BJU International (2000), 86, 581±589
The pharmacology of paediatric incontinence
P.B. HOEBEKE* and J. VANDE WALLE² *Departments of Paediatric Urology and ²Paediatric Nephrology, Ghant University Hospital, Belgium
Introduction ' the accommodation of increasing volumes of urine The clinical uropharmacology of the lower urinary tract at a low intravesical pressure and with appropriate is based on an appreciation of the innervation and sensation receptor content of the bladder and its related anatomical ' a bladder outlet that is closed and remains so during structures. The anatomy, neuroanatomy and neuro- increases in intra-abdominal pressures physiology of the bladder is reviewed. Classes of drugs are ' and absence of involuntary bladder contractions [2]. discussed in relation to the possible functional targets of pharmacological intervention and ®nally some speci®c In children the development of continence and applications in paediatric voiding dysfunction are voluntary voiding involves maturation of the nervous discussed. system and behavioural learning. Toilet training mainly depends on the cognitive perception of the maturing urinary tract. This implies a high sensibility for the Pharmacological interactions development of dysfunctions [3]. The storage and A short review of anatomy, neuroanatomy and neuro- evacuation of urine are controlled by two functional physiology is essential to understand pharmacological units in the lower urinary tract, i.e. the reservoir (the interactions. These interactions with effects on bladder bladder) and an outlet (consisting of the bladder neck, function can occur on different levels, i.e. on bladder urethra and striated muscles of the pelvic ¯oor). In the mucosa, bladder smooth muscle or bladder outlet striated bladder, two regions (Fig. 1a) are distinguishable from muscle, on receptor subtypes, on nerve terminals, on their innervation and response to pharmacological peripheral nerves and ganglia, on the spinal cord and on agents; the body, which lies cranial to the level of the some supraspinal areas. The lower urinary tract consists ureteric ori®ces, and the base, which is caudal to this of the bladder, which mainly contains smooth muscle level [4]. In the outlet two functional units are cells, and a sphincter, which mainly contains striated distinguished, an anatomical striated sphincter and a muscle. Although this is an over-simpli®cation of the real physiological internal sphincter. The internal sphincter is anatomy of the lower urinary tract, it is useful more a functional than an anatomical structure, and pharmacologically. Between the bladder and the urethral keeps the bladder neck and the proximal urethra closed sphincter there is a zone of transition where smooth during bladder ®lling. The autonomic and somatic muscle cells play the role of a functional sphincter [1]. In innervation of the bladder and the outlet are well adult urology this zone has a major role in the known. Other neuronal systems, i.e. purinergic, pepti- pharmacological treatment of infravesical obstruction, dergic, c-aminobutyric acid (GABA) and serotonin, are especially in men with BPH. Its role in paediatric known to be apparent in the bladder but their effect on pathological conditions remains unclear. The lower bladder function remains obscure. This review mainly urinary tract differs from other visceral structures by focuses on the autonomic and somatic nervous systems. its dependence on the CNS. This makes the bladder a All nerves are able to transport information from the unique organ where viscero-somatic integration takes organ to the CNS (afferent impulses), mainly a sensory places. Indeed, most autonomic nerve systems must function, and to transport information from the CNS to provide tonic activity to visceral organs. However, the organ (efferent impulses), mainly a motor function. bladder function demands a phasic autonomic activity with voluntary control. Bladder function consists of the The peripheral nerve system storage of urine and timely evacuation at socially acceptable and convenient places and times. Bladder Afferent storage requires: Nerve cells in the dorsal spinal root ganglia project their Accepted for publication 20 June 2000 axons to the bladder wall. Different kinds of receptors
# 2000 BJU International 581 582 P.B. HOEBEKE and J. VANDE WALLE
Bladder body (dome)
Bladder base Trigone Internal sphincter Proximal urethra
α Striated sphincter β a b muscarinic
α – receptor
c Muscarinic receptor d β – receptor Fig. 1. a, Two bladder regions are distinguished based on their innervation and response to pharmacological agents; the body, which lies cranial to the level of the ureteric ori®ces; and the base, which is caudal to this level. b, shows the distribution of muscarinic receptors (blue), and a- and b-adrenergic binding sites (red and green, respectively) in human bladder and urethral tissues. c, shows the effect of anticholinergic or antimuscarinic agents, i.e. a decrease in parasympathetic input to the bladder increases bladder capacity by decreasing bladder contractility. d, shows the noradrenergic effects on the bladder; whereas a-adrenergic agonists (red) increase outlet resistance, b-adrenergic agonists (green) can cause a signi®cant increase in bladder capacity.
