Because a major portion of the final common pathway in physiologic bladder contraction is stimulation of parasympathetic postganglionic muscarinic cholinergic receptor sites, agents that imitate the actions of acetylcholine might be expected to be effective in treating patients who cannot empty their bladder because of inadequate bladder contractility. Acetylcholine, which is a quaternary amine, cannot be used for therapeutic purposes because of its action at both muscarinic and nicotinic receptors; it is rapidly hydrolyzed by acetylcholinesterase and by butyrylcholinesterase (Brown and Taylor, 2006). Many acetylcholine-like drugs exist, but only bethanechol chloride exhibits a relatively selective in-vitro action on the urinary bladder and gut with little or no nicotinic action (Brown and Taylor, 2006). Bethanechol is cholinesterase resistant and causes an in-vitro contraction of smooth muscle from all areas of the bladder (see Chapter 60).
Bethanechol, or agents similar to it, has historically been recommended for the treatment of postoperative or postpartum urinary retention, but only if the patient is awake and alert and if there is no outlet obstruction. The recommended dose has been 5 to 10 mg subcutaneously. For more than 50 years, bethanechol has been recommended for the treatment of the atonic or hypotonic bladder and has been reported as effective in achieving “rehabilitation” of the chronically atonic or hypotonic detrusor (Sonda et al, 1979). This drug has also been reported to stimulate or facilitate the development of reflex bladder contractions in patients in spinal shock secondary to suprasacral spinal cord injury (Perkash, 1975).
Although bethanechol has been reported to increase gastrointestinal motility and has been used in the treatment of gastroesophageal reflux, and although anecdotal success in specific patients with voiding dysfunction seems to occur, there is little or no evidence to support its success in facilitating bladder emptying in a series of patients in whom the drug was the only variable (Finkbeiner, 1985; Barendrecht et al, 2007). In one set of trials a pharmacologically active subcutaneous dose (5 mg) did not demonstrate significant changes in flow parameters or residual urine volume in (1) a group of women with a residual urine volume greater than or equal to 20% of bladder capacity but no evidence of neurologic disease or outlet obstruction; (2) a group of 27 “normal” women of approximately the same age; or (3) a group of patients with a positive bethanechol supersensitivity test (Wein et al, 1980a, 1980b). This dose did increase cystometric filling pressure and also decreased bladder capacity threshold, findings previously described by others (Sonda et al, 1979). Short-term studies in which the drug was the only variable have generally failed to demonstrate significant efficacy in terms of flow and residual urine volume data (Barrett, 1981). Farrell and colleagues (1990) conducted a double-blind randomized trial that looked at the effects of two catheter management protocols and the effect of bethanechol on postoperative retention after gynecologic incontinence surgery and concluded that bethanechol was not helpful in this setting. Although bethanechol is capable of eliciting an increase in bladder smooth muscle tension, as would be expected from in-vitro studies, its ability to stimulate or facilitate a coordinated and sustained physiologic-like bladder contraction in patients with voiding dysfunction has been unimpressive (Finkbeiner, 1985; Andersson, 1988).
It is difficult to find reproducible urodynamic data that support recommendations for the use of bethanechol in any specific category of patients. Most, if not all, “long-term” reports in such patients are neither prospective nor double blind and do not exclude the effects of other simultaneous regimens (e.g., treatment of urinary infection, bladder decompression, timed emptying, or other types of treatment affecting the bladder or outlet), an important observation to consider when reporting such drug studies. Whether repeated doses of bethanechol or any cholinergic agonist can achieve a clinical effect that a single dose cannot is speculative, as are suggestions that bethanechol has a different mode of action or effect on atonic or decompensated bladder muscle than on normal tissue.
Bethanechol, administered subcutaneously, does cause an increased awareness of a distended bladder (Downie, 1984). This could facilitate more frequent emptying at lower volumes and thereby help to avoid overdistention, but, it would seem, only in a bladder that is capable of a contraction. O’Donnell and Hawkins (1993) administered 5 mg of bethanechol subcutaneously to 10 neurologically intact males and made the following cystometric observations: bladder volume at first desire to void decreased (220 mL to 85 mL), maximum bladder capacity decreased (380 mL to 160 mL), first desire to void occurred at a higher pressure (5 cm H2O vs. 28 cm H2O), and compliance was reduced. They concluded that bethanechol affects the ability of the bladder to accommodate volume. Patients were comfortable at a resting bladder pressure of 20 cm H2O (uncommon in their population), and the pressures at maximum bladder capacity were considerably higher than commonly seen under normal conditions. This suggested to them that either bladder pressure alone is not a significant factor in the perception of a sensation of first desire to void or that bethanechol somehow alters the threshold at which perception of desire to void occurs (because these patients showed a tolerance for increased intravesical pressure before first desire to void and at maximum bladder capacity). De Wachter and Wyndaele (2001) determined the bladder electrical threshold in healthy volunteers receiving 5 mg bethanechol subcutaneously. They found a marked decrease in the volume at which various filling sensations occurred and that the electrical threshold decreased after drug administration. De Wachter and coworkers (2003) treated 18 women with impaired detrusor contraction with subcutaneous bethanechol (5 mg four times daily) for 10 days. At the end of treatment, 61% of the patients voided without a postvoid residual volume. These investigators also found that in these women the sensation of filling and the electrical sensitivity were significantly increased compared with before treatment. The authors suggested that patients likely to respond to bethanechol can be identified by determination of the bladder electrical perception threshold.
Riedl and colleagues (2000) performed a clinical study in 45 patients with detrusor areflexia. They were tested with electromotive administration of intravesical bethanechol. Bethanechol 25 mg given orally once daily were then prescribed for 15 patients and voiding control was assessed after 6 weeks of therapy. A mean pressure increase of 34 cm H2O during the electromotive administration of bethanechol was found in 24 of 26 patients with areflexia and neurologic disease compared with only 3 cm H2O in 3 of 11 with a history of chronic bladder dilatation. Oral bethanechol restored spontaneous voiding in 9 of 11 patients who had had a positive response to the electromotive administration of bethanechol, whereas all 4 without a pressure increase during the electromotive administration of bethanechol did not void spontaneously. Riedl and coworkers (2000) concluded that electromotive administration of intravesical bethanechol can identify patients with an atonic bladder and adequate residual detrusor muscle function who are candidates for restorative measures, such as oral bethanechol and intravesical electrostimulation. Those who do not respond to the electromotive administration of bethanechol do not benefit from oral bethanechol and are candidates for catheterization.
