Antiemetic agents

Published on 07/02/2015 by admin

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Antiemetic agents

Robert J. Trainer, DO, MBA

Nausea and vomiting represent an extremely distressing and financially costly problem, the risk of which has increased as the fields of anesthesia, surgery, and cancer chemotherapy have advanced. Many drugs are now available to treat and provide prophylaxis against the myriad of situations that give rise to nausea and vomiting (Figures 98-1 and 98-2).

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Figure 98-1 Chemical activation of the vomiting center is mediated via the chemoreceptor trigger zone (CTZ), which is sensitive to the presence of toxins and poisons in the bloodstream.
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Figure 98-2 Medications used to treat nausea and vomiting and their sites of action. RAs, Receptor antagonists.

From studies in the 1950s, a model of the emetic reflex emerged (which has been subsequently validated), consisting of a chemoreceptor trigger zone (CTZ) in the area postrema and a vomiting center in the brainstem. Nausea and vomiting result from chemical or neural stimulation of the vomiting center. Chemical activation is mediated via the CTZ, which is sensitive to the presence of toxins and poisons in the bloodstream (see Figure 98-1). Neural activation occurs as a result of information coming directly from the frontal lobes of the brain, the digestive tract, and the balancing mechanism of the inner ear.

The CTZ is susceptible to stimulation from the release of dopamine and serotonin (5-HT) in the blood and cerebrospinal fluid and may also be activated by opioids and certain anesthetic agents. In addition, the release of 5-HT from the gastrointestinal tract can stimulate the CTZ. The vestibular system sends input to the vomiting center in response to changes in motion and pressure. The reflex afferent pathway from the cerebral cortex stimulates the vomiting center in response to such factors as pain, anxiety, and visual, sensory, or cognitive overload (see Figure 98-2).

Clinical scenarios in which nausea and vomiting are common include cancer chemotherapy, the postoperative period, headache syndromes, and the use of opioids. Optimization of each potentially overlapping scenario requires a tailored approach, although certain principles are worth noting. For example, factors that increase a patient’s risk for developing postoperative nausea and vomiting (PONV) include increasing age, premenopausal women, obesity, previous history of motion sickness or PONV, anxiety, gastroparesis, and type and duration of the surgical procedure (e.g., laparoscopy, strabismus, middle ear procedures). Anesthesiologists have little, if any, control over these surgical factors. However, they do have control over many other factors that influence PONV (e.g., preanesthetic medication, anesthetic drugs and techniques, and postoperative pain management). PONV has an overall incidence of approximately 34% in patients receiving a general anesthetic without preoperative antiemetic therapy, with reductions of PONV by 26% with prophylactic administration of ondansetron, dexamethasone, or droperidol. Furthermore, prevention of PONV is much more effective than treatment administered after symptoms occur. Total intravenous anesthesia is preferred over inhalation agents, and the use of nonopioid analgesics—such as ketorolac, paracetamol, nonsteroidal anti inflammatory drugs, or cyclooxygenase-2 inhibitors—are often given along with morphine as part of multimodal analgesia after major operations. The use of regional anesthesia can benefit patients who are expected to have high postoperative opiate requirements.

In an attempt to reduce the risk of PONV if patients are expected to be placed on opioid therapy, current recommendations include a bowel regimen consisting of a motility agent (senna) and a stool softener (docusate) to avoid opiate-induced constipation and consequent nausea. In patients who are able to drink, psyllium and osmotic laxatives have also been suggested as beneficial.

Today, the standard of care for prevention of chemotherapy-induced nausea and vomiting (CINV) for highly and moderately emetogenic chemotherapy is a 5-HT3-receptor antagonist, dexamethasone, with or without aprepitant or fosaprepitant.

Finally, the relatively low risk of side effects from the use of antiemetic drugs overall was confirmed in a large meta-analysis that included 737 studies involving 103,237 people and the use of eight commonly used drugs: droperidol, metoclopramide, ondansetron, tropisetron, dolasetron, dexamethasone, cyclizine, and granisetron. The authors observed that between 1 and 5 out of every 100 people experienced a mild side effect, such as sedation or headache, when given an antiemetic drug.

