As discussed previously, lubiprostone is a prostanoic acid derivative that stimulates the type 2 chloride channel (ClC-2) in the small intestine. Lubiprostone is approved for the treatment of women with IBS with predominant constipation. Its efficacy for men with IBS is unproven. The approved dose for IBS is 8 mcg twice daily (compared with 24 mcg twice daily for chronic constipation). In clinical trials, lubiprostone resulted in modest clinical benefit—only 8% more patients than with placebo. Lubiprostone is listed as category C for pregnancy and should be avoided in women of child-bearing age.
Also discussed previously, linaclotide is a guanylyl cyclase-C agonist that leads to activation of the CFTR in the small intestine with stimulation of chloride-rich intestinal secretion. It is approved for treatment of adults with IBS with constipation at an approved dose of 290 mcg once daily (compared with 145 mcg once daily for chronic constipation). In clinical trials, up to 25% more patients treated with linaclotide than with placebo demonstrated significant clinical improvement. Linaclotide is listed as category C for pregnancy and is contraindicated for pediatric patients.
Due to their high cost and lack of information about long-term safety and efficacy, the role of these agents in the treatment of IBS with constipation is uncertain. Neither agent has been compared with other less expensive laxatives (eg, milk of magnesia).
Nausea and vomiting may be manifestations of a wide variety of conditions, including adverse effects from medications; systemic disorders or infections; pregnancy; vestibular dysfunction; central nervous system infection or increased pressure; peritonitis; hepatobiliary disorders; radiation or chemotherapy; and gastrointestinal obstruction, dysmotility, or infections.
The brainstem “vomiting center” is a loosely organized neuronal region within the lateral medullary reticular formation and coordinates the complex act of vomiting through interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomotor centers. High concentrations of muscarinic M1, histamine H1, neurokinin 1 (NK1), and serotonin 5-HT3 receptors have been identified in the vomiting center (Figure 62–6).
There are four important sources of afferent input to the vomiting center: 1.
The “chemoreceptor trigger zone” or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier and is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors.
2.
The vestibular system is important in motion sickness via cranial nerve VIII. It is rich in muscarinic M1 and histamine H1 receptors.
3.
Vagal and spinal afferent nerves from the gastrointestinal tract are rich in 5-HT3 receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis leads to release of mucosal serotonin and activation of these receptors, which stimulate vagal afferent input to the vomiting center and chemoreceptor trigger zone.
4.
The central nervous system plays a role in vomiting due to psychiatric disorders, stress, and anticipatory vomiting prior to cancer chemotherapy.
Identification of the different neurotransmitters involved with emesis has allowed development of a diverse group of antiemetic agents that have affinity for various receptors. Combinations of antiemetic agents with different mechanisms of action are often used, especially in patients with vomiting due to chemotherapeutic agents.