No agreement exists as to whether cholinergic stimulation produces an increase in urethral resistance (Wein et al, 1980a, 1980b). It would appear that pharmacologically active doses do, in fact, increase urethral closure pressure, at least in patients with neurogenic DO (Sporer et al, 1978). This would of course tend to inhibit bladder emptying. As to whether cholinergic agonists can be combined with agents to decrease outlet resistance to facilitate emptying and achieve an additive or synergistic effect, the authors’ own experience with such therapy, using even 200 mg (50 mg four times a day) of oral bethanechol daily, has been extremely disappointing. Certainly, most clinicians would agree that a total divided daily dose of 50 to 100 mg rarely affects any urodynamic parameter at all. In a prospective, single-blind randomized study comprising 119 patients with underactive detrusor, Yamanishi and colleagues (2004) studied the effect of combination of a cholinergic drug (bethanechol 60 mg/day or distigmine 15 mg/day) and an α-AR antagonist (urapidil 60 mg/day). The effectiveness of each therapy was assessed 4 weeks after initialization of the therapy using the IPSS. The IPSS results remained unchanged after the cholinergic therapy but were significantly lower after the α-AR antagonist treatment and the combination therapy. With regard to the total IPSS, there were significant differences between the cholinergic and the α-AR antagonist groups and also between the cholinergic and combination groups, in favor of the latter. The average and maximum flow rates did not increase significantly after monotherapy with either the cholinergic drug or the α-AR antagonist, but they significantly increased after combination therapy compared with baseline values. Postvoid residual volume did not decrease significantly after the cholinergic drug therapy but decreased significantly after the α-AR antagonist and the combination therapies. The authors concluded that combination therapy with a cholinergic drug and an α-AR antagonist appeared to be more useful than monotherapy for the treatment of an underactive detrusor.
The question of whether bethanechol may be efficacious in a particular patient can be answered by a brief urodynamically controlled trial in which institution of therapy is the only variable. In the laboratory, a functioning micturition reflex is an absolute requirement for the production of a sustained bladder contraction by a subcutaneous injection of the drug (Downie, 1984). Patients with incomplete lower motor neuron lesions constitute the most reasonable group for a trial of bethanechol (Awad, 1985), although subcutaneous administration may be required. It is generally agreed that, at least in a “denervated” bladder, an oral dose of 200 mg is required to produce the same urodynamic effects as a subcutaneous dose of 5 mg (Diokno and Lapides, 1977).
The potential side effects of cholinomimetic drugs include flushing, nausea, vomiting, diarrhea, gastrointestinal cramps, bronchospasm, headache, salivation, sweating, and difficulty with visual accommodation (Brown and Taylor, 2006). Intramuscular and intravenous use can precipitate acute and severe side effects, resulting in an acute circulatory failure and cardiac arrest and are therefore prohibited. Contraindications to the use of this general category of drug include bronchial asthma, peptic ulcer, bowel obstruction, enteritis, recent gastrointestinal surgery, cardiac arrhythmia, hyperthyroidism, and any type of bladder outlet obstruction.
One potential avenue of increasing bladder contractility is cholinergic enhancement or augmentation. Such an action might be useful alone or in combination with a parasympathomimetic agent. Metoclopramide is a dopamine receptor antagonist with cholinergic properties (Pasricha et al, 2006). It has a central antiemetic effect in the chemoreceptor trigger zone and peripherally increases the tone of the lower esophageal sphincter, promoting gastric emptying. Its effects seem to be related to its ability to antagonize the inhibitory action of dopamine, to augment acetylcholine release, and to sensitize the muscarinic receptors of gastrointestinal smooth muscle. Some data in the dog suggest that this agent can increase detrusor contractility (Mitchell and Venable, 1985), but there are no controlled studies documenting a useful clinical effect in the treatment of detrusor underactivity.
Cisapride is a substituted piperidinyl benzamide with a number of different pharmacologic activities, including a possible direct stimulation of smooth muscle (Pasricha, 2006). Until recently it was commonly used as a prokinetic agent, particularly for gastroesophageal reflux and gastroparesis. It was also suggested that it could improve bladder contractility (Carone et al, 1993; Binnie et al, 1988; Steele et al, 2001). However, there was never any particularly convincing data that the drug improved voiding function, and it is no longer available in the United States because of its potential to induce serious and occasional cardiac arrhythmias (Smalley et al, 2000; Pasricha, 2006). The concept, however, of cholinergic enhancement or augmentation remains attractive but awaits the development of a bladder selective compound.
The reported use of prostaglandins to facilitate emptying is based on hypotheses that these substances contribute to the maintenance of bladder tone and bladder contractile activity (see Chapter 60 and Andersson, 1993; Zderic et al, 1995; Andersson, 1999a, 1999b, 1999c; Andersson and Wein, 2004, for a complete discussion). Prostaglandins and thromboxane A2 (TXA2) have been shown to be present in human bladder in the following quantitative order: PGE2 > PGE1 > PGF2α > TXA2; isolated detrusor muscle is contracted by PGF2α, PGE1, PGE2, and TXA2 (see references in Andersson and Wein, 2004). Prostanoids are synthesized locally in both bladder muscle and mucosa, with synthesis being initiated by various physiologic stimuli such as detrusor muscle stretch, mucosal injury, and neural stimulation; by ATP; and by mediators of inflammation (Andersson and Wein, 2004). Prostanoids may affect bladder activity directly by effects on the smooth muscle or indirectly through effects on neurotransmission. Possible roles mentioned by Andersson (2000a) include (1) neuromodulators of efferent and afferent neurotransmission; (2) sensitization or perhaps (3) activation of certain sensory nerves; and (4) potentiation of acetylcholine release from cholinergic nerve terminals through prejunctional prostanoid receptors. PGE2 seems to cause a net decrease in urethral smooth muscle tone; PGF2α causes an increase.
