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Published on 1 December 2001

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Pharmacotherapy of urinary incontinence

Said Ghafur
MD
Department of Urology
University of Cologne
Germany
E:said.ghafur@gmx.de

Effective therapy for incontinence requires precise diagnosis. The forms of incontinence are treated differently, so correct diagnosis is important.

Extraurethral incontinence is caused by congenital anomalies or acquired urogenital fistulae, which can develop as a result of surgery or radiotherapy or as a consequence of inflammatory or neoplastic processes. Permanent urine leakage is typical of extraurethral incontinence, in contrast to other types of incontinence where leakage is usually intermittent. After verification of the fistula, surgical correction is the only treatment.

Overflow incontinence develops when, during overdistention of the bladder, the intravesical passive pressure rises over the urethral pressure, leading to involuntary urine loss. The cause may be a central or peripheral neuropathy or nerve lesions with detrusor acontractility, such as diabetes mellitus, cerebrovascular diseases, multiple sclerosis, Parkinson’s or Alzheimer’s disease, or other neurological disturbances. A myogenic decompensation of the bladder muscle as a result of chronic subvesical obstruction can also lead to overflow incontinence. In most cases, the bladder should first be drained through a suprapubic catheter and then drug therapy evaluated.

Urinary stress incontinence is caused by incompetence of the sphincter and is characterised by involuntary urine loss during sneezing or physical activities. Pharmacological therapy plays a minor role; physical therapy is important to strengthen the pelvic muscles.

Urinary urgency and urge incontinence are the primary domain of pharmacological therapy for incontinence. There are two possible causes: pathologic hypersensitivity of the bladder (sensory urgency) or hyperactivity of the bladder muscle (motoric urgency). The urodynamic examination of sensory urge incontinence reveals early urinary urgency without detrusor activity or contractions, while motoric urge incontinence shows urinary urgency with uncontrolled detrusor contractions called idiopathic detrusor hyperactivity. Before ­beginning pharmacological therapy, other causes must be excluded, such as tumour, bladder stones, infection, bladder outlet obstruction, prostate enlargement or urethral stricture.

When the underlying cause of detrusor hyperactivity is a neurological disorder, it is called detrusor hyper-reflexia, reflex bladder or reflex incontinence. During the filling phase of urodynamic examination, involuntary detrusor contractions appear with an increase in bladder pressure, just like idiopathic detrusor hyperactivity. In addition, neurological deficits are almost always found in the clinical physical examination. The prime goal of treatment of the neurogenic form of detrusor hyperactivity is the protection of the upper urinary tract through the reduction of intravesical pressure. This can usually be achieved through pharmacological treatment, using the same agents as for idiopathic detrusor hyperactivity.

Pharmacological therapy for sensory urge incontinence is mostly ineffective, as at present the sensory nerve system cannot be influenced adequately pharmacologically. For the treatment of motoric urge incontinence (idiopathic detrusor hyperactivity and neurogenic detrusor hyperactivity) there are several effective drugs available (see Table 1). Because patients react individually, drugs should be used on a trial basis, and changed if necessary. A combination of two different drugs can increase therapeutic efficacy (for example, anticholinergics combined with myotropic spasmolytics).

[[HPE02_table1_36]]

Anticholinergic (antimuscarinic) drugs
Anticholinergics are the most important agents for ­treating detrusor hyperactivity. As well as competitive inhibition of acetylcholine on the postganglionic parasympathetic muscarinic receptors, some anticholinergics have a ganglion-blocking effect via the inhibition of nicotinic receptors. Currently used drugs lack selectivity for the bladder(1) and may cause side-effects that limit their usefulness. Several subpopulations of muscarinic receptors have been identified, and five subtypes (M(1)–M(5)) have been defined.(1,2) M(1), M(2) and M(3) receptor subtypes are characterised in human detrusor muscle by receptor binding; there is a distinct predominance of M(3) receptors.(3)

The most frequently applied anticholinergics (Table 1) are oxybutynin, propiverine, trospium chloride and propanthelin. Oxybutynin and propiverine also have direct spasmolytic and local anaesthetic effects.

