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TREATMENT OF AUTONOMIC NEUROPATHY
TREATMENT OF AUTONOMIC DYSFUNCTION
OF THE GASTROINTESTINAL TRACT (Part Three)
The autonomic control of the gastrointestinal tract is mediated by the extrinsicparasympathetic and sympathetic nervous systems and the intrinsic enteric nervoussystem. The parasympathetic input to the gut originates from the vagus and pelvicnerves from second through fourth sacral segments. The post−synaptic cholinergicneurons provide excitatory input to the gastrointestinal tract. The sympathetic nervoussystem provides inhibitory input to the gastrointestinal tract. Extrinsic sympatheticefferents arising in the intermediolateral grey column synapse in the celiac, superior,and inferior mesenteric ganglia and ramify throughout the gastrointestinal tract in thedistribution of their respective arterial trunks. The upper gastrointestinal tract isinnervated by the greater splanchnic nerve which synapses in the celiac ganglion andtravels with the celiac artery; the small intestine (mid−gut) is innervated by the lessersplanchnic nerve which synapses in the superior mesenteric ganglion and travels withthe superior mesenteric artery; and the large intestine is innervated by the lumbarsplanchnic nerve which synapses in the inferior mesenteric ganglion and travels withthe inferior mesenteric ganglion.1−3 The enteric nervous system is comprised of a myenteric plexus located between theinner−circular and outer−longitudinal smooth muscle layers (Auerbach’ s plexus) and asubmucosal plexus (Meissner’s plexus). At least five types of intrinsic enteric neuronhave been identified, and any individual neuron may contain multiple neuropeptides.2Motor excitation is mediated by the cholinergic−substance P neurons and inhibition ismediated by the dynorphin−vasoactive intestinal polypeptide neurons. Even in theabsence of extrinsic autonomic nervous system influences, the enteric nervous systemgoverns basic gut functions.2 The myoelectrical activity of gastrointestinal smoothmuscle thus may be influenced by neural input intrinsic to the gut (the enteric nervoussystem), gastrointestinal neuropeptides acting either as neurotransmitters or as circulatinghormones.
anatomically discrete areas of the gastrointestinal tract. For example, the internal analsphincter is under autonomic control, particularly tonic sympathetic excitation while thestriated muscle sphincters, both at the anus (external anal sphincter) and at the level ofthe esophagus, are also subject to extrinsic autonomic nervous system influences.
Disorders of bowel motility and peripheral neuropathy
Peripheral autonomic neuropathy may affect motility at any level of the gastrointestinal
tract. Diabetic neuropathy is the most common of the peripheral dysautonomias; and,
given its various gastrointestinal manifestations, it is not surprising that a great
experience has accrued in its management, and that therapies in diabetics have
become paradigms for trials in other diseases. Feldman reported that 76% of a random
sampling of diabetic outpatients reported one or more gastrointestinal symptoms, of
which constipation was the most common.4 Among asymptomatic patients, radiologic
evidence for gastric retention was observed in 22% in one prospective study.5
Gastric emptying is delayed in 30−50% of both type I and type II diabetics.6, 7 The termgastroparesis diabeticorum was first introduced by Kassander to describe the alteredgastrointestinal motility in diabetics.5 Food residue is retained in the stomach due toabsent or decreased gastric peristalsis compounded by lower intestinal dysmotility.8Diabetic gastroparesis may manifest as nausea, post−prandial vomiting, bloating,abdominal distension and pain, belching, loss of appetite, and early satiety. Manypatients, however, are asymptomatic despite impaired gastric motility.7 A gastric splashmay be elicited on clinical examination. Gastroparesis is also associated with thedevelopment of bezoars9 and bacterial overgrowth of stomach and small intestine,esophagitis, gastric ulcers, and gastritis.10 Gastroparesis may impair the establishmentof adequate glycemic control by mismatching plasma glucose and insulin levels. Theabsorption of orally administered drugs may also be affected.5, 11 Impaired gastric emptying is frequently associated with cardiovagal neuropathy andsmall−fiber dysfunction.12 Morphological changes in the vagus nerve are reported insome,13, 14 but not all studies.15 Recent studies have implicated hyperglycemia as acause of impaired gastric and small intestinal motility during fasting and after foodintake. Hyperglycemia, delays gastric emptying in healthy and diabetic subjects.16−19 Diarrhea and other lower gastrointestinal tract symptoms may also occur. Diabeticdiarrhea manifests as a profuse, watery, typically nocturnal diarrhea, which can last forhours or days and frequently alternates with constipation.20−22 Abdominal discomfort iscommonly associated.
The pathogenesis of diabetic diarrhea includes reduced gastrointestinal motility23 abnormalities in gut transit time24, 25 reduced alpha−2adrenergic receptor mediated fluid absorption26 bacterial overgrowth27 pancreaticinsufficiency, co−existent celiac disease28 and abnormalities in bile salt metabolism.29Fecal incontinence, due to anal sphincter incompetence or reduced rectal sensation isanother manifestation of diabetic intestinal neuropathy.26,30 Incontinence is oftenexacerbated by diarrhea.
