Structurally, the toxin is a protein made up of heavy- and light-chain components held together by a disulfide bond. It is produced as a protoxin with a molecular weight of 150 kd and cleaves into the heavy (100 kd) and light (50 kd) components. The former acts as a carrier that binds to the surface of the target cell (neuron) and allows for the latter to be translocated across the cell membrane. The light-chain component contains zinc-dependent endopeptidases whose action within the cell brings about the toxic effect.6
The mechanism of action of botulinum toxin of blocking neurotransmitter release at the cholinergic nerve terminals is thought to take place in three steps. The toxin first binds to receptors on the unmyelinated presynaptic membrane of the neuron, prior to internaliza- tion into the cell by endocytosis. The disulfide bond is then cleaved and the light-chain compo- nent is translocated into the cytosol. In the final step the light-chain component inhibits neurotransmitter release by the action of zinc- dependent endopeptidases.7
Although the process is irreversible, recovery does occur through proximal axonal sprouting and formation of new synaptic contacts. A study by de Paiva and colleagues8suggests that regen- eration of the original neuromuscular junction does take place eventually.
The first reported clinical use of botulinum toxin (type A) was by Scott9in 1981 in success- fully treating patients with strabismus. Since then, botulinum toxin has been used in the man- agement of a number of clinical conditions—
some with more success than others. Table 16.1 lists some examples of diverse clinical applica- tions of botulinum toxin.
Much of the medical treatment of constipa- tion is based on pharmacologic intervention using simple bulking agents and laxatives. The growing acceptance of the use of botulinum toxin in the treatment of anal fissure1has high- lighted the diverse clinical use of this agent, and has generated further interest in its use in patients with constipation from functional outlet obstruction.2
This chapter describes the background relat- ing to the therapeutic use of botulinum toxin, its pharmacologic properties, and its use in patients with disordered defecation. We also describe other new pharmacologic agents used in the treatment of patients with chronic constipation such as serotonin (5-hydroxytryptamine) recep- tor agonists, colchicines, and neurotrophin-3 agonists.
Botulinum Toxin: Background
Van Ermengem3 first noted that botulinum toxin, a potent neurotoxin, was produced by the gram-positive bacillus Clostridium botulinum.
However, it was not until the discovery by Burgen et al4 in 1949 that the toxin blocked neuromuscular transmission that its potential as a therapeutic tool evolved.
There are seven different types of known botulinum neurotoxin, labeled as type A to G.
Although they share a similar chemical struc- ture, the neurotoxin types are antigenically dis- tinct, resulting in variations in their potency. For example, types C and D cause disease in animals (avian botulism), whereas types A, B, E, and F can affect humans, with type A resulting in the most severe clinical effects.5
16
Botulinum Toxin and Other New Pharmacologic Approaches to Constipation
Thanesan Ramalingam and Neil J. Mortensen
161
In the United Kingdom preparations of botu- linum toxin type A are commercially available in two common forms, namely Botox® and Dysport®. Each freeze-dried vial containing 100 units (U) of botulinum toxin type A is reconsti- tuted with normal saline prior to its use. This unit measurement, the “mouse unit,” represents the potency of the agent and is based on the amount of the toxin needed to kill 50% of a group of 20-g Swiss-Webster mice within 3 days of intraperitoneal injection of the toxin. This has led to some confusion, as there appear to be dif- ferences in observed potencies between Botox and Dysport in clinical use. It is now generally accepted that for clinical purposes 1 U of Botox is approximately equivalent to 3 or 4 U of Dysport.10
The route of administration is by injection directly into the relevant overactive muscle or muscle group and is normally performed without the need for anesthesia. Potentially, the transient nature of its clinical effects confers another advantage of its use over surgery.