# 2000 BJU International 86, 581±589 PHARMACOLOGY OF PAEDIATRIC INCONTINENCE 583
(pressure, pain, temperature, tension) are able to decentralization and smooth muscle hypertrophy trigger intercept signals from the bladder and convey them to changes in adrenergic mechanisms that regulate the CNS, where they can be perceived at the spinal cord bladder/urethral function. In paediatric voiding dysfunc- level and generate re¯exes, or where they can become tion muscle hypertrophy is often apparent. There may be conscious stimuli which can be modi®ed by behaviour. a higher content of adrenergic receptors in the paediatric The receptors in the bladder form the most distal level dysfunctional bladder. where pharmacological agents can interact. Somatic innervation to the pelvic ¯oor and the perineal muscles originates in Onuf's nucleus in the anterior horn of the S2±S4 segments of the spinal cord. They form the Efferent pudendal nerve that supplies the pelvic ¯oor muscles Parasympathetic or cholinergic innervation is provided and the striated urethral sphincter [11]. However, the by the sacral parasympathetic pelvic nerves (S2±S4). The innervation of the striated urethral sphincter is still under sacral parasympathetic efferents to the lower urinary debate, as autonomic innervation has been suggested by tract are carried within the pelvic splanchnic nerves, and some [12]. are the principal excitatory input to the bladder. Radioligand studies have con®rmed that the bladder The CNS body and base (Fig. 1b) contain muscarinic receptors [5], stimulated by acetylcholine. In the bladder this stimulation Neural control of the lower urinary tract occurs at provokes a bladder contraction and a rise in intravesical different levels of the CNS and is less well understood. The pressure. These effects can be abolished by atropine, but main in¯uences are inhibition of the micturition re¯ex, not completely (atropine resistance) because there are co- inhibition of spontaneous detrusor re¯ex contractions, transmitters (e.g. ATP). Physo-stigmine, which inhibits coordination of detrusor contraction and sphincter acetylcholine degradation, also enhances bladder con- relaxation. The cerebral cortex, thalamus, hypothala- traction. However, cholinergic agonists do not cause mus, limbic system, basal ganglia, cerebellum, brain stem voiding, as they often cause simultaneous contractions of with the `pontine micturition centre' and spinal cord with the bladder and the bladder neck. There seems to be a the `sacral micturition centre', are involved [3]. From the parasympathetic activity to the urethra resulting in sacral micturition centre afferent and efferent pathways relaxation, although this is mediated by a noncholinergic connect to the lower brain stem. Two ascending tracts transmitter and is not fully understood. (the pelvic sensory in the dorsal funiculus and the Orthosympathetic or adrenergic innervation is pro- sacrobulbar in the lateral funiculus) and three descend- vided by the thoracolumbar sympathetic hypogastric ing tracts (a lateral reticulospinal tract which promotes nerve and sympathetic chain (T10-L2). The sympathetic detrusor contraction, a ventral reticulospinal tract which nerves to the lower urinary tract emerge from the inhibits detrusor contraction and a medial reticulospinal paravertebral ganglia of the lumbar sympathetic chain as tract which promotes sphincter contraction) have been the superior hypogastric plexus, which bifurcates into left described. These tracts terminate in the pontine micturi- and right hypogastric nerves. These hypogastric nerves tion centre in the anterior pons, which is inhibitory. This intermingle with the pelvic parasympathetic nerves to centre is connected to the cerebral cortex which is also form the pelvic plexus. inhibitory. Pharmacological in¯uences on the CNS will There are a- and b-adrenergic binding sites in human not be discussed systematically. bladder and urethral tissues (Fig. 1b), with b-receptors predominantly at the bladder dome and a-receptors at The pharmacology of reservoir function the base and the outlet. It is thought that the adrenergic pathways facilitate bladder storage