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Review Articles
 
 

Pharmacologic treatment of overactive bladder

Gomes, C.M, de Carvalho, F.L., Hisano, M., Bruschini, H., Srougi, M.
Clinical Urology Division and Plastic Surgery Division of the Department of Surgery,
São Paulo University Hospital of Clinics

Introduction

Overactive bladder can be described as urgency with or without urge incontinence usually with frequency and nocturia, according to the International Continence Society (ICS)1. This condition affects one sixth of the European population over 40 years. In the United States, prevalence has been estimated to be similar in men (16%) and women (16.9%)2;3, with an overall prevalence of 17%3;4. Incontinence is present in one third of the cases, with prevalence increasing with age. Total treatment cost across five European countries has been estimated at € 4.2 billion5.

Physiopathological Mechanisms

Vesical contraction is mediated by acetylcholine, a parasympathetic neuromediator responsible for the activation of muscarinic receptors. There are five known muscarinic subtypes (M1, M2, M3, M4 and M5). M2 and M3 are the most relevant subtypes in the bladder, with M2:M3 ratio being 3/1. Despite M2 vesical predominance, M3 is the subtype that directly activates bladder contraction6;7.
Although our knowledge of the physiology of the bladder has advanced, the precise etiology of overactive bladder remains poorly understood. Traditionally, etiopathogenesis has been suggested as myogenic or neurogenic in basis6;8;9, but urothelial sensory mechanisms have been recently implicated10.

Pharmacologic Therapy

Clinical pharmacotherapy is still the main treatment for overactive bladder, and is mostly peripherally targeted. Treatment principles are to increase the storage capacity of the bladder to reduce frequency and nocturia while decreasing urge and urge-incontinence episodes. In combination with drug treatment, lifestyle changes are also very important. These changes include limiting water intake, avoiding water-rich food such as fruit and vegetables, avoiding drinking 4 hours before going to sleep, quitting smoking, and loosing weight11.
Information on the existing types of drugs is provided below with emphasis on those commercially available.

MUSCARINIC ANTAGONISTS

Anticholinergics (or muscarinic antagonists) were designed to target the brain pathway controlling detrusor contraction in which acetylcholine released from parasympathetic nerves activates muscarinic receptors. Although M2 receptors predominate in the bladder, M3 receptors are more specific for contraction. Important muscarinic antagonists include oxybutynin, tolterodine, darifenacin (all available in Brazil), solifenacin, trospium and propiverin, which have level 1 evidence and grade A recommendation for overactive bladder treatment6;12. Treatment with muscarinic antagonists has been associated with a 40-70% reduction in urge-incontinence episodes and a significant, though of a lesser magnitude, decrease in urinary frequency. The problem with these anticholinergic drugs is that they have side effects, particularly on salivary output and intestinal functions, which are unpleasant enough to cause treatment discontinuation. In one representative study, only 18% of the patients continued taking anticholinergic agents for more than 6 months. The activation of M3 receptors mediates contraction not only in the bladder detrusor but also in the salivary glands and intestinal smooth muscle. Depending on the drug used, and at variable degrees, antimuscarinic side effects include reduced salivary secretion (dry mouth), ciliary muscle paralysis (blurry vision), and intestinal motility inhibition leading to constipation. Antimuscarinic agents are often contraindicated in cases of closed angle glaucoma and should be used with care in cases of infravesical obstruction because anticholinergics can precipitate urinary retention. Other side effects that may occur are dizziness, memory loss, and drowsiness as M1 receptors are present in the neocortex, hippocampus and neostriatum.
The most commonly used antimuscarinic drugs are described below.