Antidopaminergic drugs

Antidopaminergic drugs (D2-receptor antagonists) include butyrophenones (haloperidol, droperidol), phenothiazines, domperidone, and metoclopramide. The D2-receptor antagonists combined with the 5-HT3 antagonists make up the largest number of medications currently used for treating nausea. The D2-receptor antagonists are also the oldest class of medications used in this scenario. The D2 receptor in the CTZ is the primary target for all drugs currently used for preventing or treating PONV and CINV; domperidone (used primarily for nausea due to gastroenteritis) is the exception owing to its inability to cross the blood-brain barrier. Olanzapine, an antipsychotic, has antagonistic properties at the D2, acetylcholine, and 5-HT3 receptors. The well-known antiemetic effect of propofol may be due to a D2 antagonism, 5-HT3 antagonism, or a cannabinoid agonism.

Side effects

Antidopaminergic drugs should not be used in patients with Parkinson disease, restless leg syndrome, or any other disorder in which dopaminergic drugs are used to treat the signs and symptoms of the disease. Extrapyramidal reactions, sedation, diarrhea, and orthostatic hypotension can occur with all antidopaminergic drugs used in the treatment of PONV. Haloperidol is the drug in this class that is most likely to be implicated as the cause of excessive sedation, and prochlorperazine is responsible for most cases of orthostatic hypotension.

The U.S. Food and Drug Administration requires a boxed warning on droperidol related to the drug’s propensity to prolong the QT interval; therefore, patients who receive droperidol intraoperatively should have electrocardiographic monitoring for 4 h postoperatively.

Metoclopramide possesses the additional benefit of enhancing gastric emptying by selective peripheral cholinergic agonism, which is also the reason that this drug should be avoided in patients who have bowel obstruction. A boxed warning on metoclopramide highlights the risk for patients to develop tardive dyskinesia, but this adverse effect is seen most often with long-term use of the drug.

H1-receptor agonists

H1-receptor agonists include diphenhydramine and promethazine. Diphenhydramine is thought to have anticholinergic properties, resulting in antidyskinetic, sedative, and antiemetic effects, which likely occur at the level of the gastrointestinal tract, preventing vagally mediated transmission to the vomiting center. The antihistamine effect is thought to work at the level of the CTZ.

5-HT3-receptor antagonists

The 5-HT3-receptor agonists (ondansetron, dolasetron, and granisetron) bind to receptors in the CTZ and 5-HT3 receptors in the gastrointestinal tract, preventing signal transmission.

Steroids

The exact mechanism of the anti-inflammatory action of dexamethasone is unknown; however, this drug inhibits multiple inflammatory cytokines in the central and peripheral nervous systems and stabilizes plasma membranes in central and peripheral sites.

NK1 antagonists

The neuropeptide substance P shows a widespread distribution in both the central and peripheral nervous systems; after binding to the NK1 receptors, substance P regulates many biologic functions in the central nervous system, such as emotional behavior, stress, depression, anxiety, emesis, migraine, alcohol addiction, and neurodegeneration. 5-HT mediates the early vomiting process that occurs within 8 to 12 h following cisplatin-based chemotherapy, after which time substance P, acting at NK1 receptors, becomes the dominant mediator of vomiting. Aprepitant, a substance P antagonist, is typically given as a single 40-mg dose by mouth within 3 h before anesthesia. Chemotherapy regimens vary, but often consist of a 3-day course of therapy due to the risk of delayed CINV. Aprepitant is usually administered with a corticosteroid.

Cannabinoids

The proposed effects of cannabinoids (inhaled or oral) are antagonism of dopamine receptors or 5-HT3 receptors or activation of the cannabinoid receptors.

Auricular acupuncture and use of the wrist P6 point

Many theories exist as to the mechanism of action with regard to acupuncture in treating nausea and vomiting. A popular modern theory founded in the theoretical physical sciences and attempting to consolidate previous theories is the bioelectromagnetic hypothesis. In this case, a complicated interplay between biology and electrodynamic forces—in which a somato-autonomic reflex occurs—may be responsible for the effect of acupuncture on nausea.

Conclusion

Nausea and vomiting represent extremely distressing and financially costly side effects of the advancements in the fields of anesthesia, surgery, and cancer chemotherapy. Many drugs are now available to treat and prevent PONV and CINV, as well as the myriad of other situations that give rise to nausea and vomiting. Major classes of drugs commonly used today include dopamine-receptor antagonists, 5-HT3-receptor antagonists, steroids, and NK1 antagonists. The current antiemetic efficacy rate has been unable to surpass 70% to 80% in patients treated with highly emetogenic cytotoxic drugs, the most extreme challenge for antiemetic drugs. Although much research has been focused on the development of new medications and the optimal setting and timing of medication administration, one of the potential factors explaining this suboptimal response is variability in genes encoding enzymes and proteins that play a role in metabolism, transport, and receptors related to antiemetic drugs.

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