by relaxing the An overview of this aspect is given in Table 1. As storage detrusor and contracting the outlet [6]. This theory is dysfunction is often seen in paediatric voiding dysfunc- not accepted by all and remains in debate [7]. tion, these drugs will be discussed in more detail. The b-adrenergic receptor agonists increase bladder capacity and reduce the amplitude of uninhibited Pharmacological action on smooth muscle cells detrusor contractions [8]. b-antagonists like propranolol increase bladder pressure [9]. a-blockade in vivo decreases By in¯uencing smooth muscle activity the bladder the amplitude of uninhibited bladder contractions in the reservoir function can be altered. Inhibitors of smooth neurogenic bladder [10]. Although sympathetic path- muscle activity will increase bladder capacity or decrease ways appear to play a minor role in lower urinary tract the occurrence of unstable or hyper-re¯exive contrac- function, as judged by pharmacological and electro- tions. However, pharmacological stimulation of smooth stimulation data, it may be that in denervation, muscle cells is currently not possible. The site of action of
# 2000 BJU International 86, 581±589 584 P.B. HOEBEKE and J. VANDE WALLE
Table 1 The pharmacology of reservoir function and the bladder outlet
Reservoir function or outlet resistance
Level Increase Decrease
Reservoir Smooth muscle Relaxation of smooth muscle Toni®cation of smooth muscle Oxybutynin Not available Flavoxate Calcium antagonist Potassium channel openers Prostaglandin inhibitors Afferent peripheral Decrease bladder sensibility Increase bladder sensibility nerves Capsaicin (instillation) Not available DMSO (instillation) (infection) Oxybutynin Flavoxate Tricyclic antidepressants Imipramine Efferent peripheral Decrease bladder contractility Increase bladder contractility parasympathetic Anticholinergics Parasympathicomimetics nerves Atropine Acetylcholine Propantheline Betanechol chloride Hyoscyamine Others Oxybutynin Flavoxate Efferent peripheral Decrease bladder contractility Increase bladder contractility orthosympathetic b-adrenergic agonists a-adrenergic antagonist nerves Tricyclic antidepressants (no clinical use to date) Imipramine Bladder outlet Striated urethral Not available Benzodiazepines sphincter Diazeparn Baclofen Dantrolene Efferent peripheral a-adrenergic agonists a-adrenergic antagonist orthosympathetic nerves Ephedrine Phenoxybenzamine Phenylpropanolamine Prazosin Imipramine Alfuzosin these agents is distal to the cholinergic receptor salivary gland, has recently been used in children. mechanism. In adults it effectively decreased the symptoms of Oxybutynin hydrochloride, a tertiary amine, is a detrusor overactivity and caused fewer side-effects than moderately potent anticholinergic agent with strong oxybutynin. musculotropic relaxant and local anaesthetic activity Flavoxate hydrochloride directly inhibits smooth (twice that of lidocaine). In animal studies it has weak muscle, in addition to having weak anticholinergic and anticholinergic activities (8% of the potency of pro- local analgesic properties. Side-effects are rare and pantheline bromide) but strong spasmolytic effects (twice primarily anticholinergic. the effect of propantheline bromide) [13]. The side-effects Calcium antagonists; calcium is a messenger in linking are those of all antimuscarinic agents and include extracellular stimuli to the intracellular environment. inhibition of salivary secretion (dry mouth), blockade of Interference with calcium in¯ow is a very potent the ciliary muscle of the lens (disturbed accommodation, mechanism for bladder smooth-muscle relaxation. blurred vision), facial ¯ushing during exercise, tachy- Common side-effects are hypotension, facial ¯ushing, cardia, drowsiness and inhibition of gut motility, leading headache, dizziness, constipation, nausea and palpita- to constipation. tions. Because of these side-effects, calcium antagonists are Tolterodine, a new agent with a more pronounced unpopular in children. Nifedipine has a blocking effect on antimuscarinic effect on the urinary bladder than on the the noncholinergic portion of bladder contraction.