Oxybutynin

Oxybutynin hydrochloride is a tertiary amine of mixed action that has spasmolytic and antimuscarinic properties, but is not specific to muscarinic receptors (M1 e M3). The oral bioavailability of oxybutynin is reported to be about 10% as it is metabolized in the liver to N-desethyloxybutynin (N-DEO). Thus, its effect can be primarily attributed to its anticholinergic effect rather than its direct action on smooth muscles.  Oxybutynin has a half-life of 2-3 hours13, and has been implicated as the major cause of troublesome side effects. It is usually given in a dose of 5 mg 3 times a day (TABLE 1). The efficacy of oxybutynin has been demonstrated in several studies, but the high incidence of side effects causes patient compliance rates to drop14. Another formulation currently available in Brazil has a higher bioavailability that allows the administration of a single dose of 10 mg daily.
Aiming at decreasing side effects, other drug delivery systems have been developed (e.g. intravesical, transdermal, intravaginal and rectal). In patients using intermittent catheterization, intravesical oxybutynin at a dose of 0.2 mg/Kg can be an alternative to reach higher plasma levels with better tolerability. Extended-release transdermal patches are still under investigation, but seem to avoid peak plasma concentrations by maintaining oxybutynin and N-DEO plasma levels more stable with fewer side effects. The use of oxybutynin promotes a reduction in urge-incontinence episodes by up to 88%, but the incidence of dry mouth is 87% with the usual dosage against 68% with oxybutynin extended-release forms. The relative risk of dry mouth is 3.23 compared with placebo. The incidence of constipation, drowsiness and dizziness is 30-31%, 38-40% and 28-38%, respectively15;16.

Tolterodine

Tolterodine tartrate is also a tertiary amine of potent antimuscarinic action that has a 8-fold higher affinity for muscarinic receptors (M2) in the urinary bladder, compared with salivary glands, both in vitro and in vivo16;18. This affinity confers tolterodine a good tolerability profile which has been well established17. Clinical studies have demonstrated that the usual dose of 2mg twice daily (TABLE 1) reduces the number of urge-incontinence episodes in 40-60%, and micturition in 20%. Moreover, the low incidence of side effects significantly enhanced treatment compliance in comparison with oxybutynin (17).  The extended-release formulation (ER) of tolterodine (4mg once daily) is 18% more efficacious than the regular formulation. It yields more stable plasma drug levels (avoiding peaks and nadirs) and reduces urge-incontinence episodes in 71-83%. Dry mouth rates range from 12.9 to 23% with ER tolterodine against 30% with the usual dosage. In comparison with placebo, dry mouth relative risk is 3.37. The incidence of constipation, dizziness and drowsiness is 6-7%, 2% and 3%, respectively.

Darifenacin

Darifenacin is a selective muscarinic M3 receptor antagonist that reduces the effects secondary to the blockade of M1 and M2 receptors. The usual dosage is 7.5mg, that may reach 15mg after titration (TABLE 1). Among patients with overactive bladder, darifenacin efficacy in the treatment of this condition and its beneficial effect on quality of life have been well documented15;16;19. The most common adverse effects are constipation14 and 21%  at 7.5 and 15mg, respectively), visual disturbances and dry mouth (20 to 35%). The incidence of effects on the central nervous system (CNS) is very low as darifenacin has limited penetration into the CNS, which is consistent with its selectivity profile. Therefore, the absence of neurological or cardiac adverse events is one of the advantages offered by this drug20. Compared with oxybutynin, dry mouth incidence is 13% against 36%.

Solifenacin

Solifenacin is an antimuscarinic specific for M2 and M3 receptors of prolonged action that can be delivered in a single daily dose. It is available in two forms (5 and 10mg), reaches peak plasma concentration at 3 to 8 hours, and has a half life of 50 hours. It shows good clinical effect on the number of episodes of micturitions, urge and urge-incontinence and thus improve quality of life. The relative risk of dry mouth is 3.62 compared to placebo15;16;21.

Trospium

Trospium is a quaternary amine that has, over tertiary amines, the advantage of not crossing the blood-brain barrier avoiding adverse effects on the central nervous system. It has a bioavailability of 6% and affinity for M1 and M3 receptors. The recommended dose is 20 mg twice daily. It improves vesical capacity before the first contraction and thus decreases polaciuria and urge-incontinence. It has a beneficial effect on quality of life. The relative risk for dry mouth is 2.66 in comparison with placebo, and the incidence of constipation ranges from 10 to 20%15;16.

