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Figure 1 Schematic representation of the emetic reflex. AP, area postrema; CSF, cerebrospinal fluid; DMNV, dorsal medullary nucleus of the vagus nerve; NTS, nucleus of the solitary tract.

Efferent pathway Vagus Spinal Phrenic Sympathetic

Figure 1 Schematic representation of the emetic reflex. AP, area postrema; CSF, cerebrospinal fluid; DMNV, dorsal medullary nucleus of the vagus nerve; NTS, nucleus of the solitary tract.

Historically, the central pathways pivotal to the emetic pathways were referred to by vague neuroanatomic terms including chemoreceptor trigger zone and vomiting center. The application of more advanced techniques for neuronal tracing has described the network of brain nuclei that comprise the emetic reflex. The key centers are located in the dorsomedullary region of the brainstem and include the area postrema (AP), the nucleus of the solitary tract (NTS), and the dorsal medullary nucleus of the vagus nerve (DMNV). The AP is situated on the floor of the fourth cerebral ventricle, is in direct contact with the cerebrospinal fluid, and lies outside the blood-brain barrier. This structure therefore has a unique opportunity to sample the systemic environment and through its close apposition to underlying structures, such as the NTS, relays this information directly to deeper CNS nuclei. The NTS and the AP both receive sensory inputs from the periphery via the afferent vagus nerve, inputs from the proximal parts of the gastrointestinal (GI) tract being particularly important in the emetic reflex. Sensory information can then be projected to higher cortical and hypothalamic centers or integrated and processed via the DMNVas the descending limb of the emetic reflex. These descending pathways are important in many of the mechanical elements of vomiting, including contraction of the diaphragm and intercostal muscles, retroperistalsis in the proximal intestine, relaxation of the stomach, and ejection of gastric contents. In contrast, the neurophysiology of nausea is less well defined. Animal correlates of this phenomenon are challenging to establish and most meaningful data come from the clinic. To date, evidence suggests the involvement of ascending pathways from the brainstem to the hypothalamus and to regions of the cortex such as the inferior frontal gyrus, but much detail remains to be elucidated.

Prokinetic agents are often employed to reverse an inhibition of physiological GI motility that has occurred as the result of disease or iatrogenic effects, such as in diabetic gastroparesis or following the use of opioid analgesia. However, prokinetic agents can also be employed in the absence of such deficits but where an increase of baseline motility can be demonstrated to generate benefit, such as in GERD. In several disease states patient symptoms result from a reduction in motility in the GI tract. For example, in type 1 diabetes, a retardation in gastric emptying, which appears to result from a neuropathy affecting the myenteric plexus in the proximal GI tract, can be demonstrated in up to 50% of patients. In a subset of these patients, this results in a significant symptom burden, most commonly manifest as nausea, vomiting, and early satiety, and in these patients the use of prokinetic agents can improve symptoms. Similarly, reduced motility in the distal GI tract, from either iatrogenic or idiopathic causes, can result in constipation, which can become chronic and present a significant problem to patients. In both circumstances, prokinetic agents have been shown to be beneficial to patients by improving their bowel habit and other symptoms. Prokinetic agents also appear to have a significant impact in the treatment of postoperative ileus. During surgery a combination of opioid analgesia and anesthetic use, incision of the peritoneum, and handling of the intestines results in a temporary cessation of GI motility, most probably through a combination of pharmacologic, physiologic, and inflammatory events. This can generate significant postoperative problems with symptoms such as bloating inhibiting resumption of feeding and delaying patient discharge from hospital. A number of less common conditions have been described in which GI motility is profoundly inhibited, such as systemic sclerosis and intestinal pseudo-obstruction. The value of prokinetic agents in these conditions is more controversial but these data serve to illustrate that one needs to consider the pathology that underlines the patient's condition before one can select a prokinetic agent with an appropriate mechanism of action to treat them. For example, 5HT4 receptor agonists increase GI motility through the stimulation of cholinergic neurotransmission. In disease states where there is loss of acetylcholine-containing neurons, the prokinetic activity of agents such as cisapride will be attenuated.

Historically, the most common usage of prokinetic agents was in the treatment of GERD. Before the withdrawal of the prokinetic agent cisapride (2) in 2000, over half of all uses were for the treatment of GERD. However, in only a small proportion of GERD patients has a delay in gastric emptying ever been demonstrated and a relationship between degree of delay and severity of reflux has not been found. Nonetheless, it makes empirical sense that if one can pharmacologically increase the rate of emptying of gastric contents, then the opportunity for retrograde reflux of gastric material will be reduced. Importantly, in GERD patients, a substantial amount of reflux is associated with transient relaxations of the lower esophageal sphincter (LES), normal physiological events most probably triggered by distension

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