# 2000 BJU International 86, 581±589 PHARMACOLOGY OF PAEDIATRIC INCONTINENCE 585
Potassium-channel openers relax smooth muscle cells bladder capacity by decreasing bladder contractility by increasing potassium ef¯ux, and thus might be (Fig. 1c). attractive for treating detrusor instability without Atropine depresses involuntary bladder contractions of decreasing contractile ability in response to the voluntary any aetiology but in humans the effect is only partial initiation of micturition [14]. Although a theoretical (atropine resistance). Other transmitters than acetylcho- effect on bladder function is expected, currently no line may possibly be involved in bladder contraction. clinically useful agents are available. Propantheline bromide is the most commonly used Prostaglandin inhibitors or NSAIDs can theoretically oral anticholinergic agent in pathology of the lower in¯uence smooth muscle contractions but objective urinary tract. Side-effects are dry mouth, tachycardia, evidence that this occurs at the level of the bladder is blurred vision, drowsiness and constipation. The usual scant. They can even in¯uence neurotransmission to the adult dose is 15±30 mg every 6 h. In children we prefer bladder and in¯uence urethral tone during the storage to start with 7.5 mg every 8 h and depending on the phase. Apart from their direct effect they can in¯uence effect, the dose is increased to 15 mg every 8 h. bladder function by their effect on renal function Other antimuscarinic agents, e.g. glycopyrrolate, and diuresis. Side-effects are interference with platelet isopropamide, hyoscyamine, anisotropine and methyl function and adverse renal effects. bromide, have the same effect on bladder smooth muscle as propantheline. Parasympathicomimetic agents can be useful in the Pharmacological action on afferent peripheral nerves treatment of weak contractile bladders but are only rarely Increasing bladder capacity by decreasing afferent indicated in children. The best known agent is betanechol sensory input seems a reasonable treatment for chloride, which has a relatively selective action on the hypersensitivity disorders of the bladder. Apart from bladder. Side-effects like ¯ushing, nausea, vomiting, systemically administered drugs like oxybutynin, ¯avox- diarrhoea, gastrointestinal cramps, salivation and sweat- ate and imipramine, all of which have dedicated local ing are important, and limit the use of this drug, analgesic effects on bladder mucosa, it is possible to especially in children. in¯uence the bladder receptor by instilling drugs into the bladder. Efferent peripheral nerves: orthosympathetic A 50% solution of DMSO has been reported to have good to excellent results in treating interstitial cystitis b-adrenergic agonists can cause signi®cant increases in [15] but its ef®cacy in other hypersensitivity disorders of the capacity of the bladder (Fig. 1d). Terbutaline has been the bladder has not been reported. tested in clinical trials but is not commonly used; the side- Capsaicin is an irritant and algogenic compound effects include palpitations, tachycardia and tremor. obtained from the chilli pepper, and which has a Tricyclic antidepressants are useful agents for facil- highly selective effect on sensory neurones. The instilla- itating urine storage, by both decreasing detrusor tion of capsaicin into the bladder induces desensitization contractility and increasing outlet resistance. They are and inactivation of sensory neurones [2]. Because it has especially popular for treating monosymptomatic noc- the undesirable effect of inducing pain it is not applicable turnal enuresis (MNE). The precise mechanism of action in children. in enuresis remains unclear. A recent placebo-controlled As noted, oxybutynin has a potent local anaesthetic study suggested that the ef®cacy is not through their effect. Because systemic application produces signi®cant antidepressant effect [18]. Although they are known to side-effects, topical administration was introduced and have anticholinergic effects, anticholinergic drugs are has been shown to be effective in treating various bladder ineffective in MNE [19]; thus a direct noradrenergic effect conditions, e.g. instability, hypersensitivity and hyper- on the bladder could explain the observed effect (Fig. 1d). re¯exia [16]. Whether the effect is through antispas- Imipramine is the most widely used tricyclic anti- modic or local anaesthetic effects is unknown. This opens depressant for treating nocturnal enuresis in children. new possibilities, especially for patients using intermit- Imipramine has only weak anticholinergic effects on tent catheterization. Good results with long-term intra- bladder muscle; as well as adrenergic effects, they may vesical treatment have been described in children with exert a local anaesthetic-like action on the bladder. myelodysplasia [17]. Clinically, the drug is effective by decreasing bladder contractility and increasing outlet resistance. Stimulation of the b-receptor by peripheral blockade of noradrenaline Efferent peripheral nerves: parasympathetic re-uptake could account for the decrease in bladder body Anticholinergic or antimuscarinic agents decrease para- contractility, and stimulation of the a-receptors in the sympathetic input to the bladder and can in¯uence smooth muscle of the bladder base and proximal urethra