Propiverin

Propiverin is a mixed action amine, like oxybutynin, that has anticholinergic and musculotropic effects. Early studies suggest that propiverin efficacy is comparable to that of oxybutynin, but the incidence of dry mouth is lower15;22.

BETA-ADRENOCEPTOR AGONISTS

Beta-adrenoceptors are found in the bladder body and mediate vesical relaxation to noradrenaline released from the sympathethic nervous system. Thus, beta-adrenoceptor agonists may be a potential treatment for overactive bladder. β3-adrenoceptors are known to predominate in human detrusors. Other studies have shown that β-adrenoceptors in the urothelium modulate vesical function by releasing a contraction inhibitory factor. Drugs such as GW427353, a β3- agonist, are under investigation but their efficacy has yet to be demonstrated in clinical trials23.

ALPHA-1 ADRENOCEPTOR ANTAGONISTS

Studies have shown that α1A-adrenoceptors seem to influence vesical contraction. This may explain their beneficial effect on both the obstructive and irritative symptoms exerted by  α –blockers such as doxazosin and tamsulosin. Moreover, it has been postulated that α1A-adrenoceptors may act on the central nervous system and spinal cord contributing to the signaling of irritative and nociceptive responses. Nonetheless, the use of these agents in the treatment of the overactive bladder is still not indicated in routine practice23.

TACKYKININS

Tackykinins are a family of peptides including substance P, neurokinin A and neurokinin B. Tackynin release from bladder afferent acts via NK2 receptors. Experimentally, NK2 antagonists can reduce detrusor overactivity. NK1 receptors in the spinal cord can also play a role in vesical control. The clinical use of these drugs is under investigation23.

POTASSIUM CHANNEL OPENERS

Potassium channels are fundamental in the regulation of cellular excitability. Experimental studies have shown that potassium channel openers can inhibit detrusor contraction. First generation potassium channel openers lacked bladder selectivity and showed important vascular side effects. Several new drugs selective for the lower urinary tract have been developed and seemed successful in animal models. However, these results still have not been extrapolated to the human bladder in vivo23;24.

VANILLOIDS

The transient receptor potential (TRP) family of nonselective calcium channels plays an important role in many physiological processes. The vanilloid TRPV1 is formed in the sensory nerves and urothelium of the bladder and has been recently linked to the pathogenesis of bladder overactivity. Capsaicin, a potent neurotoxin, desensistizes C-fiber afferents by binding to TRPV1. Its intravesical instillation has shown some beneficial effects, but adverse events, such as vesical pain and irritation, limit its use25;26.
Resiniferatoxin, obtained from Euphorbia resinfera, is also an agonist of TRVP1 and desensitizes C-fibers. However, it is more selective and, therefore, shows fewer side effects. The vesical instillation of resiniferatoxin can increase bladder storage capacity with effects lasting for up to 4 weeks. At high doses (50-100nmol), resiniferatoxin can produce long-lasting improvements for up to 12 months in 50% of the cases. A study using 4 weekly instillations of 10nmol demonstrated that, after 3 months, there was a 62% improvement that lasted for 6 months in 50% of the patients26;27.

BOTULIN TOXIN

Botulin toxin, derived from Clostridium botulinum, is one of the most potent toxins. There are 7 toxin subtypes, the most commonly used being toxin A (BTX-A), which decreases acetylcholine release at the pre-synaptic membrane of cholinergic nerves and causes a long-lasting blockade. BTX-A ameliorates symptoms of urgency, frequency and quality of life with no significant side effects (especially urinary retention)28;29. It has been indicated in cases refractory to treatment with anticholinergics. BTX-A is applied via cytoscopy for direct injection into the detrusor muscle30. Optimal dosing and site of injection are under investigation but 100-200U have been commonly used in idiopathic cases, and 200 - 300 U in neurogenic cases. Effects last from 3 to 12 months when re-injection may be performed.