Bultitude and colleagues (1976) first reported that instillation of 0.5 mg PGE2 into the bladders of females with varying degrees of urinary retention resulted in acute emptying and in improvement of longer-term emptying (several months) in two thirds of the patients studied (n = 22). Desmond and associates (1980) reported results with intravesical use of 1.5 mg of this agent (diluted with 20 mL of 0.2% neomycin solution) in patients whose bladders exhibited no contractile activity or in whom bladder contractility was relatively impaired. Twenty of 36 patients showed a strongly positive immediate response, and 6 showed a weakly positive one. Fourteen patients were reported to show prolonged beneficial effects, all but 1 of whom had shown a strongly positive immediate response. Stratification of the data revealed that an intact sacral reflex arc was a prerequisite for any type of positive response. Tammela and coworkers (1987) reported that one intravesical administration of 10 mg of PGF2α facilitated voiding in women who were in retention 3 days after surgery for SUI. The drug was administered in 50 mL of saline solution as a single dose and retained for 2 hours. However, in these “successfully” treated patients, the average maximum flow rate was 10.6 mL/sec with a mean residual urine volume of 107 mL, and the authors stated that “bladder emptying deteriorated in most patients on the day after treatment.” Koonings and colleagues (1990) reported that daily intravesical PGF2α and intravaginal PGE2 reduced the number of days required for catheterization after SUI surgery when compared with a control group receiving intravesical saline solution.
Others, however, have reported negative results. Grignaffini and Bazzani (1998) reported on instillation of 1.5 mg of PGE2 in 50 mL of saline solution into the bladder of 50 patients on their fourth day after vaginal hysterectomy and cystourethropexy, with a control group of 60 patients. The results are presented in an interesting fashion. After catheter removal, following the PGE2 or control treatment, 58% of the PGE2-treated group voided spontaneously as compared with 48.3% of the control group. This difference was not significant. Thus, 42% of the treated group and 51.7% of the control group were in retention. Of those who were in retention, the number who were in retention for fewer than 3 days was greater in the PGE2 group (32%) versus the control group (25%), and this was statistically significant. Likewise, the number who remained in urinary retention for 3 days or longer after the initial treatment was 10% in the PGE2-treated group versus 26.7% in the control group. Stanton and colleagues (1979) and Delaere and associates (1981) reported on success utilizing intravesical PGE2 in doses similar to those reported earlier; Delaere and associates (1981) similarly reported no success using PGF2α in a group of women with emptying difficulties of various causes. Wagner and coworkers (1985) used PGE2 in doses of 0.75 to 2.25 mg and reported no effect on urinary retention in a group of patients after anterior colporrhaphy.
In a prospective randomized double-blind study, Hindley and colleagues (2004) tested the hypothesis that the combination of intravesical PGE2 and oral bethanechol are additive or synergistic in improving bladder emptying. Nineteen patients with detrusor underactivity (17 men and 2 women) were eligible and randomized to one of two treatments. One group (9 patients) received once-weekly intravesical PGE2 (1.5 mg in 20 mL 0.9% saline) plus bethanechol 50 mg four times daily for a total of 6 weeks. A second group of 10 patients received a once-weekly instillation of saline together with placebo tablets, again for 6 weeks. Although there was evidence of a pharmacologic effect, bethanechol and PGE2 had a limited therapeutic effect compared with placebo. The authors did not recommend this treatment as routine but suggested that it may be considered for the occasional treatment of a patient with detrusor underactivity.
There has been little recent activity in this area, a fact that generally means that clinicians have lost interest or that the initial optimistic results have not been confirmed. Prostaglandins have a relatively short half-life, and it is difficult to understand how any effects after a single application can last up to several months. If such does occur, it must be the result of a “triggering effect” on some as yet unknown physiologic or metabolic mechanism. Because of the number of conflicting positive and negative reports with various intravesical preparations, double-blind, placebo-controlled studies would obviously be helpful to see whether there are circumstances in which prostaglandin use can reproducibly facilitate emptying or treat postoperative retention. Potential systemic side effects of prostaglandin use include vomiting, diarrhea, pyrexia, hypertension, and hypotension (Campbell and Halushka, 1996).
de Groat and coworkers (see Chapter 60; de Groat et al, 1993; Zderic et al, 1995) have demonstrated a sympathetic reflex during bladder filling that, at least in the cat, promotes urine storage partly by exerting an α-AR–mediated inhibitory effect on pelvic parasympathetic ganglionic transmission. Some have suggested that α-AR blockade, in addition to decreasing outlet resistance, may, in fact, facilitate transmission through these ganglia and thereby enhance bladder contractility. On this basis, Raz and Smith (1976) were the first to advocate a trial of an α-AR blocking agent for the treatment of nonobstructive urinary retention. A complete discussion of postoperative retention, including the use of α-AR antagonists for its treatment, is presented elsewhere (see Chapter 65).
Endogenous opioids have been hypothesized to exert a tonic inhibitory effect on the micturition reflex at various levels (see Chapter 60) (Zderic et al, 1995), and agents such as opioid receptor antagonists therefore may offer possibilities for stimulating reflex bladder activity.
Thor and associates (1983) were able to stimulate a micturition contraction with naloxone, an opioid receptor antagonist, in unanesthetized chronic spinal cord–injured cats. The effects, however, were transient, and tachyphylaxis developed. Vaidyanathan and associates (1981) reported that an intravenous injection of 0.4 mg of naloxone enhanced detrusor reflex activity in five of seven patients with neuropathic bladder dysfunction caused by incomplete suprasacral spinal cord lesions. The maximum effect occurred within 1 to 2 minutes after intravenous injection and was gone by 5 minutes. Murray and Feneley (1982) reported that the same dose of naloxone caused, in a group of patients with idiopathic DO, an increase in detrusor pressure at zero volume and at first desire to void, a decrease in the maximum cystometric capacity, and a worsening of the degree of instability. Galeano and coworkers (1986) reported that although naloxone increased bladder contractility in the cat with chronic spinal cord injury, it also aggravated striated sphincter dyssynergia and spasticity—a potential problem in the treatment of emptying failure. Wheeler and colleagues (1987) noted no significant cystometric changes in a group of 15 spinal cord–injured patients after intravenous administration of naloxone, whereas 11 showed decreased perineal electromyographic (EMG) activity. Although an intriguing area, the concept of reversing an inhibitory opioid influence to stimulate reflex bladder activity is of little practical use at present.