# 2000 BJU International 86, 581±589 586 P.B. HOEBEKE and J. VANDE WALLE could account for the increase in outlet resistance. direct action on skeletal muscle. The effect on the bladder Side-effects include fatigue, tremor, sedation, nausea, outlet has not been con®rmed. vomiting, headache, lethargy, irritability and possible cardiotoxicity. However, these effects are rare in patients Pharmacological actions on efferent and orthosympathetic receiving smaller doses for lower urinary tract dysfunc- peripheral nerves tion [20]. Imipramine should be discontinued gradually, as abrupt cessation can cause signi®cant side-effects. It a-adrenergic agonists can increase outlet resistance, as also carries a risk of accidental poisoning if swallowed a-adrenergic receptors predominate in the bladder neck by younger siblings. The provision of good parental and proximal urethra. The side-effects of these drugs are information can prevent this. hypertension, anxiety, insomnia, headache, tremor, palpitations and respiratory dif®culties. Pharmacology of the bladder outlet Ephedrine, pseudo-ephedrine, norephidrine chloride and ephedrine sulphate have been used to treat adults An overview of this topic is also given in Table 1. with sphincteric incontinence. Good results are obtained Although outlet problems are important in children with in those patients with minimal to moderate wetting. functional and neurogenic voiding disorders, they are Currently we are using a-adrenergic agonists to treat rarely treated with drugs. The functional voiding urge syndrome in children. Children with urge syndrome disorders (`dysfunctional voiding') particularly are more often have an open bladder neck secondary to the logically treated with bladder training and pelvic-¯oor unstable contractions. An open bladder neck can provoke training. In neurogenic voiding dysfunctions drugs are further unstable contractions as the presence of urine in more frequently used in paediatric practice, as in spastic the proximal urethra can induce bladder contractions. tetraplegia and cerebral palsy. With the increasing use of Phenylpropanolamine hydrochloride is available for the a-blocking agents in adults and the availability of more treatment of nasal and sinus congestion; its effects on the speci®c a-blockers, their application may in future bladder outlet are the same as those obtained with be extended to children; the available products are ephedrine. discussed. The possible effects of imipramine on the bladder outlet have been described previously; the inhibition of noradrenaline re-uptake can provide a-adrenergic Pharmacological action on striated urethral sphincter stimulation. muscle a-blockers are currently very popular for treating There is no class of pharmacological agents that BPH. The concept of the physiological internal sphincter selectively relaxes the striated musculature of the pelvic controlled by a-adrenergic receptors in the smooth ¯oor. Three different types of drugs have been used to musculature of the bladder neck and proximal urethra treat voiding dysfunction caused by striated sphincter was popularized in the 1970s [6]. Although the activity during voiding. They are all very unspeci®c and theoretical expected effect would be best in those have important side-effects. Their main application is in patients with bladder neck obstruction, good results spastic disorders. are described in patients with detrusor sphincter Benzodiazepines potentate the action of GABA, the dyssynergia, suggesting that there may also be an major inhibitory transmitter in the spinal cord; they effect on striated sphincter tone. To date, a-blockers reduce the release of transmitters of afferent ®bres and have no application in children. Theoretically they reduce re¯ex activity in patients with spasticity. could have a place in treating obstructive outlet Diazepam is the most common drug used for this conditions, as in dysfunctional voiding. The side-effects purpose. It can be used successfully in children who are orthostatic hypotension, re¯ex tachycardia and a present with urinary retention after urethral instrumen- possible `®rst-dose phenomenon' with faintness, dizzi- tation. Whether the muscle-relaxing or