U

rinary incontinence (UI) is a major cause of admission to skilled nursing facilities (SNFs). It has obvious negative hygienic and social consequences with resulting poorer quality of life due to perceived lack of self control and self esteem. It also has medical ramifications, such as precipitation or worsening of infections, rashes, skin breakdown, and pressure ulcers.
       Management of UI with long-term indwelling catheterization has been increasingly frowned upon for medical and regulatory reasons. As a result, the use of absorbent pads/undergarments has undergone a veritable explosion over the past decade.
       The use of nonpharmacologic treatment strategies, such as pelvic muscle strengthening and biofeedback, is not always considered in SNF residents, principally due to the frequent presence of cognitive impairment. Neither are potentially useful devices and surgeries that may free the resident from UI forever.
       Interestingly, despite our society's seeming fixation on the use of medications, medications are frequently not even considered for managing UI in the SNF setting. Certainly, there are few data on the efficacy and safety of medications used to treat UI in older individuals, especially those residing in SNFs. These agents are worthy of at least an adequate trial before committing the resident to long-term use of absorbent products.
       One issue that should be considered when using medications to treat UI is their potential to interact adversely with other medications that the patient is taking. SNF residents take an average of about eight routinely scheduled and five "as needed" medications at any one time (unpublished data, PartneringCare Senior Services, Minneapolis, Minnesota). The greater the number of concurrent medications, the greater the risk of adverse drug interactions (DI). There are two types of DI: pharmacokinetic and pharmacodynamic. When one drug alters the absorption, distribution, metabolism, or excretion of another drug, this is a pharmacokinetic DI. When one drug alters the effect of another drug (enhancing or antagonizing), this is a pharmacodynamic DI. A review of the clinically important drug interactions with UI medications follows. This paper is based on a presentation made by the author at the National Association for Directors of Nursing Administration Conference in Nashville, Tennessee, in June 2002. Two reviews on this topic should be consulted for further details.1,2

Stress UI
       Stress UI responds variably to alpha-adrenergic stimulants like pseudoephedrine (Sudafed®) and estrogens. Pseudoephedrine and ephedrine are the only widely available alpha-adrenergic stimulants, since phenylpropanolamine was taken off the market due to its association with hemorrhagic strokes in young women. However, ephedrine should never be used in older individuals, as its cardiovascular risks exceed its potential benefits.
       No clinically important drug interactions occur with estrogens. However, the same cannot be said for pseudoephedrine. Alpha-adrenergic blockers, specifically alphablockers used to treat hypertension, such as prazosin (Minipress®), terazosin (Hytrin®), and doxazosin (Cardura®), are direct antagonists of the effect of pseudoephedrine and vice versa. Other alphablockers, such as tamsulosin (Flomax®) and alfuzosin (undergoing FDA review currently), which are used to treat symptomatic benign prostatic hyperplasia (BPH), as well as other antihypertensives, such as methyldopa (Aldomet®), clonidine (Catapres®), guanabenz (Wytensin®), guanadrel (Hylorel®), and labetalol (Normodyne®, Trandate®), may also be antagonized by pseudoephedrine and vice versa.

Urge UI
       Anticholinergic/antispasmodic drugs form the cornerstone of treatment of urge UI (also known as overactive bladder). Imipramine (Tofranil®), dicyclomine (Bentyl®), hyoscyamine (Levsin®, Levbid®), flavoxate (Urispas®), and propantheline (Pro-Banthine®), although occasionally used today, are largely of historical interest. The two agents with adequate supportive data are oxybutynin (Ditropan®, Ditropan XL®, Oxytrol®) and tolterodine (Detrol®, Detrol LA®).
       The major drug interactions of interest with oxybutynin and tolterodine involve the concurrent use of other drugs with anticholinergic activity (leading to pharmacologic agonism and increased toxicity) and drugs with cholinergic activity (leading to mutual pharmacologic antagonism). Many drugs used in older individuals have anticholinergic activity, either as their principal therapeutic effect or as unwanted side effects. Examples include tricyclic antidepressants, especially imipramine, doxepin (Sinequan®), and amitriptyline (Elavil®); antipsychotics (neuroleptics), especially thioridazine (Mellaril®); the antiarrhythmic disopyramide (Norpace®); the muscle relaxant cyclobenzaprine (Flexeril®); eyedrops for glaucoma, such as atropine (Isopto® Atropine), cyclopentolate (Cyclogyl®), homatropine (Isopto® Homatropine), and tropicamide (Mydriacyl®); and antiparkinsonian agents, such as biperiden (Akineton®), benztropine (Cogentin®), procyclidine (Kemadrin®), and trihexyphenidyl (Artane®). Concurrent use of one or more of these agents with oxybutynin or tolterodine may enhance each other's anticholinergic toxicity, even leading to delirium in some cases.
       The cholinesterase inhibitors, such as donepezil (Aricept®), rivastigmine (Exelon®), and galantamine (Reminyl®), which work by enhancing cholinergic neurotransmission in the brain, are used extensively in the treatment of dementia, including that in SNF residents. Using an anticholinergic drug, such as oxybutynin or tolterodine, concurrently would be expected to result in mutual pharmacologic antagonism.
       Tolterodine is metabolized by two hepatic (liver) enzymes that are very susceptible to inhibition or induction by other drugs (i.e., cytochrome P450 3A4 and 2D6). Concurrent use with hepatic enzyme inhibitors may result in accumulation of tolterodine and its active metabolite, leading to enhanced toxicity, while concurrent use with inducers may result in reduced concentrations of tolterodine and its metabolite, leading to reduced efficacy. The number of interacting medications is far too large to list here. Your consultant pharmacist can generate lists of these medications for you or you can check the excellent recent reviews of Michalets and Murray.3,4

Overflow UI
       Overflow UI is caused by urinary obstruction. The major cause amenable to drug therapy is benign prostatic hyperplasia (BPH) in males. The hormonal treatments of BPH, finasteride (Proscar®) and dutasteride (Avodart®), have no clinically important drug interactions, with the obvious exception of testosterone supplementation for hypogonadism, leading to mutual antagonism.
       Alpha-adrenergic blockers have a significant role in BPH treatment. The alphablocker/pseudoephedrine interaction has already been discussed. Prazosin, terazosin, and doxazosin may interact pharmacodynamically with other antihypertensives, leading to excessive blood pressure reduction, predisposing to syncope and falls. This is rarely an issue with tamsulosin but may be so with alfuzosin.

Conclusion
       Drugs used to treat UI may interact adversely with other concurrent drug therapies. Most of these interactions are pharmacodynamic in nature. In many cases, alternative noninteracting drugs are available, allowing one to avoid these interactions. In other cases, there may be no alternatives available and combined use with careful monitoring may be the only available course of action.