This topic includes the treatment of bladder outlet obstruction secondary to benign prostatic enlargement, and a full discussion is appropriately found in Chapters 92 and 93.
Whether one believes that there is significant innervation of the bladder and proximal urethral smooth musculature by postganglionic fibers of the sympathetic nervous system, one must acknowledge the existence of α- and β-AR sites. The smooth muscle of the bladder base and proximal urethra contains predominantly α-ARs, although β-ARs are present. The bladder body contains both varieties of adrenergic receptors, with the β-ARs (β3) variety being more common (see Chapter 60) (Zderic et al, 1995; Andersson, 2000a). The human LUT contains more α2 than α1 ARs, but adrenergically induced prostatic smooth muscle contraction and human LUT smooth muscle contraction are mediated largely, if not exclusively, by α1 ARs. There are at least three subtypes of α1 ARs, designated α1A, α1B, and α1D. Adrenergically induced smooth muscle contraction in the human LUT is mediated largely by the α1A (and in the detrusor α1D) subtype (Docherty, 1998; Harada and Fujimura, 2000; Michel et al, 2000; Schwinn, 2000; Andersson and Wein, 2004; Andersson and Gratzke, 2007). In addition to the three cloned α1 ARs, there is a possible fourth, α1L, although the α1L-AR is probably a variant of the α1A. There is a tremendous amount of information and controversy in the literature regarding the selectivity of certain α-AR blocking agents for these respective receptor subtypes. Conclusions are drawn regarding “the best” α1-AR antagonist for the treatment of at least BPH on the basis of in-vitro and in-vivo pharmacologic selectivity, but many authors note that this does not necessarily translate into functional selectivity in a given patient (Andersson, 2002c; Djavan et al, 2004). The various α-AR antagonists are dealt with in more detail in Chapter 60 (see also Andersson, 2007).
Krane and Olsson (1973) were among the first to promote the concept of a physiologic internal sphincter partially controlled by tonic sympathetic stimulation of contraction-mediating α-ARs in the smooth musculature of the bladder neck and proximal urethra. Furthermore, they hypothesized that some obstructions at this level during bladder contraction are a result of inadequate opening of the bladder neck and/or of an inadequate decrease in resistance in the area of the proximal urethra. They also theorized and presented evidence that α-AR blockade could be useful in promoting bladder emptying in such a patient with an adequate detrusor contraction but without anatomic obstruction or detrusor–striated sphincter dyssynergia. They and many others (see Wein and Barrett, 1988) have confirmed the usefulness of α-AR blockade in the treatment of what is now usually referred to as smooth sphincter or bladder neck dyssynergia or dysfunction. Successful results, usually defined as an increase in flow rate, a decrease in residual urine, and an improvement in upper tract appearance (where pathologic), could often be correlated with an objective decrease in urethral profile closure pressure.
One would expect success with such therapy to be most evident in patients without detrusor–striated sphincter dyssynergia, as reported by Hachen (1980). Mobley (1976), however, reported a startling 86% subjective success rate in 21 patients with a reflex neurogenic bladder, with a corresponding success rate of 66% in what was called “flaccid” and 57% of what was called “autonomous” neurogenic bladder dysfunction, with success being defined as postvoid residual urine volume consistently less than 100 mL. Scott and Morrow (1978), on the other hand, noted excellent results with phenoxybenzamine therapy in 9 of 10 patients with a flaccid bladder and a flaccid external sphincter and in a single patient with an upper motor neuron bladder with intact sympathetic innervation, but in only 8 of 21 patients with hyperreflexia and autonomic dysreflexia, and in none of 6 patients with an upper motor neuron bladder and sympathetic denervation (lesion between T10 and L2).
Although most would agree that α-AR blocking agents exert their favorable effects on voiding dysfunction by affecting the smooth muscle of the bladder neck and proximal urethra, information in the literature suggests that they may decrease striated sphincter tone as well; and other information suggests that they may exert some of their effects on at least the filling/storage symptoms of voiding dysfunction by decreasing bladder contractility (see previous discussion). Much of the confusion relative to whether α-AR blocking agents have a direct (as opposed to indirect) inhibitory effect on the striated sphincter relates to the interpretation of clinical observations and experimental data referable to their effect on urethral pressure in the region of the urogenital diaphragm and on EMG activity in the periurethral striated muscle of this area. One cannot tell by pressure tracings alone whether decreased resistance in this area of the urethra is secondary to a decrease in smooth or striated muscle activity. Nanninga and associates (1977) found that the EMG activity of the external sphincter decreased after phentolamine administration in three paraplegic patients and attributed this effect to a direct inhibition of sympathetic action on the striated sphincter. Nordling and associates (1981) demonstrated that clonidine and phenoxybenzamine (both of which pass the blood-brain barrier) also decreased urethral pressure in this area and yet had no effect on EMG activity. They concluded (1) that the effect of phentolamine was from smooth muscle relaxation alone; (2) that the effect of clonidine, and possibly phenoxybenzamine, was elicited mostly through centrally induced changes in striated urethral sphincter tonus; and (3) that these agents also had an effect on the smooth muscle component of urethral pressure. None of the three drugs, however, affected the reflex rise in either urethral pressure or EMG activity seen during bladder filling, and none decreased the urethral pressure or EMG activity response to voluntary contraction of the pelvic floor striated musculature. Gajewski and colleagues (1984) concluded that α-AR blockers do not influence the pudendal nerve dependent urethral response in the cat through a peripheral action but that at least prazosin can significantly inhibit this response at a central level. Thind and associates (1992) reported on the effects of prazosin on static urethral sphincter function in 10 healthy females. They found a reduction—predominantly in the midurethral area—and hypothesized that the response was caused by a decrease in both smooth and striated sphincter activity, the latter as a result of a reduced somatomotor output from the CNS. Clinically, Chancellor and coworkers (1994) reported that terazosin, a selective α1-AR antagonist, had little or no effect on striated sphincter function in spinal cord–injured patients and had no effect on functional obstruction caused by sphincter dyssynergia in these patients.