the anti-anxiety ness, palpitations and syncope. effect is responsible for the result is unknown. Side-effects Phenoxybenzamine has been the most commonly used are over-sedation and impairment of cerebral function. a-blocker in voiding dysfunction; because it is theoreti- Baclofen is thought to be a GABA agonist; it decreases cally mutagenic its use is no longer advised. excitatory transmitter release by afferent ®bres but is only Prazosin is an antihypertensive agent with effects on applicable in patients with general spasticity caused by a bladder smooth musculature; because it has important neurological lesion. It may impair the ability to walk or circulatory side-effects it is no longer used for voiding stand and must therefore be used very carefully. Other dysfunction. Terazosin, alfuzosin and other similar new side-effects include drowsiness, insomnia and dizziness. drugs are selective a1-blockers and therefore more Dantrolene is the only pharmacological agent with a selective for the urinary tract. Their use in BPH is
# 2000 BJU International 86, 581±589 PHARMACOLOGY OF PAEDIATRIC INCONTINENCE 587 currently approved but clinical trials in children are and van Mastrigt [29] showed that oxybutynin could needed. decrease detrusor contractility and the degree of re¯ux. The usual reported dose is 0.3±0.5 mg/kg/day given in Pharmacological treatment of paediatric voiding three doses. dysfunction Tolterodine has recently been used to treat detrusor instability in children [30]; its safety and ef®cacy were con®rmed. There was a dose-related decrease in the Monosymptomatic bedwetting number of micturitions and number of incontinence Although nonpharmacological treatments, e.g. condi- episodes; 1 mg twice daily seems to be the optimal dose tioning therapy with an alarm system, are better for for children aged 5±10 years. MNE, pharmacotherapy continues to be popular among Propantheline bromide, a pure anticholinergic agent, physicians and families [21,22]. Antidepressants, anti- is safe in older children; the initial dose in children cholinergics and prostaglandin inhibitors are discussed. >6 years old is 7.5 mg three times daily. If no side-effects Tricyclic antidepressants; although the mechanism of are reported the dose can be increased to 15 mg three action of these agents is currently unknown (e.g. times daily. antidepressant effect, antispasmodic and/or anticholin- Although the exact site of action of imipramine ergic effect, alterations in arousal and sleep, increase in remains unclear it is has con®rmed bene®cial effects on ADH levels, adrenergic reuptake blockade) several studies bladder storage function. As imipramine may have an have con®rmed their bene®ts in MNE [18,23]. Drugs like adrenergic agonist action there is a place for combining it imipramine are generally not given to children under the with antispasmodic or anticholinergic drugs. To treat age of 6 years. Possible side-effects and risks of accidental daytime incontinence imipramine is given three times poisoning must be considered when prescribing these daily, which increases the risk of side-effects and toxicity; drugs. On a body-weight basis the recommended starting thus careful clinical monitoring is warranted. A dose of dose is 0.9±1.5 mg/kg, given 1±2 h before bedtime. 10±25 mg (in children over 12 years old) three times Anticholinergic agents have no place in the treatment daily is usual. of MNE. In the only double-blind controlled study in children with MNE, oxybutynin was shown to be no Detrusor hypersensitivity with no instability is dif®cult to better than placebo [24]. treat, but drugs having a local anaesthetic action on the Prostaglandin inhibitors have been used successfully for bladder mucosa can be used. Oxybutynin and ¯avoxate treating MNE [25,26]. A direct effect on bladder smooth also have the advantage of having antispasmodic and muscle or indirect effect on diuresis, by in¯uencing the GFR anticholinergic activities. and ADH, have been proposed as mechanisms of action in nocturnal enuresis. Although both the cited studies were Dysfunctional voiding (overactivity of the pelvic ¯oor placebo-controlled, the use of prostaglandin inhibitors in muscles during micturition) responds best to bladder MNE is currently not recommended. and pelvic-¯oor training. Drugs are currently not used for treating this condition, although theoretically there is a place for those drugs acting on outlet resistance. With Urinary incontinence more selective drugs available, prospective double-blind In paediatric functional voiding dysfunction most studies are awaited to con®rm their ef®cacy in in-continence problems are related to storage-phase dysfunctional voiding. Phenoxybenzamine and dysfunctions, mainly detrusor instability (motor urgency) diazepam have