Antispasmodic Agents

Chapter 41 Antispasmodic Agents


Brain–Gut Axis

The term brain–gut axis refers to the bidirectional neural processing of information between the central nervous and digestive systems. The brain–gut axis plays an essential role in the regulation of gastrointestinal (GI) motility, secretion, digestion, absorption, and blood flow; in the regulation of appetite, energy balance, and metabolism; and in the modulation of mucosal immunity (see Chapter 1). In turn, the brain receives interoceptive input (i.e., endogenous stimuli) from the GI tract, integrates this information with other systems input, and transmits integrated feedback back to the end-organs of the GI tract. The brain–gut axis is designed to optimize homoeostasis during minor physiologic perturbations and to adapt GI function to the overall state of the animal.1 In health, the great majority of interoceptive input does not reach the level of consciousness in the brain, but serves primarily as input to an autonomic reflex pathway. Brain–gut dysfunction underlies the clinical signs of the functional GI disorders such as irritable bowel syndrome, and it might mediate the development of stress-induced relapses in inflammatory bowel disease (IBD).1

Irritable Bowel Syndrome

Irritable bowel syndrome (IBS) is a human chronic GI tract disorder of unknown origin that is characterized by abdominal pain and altered bowel habits in the absence of detectable biochemical or structural abnormalities.2 IBS is one of the most common functional GI disorders with an estimated prevalence of 10% to 15% in Western adult populations. Direct and indirect costs of IBS reach up to $30 billion per year in the United States alone.2 IBS is commonly subdivided into different phenotypes, depending upon the most prevalent bowel habit: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), and mixed features IBS (IBS-M).3 Symptom complex differentiation is an important strategy in the diagnosis and treatment of the disorder. Because of the inability of animal species to describe clinical signs such as abdominal pain and discomfort, IBS is not as well-defined in veterinary medicine. Nonetheless, recurring vomiting and diarrheal disorders are seen in companion animals, abdominal discomfort is readily detected on physical examination, the clinical features are unaccompanied by mucosal morphologic change, and the pathogenesis is assumed, therefore, to be of functional or physiologic origin.4

Pathophysiology of Irritable Bowel Syndrome

The pathophysiology of IBS is incompletely understood, although it is considered to have both peripheral and central mechanisms.1

Peripheral Mechanisms

Mast Cells

Increased mast cell numbers or density, alterations in mast cell–nerve interactions, and increased release of mast cell mediators have been reported in the epithelial biopsy samples of IBS patients.1,7 Mast cells can be activated by immunoglobulins, neuropeptides, and cytokines to secrete mediators without degranulation. They can release many signaling molecules, including histamine, serotonin, corticotropin-releasing factor (CRF), and proteases. Alterations in these signaling systems have been implicated in the pathophysiology of IBS, and mediator-specific receptor antagonists have been suggested as possible therapies. A particularly interesting aspect of mast cell regulation is the close juxtaposition of mast cells with noradrenergic, cholinergic, and peptidergic nerve endings in the villus epithelium (see Fig. 1-17). Persistent alterations in the spatial and functional relationships between mast cells and nerve endings are a plausible mechanism for recurrent abdominal pain.1,7

Epithelial Permeability

Increased epithelial permeability has been reported in many IBS patients, including animal species.8 Multiple mechanisms of increased permeability have been proposed with differing underlying trigger mechanisms, including stressors and mucosal inflammation. Mast cell mediators, such as CRF and proteases, have been implicated in mediating permeability changes in the GI tract and in pain sensitization.1,9

Central Mechanisms

Enhanced Stress Responsiveness

First-symptom onset or symptom exacerbation in IBS has been linked to psychosocial stressors and enhanced visceral perception. Upregulation of central stress and arousal circuits has been postulated.1,11 Central CRF-CRF1 receptor signaling has been impugned in mediating some forms of acute and chronic stress-induced visceral hyperalgesia. Increased responsiveness of stress and arousal circuits is likely to contribute to the increased activity of the sympathetic nervous system observed in IBS patients, and may play a role in altered mast cell function.7

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Jul 10, 2016 | Posted by in INTERNAL MEDICINE | Comments Off on Antispasmodic Agents

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