α-AR blocking agents have also been used to treat both bladder and outlet abnormalities in patients with so-called autonomous bladders—such as those with myelodysplasia, sacral spinal cord or infrasacral neural injury, and voiding dysfunction after radical pelvic surgery (Wein and Barrett, 1988). Decreased bladder compliance is a common clinical problem in such patients, and this, along with a fixed urethral sphincter tone, results in the paradoxical occurrence of both storage and emptying failure.
This was the α-AR antagonist originally used for the treatment of voiding dysfunction (see Te, 2002). Phenoxybenzamine has blocking properties at both α1- and α2-AR sites. The initial adult dosage of this agent is 10 mg/day, and the usual daily dose for voiding dysfunction is 10 to 20 mg. After discontinuation, the effects of administration may persist for days, because the drug irreversibly inactivates α-ARs and the duration of effect depends on the rate of receptor synthesis (Hoffman and Lefkowitz, 1996). Side effects affect approximately 30% of patients (Kirby, 1999) and include orthostatic hypotension, reflex tachycardia, nasal congestion, diarrhea, miosis, sedation, nausea, and vomiting (secondary to local irritation). It has mutagenic activity in the Ames test, and repeated administration to animals can cause peritoneal sarcomas and lung tumors (Westfall and Westfall, 2006). Although this agent has been in clinical use for some 35 years without clinically apparent oncologic associations, one must now consider the potential medicolegal ramifications of long-term therapy, especially in younger persons. A reassessment of the use of phenoxybenzamine for treatment of urinary tract disorders was made by Te (2002).
Prazosin was the first potent selective α1-AR antagonist (see Westfall and Westfall, 2006) used to lower outlet resistance (Andersson et al, 1981). The duration of action is 4 to 6 hours; therapy is generally begun in daily divided doses of 2 to 3 mg. The dose may be very gradually increased to a maximum of 20 mg daily, although seldom has anyone used more than 9 to 10 mg daily for voiding dysfunction. The potential side effects of prazosin are consequent to its α1-AR blockade. Occasionally there occurs a “first-dose phenomenon,” a symptom complex of faintness, dizziness, palpitation, and, infrequently, syncope, thought to be caused by acute postural hypotension. The incidence of this can be minimized by restricting the initial dose of the drug to 1 mg and administering this at bedtime. Other side effects associated with chronic prazosin therapy are generally mild and rarely necessitate withdrawal of the drug.
Terazosin and doxazosin are two highly selective postsynaptic α1-AR antagonists. They are readily absorbed with high bioavailability and a long plasma half-life, enabling their activity to be maintained over 24 hours after a single oral dose. Both of these agents have been evaluated with respect to their efficacy in patients with LUTS and decreased flow rates presumed secondary to BPH. Their efficacy in decreasing symptoms and raising flow rates has been shown to be superior to placebo and similar to that of prazosin (Kirby, 1999). Their safety profiles have been well documented as a result of their widespread use over several years for the treatment of hypertension. Side effects are related to peripheral vasodilatation (postural hypotension), and both drugs have to be started at a low dose and titrated to obtain an optimum balance between efficacy and tolerability. Dizziness and weakness are sometimes observed, and these are presumed secondary to CNS actions. These drugs are marketed for the treatment of hypertension as well as LUTS presumed secondary to BPH.
Alfuzosin and tamsulosin, both highly selective α1-AR blockers, have appeared and are marketed solely for the treatment of BPH because of some reports suggesting preferential action on prostatic rather than vascular smooth muscle (Kirby, 1999; Djavan et al, 2004). Marketing claims aside, whether there is any difference in the efficacy/side effect profiles of these individual agents remains a topic of controversy. Both are able to be administered once daily and without titration. Available data suggest that retrograde ejaculation and rhinitis are more common with tamsulosin, whereas dizziness and asthenia are more common with terazosin and doxazosin (Djavan et al, 2004).
Silodosin is a novel highly selective α1A-AR antagonist (Yoshida et al, 2007). Clinical data (Kawabe et al, 2006) showed that silodosin showed significant improvement in LUTS associated with BPH, as well as in quality of life. The improvements were observed in both voiding and storage symptoms. Long-term study revealed that the efficacy and safety was sustained for 1 year. The most common adverse event in the silodosin group was abnormal ejaculation, which occurred in 22% of cases (Kawabe et al, 2006). Adverse events associated with lowering of blood pressure were low.
Agents with α-AR blocking properties at various levels of neural organization have been used in patients with very varied types of voiding dysfunction—functional outlet obstruction, urinary retention, decreased compliance, and DO. The authors’ own experience would suggest that a trial of such an agent is certainly worthwhile, because the effect or noneffect will become obvious in a matter of days and any pharmacologic side effects are, of course, reversible. However, our results with such therapy for non–BPH-related voiding dysfunction have been somewhat less spectacular than those of at least some other investigators.