Constipation Caused by Dysfunction of the Pelvic Floor Muscles
It is acknowledged that in a proportion of patients with chronic constipation, the symp- toms are due to obstructed defecation caused by dysfunction of the pelvic floor musculature.2Ini- tially labeled as puborectalis syndrome11but also
often described as anismus,12it is characterized by the failure of the puborectalis muscle to relax or by its paradoxical contraction during efforts to defecate. In the normal course of events the puborectalis muscle and the external anal sphincter relax, allowing the anorectal angle to straighten to accommodate defecation through a patent anal canal.
In patients with chronic constipation and pelvic floor dysfunction, injecting botulinum toxin into the puborectalis muscle weakens or paralyzes the overactive muscle and causes straightening of the anorectal angle to allow easier defecation. It was first used in patients with obstructed defecation in 1988 by Hallan and colleagues.13 In their study, seven patients with obstructed defecation diagnosed using electromyographic (EMG) studies and dynamic proctography, received botulinum toxin injec- tion to the puborectalis muscle. Taking an empirical dose of 3 ng botulinum toxin (approx- imately equivalent to 60 U of Botox), four patients derived benefit from the treatment. This finding was based on symptom questionnaires as well as a reduction in the maximum squeeze pressure on anorectal manometry and an increase in the anorectal angle on posttreatment proctography analysis. However, of the remain- ing three patients, one did not derive any benefit, and two suffered from symptoms of inconti- nence during the treatment period.
In another study, Joo and colleagues14demon- strated some success in using botulinum toxin to treat four patients with obstructed defecation who had failed to respond to conventional biofeedback treatment. They used between 6 and 15 U of botulinum toxin injected into the pub- orectalis muscle or external anal sphincter under EMG guidance. They found that although all four patients showed both subjective and objective (EMG results) improvement initially, long- term benefits were seen in only two of the four patients after 3 months.
Maria and colleagues,15in a study involving three patients with outlet obstruction constipa- tion, injected 30 U of botulinum toxin into the puborectalis muscle as treatment. At 8 weeks following treatment, these patients’ symptoms improved as indicated by their reduced laxative or enema use. The authors also showed, using proctography, that there was significant increase in the anorectal angle and a decrease in the anal tone during straining, when compared with pre- treatment baseline values.
Table 16.1. Examples of the diverse clinical applications of botulinum toxin
Disorders of involuntary muscle activity Cervical dystonia (torticollis) Blepharospasm (eyelid apraxia) Writer’s cramp
Hemifacial spasm Tics
Disorders of localized muscle spasms/pain Chronic lower back pain
Tension headache
Other disorders of inappropriate muscle overactivity Strabismus
Nystagmus Anal fissure
Pelvic floor dysfunction (incl. anismus, vaginismus) Achalasia
Detrusor-sphincter dyssynergia Cosmesis
Wrinkles, frown lines
obstructed defecation, there are several aspects regarding its use that need to be highlighted and addressed. First, any beneficial effects of botu- linum toxin injections appear to be short-lived.
Joo and colleagues14 found that only 50% of the patients in their study remained well at 3 months. In a study by Shafik and El Sibai,21 symptomatic improvement in their patients was noted for a mean duration of only 5 months. In the study by Ron et al16mentioned earlier, 11 of the 25 patients required at least two treatments with botulinum toxin during the 1-year follow- up period. This diminished clinical response with repeated injections may be due to the devel- opment of neutralizing antibodies to the toxin, resulting in immunoresistance.22
Second, there does not seem to be any consis- tency regarding the optimum dose required to reverse the effects of paradoxical puborectalis contraction. As it has been suggested that the effective therapeutic dose should be propor- tional to the mass of the muscle injected,23the lack of a standard therapeutic dose is not sur- prising. This is further compounded by, as previously mentioned, the lack of dose stan- dardization of botulinum toxin between the commercially available preparations. Addition- ally, there is also some debate about the pre- ferred site of injection in patients with anismus.
Injection of botulinum toxin into the external anal sphincter alone appears to confer sympto- matic improvement in some patients with pub- orectalis syndrome.14
Third, although botulinum toxin injections are generally well tolerated, like any other ther- apeutic agent it is not without side effects.