Several studies have shown the improvement of subjective symptoms and objective urodynamic parameters under oral therapy with oxybutynin. In a multicentre placebo-controlled double-blind study, the anticholinergic effect of oxybutynin was compared with propanthelin. Bladder capacity increased with oxybutynin (5mg two–three times daily) by up to 33%, with propanthelin 18% and with placebo 9%. The urge symptom improved by 58% with oxybutynin and 45% with propanthelin, although the placebo effect was 43%.(4) The treatment of detrusor hyper-reflexia with trospium chloride (20mg twice daily) showed an increase in functional bladder capacity in the majority of the paraplegic patients, a significant reduction in detrusor pressure, and an increase in bladder compliance.(5)

These studies show the efficacy of anticholinergics for motoric urge incontinence or detrusor hyper-reflexia, and that improvement is based to a significant degree on the placebo effect. Application is limited due to the frequency of side-effects, such as dry mouth, accommodation disturbance, mydriasis, nausea, constipation, tachycardia, glaucoma and disturbance of bladder emptying, which can occur at the start of therapy in 80% of cases. In most cases, side-effects reduce in the first month of treatment, or after dose reduction. In about 10% of cases, side-effects are strong enough to stop therapy.

Contraindications for the use of anticholinergics include tachyarrhythmia, cardiac insufficiency, glaucoma, gastrointestinal obstruction, subvesical obstruction, gastrointestinal atony and myasthenia gravis.

Tolterodine is a new potent competitive muscarinic receptor antagonist for the treatment of urinary urgency and urge incontinence.(6–8) This drug has no selectivity for M(3) muscarinic receptors, but still shows some selectivity for the bladder over the salivary glands.(9) In a placebo-controlled study comparing tolterodine (2mg twice daily) with oxybutynin (5mg three times daily) in 293 patients with detrusor instability, both drugs were equally effective in reducing frequency of micturition and number of incontinence episodes. However, tolterodine appeared to be better tolerated.(10)

Darifenacin is a new, highly-selective anticholinergic M(3) receptor antagonist, which is in phase III of clinical evaluation. It promises a significant reduction of side- effects.(11) The drug reduces the total number, maximum amplitude and duration of unstable bladder contractions.(12) It is being further evaluated clinically in the treatment of bladder overactivity.

Other drugs
Spasmolytics, papaverine-like substances, have a direct effect on nonstriated muscle cells. They inhibit the decomposition process of cyclic-AMP (adenosine monophosphate). This leads to a decrease in the intracellular availability of calcium and therefore to a reduced contractility of the nonstriated muscle cell. Flavoxate is the most widely used drug in this group of substances. In addition to its directly myotropic relaxing effect, flavoxate has a low anticholinergic and local anaesthetic effect.

Capsaicin, the pungent ingredient in red peppers, is believed to cause desensitisation of C-fibre sensory afference by initially releasing and emptying the stores of neuropeptides, and then by blocking further release.(13) Intravesical capsaicin (1–2mM) has been used with success in patients with bladder hyperactivity due to neurological disorders, such as multiple sclerosis, or traumatic chronic spinal lesions. The effect of treatment may last for 2–7 months.(14) Side-effects include discomfort and a burning sensation at the pubic-urethral level during installation. This can be overcome by first using lidocaine, which does not interfere with the beneficial effects.(15)

Resiniferatoxin has a similar effect to capsaicin and has been shown to be approximately 1,000 times more potent in stimulating bladder activity.(16) It is an interesting alternative, but further investigations are needed.

Drugs for stress incontinence
Many factors are involved in stress urinary incontinence, including urethral support, vesical neck function and the function of the urethral muscles.(17) Anatomical factors cannot be treated pharmacologically. Since women with stress incontinence have lower resting urethral pressures than continent women,(18,19) it seems logical to increase urethral pressure to improve the condition. There is strong pharmacological evidence that a substantial part of urethral tone is mediated through stimulation of a-adrenoceptors in the urethral smooth muscle by released noradrenaline.(20) Lack of mucosal function may be a contributing factor to stress incontinence, mainly in elderly women with low oestrogen.

The pharmacological treatment of stress incontinence aims to increase intraurethral pressure by increasing tone in the urethral smooth muscle. Several drugs with agonistic effects on a-adrenoceptors have been tried: midodrine, norfenifrine, ephedrine and norephedrine seem to be the most widely used.