Constipation is the most frequently reported gastrointestinal autonomic symptom and isfound in up to 60% of diabetics.4 The pathophysiology of diabetic constipation is poorlyunderstood but may reflect intestinal denervation and loss of the post−prandialgastrocolic reflex.31 Pharmacotherapy of bowel hypomotility
An increase in dietary fibre (up to 25 g/day), with water (10 ounces four times per day)
and exercise is the first line of therapy for most patients. The use of psyllium (up to 30
g/day) or methylcellulose (up to 6 g/day) with a concomitant increase in fluid intake will
further increase stool bulk. Appropriate caution must be exercised with these agents for
example high fiber may be disadvantageous in diabetic gastroparesis, because of
distension and cramping pain that can be associated with its use or because of the
potential of bezoar formation.
Stool softeners (e.g. docusate sodium 100−500 mg/day) or lubricants (e.g. mineral oil)together with an osmotic laxative (e.g. lactulose 15−60 ml/day) may be used if theabove measures are ineffective. Glycerin suppositories or sodium phosphate enemasstimulate evacuation by promoting fluid retention in the rectum. (See Table 1) The contact cathartics such as the diphenylmethane derivatives (phenolphthalein andbisacodyl), the anthraquinones (senna and cascara) should be used sparingly −although the use of these agents cannot be avoided in patients with constipation due toautonomic failure. Extensive use of these agents may damage the myenteric plexusproducing cathartic bowel.
One or more of three general mechanisms of action have been described for thelaxatives a group. First, a given drug may increase intestinal bulk because of itshydrophilic or osmotic properties; second, it may decrease the net absorption ofelectrolytes and water by the intestinal mucosa by damaging the enterocytes orweakening intercellular junctions; third, it may have its effects by enhancing intestinalmotility and thus reducing fluid and electrolyte absorption.
The individual agents may be classified by their response latency and clinical effects.
Softening of feces over one to three days occurs with the bulk forming preparations anddocusates; diphenylmethane and anthraquinone laxatives; and a watery evacuation in one to threehours occurs with the saline cathartics, such as magnesium citrate and milk ofmagnesia.32−38 The benzamide, metoclopramide (5−20 mg orally, 30 minutes before meals and atbedtime), accelerates gastric emptying and has a central antiemetic action.
Metoclopramide action is inhibited by atropine and is not affected by vagotomy,suggesting that its mode of action, which is primarily on antral motor activity, involvesrelease of acetylcholine from intramural cholinergic neurons or direct stimulation ofantral muscle by intact postganglionic cholinergic neurons.39−43 A dopaminergicmechanism has been inferred from studies demonstrating that levodopa−relatedinhibition of gastric emptying is reversed by metoclopramide.41, 44 In diabetics with concurrent gastroparesis and constipation, metoclopramide wasassociated with improvement in both symptoms.42 Battle, et al.45 have observed thatmetoclopromide has a dose−related stimulatory effect on colonic myoelectrical and motor activity in normal and diabetic patients, although other authors have noted nomajor effect on colonic motility.39, 46 Tolerance to metoclopramide therapy has been described.44 Patients maintained in thelong term on metoclopramide theoretically may be at risk for the development of tardivedyskinesia and other dopamine−antagonist−related side effects. Concurrent renalfailure may increase risk for acute toxicity.47 The cholinomimetic bethanecol has beenused in combination with metoclopramide and in cases of metoclopramide resistance.4, 48 Erythromycin and related macrolide compounds exhibit strong in vitro affinity for motilinreceptors and have agonist properties that mimic the prokinetic action of exogenousmotilin, a gastrointestinal polypeptide.49, 50 Infusions of motilin in diabetics withgastroparesis result in accelerated gastric emptying, but therapeutic use of the agent islimited by its need for intravenous administration and by its short half−life.51 In humanstudies52 single intravenous doses of erythromycin shortened post−prandial, gastric−emptying time for both liquids and solids to normal levels in diabetics withgastroparesis. After four weeks of treatment with oral erythromycin (250 mg threetimes per day), gastric emptying continued to exhibit improvement, though not to thedegree noted after a single parenteral administration.
Cisapride is a cholinomimetic agent which increases motility in esophagus, stomach,and bowel by enhancing release of acetylcholine from neurons of the myenteric plexus.