been used for this condition but are not and detrusor hypersensitivity (sensory urgency). recommended because they have important side-effects Dysfunctional voiding, which is sphincter activity [31]. during voiding, is a voiding-phase dysfunction that can maintain the storage-phase dysfunctions. Neurogenic voiding dysfunctions (congenital malformations of the CNS) Detrusor instability Theoretically, detrusor instability can be treated by antispasmodics, anticholinergics and In children with a neurogenic bladder the combination of adrenergic agonists. Oxybutynin has antispasmodic and a high-pressure hyper-re¯exive bladder with a closed anticholinergic effects and has been used most for this sphincter caused by detrusor sphincter dyssynergia indication; the drug is safe in children [27]. Reports of an carries a risk of subsequent urinary tract changes, e.g. effect in treating daytime wetting in children are sparse. re¯ux and hydronephrosis. The prophylactic use of clean Aubert et al. [28] reported an 87% success rate in a group intermittent catheterization with concomitant anti- of 77 children with daytime incontinence. Scholtmeijer cholinergic medication prevents urinary tract damage
# 2000 BJU International 86, 581±589 588 P.B. HOEBEKE and J. VANDE WALLE
[32±34]. Oxybutynin is used most often and is safe even distributions of cholinergic and adrenergic nerves. Am J in neonates, at doses of 0.1 mg/kg three times daily. Anat 1966; 119: 405±27 There may be a place for a-blockers in treating bladder 5 Lepor H, Gup D, Shapiro E, Baumann M. Muscarinic hyper-re¯exia; in neurogenic bladders there is a pro- cholinergic receptors in normal and neurogenic human liferation of a-adrenergic receptors in the bladder body bladder. J Urol 1987; 137: 782 6 Krane RJ, Olsson C. Phenoxybenzamine in neurogenic [35,36] and a-blocking agents have an effect on detrusor bladder dysfunction: a theory of micturition. J Urol 1973; hyper-re¯exia [37±39]. However, to date there have been 110: 650±2 no further clinical trials. Furthermore, the action of a- 7 Nordling J. In¯uence of the sympathetic nervous system on blocking agents on the bladder outlet may account for lower urinary tract in man. Neurourol Urodynam 1989; 2:3 some of the effects obtained with a-blockers in neuro- 8 Norlen L, Sundin T, Waagstein F. Beta adrenoceptor genic bladders. There is a theoretical place for drugs that stimulation of the human urinary bladder in vivo. Acta decrease outlet resistance (at the level of the striated Pharmacol Toxicol 1978; 43: 26±30 sphincter and the internal sphincter) in treating detrusor 9 Kaplan PE, Nanninga JB. Augmentation of bladder sphincter dyssynergia but their use has not been reported contractility after beta-adrenergic blockade in spinal cord in children. As their effect will include more problems injured patients. Acta Neurol Scand 1980; 61: 125±30 with incontinence, they will have limited use for treating 10 Jensen D. Pharmacological studies of uninhibited neuro- neurogenic dysfunctions in children. genic bladders. II. The in¯uence of cholinergic excitatory and inhibitory drugs on the cystometrogram of neurological patients with normal and uninhibited neurogenic bladder. Congenital structural abnormalities Acta Neurol Scand 1981; 64: 175±95 11 Tanagho EA, Schmidt RA, Gomes de Araujo C. Urinary Congenital structural abnormalities (exstrophy, caudal striated sphincter: what is its nerve supply? Urology 1982; regression sequence, PUV and other urethral anomalies) 20: 415±7 cover a wide range of bladder dysfunctions. The 12 Walsh PC, Donker PJ. Impotence following radical prosta- description of the bladder dysfunction in these conditions tectomy: insight into etiology and prevention. J Urol 1982; depends mainly on urodynamic data and treatment is 128: 492±7 adapted to urodynamic ®ndings. The details of the 13 Fredericks CM, Anderson GF, Kreulen DL. A study of the treatment of these complex dysfunctions is beyond the anticholinergic and antispasmodic activity of oxybutynin scope of this review and will not be addressed. However, on rabbit detrusor. Invest Urol 1975; 12: 317±9 the general information on the drugs described above is 14 Malmgren A, Andersson KE, Fovaeus M, SjoÈgren C. Effects of also applicable in these conditions. cromakalim and pinacidil on normal and hypertrophied rat detrusor in vitro. J Urol 1990; 143: 828±34 15 Sant G. Intravesical 50% dimethylsulfoxide in the treatment Conclusion of interstitial cystitis. Urology 1985; 4 (Suppl): 17 16 Brendler CR, Radebaugh LC, Mohler JL. Topical oxybutynin Although many drugs are available for treating bladder chloride for relaxation of dysfunctional bladders. J Urol dysfunctions, their application in children is limited, 1989; 141: 1350±2 largely because of the side-effects arising