Oral Pharmacologic Therapy
The most commonly used medications to treat OAB have anticholinergic properties. Anticholinergics are competitive inhibitors of acetylcholine at muscarinic receptors (mainly the M3 receptor subtype), and they thereby inhibit involuntary bladder contractions.[19] The effective dose is found by titration of the medication until symptoms are relieved. The side effects of anticholinergic medications include dry mouth, dry eyes, blurred vision, constipation, esophageal reflux, drowsiness, dizziness, palpitations, and heat intolerance. These side effects limit dosing and often decrease patient compliance (Table 3). Anticholinergic agents are contraindicated in patients with untreated closed-angle glaucoma and obstructive uropathy.
This is a truly exciting time for the treatment of urinary incontinence. For the first time in over 25 years (since the approval of oxybutynin in 1972), better medications are available for the overactive bladder. With the recent approval of tolterodine and oxybutynin XL, we believe that the list of agents previously considered first- and second-line medications for the overactive bladder needs to be revised. State-of-the-art treatment of OAB in 1999 includes tolterodine and oxybutynin XL as the first-line therapy.
The economic costs of urinary incontinence have not been well studied. Direct costs include medical evaluations, diagnostic tests, pharmaceutical and surgical therapies, as well as consequence costs (urinary infections) and routine care costs (pads/laundry). The last of these contribute most of the total direct costs of urinary incontinence, according to estimates from Wagner and Hu.[20] However, with the new spotlight and improved efficacy of medical therapy, a future cost shift can be anticipated, in that total pharmaceutical costs may rise, but diagnostic and routine costs may diminish. The cost savings would be significant, in light of the increasing population "at risk" for OAB. Moreover, more people are now seeking medical therapy for OAB.
Oxybutynin was the "gold-standard" anticholinergic agent for over a quarter of a century. Oxybutynin is an effective drug, but patient compliance is poor due to its side effect profile. Dry mouth is the major side effect and the most common reason patients discontinue its use. Dosing ranges from 2.5 mg to 5 mg 3 to 4 times daily. The most typical dosage is 5 mg 3 times a day. Subjective improvement is reported by 50% to 80% of patients with detrusor instability.[21] However, objective urodynamic improvement occurs in only 40%.[22] In the more than 15 years' personal experience of one author (MBC),about half of the patients taking oxybutynin, even if the medicine helps them greatly, will stop the pill because of severe dry mouth. The recent study of Amarenco and colleagues[23] demonstrated, on the basis of a quality-of-life scale, the very high rate of improvement and tolerance of oxybutynin, 2.5 mg tid, in a prospective, open, multicenter trial including 1701 women. The observance rate was 97%, and side effects were reported only for 8%. These results have been obtained on the basis of a patient's self-management of oxybutynin doses to a maximum of 5 mg tid if necessary, optimizing the ratio of benefits to side effects.
A once-a-day controlled-release formulation of oxybutynin was released for general use in the United States in early 1999. The efficacy and effectiveness of the long- and short-acting formulations are comparable.[24] Ditropan XL (OROS, Alza Corp) uses a push-pull osmotic system, which has been successfully used in other drug products (Glucotrol XL and Procardia XL). A semipermeable membrane surrounds a bilayer core. One compartment contains oxybutynin chloride, while the other is composed of osmotically active elements. When exposed to water in the gut, the osmotic compartment expands to push the hydrated drug through a tiny laser-drilled hole in the membrane and into the circulation.[25] This system maintains consistent release of medication over 24 hours, and it averts the peaks seen with immediate release oxybutynin. The pharmaco*kinetics of this delivery system (ie, flat concentration profile) may help explain less severe dry mouth reported with once daily oxybutynin than with immediate release oxybutynin (24.5% vs 46.2%) in a multicenter, randomized, double-blind study.[24] The latest research also suggests that with oxybutynin XL, most of the drug absorption occurs in the large intestine rather than the stomach, in contrast to other anticholinergic drugs. This different site of drug absorption limits the formation of oxybutynin metabolites (N-desethyl-oxybutynin).[26,27] Oxybutynin metabolites rather than oxybutynin chloride may be responsible for most of the side effects, including dry mouth.[28]
In 1998, the FDA approved a new antimuscarinic drug called tolterodine. In studies in cats in vivo, tolterodine has had a higher selectivity to the bladder, which may explain the lower incidence of dry mouth.[29] Initial reports show this drug is as efficacious as oxybutynin in the reduction of urgency and detrusor instability. The usual dosage is 2 mg bid. Clinically, tolterodine appears to be much better tolerated than oxybutynin due to its decreased salivary gland activity.[30] In the same study, tolterodine was found to be better tolerated than oxybutynin despite an oxybutynin dosage reduction to 2.5 mg tid. In a meta-analysis of 4 multicenter prospective trials of 1120 patients, moderate-to-severe dry mouth was reported in 6% of the placebo group, 4% of those receiving 1 mg bid of tolterodine, 17% of those receiving 2 mg bid of tolterodine, and 60% of those patients receiving a conventional dosage of 5 mg tid of oxybutynin.[31] There have been no direct comparative studies of oxybutynin XL and tolterodine to date.