In the future there may be other pharmacologic mechanisms that are explored to produce relaxation in the smooth muscle of the bladder neck, urethra, or prostatic stroma. Nitric oxide is a neurotransmitter capable of producing smooth muscle relaxation, at least in the female rabbit urethra, pig urethra, and human bladder neck (Andersson and Persson, 1993; Andersson and Wein, 2004). A selective nitrergic action on bladder neck and urethral smooth muscle is an interesting theoretical possibility, and Mumtaz and coworkers (2000) suggest that a topical intraurethral nitric oxide donor could induce urethral smooth muscle relaxation without affecting bladder smooth muscle function and that this is a possible clinical avenue of exploration. Mamas and associates (2001, 2003) hypothesized that augmentation of external sphincter nitric oxide could be an effective pharmacologic therapy for detrusor–striated sphincter dyssynergia. In a functional urodynamic study, Reitz and coworkers (2004a) assessed the effect of the nitric oxide donor isosorbide dinitrate on the external urethral sphincter. Magnetic stimulation of the sacral roots was performed in eight healthy males to evoke reproducible contractions of the external urethral sphincter. Sublingual administration of isosorbide dinitrate (10 mg) could significantly reduce the resting pressure of the external urethral sphincter for at least 1 hour. The maximum contractile strength measured as the maximum urethral closure pressure during single pulse and continuous magnetic stimulation of the sacral roots also decreased significantly. Nitric oxide did not induce a significantly faster fatigue of the external urethral sphincter during continuous magnetic stimulation of the sacral roots. The authors suggested that nitric oxide donors could offer a new pharmacologic approach to treat urinary retention due to an overactive or nonrelaxing external urethral sphincter. In a later study on 12 male spinal cord–injured patients presenting with neurogenic DO and detrusor–striated sphincter dyssynergia, Reitz and coworkers (2004b) found that nitric oxide significantly reduced external urethral sphincter pressures at rest (P < .05) and during dyssynergic contraction (P < .05) while bladder pressures at rest and during contraction as well as the reflex volume remained unchanged. In patients who used suprapubic tapping for bladder emptying the mean post-triggering residual volume was significantly reduced (P < .05). Their conclusion based on their findings was that nitric oxide donors could offer a potential pharmacologic option to treat detrusor–striated sphincter dyssynergia in spinal cord–injured patients.
There is no class of pharmacologic agents that will selectively relax the striated musculature of the pelvic floor. Three different types of drugs have been used to treat voiding dysfunction secondary to outlet obstruction at the level of the striated sphincter: the benzodiazepines, dantrolene, and baclofen. The benzodiazepines are classified as antianxiety agents (Baldessarini, 2006) and as sedative/hypnotics, muscle relaxants, and anticonvulsants (Charney et al, 2006). Dantrolene and baclofen are characterized as antispasticity agents (Standaert and Young, 2006; Taylor, 2006). Baclofen and diazepam exert their actions predominantly within the CNS, whereas dantrolene acts directly on skeletal muscle. Unfortunately there is no completely satisfactory form of therapy for alleviation of skeletal muscle spasticity. Although these drugs are capable of providing variable relief in given circumstances, their efficacy is far from complete; and troublesome muscle weakness, adverse effects on gait, and a variety of other side effects minimize their overall usefulness as treatments of spasticity (Standaert and Young, 2006; Taylor, 2006).
GABA and glycine have been identified as major inhibitory transmitters in the CNS (Andersson and Wein, 2004; Bloom, 2006). GABA is the most widely distributed inhibitory neurotransmitter in the mammalian CNS. GABA receptors have been divided into three types. The GABAA receptor directly gates a chloride ionophore and has modulatory binding sites for benzodiazepines, barbiturates, neurosteroids, and ethanol (Bloom, 2006). The GABAB or metabotropic receptor couples to Ca2+ and K+ channels by means of G proteins and second messenger systems. It inhibits adenylate cyclase, activates K+ channels, and reduces Ca2+ conductance. The GABAB receptor is activated by baclofen and is resistant to drugs that modulate GABAA receptors. There is a third type of GABA receptor, the GABAC, that is less widely distributed than the A and B subtypes (Bloom, 2006). GABA appears to mediate the inhibitory actions of local interneurons in the brain and presynaptic inhibition within the spinal cord (Bloom, 2006). Glycine receptors are prominent in the brain stem and spinal cord and have many features analogous to the GABAA receptor.
Benzodiazepines potentiate the action of GABA by promoting GABA binding to the GABAA receptor (Baldessarini, 2006; Charney, 2006). Benzodiazepines are extensively used for the treatment of anxiety and related disorders (Baldessarini, 2006), although pharmacologically they can also be classified as centrally acting muscle relaxants. The generalized anxiety disorder that is responsive to pharmacotherapy with these agents is characterized by unrealistic and/or excessive anxiety and worry about life circumstances (Shader and Greenblatt, 1993). Specific symptoms can be related to motor tension, autonomic hyperactivity (frequent urination can be a manifestation of this, as well as nausea, vomiting, diarrhea, and abdominal distress), and excessive vigilance. Other common uses have included treatment of insomnia, stress-related disorders, muscle spasm, and epilepsy and as preoperative sedation (Lader, 1987). Side effects include nonspecific CNS depression—manifested as sedation, lethargy, drowsiness, a feeling of slowing of thought processes, ataxia, and decreased ability to acquire or store information (Shader and Greenblatt, 1993; Baldessarini, 2006). Some believe that any muscle relaxation effect in clinically utilized doses is caused by the CNS depressant effects and cite a lack of clinical studies showing any advantages of these agents over placebo or aspirin in this regard (Baldessarini, 2006; Charney et al, 2006). Effective total daily doses of diazepam, the most widely used agent of this group, range from 4 to 40 mg. Other benzodiazepine anxiolytic agents include chlordiazepoxide, clorazepate, prazepam, halazepam, clonazepam, lorazepam, oxazepam, and alprazolam.
Few references are available that provide evaluable data on the use of any of the benzodiazepines in the treatment of functional obstruction at the level of the striated sphincter. Opinions, however, are commonly expressed, at least in regard to diazepam. The authors have not found the recommended oral doses of diazepam to be effective in controlling the classic type of detrusor–striated sphincter dyssynergia secondary to neurologic disease. If the etiology of incomplete emptying in a neurologically normal patient is obscure, and the patient has what appears to be inadequate relaxation of the pelvic floor striated musculature urodynamically (e.g., dysfunctional voiding, occult neuropathic bladder, the Hinman syndrome), a trial of such an agent may be worthwhile. The rationale for use is either that of relaxation of the pelvic floor striated musculature during bladder contraction or that of such relaxation removing an inhibitory stimulus to reflex bladder activity. Improvement under such circumstances may simply be caused, however, by the antianxiety effect of the drug, or by the intensive explanation, encouragement, and modified biofeedback therapy that usually accompanies such treatment in these patients.