Duloxitine, a combined noradrenaline and 5-HT reuptake inhibitor, has been shown in animal experiments to increase the neural activity of the external urethral sphincter, and to increase bladder capacity through effects on the CNS.(21) The drug is still in clinical trials.

Oestrogen-sensitive tissues of the bladder, urethra and pelvic floor play an important role in the continence mechanism. Oestrogens improve the maturation index of urethral squamous epithelium, increase the urethral closure pressure and improve abdominal pressure transmission to the proximal urethra. The sensory threshold of the bladder may also be raised.(21) Oestrogen in the treatment of stress incontinence has been controversial, even though there are a number of reported studies and some have yielded promising results. Hormone replacement therapy does appear to improve irritative symptoms of frequency and urgency, possibly by reversing urogenital atrophy. Treatment may need to be given for a long time before any benefit is seen.

References

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  2. Caulfield MP. Muscarinic receptors – characterization, coupling and function. Pharmacol Ther 1993;58(3):319-79.
  3. Kondo S, et al. Muscarinic cholinergic receptor subtypes in human detrusor muscle studied by labeled and ­nonlabeled pirenzepine, AFDX-116, and 4DAMP. Urol Int 1995;54:150-3.
  4. Cardozo LD, Stanton SL, Robinson H, Hole D. Evaluation of flurbiprofen in detrusor instability. BMJ 1980;2:281-2.
  5. Madersbacher H, et al. Hochdosierte Applikation von Tropsiumchlorid zur Therapie der Detrusorhyperreflexie. Urologe 1991;30:260.
  6. Nilvebrant L, et al. Tolterodine – a new bladder selective antimuscarinic agent. Eur J Pharmacol 1997;327:195-207.
  7. Nilvebrant L, et al. Tolterodine – a new bladder selective muscarinic ­receptor antagonist: preclinical ­pharmacological and clinical data. Life Sci 1997;60: 1129-36.
  8. Hills CJ, et al. Tolterodine. Drugs 1998;5:813-20.
  9. Stahl MMS, et al. Urodynamic and other effects of tolterodine: a novel antimuscarinic drug for the treatment of detrusor overactivity. Neurourol Urodyn 1995;14:647-55.
  10. Abrams P, et al. Efficacy and ­tolerability versus placebo in patients with detrusor instability. J Urol 1997;15;103. Abstract no. 402.
  11. Alabaster VA. Discovery and development of selective M3 antagonists for clinical use. Life Sci 1997;60:1053-60.
  12. Rosario DJ, et al. A pilot study of the effects of multiple doses of the M3 muscarinic receptor antagonist ­darifenacin on ambulatory parameters of detrusor activity in patients with detrusor instability. Neurourol Urodyn 1995;14:464-5.
  13. Maggi CA. The dual sensory and efferent function of capsaicin-sensitive primary sensory neurons in the urinary bladder and urethra. In: Maggi CA, editor. The autonomic nervous system. Volume 6. London: Harwood Academic Publishers; 1993: 383-422.
  14. Fowler CJ, et al. Intravesical capsaicin for neurogenic bladder dysfunction. Lancet 1992;339:1239.
  15. Chandiramani VA, et al. Urodynamic changes during therapeutic intravesical instillations of capsaicin. Br J Urol 1996;77:792-7.
  16. Ishizuka O, et al. Urodynamic effects of intravesical resiniferatoxin and capsaicin in conscious rats with and without outflow obstruction. J Urol 1995;154:611-16.
  17. Delancay J. The pathophysiology of stress urinary incontinence in women and its implications for surgical treatment. World J Urol 1997;15:268-74.
  18. Henriksson L, et al. The urethral pressure profiles in continent and stress incontinent women. Scand J Urol Nephrol 1979;13:5-10.
  19. Hilton P, Stanton SL. Urethral pressure measurement by microtransducer: the results in symptom-free women and in those with genuine stress incontinence. Br J Obstet Gynaecol 1983;90:919-33.
  20. Andersson K-E. The pharmacology of lower urinary tract smooth muscle and penile erectile tissues. Pharmacol Rev 1993;45:253-308.
  21. Thor KB, Katofiasc MA. Effects of duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, on central neural control of lower urinary tract function in the chloralose ­anesthetized female cat. J Pharmacol Exp Ther 1995;274:1014-24.


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