In contrast to metoclopramide, cisapride lacks dopamine blocking activity. It has beentried with some success in several clinical conditions including idiopathic gastric stasis53intestinal pseudo−obstruction54−56 chronic constipation associated with laxative use57 indiabetics with constipation58 and in diabetic gastroparesis.59 In a comparison ofintravenously administered doses of cisapride and metoclopromide, cisaprideaccelerated post−prandial emptying to a slightly greater degree.59 Unfortunately, due toan increased incidence of ventricular arrhythmias, this agent is no longer available forgeneral use.60 The somatostatin analogue, octreotide, may stimulate intestinal motor complexes andthis agent has been used to treat sclerodermatous pseudo−obstruction.61 Somatostatin,however, is known to impair motor responses to feeding62 and treatment with octreotidein other conditions has been associated with hypomotility and bacterial overgrowth.63Clinical experience to date with octreotide suggests that its various side effects maypotentially limit therapeutic use.
Nausea and abdominal cramping pain occur with Fat malabsorption and cholelithiasis have been Domperidone, a peripheral antidopaminergic agent, may provide symptomatic relief inpatients with gastroparesis64−66 although it is not clear that the medication improvesobjective measures of gastric emptying.67, 68 Koch69 observed that gastric "dysrhythmias,"as determined by electrogastrogram, normalized in six patients treated withdomperidone over six months, although only minimal improvement was noted in gastricemptying over the same period.
The synthetic prostaglandin E1 analog, misoprostol, enhances intestinal motility andaffects intestinal fluid and electrolyte secretion. Preliminary studies suggest that thisagent may be of benefit in refractory constipation.70 Rare patients who do not respond to medical therapy may require colonic surgery.
Such patients should have documented slow colonic transit time and intact rectalsphincter function.
Pharmacotherapy of bowel hypermotility
Diabetic diarrhea best exemplifies the diagnostic subtleties that are involved in the
evaluation and treatment of neurogenic diarrheal conditions. Prior to the diagnosis of
neurogenic diarrhea, other causes must systematically be excluded. Diarrhea as a
result of bacterial overgrowth has been a subject of some controversy. One theory
regarding the pathogenesis of diabetic diarrhea holds that gastric and small bowel
hypomotility may predispose to the proliferation of bacteria, which deconjugate bile
salts and thus inhibit micelle formation. Steatorrhea and diarrhea result indirectly as a
consequence of neurogenic dysmotility.4
A trial of antibiotic therapy (tetracyclines, metronidazole, or cephalosporin) is thereforeconducted in most patients with unexplained chronic diarrhea, especially whensteatorrhea is present. Bile acid malabsorption may be treated with cholestyramine.
Treatment with prokinetic agents (see above) may also improve diarrhea. Should thesemeasures fail, opioid agonists should be used. These agents decrease peristalsis andincrease rectal sphincter tone. The synthetic opioids (diphenoxylate and loperamide)are preferable to alcohol solutions of opium. In the individual case, empiricmanagement with antibiotics, opiates, prokinetic agents, psyllium, anticholinergics, andothers is often required.32 An alternative theory implicates a dysregulation of alpha−2 adrenoreceptor mediatedintestinal ion transport in diabetic diarrhea. Clonidine, a specific alpha−2−adrenergicreceptor agonist, may be used to treat diarrhea in doses of up to 1.2 mg per day.26 The somatostatin analogue, octreotide, has been studied as a potential antidiarrhealagent in small numbers of patients with various conditions.71 As noted above, it mayhave a prokinetic action, but somatostatin has also been shown to inhibit stimulatedwater secretion in gut. 4 Fecal incontinence
Studies of idiopathic fecal incontinence have found delayed conduction in pudendal
nerves supplying the external sphincter and denervation changes in pelvic muscles.
Impaired rectal sensation may be responsible for incontinence in such cases, since
detecting the presence of stool in the anal canal is essential to normal continence.
Other authors have argued that the neuropathy is secondary to prolonged straining at
stool and traction on pudendal nerves.
Medical treatments generally attempt to rectify conditions that are either associatedwith or predispose to fecal incontinence. Use of high−fiber diets and bulking agentsmay be beneficial, since a semi−formed stool is more easily controlled than liquid feces.
Fecal disimpaction is indicated in some cases. Daily tap water enemas aid in clearingresidua in the rectum between evacuations and may allow for functional continence.
Antidiarrheal agents may benefit patients for whom incontinence and diarrhea coexist.
Biofeedback based on the patient’s perception of a distensible balloon in the rectumand training to increase external sphincter pressure has met with success in somereports, although the response to biofeedback is likely dependent on the state ofafferent pathways from the rectum.
A majority of patients who undergo surgical sphincter repair may regain continence forsolid stool, although the presence of pelvic floor neuropathy is associated with pooreroutcome. Other surgical interventions, including colostomy, artificial anal sphincters,and creation of a reconstructed with muscle grafts may be necessary in treatment−resistant cases.30, 72 Pharmacotherapy of bowel hypomotility
Bulk Agents
Laxatives and Cathartics:
LactuloseSorbitolMagnesium SaltsSodium PhosphatePolyethylene glycol−saline solutionsGlycerin suppositories PhenolphthaleinBisacodyl tablets or suppositories Stool Softeners and Lubricants:
Prokinetic Agents
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