Drug-Induced Urinary Incontinence

Kiran Panesar, BPharmS (Hons), MRPharmS, RPh, CPh

Disclosures

US Pharmacist. 2014;39(8):24-29. 

In This Article

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 Antagonist

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]

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