Baclofen depresses monosynaptic and polysynaptic excitation of motor neurons and interneurons in the spinal cord by activating GABAB receptors (Standaert and Young, 2006). Baclofen’s primary site of action is in the spinal cord, but it is also reported to have activity at more rostral sites in the CNS. Baclofen has been found useful in the treatment of skeletal spasticity from a variety of causes (especially amyotrophic lateral sclerosis) (Standaert and Young, 2006). Determination of the optimal dose in an individual patient requires careful titration. Treatment is started at an initial dose of 5 mg twice daily, and the dose is increased every 3 days up to a maximum daily dose of 20 mg four times a day. With reference to voiding dysfunction, Hachen and Krucker (1977) found a daily oral dose of 75 mg ineffective in patients with striated sphincter dyssynergia from traumatic paraplegia, whereas they found a daily intravenous dose of 20 mg highly effective. Florante and colleagues (1980) reported that 73% of their patients with voiding dysfunction secondary to acute and chronic spinal cord injury showed lower striated sphincter responses and decreased residual urine volumes after baclofen treatment, but only with an average daily oral dose of 120 mg. Potential side effects of baclofen include drowsiness, insomnia, rash, pruritus, dizziness, and weakness. This drug may impair a person’s ability to walk or stand and is not recommended for the management of spasticity caused by cerebral lesions or disease. Sudden withdrawal has been shown to provoke hallucinations, anxiety, and tachycardia; hallucinations during treatment, which have been responsive to reductions in dosage, have also been reported (Roy and Wakefield, 1986).
Drug delivery often frustrates adequate pharmacologic treatment, and baclofen is a good example of this. GABA’s hydrophilic properties prevent its crossing the blood-brain barrier in sufficient amounts to make it therapeutically useful. For oral use, the more lipophilic analogue baclofen was developed. However, its passage through the barrier is likewise limited, and it has proved to be a generally insufficient drug when given orally to treat severe somatic spasticity and micturition disorders secondary to neurogenic dysfunction (Kums and Delhaas, 1991).
Intrathecal infusion bypasses the blood-brain barrier; cerebrospinal fluid levels 10 times higher than those reached with oral administration are achieved with infusion amounts 100 times less than those taken orally (Penn et al, 1989). Direct administration into the subarachnoid space by an implanted infusion pump showed initially promising results for not only skeletal spasticity but also striated sphincter dyssynergia and DO.
Nanninga and colleagues (1989) reported on such administration to seven patients with intractable spasticity. All patients experienced a general decrease in spasticity, and the amount of striated sphincter activity during bladder contraction decreased; six showed an increase in bladder capacity. Four previously incontinent patients were able to stay dry with CIC. The action on DO is not unexpected, given its spinal cord mechanism of action, and this inhibition of bladder contractility when administered intrathecally may in fact prove to be its most important benefit. Laubser and associates (1991) studied nine spinal cord–injured patients with refractory spasticity using an external pump to initially test the response. Eight showed objective improvement in functional abilities; three of the seven studied urodynamically showed an increase in bladder capacity. Kums and Delhaas (1991) reported on nine paraplegic or quadriplegic males (secondary to trauma or multiple sclerosis) with intractable muscle spasticity treated with intrathecal baclofen. After a successful test period through an external catheter, a drug delivery system was implanted and connected to a spinal catheter. Doses per 24 hours ranged from 74 to 840 µg. Patients were studied before and 4 to 6 weeks after initiation of therapy. Mean residual urine volume fell from 224 to 110 mL (P = .01), mean urodynamic bladder capacity rose from 162 to 263 mL (P = .005), and pelvic floor spasm decreased at both baseline and at maximum bladder capacity (P < .005 and < .025, respectively). Three subjects became continent. Additionally, CIC was no longer complicated by adductor spasm. Bushman and associates (1993) reported an increase in bladder storage in three individuals with hereditary spastic paraplegia treated with intrathecal baclofen. Tolerance to intrathecal baclofen with a requirement for increasing doses may prove to be a problem with long-term chronic use, and studies are under way to investigate this. Vaidyanathan and colleagues (2004) reported a case with insidious development of autonomic dysreflexia and hydronephrosis due to dyssynergic voiding after discontinuation of intrathecal baclofen therapy. They recommended that in spinal cord–injured patients, in whom intrathecal baclofen therapy is terminated, close monitoring of the urologic status is needed.
Dantrolene exerts its effects by a direct peripheral action on skeletal muscle (Standaert and Young, 2006; Taylor, 2006). It is thought to inhibit the excitation-induced release of Ca2+ ions from the sarcoplasmic reticulum of striated muscle fibers, thereby inhibiting excitation-contraction coupling and diminishing the mechanical force of contraction. The blockade of Ca2+ release is not complete, however, and contraction is not completely abolished. It reduces reflex more than voluntary contraction, probably because of a preferential action on fast-type, as compared with slow-type, skeletal muscle fibers. It has been shown to have therapeutic benefits for chronic spasticity associated with CNS disorders.
The drug has been reported to improve voiding function in some patients with classic detrusor–striated sphincter dyssynergia and was initially reported as being very successful in doing so (Murdock et al, 1976). Therapy in adults is recommended to begin at a dose of 25 mg daily, and this is gradually increased by increments of 25 mg every 4 to 7 days to a maximum oral dose of 400 mg given in four divided doses. Hackler and coworkers (1980) achieved improvement in voiding function in approximately half of their patients treated with dantrolene but found that such improvement required oral doses of 600 mg daily. Although no inhibitory effect on bladder smooth muscle seems to occur (Harris and Benson, 1980), the generalized weakness that dantrolene can induce is often significant enough to compromise its therapeutic effects. Other potential side effects include euphoria, dizziness, diarrhea, and hepatotoxicity. Fatal hepatitis has been reported in 0.1% to 0.2% of patients treated with the drug for 60 days or longer, and symptomatic hepatitis may occur in 0.5% of patients on treatment for more than 60 days, whereas chemical abnormalities of liver function are noted in up to 1%. The risk of hepatic injury is twofold greater in females (Ward et al, 1986).