Although its effect diminishes with increasing distance from the injection site, diffusion to nearby muscle or tissues is possible causing muscle weakness.24For example, patients receiv- ing botulinum toxin injections for torticollis may develop dysphagia.5In relation to the pelvic floor muscles, excessive weakness can result in symptoms of incontinence.13Potentially, weak- ness of distant muscles or generalized muscle weakness is possible by hematologic spread of the toxin, but this is believed to be very rare.25
The use of botulinum toxin is not recom- mended in pregnant or breast-feeding patients, and it should also be used under close supervi- sion in patients with disturbed neuromuscular junction transmission, such as in patients with myasthenia gravis or during treatment with aminoglycosides.7
Ron et al,16in one of the larger studies to date, treated with botulinum toxin 25 consecutive patients with a history of constipation and outlet obstruction. The patients were randomly allo- cated to receive either 10 U of botulinum toxin on each lateral aspect of the puborectalis muscle or 20 U as a single injection to the posterior aspect of the muscle. Over the 1-year follow-up period, 11 patients received at least two treat- ments with botulinum toxin. There were significant improvements in balloon expulsion tests, manometric relaxation, and straining patterns (on a visual analogue scale) in these patients at 3 months. The authors suggest that the posterior injection site did not confer better results.
Albanese and colleagues17 observed that injecting botulinum toxin into the puborectalis muscle relieved symptoms of constipation in a patient with Parkinson’s disease. They followed up this single case report with a prospective study of 18 Parkinson’s disease patients with obstructed defecation, in which the authors injected 100 U of botulinum toxin into the pub- orectalis muscle of the patients under ultra- sound guidance.18Two months after treatment they were able to show that there were significant reductions in anal tone during straining and increase in the anorectal angle (measured with dynamic proctography) in these patients when compared with their baseline values.
In some patients with symptoms of obstructed defecation a rectocele, a herniation of the anterior rectal wall into the lumen of the vagina, may be present. Although the etiology of rectocele is unclear, it has been suggested that there may be an association between rectoceles and the paradoxical contraction of the puborec- talis during evacuatory efforts.19
Maria and colleagues20used botulinum toxin to treat 14 female patients with symptoms of obstructed defecation who also had rectoceles;
30 U of botulinum toxin were injected in divided doses into either side of the puborectalis muscle and anteriorly in the external anal sphincter.
There was symptomatic improvement in nine patients at 2 months. Furthermore, there were significant decreases in the mean sizes of the rectoceles together with increases in the mean anorectal angles when compared with pretreat- ment values.
Despite the fact that there seems to be increas- ing support for the role of botulinum toxin in the treatment of constipated patients with
Although the use of botulinum toxin in patients with obstructed defecation seems promising, it would be premature to entirely support its use. Nearly all studies relating to its use in this group of patients involve small patient numbers. Now larger, double-blinded, randomized studies are needed.
Other New Pharmacologic Approaches
Although the use of botulinum toxin appears to have captured the interest of surgeons for its use predominantly in patients with obstructed defecation, among physicians it is the use of sero- tonin (5-hydroxytryptamine, 5-HT)–modulating drugs in the treatment of patients with func- tional gastrointestinal disease such as chronic constipation that has generated interest.26
Serotonin-Modulating Drugs
The idea that serotonin played a role in peristal- sis was first suggested by Bulbring and Crema27in 1959, but it is only recently that serotonin (5-HT) mechanisms in the gut are being manipulated.
Nearly 80% of total body serotonin is found in the gastrointestinal tract, and the vast majority of this compound is contained within the gran- ules of the enteroendocrine cells.28These cells lie at the base of the crypts and are able to detect changes in the lumen via apical microvilli.