from their low 17 Painter KA, Vates TS, Bukowski TP et al. Long-term speci®city. Future objectives include the development of intravesical oxybutynin chloride therapy in children with more selective drugs to extend the possibilities for myelodysplasia. J Urol 1996; 156: 1459±62 pharmacological therapy in paediatric voiding dysfunc- 18 Smellie JM, McCrigor VS, Meadow SR, Rose SJ, Douglas MF. tion, and a greater understanding of the innervation of Nocturnal enuresis: a placebo controlled trial of two the normal bladder and that in pathological conditions. antidepressant drugs. Arch Dis Child 1996; 75: 62±6 Further research in this ®eld will open new perspectives 19 Wallace IR, Forsythe WI. The treatment of enuresis: a for pharmacological treatment. placebo controlled clinical trial of propantheline, propanthe- line and phenobarbitone and a placebo. Br J Clin Pract 1969; 23: 207±10 20 Montanari G, Baraldo M, Zara G, Benetello P, Secchieri S, References Furnalut M. Side effects of imipramine therapy in enuretic 1 Tanagho EA, Meyers FH. The `internal sphincter': is it under children. Pharmacol Res 1990; 22 (Suppl 3): 3 sympathetic control? Invest Urol 1969; 7: 79±89 21 Foxman B, Burciaga Valdez R, Brook RH. Childhood 2 Wein A. Pharmacology of incontinence. Urol Clin North Am enuresis: prevalence, perceived impact and prescribed 1995; 22: 557±77 treatments. Pediatrics 1986; 77: 482±7 3 de Groat WC. Anatomy and physiology of the lower urinary 22 Miller K, Atkin B, Moody ML. Drug therapy for nocturnal tract. Urol Clin North Am 1993; 20: 383±401 enuresis. Current treatment recommendations. Drugs 1992; 4 Elbadawi A, Schenk EA. Dual innervation of the mam- 44: 47±56 malian urinary bladder: a histochemical study of the 23 Jorgensen DD, Lober M, Christiansen J, Gram LF. Plasma
# 2000 BJU International 86, 581±589 PHARMACOLOGY OF PAEDIATRIC INCONTINENCE 589
concentration and clinical effect in imipramine treatment of ization in children with vesical dysfunction. J Urol 1978; childhood enuresis. Clin Pharmacokinetics 1980; 5: 386±93 119: 551±4 24 Lovering JS, Tallett SE, McKendry JBJ. Oxybutynin ef®cacy 33 Joseph DB, Bauer SB, Colodny AH et al. Clean intermittent in the treatment of primary enuresis. Pediatrics 1988; 82: catheterisation of infants with neurogenic bladder. 104±6 Pediatrics 1989; 84: 78±82 25 Al-Waili NS. Indomethacin suppository to treat primary 34 Baskin LS, Kogan BA, Benard E. Treatment of infants with nocturnal enuresis: double blind study. J Urol 1989; 142: neurogenic bladder dysfunction using anticholinergic drugs 1290±2 and intermittent catheterization. Br J Urol 1990; 66: 532±4 26 Metin A, Aykol N. Diclofenac sodium suppository in the 35 Dahlstrom A. The adrenergic innervation of the urinary treatment of primary nocturnal enuresis. Int Urol Nephrol bladder in the cat and man in the normal state and after 1992; 24: 113±7 parasympathetic denervation. Acta Pharmacol Toxicol 1978; 27 Diokno AC, Lapides J. Oxybutynin: a new drug with 4: 19±25 analgesic and anticholinergic properties. J Urol 1972; 36 Jensen D Jr. Altered adrenergic innervation in the unin- 108: 307±9 hibited neurogenic bladder. Scand J Urol Nephrol 1981; 15: 28 Aubert D, Cencig R, Royer M. Le traitement par le 60 chlorhydrate dk oxybutynine des incontinences urinaires 37 Jensen D Jr. Uninhibited neurogenic bladder treated with de lk enfant et des eÂtats d'hyperactivite veÂsicale. Ann PeÂdiatr prazosin. Scand J Urol Nephrol 1981; 15: 229±33 (Paris) 1986; 33: 629±34 38 Bouchot O, Buzelin JM, Labat JJ. Ef®cacite aÁ long terme des 29 Scholtmeijer RJ, van Mastrigt R. The effect of oxyphe- meÂdicaments anticholinergiques et alpha-bloquants sur le nonium bromide and oxybutynin hydrochloride on deÂtrusor d'enfants atteints de myeÂlomeÂningoceÁle. JDk Urol detrusor contractility and re¯ux in children with 1988; 94: 83±6 vesicoureteral re¯ux and detrusor instability. J Urol 39 Amark P, Beck O. Effect of phenylpropanolamine on 1991; 146: 660±2 incontinence in children with neurogenic bladders. A 30 HjaÈlmas K, HellstroÈm AL, Mogren K et al. Safety, ef®cacy double-blind crossover study. Acta Paediatr 1992; 81: and pharmacokinetics of tolterodine in paediatric patients 345±50 with overactive bladder. Invited lecture of 2nd Congress of the ICCS, Denver August, 1999 31 Smey R, Firlit CF, King LR. Voiding pattern abnormalities in Authors normal children: results of pharmacologic manipulation. P.B. Hoebeke, PhD, Paediatric Urologist. J Urol 1978; 120: 574±7 J. Vande Walle, PhD, Paediatric Nephrologist. 32 Hilwa GM, Perlmutter A. The role of adjunctive drug Correspondence: Department of Paediatric Urology, Gent therapy for intermittent catheterization and self catheter- University Hospital, De Pintelaan 185, B-9000 Gent, Belgium.
# 2000 BJU International 86, 581±589