Dosing ranges from 15 to 30 mg every 6 to 8 hours. The drug has strong anticholinergic side effects. Although it was available before oxybutynin, it has one of the highest side effect profiles. We consider this agent a low-priority second-line choice at this time. It cannot (regulatory rules) be prescribed for bladder dysfunction but may be prescribed for bowel dysfunction in many countries, including France.
Dicyclomine hydrochloride (Bentyl) has a direct relaxant effect on smooth muscle in addition to an antimuscarinic action. An oral dose of 20 mg, taken 3 times daily, has been reported to increase bladder capacity in patients with detrusor hyperreflexia.[32]
Flavoxate hydrochloride (Urispas) is another compound that has been reported to have a direct inhibitory action on smooth muscle in addition to anticholinergic and local analgesic properties. The recommended dose is 100 to 200 mg 3 or 4 times daily. Although clinical improvement has been reported in patients with unstable bladders,[33] other studies report no effect on detrusor hyperreflexia in an elderly population. Chapple and associates[34] reported on a double-blind, placebo-controlled, crossover trial of flavoxate in idiopathic detrusor instability. The drug's theoretic advantage would be to maintain good bladder contractility during micturition. The results revealed no advantage of flavoxate over placebo. AHCPR guidelines do not recommend its use.
Hyoscyamine acts as a parasympatholytic agent which causes smooth muscle relaxation. Like the other anticholinergic agents, it is contraindicated in untreated closed-angle glaucoma and obstructive uropathy.
The tricyclic antidepressants (TCAs) block the reuptake of the neurotransmitters norepinephrine and serotonin. The exact mode of action on the lower urinary tract has not been clearly demonstrated. TCAs exert anticholinergic as well as musculotropic effects. TCAs also increase bladder outlet resistance. The combination of both anticholinergic effects and increased bladder outlet resistance allows for better storage of urine. For the unstable bladder, imipramine is the most commonly used TCA. The usual starting dosage is 25 mg/d in a single dose. There appears to be a poor correlation between plasma level and clinical effect. However, unlike the anticholinergics, imipramine builds up a blood level over a period of several weeks and may take that long to show an effect. Its effect may not be apparent for at least that length of time. The dose is increased by 25 mg per week until the patient is clinically well or has anticholinergic side effects.
The side effect causing the most concern is cardiac toxicity, and thus pretreatment electrocardiography is reasonable. Conduction abnormalities should alert the clinician to avoid this drug. Side effects of less concern include dry mucous membranes, sleep disturbances, personality changes, anxiety, and change in appetite. TCAs are contraindicated with use of monoamine oxidase inhibitors.
In our experience, the effects of imipramine on the bladder and urethra are often additive to those of anticholinergic agents. Consequently, a combination of imipramine and oxybutynin is sometimes especially useful. Tricyclic antidepressants for the overactive bladder should be used only in patients carefully evaluated according to the AHCPR 1996 guidelines.[35]