Factors that modulate the release of 5-HT from these cells include mechanical stimuli such as luminal pressure changes, bacterial toxins (e.g., cholera toxin), and drugs.26Furthermore, receptor-mediated stimulation and inhibition via adrenergic, purinergic, and muscarinic receptors exist. These receptors are thought to act by modulating intracellular calcium, a surge of which is associated with 5-HT release.29
With over 21 different receptor subtypes avail- able for 5-HT to bind to and exert an effect, it is not surprising that our knowledge of the mech- anism of action of 5-HT is incomplete. In a recent review of 5-HT–modulating drugs for functional gastrointestinal diseases by Spiller,26 the diverse 5-HT gastrointestinal effects with regard to motility, peristalsis, secretion, and sensation were highlighted.
In relation to the use of 5-HT in patients with slow-transit or functional constipation, therapy
has been primarily aimed at modulating the 5- HT4receptor. It has been shown that in some of these patients the impaired colonic motility was caused by a decrease in frequency and duration of high-amplitude giant migrating contrac- tions30 and an associated reduction in the number of mass movements.31Studies using 5- HT4receptor agonists have shown its prokinetic properties in stimulating the peristaltic response32and enhancement of giant migrating colonic contractions in an animal model.33 Its use in healthy volunteers resulted in increased stool frequency and consistency, with shortened colonic transit times.34
In relation to peristalsis, the mechanism of action of 5-HT4 appears to involve the release of neurotransmitters such as calcitonin gene- related peptide (CGRP), substance P, and vasoac- tive intestinal peptides (VIPs).32 Mucosal stimulation releases 5-HT,whose action on 5-HT4
receptors activates primary afferent neurons within the submucosa to cause a release of CGRP and substance P. This release results in contrac- tion of the circular muscle proximally while the simultaneous release of VIP relaxes the same muscle distally. It seems that these peristaltic effects are blocked by 5-HT4(and 5-HT3) recep- tor antagonists.32In in-vitro animal experiments, a highly selective 5-HT4 receptor agonist has been shown to facilitate cholinergic and excita- tory nonadrenergic, noncholinergic (NANC) neurotransmission to enhance motility.35
Cisapride, a 5-HT4 agonist, was shown to benefit patients with functional constipation.36 However, the demise of Cisapride use due to its potentially lethal cardiac side effects led to inter- est in newer 5-HT4agonists, such as Tegaserod and prucalopride. Tegaserod has been shown to have effects on visceral sensation and to acceler- ate colonic transit time. It has therefore been primarily used in irritable bowel syndrome (IBS) patients with constipation.37Prucalopride is probably a more potent laxative than Tegaserod. Since its increased potency may cause symptoms of abdominal cramps, its use has been directed toward patients with severe constipa- tion rather than constipated IBS patients.26
Prucalopride
Several recent double-blind, randomized clinical studies have shown the benefits of using prucalopride in the treatment of patients with
knowledge that 5-HT3 antagonists inhibit colonic motility in healthy humans42and help in diarrhea-predominant IBS patients.43
Colchicine and Neurotrophin-3
Preliminary studies using other new approaches to treat patients with constipation include the old and the new, such as the use of colchicine44 and neurotrophin-3 (NT-3)45 agonists, respec- tively. The latter agent belongs to the family of protein growth factors, neurotrophins, involved in the growth, development, and function of neurons. A double-blind, randomized study comparing five treatment schedules using NT-3 with placebo showed statistically significant improvements in stool frequency, consistency, and passage in one arm of the treatment group when compared with placebo.45This study high- lighted the fact that the optimum therapeutic dose of NT-3 is yet to be established, and its route of administration by subcutaneous injection may make its use less desirable.
Colchicine, an alkaloid prepared from the dried seeds and corns of Colchicum autumnale, the autumn crocus or meadow saffron, has well-established clinical use in the treatment of patients with acute gout and in patients with familial Mediterranean fever. One of its common side effects, diarrhea, has led to its use in treat- ing patients with refractory constipation.46In a small randomized, double-blind study of 16 patients treated with 0.6 mg of colchicine three chronic constipation.38–40 Emmanuel et al38
and Sloots et al39showed statistically significant improvements in the patients taking 1 mg of prucalopride compared with those on placebo in relation to stool frequency, consistency, and the need to strain. Although there was evidence to suggest improvements in transit times, this did not appear statistically significant when com- pared to placebo, perhaps supported by the fact that some patients with chronic constipation may have normal colonic transit times.