One agreed-on use of dantrolene is to acutely manage malignant hyperthermia, a rare hereditary syndrome characterized by vigorous contraction of skeletal muscle precipitated by excess release of Ca2+ from the sarcoplasmic reticulum, generally in response to neuromuscular blocking agents or inhalational anesthetics. Almost all hospital pharmacies stock parenteral dantrolene for this purpose. Virtually no one currently uses dantrolene for the treatment of voiding dysfunction.
As mentioned previously, BoNT is an inhibitor of the release of acetylcholine and other transmitters at the neuromuscular junction of somatic nerves in striated muscle and of autonomic nerves in smooth muscle (Simpson, 2004). It is interesting that it produces enough weakness of the muscle to prevent or considerably ameliorate spasm or involuntary contraction but not to completely block voluntary control, a phenomenon hypothesized to occur because more active neuromuscular junctions are more likely than less active junctions to be blocked by the effect of the drug (Hallett, 1999). Its urologic use for the treatment of detrusor–striated sphincter dyssynergia was first reported by Dykstra and colleagues (Dykstra and Sidi, 1990; Dykstra et al, 1998). Injections were performed weekly for 3 weeks, achieving a duration of effect averaging 2 months. The only side effects reported in these articles were transitory limb paresis and transitory exacerbation of autonomic hyperreflexia. Fowler and coworkers (1992a) used BoNT in six women with difficult voiding/urinary retention secondary to what is now called the Fowler syndrome (manifested by abnormal myotonus-like EMG activity in the striated urethral sphincter). Although no patient had improved voiding characteristics (a fact attributed to the type of repetitive discharge activity), three women did develop transient SUI, a positive effect of sorts, indicating that the sphincter muscle had indeed been weakened. Petit and associations (1998) reported on the endoscopic injection of BoNT, 150 IU, into the striated urethral sphincter, using a four-point injection technique (the medication was diluted to 4 mL with saline solution). Seventeen patients with spin cord injury or spinal cord disease were treated, and evaluation 1 month after treatment disclosed the following positive results: (1) a decrease in postvoid residual by an average of 176 mL; (2) a decrease in bladder pressure during an emptying contraction by an average of 19 cm H2O; and (3) a decrease in urethral pressure during an emptying bladder contraction by an average of 24 cm H2O. The authors judged voiding to be improved in 10 patients. Side effects included the new appearance of SUI in 2 patients and exacerbation of preexisting incontinence in 3 patients. The duration of the effect was variable, but no less than 2 to 3 months. There were no adverse effects on striated muscle elsewhere. The authors concluded that BoNT was a promising treatment for striated sphincter dyssynergia in certain patients refractory to CIC or surgery. Gallien and associates (1998) injected BoNT transperineally in five men with traumatic quadriplegia and striated sphincter dyssynergia. Using a total initial dose of 100 units, divided into four injections of 25 units each, the authors noted what they called improved bladder function in all patients, with a significant decrease in residual urine volume (however, on examining the figures, the mean reduction was only 14 mL, with one of the patients requiring a second set of injections). The maximum urethral closure pressure on average did not change, the maximum detrusor pressure during an emptying episode decreased 5 cm H2O, and the functional detrusor capacity increased by an average of 89 mL. Urinary catheterization was able to be stopped in two patients, and autonomic hyperreflexia dramatically decreased in intensity in four patients. The time to improvement was 10 to 21 days, and the duration was 3 to 5 months. No patient had significant side effects. Wheeler and associates (1998) reported on three men with spinal cord injury, all with emptying problems related to striated sphincter dyssynergia. The sphincter was injected transperineally with BoNT, using EMG control for localization. Two of the patients reported excellent results. Schurch and associates (1996) used both transurethral and transperineal injections in 24 male spinal cord–injured patients with voiding dysfunction secondary to striated sphincter dyssynergia. They judged that in 21 of these patients, striated sphincter dyssynergia was significantly improved with a concomitant decrease in postvoid residual urine volume in “most cases.” Nine of 24 patients had a decreased postvoid residual volume from 450 to 50 mL; in 7 patients, the residual urine volumes were less than 50 mL to begin with and remained unchanged; and in 8 patients, the postvoid residual urine volumes were high and remained unchanged. The authors commented that transurethral injections appeared to be more effective, at least in reductions in maximum urethral closure pressure, than did transperineal injections. They noted no side effects. de Seze and colleagues (2002) performed a double-blind lidocaine-controlled study in 13 patients with spinal cord disease and detrusor–striated sphincter dyssynergia and demonstrated the superiority of BoNT compared with lidocaine in improving clinical symptoms and increased urethral pressure.
There are several reviews summarizing the uses of BoNT injection (Cruz and Silva, 2004; Rackley and Abdelmalak, 2004; Reitz et al, 2004; Smith and Chancellor, 2004; Ghei et al, 2005; Sahai et al, 2005; Dmochowski and Sand, 2007; Karsenty et al, 2008; Andersson et al, 2009). A potential side effect is the spread to nearby muscles, particularly when high volumes of BoNT are injected. Distant effects can also occur, but distant weakness or generalized weakness, owing to the toxins spreading in the blood, is very rare. BoNT should be used only under close supervision in patients with already disturbed neuromuscular transmission or during treatment with aminoglycosides.
Theoretically, any agent that promotes striated sphincter relaxation in a uroselective manner could be used to decrease outlet resistance and facilitate voiding dysfunction. Yoshiyama and associates (2000) describe the intravenous use of α-bungarotoxin as improving voiding in spinal cord–injured rats. The drug is a toxin extracted from the venom of a Formosan snake; it selectively blocks nicotinic receptors without influencing transmission in autonomic ganglia. Although a long way from clinical use, nicotinic receptors in the striated sphincter have been shown to be a potential target for drug therapy for striated sphincter dyssynergia.
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