, and calcium channel blockers that may lead to urinary incontinence. It is important to keep in mind that some incontinence patients taking these medications may be too embarrassed to discuss their condition voluntarily.

REFERENCES

1. Tsakiris P, Oelke M, Michel MC. Drug-induced urinary incontinence. Drugs Aging. 2008;25:541-549.
2. Drake MJ, Nixon PM, Crew JP. Drug-induced bladder and urinary disorders. Incidence, prevention and management. Drug Saf. 1998;19:45-55.
3. Anger JT, Saigal CS, Litwin MS; Urologic Diseases of America Project. The prevalence of urinary incontinence among community dwelling adult women: results from the National Health and Nutrition Examination Survey. J Urol. 2006;175:601-604.
4. Thom DH, van den Eeden SK, Ragins AI, et al. Differences in prevalence of urinary incontinence by race/ethnicity. J Urol. 2006;175:259-264.
5. Nazir T, Khan Z, Barber HR. Urinary incontinence. Clin Obstet Gynecol. 1996;39:906-911.
6. Chutka DS, Fleming KC, Evans MP, et al. Urinary incontinence in the elderly population. Mayo Clin Proc. 1996;71:93-101.
7. Gibbs CF, Johnson TM II, Ouslander JG. Office management of geriatric urinary incontinence. Am J Med. 2007;120:211-220.
8. Rogers RG. Clinical practice. Urinary stress incontinence in women. N Engl J Med. 2008;358:1029-1036.
9. American College of Obstetricians and Gynecologists. Urinary incontinence in women. Obstet Gynecol. 2005;105:1533-1545.
10. Vasavada SP. Urinary incontinence. Medscape. http://emedicine.medscape.com/article/452289-overview#showall. Accessed May 15, 2014.
11. Patel AK, Chapple CR. Urodynamics in the management of female stress incontinence—which test and when? Curr Opin Urol. 2008;18:359-364.
12. Curtis LA, Dolan TS, Cespedes RD. Acute urinary retention and urinary incontinence. Emerg Med Clin North Am. 2001;19:591-619.
13. Andersson KE, Lepor H, Wyllie MG. Prostatic alpha 1-adenoreceptors and uroselectivity. Prostate. 1997;30:202-215.
14. Ruby CM, Hanlon JT, Boudreau RM, et al; Health, Aging and Body Composition Study. The effect of medication use on urinary incontinence in community-dwelling elderly women. J Am Geriatr Soc. 2010;58:1715-1720.
15. Marshall HJ, Beevers DG. Alpha-adrenergic blockade and urinary incontinence. J Hypertens. 1993;11:1152-1153.
16. Raz S. Adrenergic influence on the internal urinary sphincter. Isr J Med Sci. 1974;10:608-611.
17. Kleeman FJ. The physiology of the internal urinary sphincter. J Urol. 1970;104:549-554.
18. Fernandez PG, Sahni S, Galway BA, et al. Urinary incontinence due to interaction of phenoxybenzamine and alpha-methyldopa. Can Med Assoc J. 1981;124:174-175.
19. Ambrosini PJ, Nurnberg HG. Enuresis and incontinence occurring with neuroleptics. Am J Psychiatry. 1980;137:1278-1279.
20. Shapiro AK. Pimozide-induced enuresis. Am J Psychiatry. 1981;138:123-124.
21. Kiruluta HG, Andrews K. Urinary incontinence secondary to drugs. Urology. 1983;22:88-90.
22. Ambrosini PJ. A pharmacological paradigm for urinary incontinence and enuresis. J Clin Psychopharmacol. 1984;4:247-253.
23. Van Putten T, Malkin MD, Weiss MS. Phenothiazine-induced stress incontinence. J Urol. 1973;109:625-626.
24. Fuller MA, Borovicka MC, Jaskiw GE, et al. Clozapine-induced urinary incontinence: incidence and treatment with ephedrine. J Clin Psychiatry. 1996;57:514-518.
25. Clark N. Conventional antipsychotic and clozapine-induced urinary incontinence. JCPNP. 2003:2(2). https://cpnp.org/_docs/resource/jcpnp/urinary-incontinence.pdf. Accessed May 19, 2014.
26. Fantl JA, Wyman JF, Wilson M, et al. Diuretics and urinary incontinence in community-dwelling women. Neurourol Urodyn. 1990;9:25-34.
27. Peron EP, Zheng Y, Perera S, et al; Health, Aging, and Body Composition (Health ABC) Study. Antihypertensive drug class use and differential risk of urinary incontinence in community-dwelling older women. J Gerontol A Biol Sci Med Sci. 2012;67:1373-1378.
28. Landi F, Cesari M, Russo A, et al. Benzodiazepines and the risk of urinary incontinence in frail older persons living in the community. Clin Pharmacol Ther. 2002;72:729-734.
29. Elliott CS, Comiter CV. The effect of angiotensin inhibition on urinary incontinence: data from the National Health and Nutrition Examination Survey (2001–2008). Neurourol Urodyn. August 29, 2013 [Epub ahead of print].
30. Shamliyan TA, Kane RL, Wyman J, Wilt TJ. Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women. Ann Intern Med. 2008;148:459-473.
31. Carnovale C, Perrone V, Borsadoli C, et al. A case of urinary incontinence by hydroxychloroquine in a geriatric patient. J Clin Pharm Ther. 2013;38:169-171.

To comment on this article, contact rdavidson@uspharmacist.com.