The study by Coremans et al40 showed that patients on 4 mg of prucalopride daily had sta- tistically significant improvements in stool con- sistency when compared to the placebo group.
However, they did not show similar improved outcomes for stool frequency and the need to strain.
A range of dosages has been used in these studies, but it seems that a daily dose of 1 or 2 mg is generally well tolerated. Since it has a half- life of 24 hours, a single daily dose has been recommended.
The most frequent adverse effects reported include abdominal cramps, nausea, diarrhea, and flatulence relating to the secretory and pro- kinetic effect of the drug.
Finally, in relation to the use of 5-HT–
modulating drugs in patients with chronic con- stipation, there has been interest recently in new thiazole derivatives as potent and selective 5-HT3
receptor agonists for the treatment of constipa- tion.41This therapeutic approach is still in its early research stages but has its basis in the
Table 16.2. Characteristics of new pharmacologic agents used in the management of patients with constipation
Agent: Botulinum toxin Prucalopride Tegaserod Colchicine Neurotrophin-3 Class of drug: Bacterial neurotoxin Aminoguanidine Aminoguanidine Alkaloid Protein
(polypeptide) indole indole
Mechanism of action: Neuromuscular Selective 5-HT4 Selective 5-HT4 Unknown Unknown blockade (of acetyl agonist partial agonist
choline release)
Proposed indication: Anismus Slow-transit Constipation- Refractory Slow-transit constipation predominant constipation constipation
irritable bowel syndrome
Proposed therapeutic N/A N/A Range: 6 mg b.i.d. N/A N/A
dose: Range: 6–100 U 1–4 mg o.d. 0.6 mg t.i.d. 9 mg thrice/week
Route of Intramuscular Oral Oral Oral Subcutaneous injection
administration: injection
Side effects Fecal incontinence Headache, nausea, Headache, diarrhea, Diarrhea, nausea, Injection site irritation, abdominal pain, abdominal pain, vomiting, nausea, flushing, diarrhea, flatulence abdominal upper respiratory tract
flatulence pain infections, paresthesia
times a day, the treatment group showed statis- tically significant improvements in bowel move- ments and colonic transit times compared to the placebo group.44
The mechanism of action of colchicine on the gastrointestinal tract is unclear, although it has been suggested that it is involved in prosta- glandin synthesis, intestinal secretion, and bowel motility.47 Its long-term use in patients with familial Mediterranean fever has shown the drug to be relatively free of side effects.47
The new pharmacologic approaches des- cribed in this chapter aim to benefit patients with chronic constipation by improving either gastrointestinal motility or evacuatory function.
Better appreciation of the complex role of pelvic floor muscles in defecation has led to the rela- tively novel use of botulinum toxin in patients with obstructed defecation. Initial results, although encouraging, are inconclusive, with larger, randomized studies now needed. It would also help to have a more accurate method of assessing the biologic activity (effective thera- peutic dose) of botulinum toxin use.
The use of serotonergic drugs, in particular 5- HT4receptor agonists, suggests benefit in their use in patients with slow-transit constipation.
Nonetheless, evidence of the safety and efficacy of their long-term use is awaited. The use of colchicine and NT-3 in the treatment of patients with chronic constipation is still in the early stages of evaluation. Table 16.2 summarizes the main characteristics of the therapeutic agents discussed in this chapter.
Conclusion
The main thrust of treating patients with chronic constipation remains pharmacologic.
Increased use of these agents is appealing because their safety profile is much more accept- able than is the one following colectomy for constipation. Continuing improvements in our knowledge of gastrointestinal motility as well as the physiology of defecation will no doubt help home in on specific pharmacologic targets to benefit these patients.
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