Drugs acting on the central nervous system:

  1. Drugs that stimulate g-aminobutyric acid (GABA) receptors: GABA acts on specific receptors in the CNS and the periphery inhibiting detrusor contraction. In the CNS, GABA and glycin are probably the most important inhibitory mediators. The drugs acting on this level tend to inhibit the micturition reflex. Baclofen, the main drug in this class, depresses motor neurons and interneurons in the spinal cord by acting as a GABAB agonist. Although its primary site of action is the medulla, baclofen also acts on higher levels. Its effect on spasticity results from the normalization of interneuronal activity and reduction in motor neuronal activity31. Baclofen is useful in the treatment of skeletal muscle spasticity related to multiple sclerosis, rachi medullar trauma, etc. Dosage is usually titrated, starting as 5 mg twice a day progressively increased to a maximum of 20 mg 4 times a day. Side effects include dizziness, insomnia, skin problems, itching and weakness. This drug should be stopped gradually32. Oral baclofen reaches only low concentrations in the spinal fluid and has little effect on the urinary tract. However, it may be administered intrathecally using a pump system. Besides relieving lower limb spasticity, intrathecal baclofen reduces vesical-sphyncter dyssynergy and detrusor overactivity33;34. Thus, this drug is generally reserved for patients with neurogenic detrusor overactivity associated with limb spasticity.
  2. Drugs that increase serotonin (5HT) and noradrenaline (Nor) in the CNS: Studies have shown that Nor and 5HT inhibit vesical contraction in animals with chemically-induced overactive bladder, besides increasing electromiographic sphyncter activity. These findings would then support the use of drugs such as duloxetine, inhibitors of the reuptake of 5HT and Nor (increasing synaptic concentration) to treat detrusor overactivity. However, clinical trials have demonstrated that, despite improving sphyncter function, these drugs are not effective in treating the overactive bladder35;36.
  3. Tricyclic antidepressants: Several tricyclic antidepressants, particularly imipramine, have been long used in the treatment of detrusor overactivity Imipramine has complex pharmacologic effects including marked systemic anticholinergic actions and blockade of the reuptake of serotonin37. Peripherally, imipramine shows an important anticholinergic action, but its direct effect on detrusor muscles is small. It seems to directly potentiate detrusor relaxation. The usual dose used is 25 mg orally taken 3-4 times daily. Half of this dose is recommended for elderly patients. Imipramine mechanism of action allows its use in association with antimuscarinics. In children with enuresis, the administration of 0.25 mg/Kg/day (in 2-3 divided doses) is recommended.
    In addition to the side effects commonly exerted by anticholinergics, imipramine may induce adverse events related to its action on the CNS such as weakness, fatigue, symptoms of Parkinson disease and reduced level of consciousness. In patients with cardiac disorders it may produce arrhythmia. Children are particularly sensitive to the cardiotoxic effects of this drug that should, therefore, be carefully used in this population. 42 like other tricyclic antidepressants, imipramine should not be used in association with monoamine oxidase inhibitors as the potentialization of inhibitory effects may lead to coma38;39.
Table 1. Pharmacologic agents available in Brazil for the treatment of overactive bladder.

Anticholinergic agents

Dose* (adults)

Oxybutynin hydrochloride (Retemic, Incontinol, Urazol, Frenurin)

5 mg 3x/ day
10 mg LP **1x/ day

Tolterodine tartrate (Detrusitol)

2 mg 2x/ day
4 mg LP** 1x / day

Darifenacin (Enablex)

7.5 mg 1x/ day

Imipramine

25 mg 2-3x/ day

*Standard recommended dose. Lower doses may be necessary for children, the elderly and patients with comorbidities
**Extended release
 
 
 
 
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